There’s a slightly overwhelming amount of data, including 861 clinical trials across posters and oral presentations. So, to help get your head around what’s to come, here we rank it all, by therapeutic novelty.

By our analysis, 14 of the 861 clinical trials test a new therapeutic target (Novelty Tier 1), 29 a new modality for a known target (Novelty Tier 2), 134 differentiate on a known target (Novelty Tier 3), 9 use a new combination of established mechanisms (Novelty Tier 4), and 675 use an established treatment in a new way (Novelty Tier 5) — as follows.

This analysis — novelty — is quite different from clinical significance. To demonstrate that, the following figure, which we put together, shows the late-breakers at the ‘Presidential Symposium’ sessions (the potentially practice-changing talks judged to be most important). Of these, we rank none as Novelty Tier 1, two as Tier 2, one Tier 3, none Tier 4 and nine Tier 5.

The 14 clinical trials presenting new data for genuinely first-in-class medicines are shown in the table below.

Here’s a bit more detail on each of those programs.

1. LRK-4189 (Larkspur, Private): The first clinical degrader of PIP4K2C, a lipid kinase that helps cancer cells survive metabolic stress and evade immune surveillance.

2. TTX-MC138 (TransCode, ): The first clinical miR-10b antisense oligonucleotide, which inhibits a metastasis-associated microRNA.

3. Zolucatetide (Parabilis, ): The first clinical drug to directly disrupt β-catenin–TCF interactions, blocking oncogenic Wnt signalling.

4. MDX-124 (Medannex, Private): The first clinical annexin A1 antibody — to inhibit tumor growth, migration and immune evasion.

5. BI-1808 (BioInvent, ): The first clinical TNFR2 antibody — to deplete immunosuppressive regulatory T cells.

6. PBP1510 (Prestige Biopharma, 950210): The first clinical antibody targeting PAUF, a secreted protein associated with pancreatic cancer progression, metastasis and immunosuppression.

7. ASP1570 (Astellas, 4503): The first clinical DGKζ inhibitor — aiming to remove an intracellular brake on T cell activation.

8. RSO-021 (RS Oncology, Private): The first clinical mitochondrial PRX3 inhibitor — to overwhelm cancer cells’ antioxidant defences, triggering oxidative stress and cell death.

9. Bexmarilimab (Faron, FARN): The first clinical CLEVER-1/STAB1 checkpoint inhibitor — to reprogram immunosuppressive macrophages.

10. Raludotatug deruxtecan (Daiichi Sankyo, 4568): The first CDH6-targeted ADC to reach phase 2/3.

11. Prifetrastat (Pfizer, ): The first clinical KAT6A/B histone acetyltransferase inhibitor — to disrupt epigenetic programs sustaining hormone-dependent breast cancer.

12. Sigvotatug vedotin (Pfizer, ): The first integrin β6-targeted ADC to reach phase 3. This trial was negative.

13. PTT-4256 (Pathios, Private): The first clinical GPR65 antagonist — to reverse acid-driven immunosuppression within the tumor microenvironment. This trial was negative.

14. Alpitatug satetraxetan (Johnson & Johnson, ): The first clinical KLK2-targeted actinium-225 radiotherapy — delivers alpha radiation to prostate cancer cells. This trial was negative.

Here’s the full analysis of all trials, starting with the Novelty Tier 2 trials:

Read more

There have been 46 new drug approvals, 23 of which (by our count) have genuinely novel mechanisms of action. The record of new drugs approved in a year, by the way, is 59 — set in 2018.

For the following analysis we scoured for advances that changed practice, stood out in late-stage trials, or demonstrated a new therapeutic concept. To do the research, we used Consensus.

1. First-in-class medicines in cancer

There has been plenty to get excited about in cancer treatment.

The first approved pan-RAS inhibitor

Revolution Medicines’ daraxonrasib delivered the first real step change in survival for pancreatic cancer. Daraxonrasib acts as a ‘molecular glue’ that locks RAS — the main oncogenic driver in pancreatic cancer — into an inactive three-part complex with cyclophilin A. It targets multiple RAS isoforms, both mutant and wild-type, and inhibits the active, GTP-bound form of RAS, known as RAS(ON) — a more potent approach than inhibiting inactive RAS(OFF).

In the second-line setting, it doubled median overall survival while improving quality of life and reducing pancreatic cancer-related pain.

RAS breakthroughs beyond daraxonrasib

One of the things I like most about medicine is that, as soon as a promising new drug arrives, the race to improve it begins. In animal studies, drugs that inhibit both the ON and OFF states of RAS are more effective — which makes a lot of intuitive sense.

There’s room to improve tolerability, too. Because daraxonrasib targets several RAS isoforms — including the wildtype form expressed in skin — it can cause a serious rash.

Verastem’s VS-7375 aims to improve on both, through specific targeting of the G12D mutant, in both its ON and OFF states. The data are still early — phase 1/2 — but the objective response rate of 50% is higher (cross-trial) than daraxonrasib, with substantially less rash.

We put together the data that’s been collected for RAS inhibitors in second-line pancreas cancer — including daraxonrasib and VS-7375 — in this figure.

Another way to improve on daraxonrasib would be with combination therapies.

Around 30% of pancreatic cancers have lost the metabolic enzyme MTAP, leaving them vulnerable to PRMT5 inhibition — through a mechanism known as synthetic lethality. Without MTAP, the metabolite, MTA, accumulates and partially inhibits PRMT5, making cancer cells critically dependent on the activity that remains. Further pharmacological PRMT5 inhibition triggers lethal defects in RNA splicing.

In a small phase 1/2 trial, Tango Therapeutics found that adding a PRMT5 inhibitor to daraxonrasib, in patients whose tumours have lost MTAP, achieved an unprecedented objective response rate above 90%. Here are those results, as well as the results with the other combination approaches that are emerging.

The first approved PROTAC

Many proteins (like RAS) are difficult to target with conventional drugs. Proteolysis-targeting chimeras — PROTACs — take a different approach: instead of blocking a protein, they degrade it. That opens the possibility of drugging new targets, improving target suppression, and overcoming drug resistance.

In May, Pfizer’s vepdegestrant, which recruits an E3 ligase to degrade the estrogen receptor, became the first approved PROTAC — for breast cancer.

The first drug to beat pembrolizumab on overall survival

In every year from 2023-2025, the PD1 inhibitor, pembrolizumab, was the world’s top-selling drug (doing $25.0B, $29.5B and $31.7B revenue in those years) — because it’s so effective across so many cancers.

Akeso’s ivonescimab is a bispecific antibody that blocks PD1, restoring T cell antitumour activity, as well as VEGF. Blocking VEGF inhibits tumour angiogenesis, and improves infiltration by T cells (that are also unleashed by PD1 blockade). Its design enables cooperative binding to PD1 and VEGF, concentrating checkpoint blockade in VEGF-rich tumour environments.

In September, ivonescimab beat pembrolizumab in a head-to-head phase 3 trial in advanced lung cancer, extending median overall survival from 22.6 to 30.8 months.

A biparatopic antibody in gastric cancer

Exemplified by ivonescimab, we’re seeing an explosion of multispecific drugs — that are beating their monospecific alternatives in trials. Jazz Pharmaceuticals’ zanidatamab is another good example. It’s a biparatopic antibody, which means it binds two different sites on the same protein: the oncogenic receptor HER2.

As well as blocking downstream signalling, this allows zanidatamab to bring HER2 molecules together into clusters, centred on a zanidatamab hexamer. Those clusters activate complement-mediated cancer-cell killing — something its monospecific counterpart, trastuzumab, does not do. In a head-to-head trial (in HER2-positive gastro-oesophageal adenocarcinoma) zanidatamab outperformed trastuzumab — and was FDA approved for this indication.

The world’s first bispecific antibody-drug conjugate

China approved the world’s first bispecific antibody–drug conjugate (ADC). It binds both EGFR and HER3 (not HER2!) which are often co-expressed on the cell surface. The bispecific design means it binds with more avidity: it’s harder to detach, promotes receptor clustering, and improves delivery of the payload. Cells with low EGFR can also be captured through HER3.

It’s approved in China for nasopharyngeal carcinoma and esophageal squamous-cell carcinoma, with positive readouts in triple negative breast cancer and lung cancer - and ongoing trials in a spectrum of other cancer types. The drug’s name is izalontamab brengitecan (iza-bren) — BMS owns the rest-of-world rights, and is now taking this global.

The first phase 3 trial to show an overall survival benefit for a B7-H3 ADC

B7-H3 is widely expressed across solid tumours, but it’s not yet been targeted by any approved ADCs. Risvutatug rezetecan, or Riz-Rez, is a B7-H3 ADC. In second-line small-cell lung cancer, it extended median overall survival from 10.3 months (with the standard-of-care chemotherapy, topotecan) to 18.5 months — the first phase 3 demonstration of an overall survival benefit for a B7-H3 ADC in any cancer.

The drug was discovered and developed by China’s Hansoh, which licensed the rights outside China to GSK. GSK is now repeating the trial outside China.

The results open the door to an entirely new class of treatments.

2. First-in-class medicines for cardiovascular disease

Cardiovascular disease remains the world’s leading cause of death. This year there have been new drug approvals, alongside promising results from earlier, newer approaches.

Approval of an oral PCSK9 inhibitor, enlicitide, for LDL cholesterol

PCSK9 plays a key role in LDL cholesterol metabolism. We know it’s an important target because people born with inactivating variants have low LDL cholesterol — and a low lifetime risk of cardiovascular disease. This is also why we know that living without it is safe.

That human genetic evidence has helped establish PCSK9 as (probably) our strongest target for cholesterol lowering — and we are now targeting it from every direction: siRNAs, monoclonal antibodies and, this year, a once-daily pill.

Merck’s oral PCSK9 inhibitor, enlicitide, reduced LDL cholesterol by more than 60% on top of statin therapy — almost twice the reduction achieved with the combination of two other non-statin drugs, bempedoic acid and ezetimibe.

Genetic editing of PCSK9 to lower LDL

We can now lower PCSK9 with a daily pill, a monthly antibody or a six-monthly siRNA. What about a one-off therapy? This still sounds futuristic, but it may be closer than it seems. This year, phase 1 data from Verve and Lilly’s PCSK9 base editor showed that a single intravenous infusion could reduce LDL cholesterol by as much as 60%.

Approval of aldosterone synthase inhibitor, baxdrostat, for hypertension

The other major cardiovascular risk factor is high blood pressure (hypertension). Treatment-resistant hypertension is common, affecting ~7-10 million adults in the US. AstraZeneca’s baxdrostat, which was approved in May, uses an established mechanism — aldosterone inhibition — but in a differentiated way to circumvent side-effects: blocking the synthesis of aldosterone altogether.

This resulted in an average systolic blood pressure lowering of 14.0 mmHg. For context, this would translate to ~26% lower risk of a cardiovascular event (for enlicitide, its lowering of ~1.5 mmol/L in LDL cholesterol would translate to ~31% lower risk) — shown in this figure.

Not everything worked

It’s not all been positive in cardiovascular disease. We’ve seen two major failed trials, too — Novartis’ pelecarsen, which lowers lipoprotein(a), failed to prevent cardiovascular events as secondary prevention in patients with high Lp(a), and Novo’s IL6 inhibitor, ziltivekimab, failed to prevent cardiovascular events as secondary prevention in patients with chronic kidney disease and high inflammation.

3. First in class medicines in autoimmune disease

Obefazimod in ulcerative colitis

In ulcerative colitis, 12 medicines from 6 classes are approved (anti-TNF, anti-integrin, anti-IL12/23, anti-IL23, JAK inhibitors, and S1P modulators), the best of which reach clinical remission in only ~40% of patients and (the better, harder, more objective target) endoscopic remission in ~25% . One thing’s clear: we need new modes-of-action.

This year Abivax presented phase 3 data for their brand new mechanism with obefazimod, a daily oral pill that induces expression of miRNA-124, an anti-inflammatory miRNA. It seems to do this through modulation of the aryl hydrocarbon (AH) receptor.

To compare efficacy between different medicines, we did the network meta-analysis — here’s how they each stack up against each other (blue is a statistically significant beat, grey is not) — obefazimod is top of the pack.

Read more

Background

It’s true that Chinese biotechs produce a lot of copycat (‘me-too’) drugs. But some of the most novel medicines are made in China, too, and now most deal value goes to Chinese biotech — 68% of all deal money this year (compared to 4% only 5 years ago). And about 50% of the world’s phase 1 trials (which test new drugs) happen in China. To see the medicines of the future, we have to look towards China.

Landscape of the new drugs

According to our analysis, China has cleared 160 novel drugs for first-in-human clinical trials this year — so far.

The most common indications are shown in the figure below. The biggest group is oncology, followed by infectious disease, then immunology.

The most common novel modalities, as follows, are antibody-drug conjugates (ADCs) and biologics.

The most novel programs

There are a lot of interesting programs here.

The most novel infectious disease programs

A selective gasdermin D inhibitor (PTT-121)

Made by: Pyrotech Therapeutics; China application number: CXHL2600780.

This is the first selective gasdermin D inhibitor to enter human trials — for septic shock, which is associated with about 20% of all deaths globally, but we lack any disease-modifying, host-directed medicines. In sepsis, infection triggers pyroptosis, an inflammatory form of cell death where a protein called gasdermin D forms pores in immune cell membranes. This causes cell rupture and can lead, ultimately, to multiorgan failure.

Sepsis has been a graveyard of clinical development (we reviewed it here) and, though there are a number of pre-clinical gasdermin D inhibitors, none have reached clinical trials yet.

Pyrotech Therapeutics’ drug, which was dosed into the first healthy volunteers on 1 September, blocks formation of gasdermin D pores, cutting off the execution step of pyroptosis (while leaving upstream pathogen sensing intact).

Here are all of the most novel programs, divided by indication, and the complete analysis:

The most novel cancer programs

ILT2 × ILT4 × CSF1R trispecific antibody (AK150)

Made by: Akeso; China application number: CXSL2501152.

This is the only trispecific ILT2/ILT4/CSF1R antibody in clinical trials — it’s designed to dismantle several layers of immune suppression, and it’s being tested for advanced solid tumours.

Blocking ILT2 releases inhibition of natural killer cells and T cells; blocking ILT4 reprograms and releases myeloid cells; and blocking CSF1R removes suppressive tumour-associated macrophages.

PD-L1 × VEGFR2 bispecific TOP1 ADC (JSKN027)

Made by: Alphamab Oncology; China application number: CXSL2501089.

This is a first-in-class PD-L1/VEGFR2 bispecific antibody-drug conjugate (ADC), with a TOP1 inhibitor payload, for advanced solid tumours. It simultaneously inhibits immune suppression, blocks the tumour blood supply, and adds direct cytotoxic killing.

STEAP1 × CD3 × CD28 trispecific T cell engager (HLX3902)

Made by: Henlius; China application number: CXSL2600400.

STEAP1 is highly expressed on prostate cancers, making it a good address to physically recruit T cells. CD3 provides the activation signal that triggers T cell killing; CD28 provides the co-stimulatory signal — particularly important in prostate cancer’s immune-cold microenvironment.

B7-H3-targeted sialidase (HLX316 / E-688)

Made by: Henlius/Palleon Pharmaceuticals; China application number: CXSL2501134.

The first tumour-targeted enzymatic desialylation therapy to enter the clinic. Guided to B7-H3-expressing tumour cells, it enzymatically strips immunosuppressive sialic acids from the tumour surface (in a completely PD1-independent manner). In other words: a potentially new cancer immunotherapy.

FOLR1/MSLN trispecific ADC (VBC106)

Made by: VelaVigo; China application number: CXSL2600684.

Mesothelin (MSLN) is often co-expressed with FOLR1 in ovarian, endometrial and lung cancers. Targeting both antigens means cells can be captured when FOLR1 is low but MSLN is high (or vice versa). This molecule leverages biparatopic targeting of FOLR1 (it binds via two different epitopes in the same molecule), increasing avidity and internalisation of the TOP1 inhibitor payload.

The most novel cardiometabolic programs

Read more

This is research not investing advice!

Do smaller companies generate better returns?

To test whether smaller companies themselves generate better returns (irrespective of specialist ownership) we separated the companies into the smallest and biggest thirds by market cap, rebalanced quarterly, and measured their subsequent compounded returns from 2017 to 2026.

The average annualized returns for the smallest third of companies was -11.7%, and +8.3% for the biggest third. The pattern is clear: smaller companies tend to do worse.

Do smaller companies — with more specialist investors — generate better returns?

So smaller companies actually do worse — but what if they are split by specialist concentration?

We found that, for both the biggest and smallest companies, higher specialist concentration predicts higher returns — and more-so for the small companies. Small companies in the top decile of specialist ownership averaged +26.2% annualized returns (+17% for the big companies); small companies in the bottom decile of specialist ownership annualized -24.4% (-3.2% for the big companies).

So, this successfully reproduces the Verdad analysis, which begs the next question: which of today’s smallest companies have the highest concentration of specialist investors? Here are those companies:

This score doesn’t take the science itself into account, but, out of curiosity, these are the lead programs for the top 10:

1. LeonaBio : Lasofoxifene — oral selective estrogen receptor modulator for ESR1-mutant ER+/HER2− metastatic breast cancer.

2. Xilio : XTX501 — tumor-activated PD1 × masked IL2 bispecific for NSCLC/solid tumors.

3. ImageneBio : Olevaprubart/IMG-007 — long half-life, non T cell-depleting anti-OX40 antibody in phase 2b for atopic dermatitis.

4. iBio : IBIO-600 — very long acting dual specificity anti-myostatin/GDF11 antibody to preserve muscle in obesity.

5. Boundless Bio : Pending a merger with Serapha — one-time in vivo base editor in alpha-1 antitrypsin deficiency.

6. Traws Pharma : Tivoxavir marboxil (TXM) — long-acting influenza cap-dependent endonuclease inhibitor.

7. Kalaris : TH103 — engineered VEGF trap with retinal tissue anchoring for wet age-related macular degeneration.

8. Karyopharm : Selinexor + ruxolitinib — XPO1 + JAK inhibition for first-line myelofibrosis.

9. Context : CTIM-76 — CLDN6 × CD3 T cell engager for solid tumors.

10. Eloxx : Exaluren — oral ribosome-modulating nonsense-mutation readthrough drug for Alport syndrome.

Here are the companies in the bottom decile, which annualized at an average of -24.4% over the last 10 years, and the full ranking:

Read more

We spoke about the data needed to do this, who the customer is, and about this year’s big trials (Novo Nordisk’s ZEUS trial, Novartis’ Lp(a)HORIZON trial, Abivax’s ABTECT trial).

The full episode is on Youtube and Spotify!

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My key takeaways

1. A quantitative approach for drug development

Pheiron’s idea is to use quantitative assessments (rather than human intuition) to help drug development - a bit like Moneyball, for pharma. They ask how much each evidence source increases the probability that a drug program succeeds, then backtest this against historical clinical outcomes.

Their analysis suggests that evidence quality varies enormously: rare human genetic evidence is particularly predictive, while some high-throughput expression or perturbation data adds surprisingly little. Crucially, they separate biological support from trial-specific probability of success - good biology can still fail in a badly designed trial.

2. The data that underpin predictions

Pheiron are human evidence maximalists. Their core inputs are individual-level human data: genetics, electronic health records, biobanks, hospital cohorts, multi-omics, tissue and cell datasets, plus clinical precedent and trial data. Their stack currently covers roughly 4.8 million individuals, hundreds of cell types and 50+ tissues, supplemented by essentially every relevant public database. AI agents retrieve and analyse these data rather than merely summarising literature. The key principle is that more data is not necessarily better: each source is weighted according to demonstrated predictive validity.

3. The prediction for Novo Nordisk’s ZEUS trial

Novo Nordisk's trial for an inflammation-blocking IL6 inhibitor just failed to prevent heart attacks in a major phase 3 trial. Pheiron predicted this at a 66% probability of success.

Why it should have worked:
- Precedent for the axis (from IL1β inhibition).
- Strong genetic evidence for the IL6 pathway.
- Convincing target engagement (reduction of inflammation - hsCRP) in previous trials.

Why it may have failed:
- Limited genetic evidence for the IL6 ligand.
- Questionable translatability of lifelong genetic loss to transient pharmacological inhibition.
- The previous clinical evidence (with IL1β) is strongest on non-fatal myocardial infarction, but the composite endpoint in this trial (which includes stroke) could dilute the effect.

4. The prediction for Abivax’s ABTECT trial

Pheiron gave obefazimod a 54% probability of success in its phase 3 trial for ulcerative colitis. It ultimately hit the efficacy endpoint decisively, outperforming what Pheiron expected. Their conservatism came from expecting efficacy to reduce during longer-term treatment - and from predicting bigger tolerability problems than the drug actually had.

Pheiron modelled obefazimod primarily as an miR-124 inducer, whereas the precise mechanism, it has emerged, is probably AhR modulation. It would be interesting to see if the probability of success would change if this altered mode-of-action was modelled instead.

5. The prediction for Novartis’ Lp(a) HORIZON trial

Pheiron gave Novartis’ Lp(a) HORIZON trial of pelacarsen a 49% probability of success, despite viewing Lp(a) itself as unusually strong biology. In the trial, pelacarsen did lower Lp(a) but did not lower cardiovascular events.

Pheiron’s concern was mainly the trial and population, not whether Lp(a) causally contributes to cardiovascular disease. Patients were already receiving substantial background cardiovascular therapy (statins, ezetimibe, PCSK9 inhibitors, GLP1s, SGLT2 inhibitors) leaving only a limited fraction of residual risk that Lp(a) lowering could modify. In Pheiron’s framework, HORIZON is a great example of strong target biology but much less certain clinical-trial success.

Follow Thore on X, here, and here is Pheiron’s Substack:

Engineering Biological Alpha

Insights on biological alpha: knowing what biology will work in humans early enough to change the outcome of a drug program.

By Pheiron

Thank you for reading/watching! The full transcript is here:

Full Transcript

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Their model, which they describe in a white paper, has 5 domains:

1. Ownership by biotech specialist institutional investors

2. Stock purchases by C-suite insiders

3. Short interest

4. Peer momentum (trailing returns of scientifically similar companies)

5. Value factor (spending as a proportion of market cap)

Each of these predicts forward returns, and, because they are mostly independent, it’s the combination that really filters the good from the bad. The top fifth of companies returned 21% annually; the bottom fifth returned -17%.

What Verdad did not do is rank today’s companies, so we present it here: the full ranking of the 589 US-listed biotech companies.

This is research — not investing advice; for interest and information only!

According to our implementation of the model, the top 10 companies are as follows:

These companies tend to have a concentration of biotech specialist investors, recent insider buys, low short interest, strong peer momentum, and look cheap according to the value factor.

The model doesn’t directly assess the probability of clinical trial success, but most of these top companies have novel science, with programs based on solid biology. The lead programs of the top 10 are:

1. ImageneBio — Non-depleting OX40 antagonist for autoimmune diseases.

2. Sutro Biopharma — Tissue Factor-targeted antibody-drug conjugate.

3. Acrivon Therapeutics — CHK1/2 inhibition for gynecologic cancers.

4. MoonLake Immunotherapeutics — IL-17A/F-blocking nanobody for hidradenitis suppurativa and psoriatic arthritis.

5. Adicet Bio — Off-the-shelf CD20-targeted gamma-delta CAR-T therapy for autoimmune diseases.

6. Zentalis Pharmaceuticals — WEE1 inhibitor for Cyclin E1-positive, platinum-resistant ovarian cancer.

7. Odyssey Therapeutics — Oral RIPK2 scaffolding inhibitor for ulcerative colitis.

8. ALX Oncology — CD47 blocker combined with antibody therapies for HER2-positive breast and gastric cancers.

9. Alumis — Oral TYK2 inhibitor for plaque psoriasis and systemic lupus erythematosus

10. CNS Pharmaceuticals — Seeking new neurology and oncology assets; former lead for glioblastoma is now offered for out-licensing.

Here are the bottom 10, and the full ranking:

Read more

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1. Daraxonrasib gets FDA-approved!

The first RAS-targeted drug for pancreatic cancer has been FDA-approved! Revolution Medicines’ daraxonrasib is a once-daily oral drug that inhibits RAS in its active, “ON” state — including several of the RAS mutations that drive the vast majority of pancreatic cancers.

The label is very broad: it’s approved “for the treatment of adult patients with metastatic pancreatic adenocarcinoma who have received at least one prior systemic therapy or who are not candidates for multiagent systemic therapy”. Though the trial was done in the second (or later) line, some have said this soft label could also allow daraxonrasib to be used even in the first-line setting.

The approval comes just over two months after Revolution Medicines presented the full phase 3 data at ASCO, where daraxonrasib increased median overall survival to 13.2 months, compared with 6.7 months with chemotherapy. I was lucky enough to be in the room for the presentation — and recorded the standing ovation it received here.

Rasonque — “RAZ-on-cue” — will be the name. It becomes the 34th new medicine FDA-approved this year. It took 135 days from the data to the approval — by far the fastest of the year.

Source: Revolution Medicines in the New England Journal of Medicine and the FDA.

2. Success for a personalized cancer vaccine

Moderna’s personalized mRNA vaccine was successful at extending recurrence-free and metastasis-free survival in a phase 3 trial, in patients with resectable melanoma (specifically, completely resected stage IIB–IV melanoma). This is the first ever phase 3 success for an mRNA cancer vaccine.

Patients had surgery, then vaccines made with up to 34 personalized neoantigens — this was dosed 9 times alongside immune-stimulating pembrolizumab.

There is no actual efficacy data yet, and no overall survival data, either, so the results below are from the phase 2b trial.

Moderna are running this same personalized vaccine in other cancer types: resected and metastatic non-small cell lung cancer, renal cell carcinoma, bladder cancer, and metastatic melanoma. Beyond this, there are 494(!) therapeutic cancer vaccines in development: 241 in phase 1, 220 in phase 2, 33 in phase 3, and 11 approved globally (only two in the US). If you are interested, here is a comprehensive map of the landscape.

In other cancer vaccine news, Biontech also had a trial readout this week, which was, unfortunately, resoundingly negative. The indication they picked was microsatellite stable colorectal cancer. This is a very immune-cold cancer type, so maybe not so surprising to see the failure.

I spoke about all of this with a cancer vaccine scientist this week, check it out here!

Source: Moderna.

3. Activating Tregs treats eczema

T-regulatory cells (Tregs) dampen inflammation. Last year, their discovery won the Nobel Prize, and now they're being used to make new medicines! Nektar Therapeutics made an antibody to stimulate the cytokine that expands Tregs, IL2. In a phase 2 trial, it worked in atopic dermatitis (eczema).

The concern about IL2 agonism is that it could also expand cytotoxic T cells, which could cause widespread immune damage — but Nektar’s drug, rezpegaldesleukin, is PEGylated, which means it binds less well to effector T cells and it’s biased to Tregs (because they have high CD25, which helps capture the PEGylated drug).

As for the name, rezpegaldesleukin: Rez- is a distinguishing prefix, -peg- is because it's PEGylated, and -aldesleukin is the name for recombinant human IL2.

In the trial, circulating Tregs rose up ~6-fold, with corresponding reductions in inflammatory biomarkers. This is good proof-of-concept that restoring immune tolerance — rather than simply blocking inflammatory cytokines — can improve disease. Indeed, in the trial, there was no increased risk of infection. Phase 3 up next!

Source: Nektar Therapeutics in The Lancet.

4. How common is atherosclerosis, really?

Researchers in Denmark and Spain did a prospective cohort study with 16,808 healthy adults (ages 18 to 70) who had no prior history of cardiovascular disease. To look for silent (asymptomatic) atherosclerosis, they did imaging:

• 3D vascular ultrasounds, to examine the carotid (neck) and femoral (leg) arteries.

• CT Scans (angiography and noncontrast) to examine the coronary arteries.

They found that atherosclerosis begins much earlier than we thought — for example, about 20% of 30 year old men already have atherosclerosis.

This rise of atherosclerosis, with age, is exponential.

To me this shows the importance of early intervention and prevention. The good news is we really do have (almost) all of the tools to intervene and prevent this — including for the big 3: LDL cholesterol, high blood pressure and obesity (smoking is the other one).

For more on cardiovascular prevention and how to solve it, listen to my interview with Sek Kathiresan, who is pioneering one-and-done lipid-lowering therapies to prevent heart disease.

Source: University of Copenhagen and University of Madrid in NEJM.

Read more

Dr. Tiffany Ma is a senior scientist at Infinitopes, a spin-out from Oxford University. She helped make one of their current vaccines, for esophageal cancer, which they just started a clinical trial for, with the first patient dosed last month!

This episode is brought to you by my partners at Consensus, the AI agent for literature research and medical questions. Get a free trial with my link!

Moderna’s positive phase 3 trial in melanoma

Moderna (in collaboration with Merck) last week press-released the phase 3 trial data for their mRNA cancer vaccine, in resectable high-risk melanoma. Patients had melanoma removed by surgery, then Moderna built personalized vaccines based on that specific patient’s mutations — the neoantigens. The vaccine was given alongside the immune reactivating antibody, pembrolizumab.

It’s just a press release — with no actual data yet — but the vaccine improved metastasis-free and recurrence-free survival. There’s no data on overall survival yet either, which is of course the most important thing. On the news, Moderna’s stock price had the biggest one-day rise in S&P 500 history — about $50 billion in market cap…

The cancer-vaccine landscape

Globally, there are 241 vaccines in phase 1 clinical trials; 220 in phase 2; 33 in phase 3, and 11 approved globally (two in the US). So, although it’s true that they haven’t become fully standard of care, there has been some success — and it’s an interesting little stat that there are two approved in dogs.

Tiffany Ma:

Just to say the ones that are approved aren’t really true neoantigen cancer vaccines. The first one is BCG, in bladder cancer, which is just a weakened bacteria that acts as an immunostimulant. And the second one is a cell therapy for prostate cancer, a dendritic cell vaccine. Which is where you just take out the dendritic cells from the patients and then retrain them and then inject them back into the patient. There hasn’t been mRNA vaccine success, peptide vaccine success, or viral vector vaccine success before.

So Moderna’s news was such a milestone for the cancer vaccines world, because this is the first neoantigen based vaccine to get to this stage of success in a phase three trial.

How does Moderna’s cancer vaccine work?

I thought we should go back to some basics, for those of us not in the biotech world. There are three phases of clinical trials. Phase one is usually for safety, phase two is for efficacy, and phase three is for seeing whether or not your drug beats the current gold standard therapy that’s being used in the clinic. And cancer vaccines in general, it’s a drug that teaches the immune system what a cancer cell looks like, so that the immune system can recognize the cancer cells and kill them.

Vaccines educate your immune system, whether it’s a flu jab or a COVID vaccine, and then your immune system goes around your body like the police, and kills them. And this part is a bit sciencey but I think it’s important for people to understand how cancer vaccines work, and that’s the mechanism of HLA molecules presenting these little peptides on the surface of your cell.

You can think of your cell as a house with windows, and the windows are your HLA molecules, and their job is to show this flag with patterns and wave it to the outside world. And then your immune cells, your T cells come by like policemen and check the badge, check that flag to see whether or not you’re a healthy cell. And if you happen to be a cell that’s infected by a virus or you happen to be a cancerous cell, then the T cell would be able to tell by reading that flag, the patterns of the flag specifically that you’re showing on the window.

The vaccine is teaching T cells: this is what flag you should be looking for, and then once it comes across a cancer cell then it will know to destroy it.

Immune checkpoint blockade — pembrolizumab — unleashes T cells into a immune system which is already trained by the cancer vaccine. So they work together, they’re synergistic. And this is what Moderna used in their phase three trial.

Why have cancer vaccines struggled in the past?

Why they’ve had a checkered history is because of a whole host of problems.

The first problem is target selection. So, finding the right target is actually quite tough and it wasn’t until recent RNA, DNA and protein sequencing technologies that they got really robust that we were able to find really good targets. What makes a good target is something that is not expressed on your healthy cells and something that’s expressed only on tumor cells. And if you pick something that’s even expressed at a relatively low level on your healthy cell, you can imagine there’s going to be side effects.

The second issue is tumor heterogeneity. Tumors mutate very quickly, especially some types over others. And that means even though your vaccine might work on this part of the tumor, it might not work on another part of the tumor. They might have different clones or different populations of tumor cells.

The third problem is immune escape. Tumor cells are very clever and they know how to hide from the T cells, the policemen of your body, in multiple ways. Losing antigen presentation is one of them and expressing cells that suppress T cell infiltration is another one of them.

The fourth is clinical trial design. You want to give the vaccines to people who have a working immune system and, unfortunately, if you give it to people who have late-stage metastatic cancer their immune system might not be able to put up as good of a fight anymore.

The fifth is manufacturing — expensive and hard to scale — and, again not until recent years that we got the tech to do it at nearly an affordable level.

And the last one is delivery, which is something probably Moderna’s proud of — getting the actual vaccine into the cell can be quite tough as well.

How do you overcome those challenges?

Moderna’s is a personalized vaccine i.e. each patient gets their own bespoke vaccine. So for that you have to wait until the patient’s tumor is resected. After the surgeon takes it out, you then take it to the lab and you do deep sequencing. You do DNA sequencing and RNA sequencing to identify the mutations that the tumor has and you use these fancy computational models, obviously some of them involving machine learning.

Then you find these targets that we call neoantigens. And if you are Moderna then you’re making an mRNA vaccine with up to 34 targets strung together so then they can be translated by the cell once they get in. The whole process takes like 6 to 12 weeks.

I guess that overcomes the target problem, because you’re building it based on the neoantigens from that person’s tumor?

That’s only half true I will say. Because yeah the good thing is it’s personalized. So you might find things that are specific to your tumor and not to another person’s tumor.

But unfortunately mother nature doesn’t turn every mutation into a peptide that’s then presented on the surface of your cell — actually less than 1% of those DNA mutations are eventually expressed as peptides on your cell. So they’re not actually the most precise way of selecting targets — but it is efficient, because sequencing technologies have gotten so good and so cheap and scalable now that we’ve really mastered next-gen sequencing, you can do it for each patient. Moderna are predicting from DNA and RNA level what might be there on the peptide level.

In order to go straight to what’s being expressed on the surface of the cells, you need to do mass spectrometry, and specifically a technique called immunopeptidomics, which is what Infinitopes does and that’s why we call it our precision immunomics platform — because we don’t predict, we measure what’s actually being expressed on the surface of the cells by MHC I.

You mentioned that Moderna are leaving ~99% of the potential targets on the table using their neoantigen approach?

That’s what I would argue, whereas the Infinitopes approach takes all of that into consideration. The technology has limits, but yes we basically see as much as we can detect using the current mass spec technologies, on the surface of the cell. So we start from what’s actually there instead of doing guesswork and computational work.

But the caveat is mass specs are a lot harder to operate than DNA and RNA sequencers. So that’s our moat. If you can find someone who’s really good at mass spec and immunopeptidomics, you can build a cancer vaccines company out of it and that’s what the Infinitopes co-founders did.

The second thing you mentioned was heterogeneity of the tumor and how that can affect things. From the Moderna point of view, I can imagine that the 34 neoantigens they load into the vaccine addresses that issue?

The jury is still out on that one in the cancer vaccines world. Because if you treat your T cells like a person, you can’t distract the person with too many targets, but at the same time, you want more shots on goal. So if your target number one isn’t actually expressed on the surface of the cell, then you’ve got like the 33 other targets and you pray that at least one or two of them might actually be there. But there’s a maximum limited by manufacturing and by the biology — you can’t just put a huge string of epitope in there.

The third one you said was immune escape. Does adding pembrolizumab — anti-PD-1 — address that?

Yeah, exactly. It’s definitely very synergistic especially in melanoma which is the low-hanging fruit indication for cancer vaccines just because melanoma is famously known for having a high tumor mutational burden, which means they have lots of mutations for you to find — so it’s like the level one of cancer vaccines.

On trial design, so you said that previously we were putting vaccines into late-stage metastatic patients and of course with the melanoma trial from yesterday as well as your trial, it is in patients with resectable disease, right?

Yeah. It is in resectable disease, which is a really important consideration because at that point we assume that the patient still has a working immune system but then when you try to teach the immune system it will actually be effective. Usually at that stage, the point is not to prevent people from getting cancer ever, but it’s to prevent these leftover bits of cancer cells that your surgeon couldn’t resect probably because they don’t want to resect too much of your tissue right or they couldn’t spot it.

And those bits that are left behind are usually what causes relapse and recurrence. So the cancer vaccine does its job by teaching the immune cells. So then after the surgery the T cells do their job of killing the leftover cancer cells that the surgeon didn’t remove.

You mentioned the moat of Infinitopes was in the mass spec platform and in measuring rather than predicting.

Yeah that’s one of our moats. Our delivery platform is actually a moat as well.

It’s an engineered viral vector, that can be very immunogenic as well and cause a very long-lasting T cell response, which you want in the body. You want it to be there months or even years after you’ve had the vaccine. So then if a little cancer cell pops up and it was hiding, then your T cells are like, “Oh, you’re dead.”

And the delivery platform for Moderna is mRNA, right?

Yeah, exactly. And a lipid nanoparticle. They usually go hand in hand, but they’re very short-lived, which might mean you need multiple shots of the vaccine, whereas with viral vector, you may not need so many shots. So that adds up in terms of how costly it would be, how many times you would require the patient to go to the clinic. And the Moderna one is given nine times.

But the good thing about mRNA is you don’t even have to get to the nucleus. You just translate it into the target. The bad thing is it’s also exposed to all these things in a cell that can get rid of it, metabolize it very quickly. So you need way more shots of it.

And the other thing you said was on manufacturing.

There’s obviously a big difference between Moderna’s manufacturing versus Infinitopes’ manufacturing. Because for Infinitopes, whereas Moderna gives it in an adjuvant setting i.e. after the tumor has been resected, because you need 6-12 weeks to make the vaccine before you can give it back to the same patient. Infinitopes is making an off-the-shelf solution, which would in theory be a lot cheaper. We are finding targets that are shared between many different patients but they’re very precise because as I said we’re not predicting.

We did our discovery work by sourcing many different tumor samples from the same cancer type, and then we see what’s being shared — and we’re going to be really confident from our very precise and very in-depth mass spec combined with very cutting edge computational techniques to find those targets.

And a lot of those targets, they’re very interesting — there are different sources of targets. They could come from viral sources — famous ones like HPV, but it’s not just the canonical genome. There are people now looking at the dark genome, which is actually 99% of our DNA that doesn’t code for the classic proteins in our body. More and more companies in the cancer vaccine space are finding — wow — some of these dark genome targets are good cancer vaccine targets.

I’m going to ask you about the dark genome later but… I can definitely see that off-the-shelf is probably cheaper and faster. But my criticism would be that on measure not predict, I see that you’re measuring the antigens on the MHC, but I would argue that you’re measuring the antigens that are on the MHC of different patients — the test patients, and not the patients you’re actually giving the vaccine to.

We’re also going to measure the antigens on the patients that we’re giving the vaccine to. So, in case they don’t get a response, we can measure their immunopeptidome and be like, “Oh, it wasn’t there in the first place and that’s why it didn’t work.” But we designed our vaccine in such a way that it’s HLA-matched. So, the patient has to have the right HLA type, before they get our vaccine, to maximize the chances of success.

So, if you select for the HLA type subtype then you increase the chance of success? But the other thing that you do is you subdivide the market. You make the market smaller, because there’s fewer patients that have that HLA subtype. Whereas with the Moderna one, it’s not HLA matched, it’s for everyone.

It’s just not scalable. You have to make one vaccine per person. So there’s no right or wrong way. I think we’re all trying to move towards the same goal of making the right vaccine for the right patients, and that might mean their disease profile or whether or not they have deep pockets and healthcare system. And there’s always trade-off for every choice on the targeting, on the delivery system, etc.

I was super curious. When the news came in yesterday from Moderna, how was the reaction at Infinitopes?

I think we love that honestly. Even though they’re technically a competitor, we think they’re doing a great thing for the field because now for cancer vaccines people, it’s no longer a question of do cancer vaccines work, it’s how do we make them even better? And which ones are the right cancer vaccines for the right patients? So, it’s exciting times.

Infinitopes’ approach

Infinitopes’ mantra is right targets, right vectors, right patients, right time. Could you talk us through each of those and what it means?

Targets, like I mentioned, you can have a very focused approach. You could be a company that just looks for viral elements etc, or you can cast a wide net and just look for as many differences as you can between normal cells and cancer cells.

Or you can do the Moderna approach which is finding targets that are just so specific to one patient. So you can pick your approach and then obviously in the within targets you also have the discovery process of those targets. Are you doing RNA or DNA sequencing? Are you using mass spec? What computational techniques are you using? So that’s the first part.

Second part, right vectors and that goes back to is it a dendritic cell vaccine, peptide vaccine, DNA, mRNA, viral vector, and the differences between those.

And then right patients, so personalized versus off-the-shelf and are these early stage patients or late-stage patients?

And finally, right time — when in their treatment regimen are you giving them the vaccine? So is it preventative like we’re seeing with some of the Lynch syndrome vaccines that are being developed or BRCA vaccines or is it neoadjuvant, adjuvant or even metastatic in the future?

In that context, I wonder if you could tell us about the trial that you guys are running, how it works and when the vaccine is getting given.

Our trial is a really exciting phase 1/2a. So, we’re doing phase one and a bit of the two at the same time. It’s a 60 patient trial in esophageal adenocarcinoma. We have eight patients for the safety dosing parts and then 52 for the 2a part.

It’s going to be given before the surgery and after the surgery. Usually, esophageal adenocarcinoma patients get chemo-surgery-chemo. So here we’re doing chemo, Infinitopes vaccine, surgery, and then Infinitopes vaccine (with or without immunotherapy). And then the readouts — the best readouts are overall survival or recurrence-free survival. But in the meantime, we can look at other readouts like circulating tumor DNA, which can be measured by companies like Personalis, who are very famous for having very high sensitivity for detecting leftover presence of cancer cells. This is what’s called minimal residual disease (MRD) and you need to be able to detect such small presence of circulating tumor DNA — the DNA that’s leaked out from cancer cells — to be able to tell the patient hey you need to come back to the clinic.

And that’s one of the issues of the trial, right? Because it takes a long time for recurrence to happen sometimes. So you might have to run the trial for a very very very long time. But if you look at the ctDNA, then you can see the recurrence on the molecular level on the DNA level much sooner.

Exactly. So people use it as a proxy for whether or not their drug is working. But the time point really matters as well because sometimes there’s a bit controversy about the ctDNA among scientists because the moment you attack the tumor, you’re going to see a sudden increase in circulating tumor DNA because you’ve just killed tumor cells and they burst. But then hopefully after the initial increase, you see a decrease again. It depends on the kinetics of the drug and the patient.

The dark genome

You mentioned earlier the dark genome and the 99% of the genome which is not coding, and how that can help you build better vaccines.

Just to go back to basics, the coding part of the genome just refers to genes in your DNA that eventually become proteins.

The classical 20,000 genes that we call the coding parts of the genome. But the rest of the DNA, for many years, scientists have called it “junk DNA” because they have no idea what it’s there for. But recently (and when I say recently I mean like the past 10 20 years) scientists have found that it performs really important regulatory functions in the cell.

It could be these regulatory RNAs like circular RNAs can come from the dark genome. There are microproteins that can come from the dark genome. And these regions they sometimes produce peptides that end up as neoantigens on the surface of your cell. They can come from alternative splicing, certain retroviral elements or even like when the ribosome makes mistakes and slips when it’s reading the mRNA that can also produce neoantigens from the dark genome. So, it’s basically anything that’s not defined classically as a coding, protein part of the DNA.

So the mass spec approach is a better, more sensitive approach to to pick that up?

I would argue yes. But you also want to match it with other types of sequencing, which is what I’m sure all the companies are doing.

And there’s this concept of which we didn’t mention actually — tumor-associated versus tumor-specific antigens?

Tumor-associated antigens have been found in the past they’re basically proteins or targets that are expressed by healthy cells but usually at a low level, but they’re overexpressed by cancer cells which is why it’s just associated but it’s not specific to cancer cells — like HER2. Whereas tumor-specific ones are literally only expressed by cancer cells.

And if we are able to characterize the dark genome, can we find more tumor-specific antigens and therefore make better vaccines?

Yeah, perhaps there are some really interesting studies that found some tumor antigens that came from the unmutated genomic sequences, but they’re from the non-coding part. It’s just that they’re now being aberrantly expressed into proteins and then peptides. So, it doesn’t mean that looking at mutations will get you the best targets. Sometimes you have to look at perhaps what’s being expressed that’s not normally expressed.

So there are lots of creative ways to think about it, and each company has their own spin on it.

The future

One of the ideas for the future: vaccines for prevention?

There are trials ongoing for cancer prevention in patients with Lynch syndrome or BRCA mutations, but there are also broader ideas — vaccinating pre-cancerous states, like colon polyps, pancreatic cysts or Barrett’s esophagus.

I think that’s definitely part of the future. The only difficult thing about them is you have to wait for so long, to see the effectiveness of these vaccines, which is usually why they’re being led by academics and not by companies.

How do we actually, practically, do cancer vaccine trials for prevention?

I think you have to enrich for the very high-risk patients — at least initially — and then you’re going to have to do things like surrogates and ctDNA, and maybe even look at the CD8s. And you can also look at whether or not the T cells themselves — the expanded pool — whether or not they have the receptor that’s specific to your cancer vaccine target. You can do TCR sequencing.

The only issue then you’d have to prove to the regulators that that does indeed correlate with reduced progression to cancer, which is then going to be a little bit difficult. Only time can tell unfortunately, which is why these things take so long.

Another idea for the future: vaccines against immune-cold and metastatic cancers.

For the immune-hot cancer types — melanoma, mismatch repair-deficient colon cancer, lung cancer — I think cancer vaccines are very likely to work alongside immune-stimulating therapy. But you have to think about therapeutic vaccines for some of the diseases which are not so immune-hot — but where they have serious unmet needs.

Like glioblastoma and pancreas cancer — I think those are the going to be the challenges for cancer vaccines. I had a look at the indications where most of the cancer vaccines are being trialled, and it goes — melanoma, lung cancer, glioblastoma — so there’s a lot of attention for cancer vaccines in glioblastoma, which I think would be really good because it’s totally unmet as as it stands by therapies.

Some creative ideas are to vaccinate against the population of cells that’s making the tumor immune-cold — like a specific T cell subtype subgroup, like Tregs.

And I think eventually what excites me is not just preventing cancer from coming back. It’s if we’re able to administer a cancer vaccine to a metastatic patient and make it work. That’ll be amazing. Especially in an originally immune-cold setting.

Are you guys working on that?

Oh, sure.

Thank you very much to Dr. Tiffany Ma for the illuminating conversation!

This episode is brought to you by my partners at Consensus, the AI agent for literature research and medical questions. Get a free trial with my link!

Sek is a cardiologist and an academic. He made many of the initial discoveries of targets for cardiovascular prevention, based on human genetics — some of which later became medicines, including NPC1L1, the target of ezetimibe, APOC3, the target of olezarsen, and ANGPTL3, the target of evinacumab. He also discovered that HDL is not causally related to heart disease, and that clonal haematopoiesis is a causal risk factor for heart disease.

He started Verve Therapeutics to make one-and-done lipid-lowering medicines, and the company was acquired by Eli Lilly in 2025 for up to $1.3B. The Verve pipeline includes base editors targeting PCSK9, ANGPTL3 and lipoprotein(a).

Sek is now also the head of obesity research at Lilly. So, really at the forefront of many of the most exciting parts of medicine and biotech — and a perfect person to speak to at this time.

Sek:

I consider my career in three phases. Phase one, roughly the first 10 years, was really learning human biology and medicine. So I trained in internal medicine, in cardiology.

The second phase, about another 10-15 years, is research. After finishing clinical training I spent five years as a post-doc fellow in human genetics. This is the early days of human genetics, 2003 to 2008. The human genome sequence had just been completed and I learned human genetics at the Broad Institute and the Framingham Heart Study, to understand the correlation between genotype and phenotype. And really focused on two phenotypes. One is cholesterol levels in the population. The second is heart attack (myocardial infarction, coronary artery disease) in the population, to try to decipher the inherited basis for those two phenotypes.

Then the third phase, which started in 2018, is around entrepreneurship and taking some of the insights from that second phase and trying to make medicines to improve patients’ lives based on those genetic insights.

The ANGPTL3 story is particularly resonant to me because back in 2008, we made the initial observation of people who completely lack this gene. There was a family in St. Lewis, a very large three generation family where LDL cholesterol being very low and triglycerides being very low ran in the family — as if a single gene was responsible for that. In the second generation, multiple people had the phenotype of very low lipids — that we called familial combined hypolipidemia. We ended up taking two family members and sequencing the entire exome, back in 2009.

The reason they had the low lipid levels were they were human knockouts for the ANGPTL3 gene. We went on to show that there are hundreds of people around the world that had this phenotype. They were healthy, they had the low lipids. As a result there have been medicines in development targeting this gene, both a monoclonal antibody and now an siRNA, and then we’re developing at Verve, a gene editing approach as well.

At Verve, the main program is a one-and-done cholesterol-lowering medicine.

The PCSK9 program at Verve is a one-time therapy that turns off the PCSK9 gene in the liver permanently, and leads to LDL reduction hopefully lifelong. And we have that program heading into phase two. The phase one data was just presented a couple of months ago at the European Atherosclerosis Society meeting and a simultaneous publication in the New England Journal of Medicine. So I would urge the listeners to track that paper down. It really nicely summarizes the progress we’ve made with this new technology. This is a base editor. The goal here is to make a single spelling change in the DNA of the liver in the PCSK9 gene to turn the gene off and to really give that protection that some people naturally got by having the gene turned off.

We were able to show in that paper that yes, we can turn off the gene in the liver. The LDL came down between 50 to 60% on average. And it was durable. We showed durability data extending out to 18 months in that study. And I think this kind of editing in the liver is likely to be durable for a long time, probably a lifetime.

The paper Sek mentions is here:

Hepatocytes regenerate throughout life, and some patients also have metabolic liver disease and fibrosis — which are those same patients that have high LDL cholesterol. Does the regeneration or these comorbidities affect the longevity of the therapy?

We’ve looked at this pretty closely and the DNA editing really looks like it’s going to be durable probably for a lifetime. Despite the fact that the liver regenerates, when we first do the therapy all the cells that are responsible for liver regeneration. So when they divide they carry forward the edit. That’s probably what’s happening. And the reason I can say with reasonable confidence that it’s going to be durable for a long time is that there are groups that have shown editing in monkeys is durable for more than seven, eight years now.

In patients the furthest durability is for a different target called TTR by a company called Intellia, and they have now four, almost five years of durability in some of their earliest patients treated. So this really looks quite different actually from viral vector gene therapy which is another form of potential one and done, where there it’s been a little less clear that it’s going to be truly durable for a lifetime — but I think the in vivo gene editing looks quite different than that.

On the competitive landscape of PCSK9, which, like many high conviction targets, we’re hitting from many different angles. Enlicitide, a once daily pill for PCSK9 inhibition; monoclonal antibodies once every two or four weeks; inclisiran, once every six months. How do you view the competitive landscape and how the PCSK9 base editor, Verve 102, might fit in?

Ultimately, different patients will make different choices. For some, I think the idea of a one-time therapy and being done with it after that is going to be particularly appealing. I think particularly people who are younger, who don’t want to face the burden of lifelong therapy. And so we’ve done some surveys of patients, to understand at this present time what the patient preferences are. It turns out when given those four choices, we surveyed about 500 people who have high cholesterol or have had heart disease.

40% choose daily pills (like enlicitide); 5-6% choose twice-monthly injections (like evolocumab); 14% choose twice-yearly injections (like inclisiran); ~33% choose the one-time treatment (Verve-102). People will make different choices.

Adherence is an issue as well, right? Especially for once daily therapies. The adherence to statins drops off to ~50% over the course of a year, whereas of course with a one-and-done therapy, there is really no adherence issue at all.

This is the major insight that led us to start Verve — this idea that lifelong low cholesterol is probably the answer to heart disease. So if everybody had their LDL cholesterol between 35 and 50 mg/dl for their whole life, we may not have any coronary heart disease. Let me say that again. If everybody’s cholesterol was between 35 and 50 lifelong, there may be no heart attack in the world. Now, heart attack is the leading cause of death in the world, so this is a bold statement that I’m making but I think this is true and the conviction behind that insight is what led us to start Verve.

A couple things that people ask when I say this. One is, is it safe to have the cholesterol 35 to 50 lifelong? The average in the United States is like 120, and people think average is normal. Average is not normal. We’re not meant to live at 120. So, what are we meant to live at? What is a healthy range? It turns out, let’s look at a range when we’re born, babies, or range in rural China before industrialization, where there’s actually very little heart disease. Well, it turns out babies’ cholesterol is between 35 and 50. And babies require a lot of cholesterol, because there’s myelinization ongoing in the brain. It’s just in the last several hundred years for industrialization, diet, lifestyle has really shifted that cholesterol curve population-wide to now where the average is 120, but the average is not normal.

What about smoking, diabetes, inflammation, hypertension?

There are a few other drivers for sure, and I think the three major drivers that we’ve seen from human genetics work are cholesterol, blood pressure and weight. Those are probably the main if not the only drivers of atherosclerosis. Ultimately you want to tackle all of them, but really the key driver in my mind, that’s necessary and sufficient to drive atherosclerosis, is cholesterol.

Cardiovascular medicines are typically approved on the basis of surrogate endpoints (lowering LDL cholesterol) without necessarily having to prove a risk a reduction in cardiovascular events — will the same be true of your medicines?

We are anticipating, based on precedent, that our medicines would get approval based on LDL lowering for a couple of reasons. One is the best understood relationship in all of medicine is really the reduction in LDL and its subsequent effect on reduction in hard heart events. In particular for the PCSK9 target, we have now like four different outcomes trials that essentially have proven this and several more ongoing. So I think that’s the precedent with which we anticipate approval, based on LDL lowering.

On the Stripe podcast with Dave Ricks, the CEO of Lilly, he mentioned the need for innovation on pricing for a medicine like this — do we do a one-time high price or actually, what he suggested, is a subscription model where you pay on a monthly basis if the LDL is still lowered — and if it’s not lowered then you don’t pay. Is that the kind of model that you anticipate?

I think it’s a little too early to talk specifically about pricing for our medicines except to make a couple of points. One is, when people think about one-time medicines, they’re thinking automatically a huge price tag. Because the earlier medicines in this space have all focused on rare disease. We’re not focused on rare disease. We’re literally focused on the most common problem in the world, coronary heart disease. So, we have a lot of patients that we need to treat to help. So, it’s not rare. The second is the cost of goods to how much does it cost to make this stuff. Our medicine, unlike the previous gene editing gene therapies, can be made very cost-effectively because it’s mRNA packaged in a lipid nanoparticle and we know that kind of product can be made very cost-effectively. Based on those two features we don’t we anticipate pricing to be way different than the millions of dollars per dose for current one-time therapies.

We think, ultimately, our pricing will be much more like other one-time procedures in cardiovascular medicine. In fact, that’s the way I think about our medicine. Less a drug, more like a molecular surgical procedure. I’m not putting in a catheter to insert a stent, but rather what I’m doing is I’m infusing something that will go to the liver and make a single spelling change in every liver cell. Kind of like a micro scalpel.

The technology focuses on base editing, and has no off switch. Do you anticipate any resistance from patients or prescribers with this kind of approach?

I think that we have to document the safety over time. There are two aspects to the safety of these medicines. As I said, it’s delivered by a peripheral IV. So just a simple IV in the arm, dripped in over about four hours and then you’re done.

In terms of safety, first there’s acute safety, around the infusion. Sometimes the infusion can cause a little bit of challenge to the liver acutely, but we’ve got a good handle on that. We monitor the patients and our current drug product has very minimal effects on the liver. Then there’s the long-term safety. People worry that having the cholesterol low for a long time, and the PCSK9 gene turned off for a long time? That’s one issue. The second is, might you be making a spelling change somewhere else in the genome and causing a problem? For example, in a cancer-causing gene and leading to cancer. Those are the two major issues long term.

There are people walking around who have this gene switched off either one copy or two copies and, lifelong and they’re totally fine. There’s nothing we found wrong with them. And there are millions of patients now who have received the PCSK9 inhibitors for many years and there are no adverse signals that have emerged. So there’s both genetic and pharmacologic validation of the safety of turning off this target, and having the cholesterol low. So that’s very reassuring.

And then on the off-target issue, we’ve looked very carefully to see if we making any spelling changes anywhere else in the genome beyond the intended spot, and we don’t find that. And on top of that, we’ll be following all the patients in our trial for 15 years. This is a requirement by US and ex-US regulators. So, we’ll be able to track them for safety. At the time of approval, hopefully we’ll have at least three to five years of follow-up in a lot of the patients and that should give people reassurance on the safety and then even longer follow-up will come over time. So, I think that we’ll have a pretty good safety database to reassure people.

And then on top of that, there are lots of things we do in medicine that are permanent. And the number one thing is surgery. Every surgery is permanent — we don’t reverse surgeries typically, and patients take it up all the time if you explain the benefits and the risks.

As the head of obesity research at Lily, I’m curious about the problem that you’re aiming to solve and how you’re solving it.

There are several unmet needs that we’re trying to address and I’ll just go through them each. One is: can we get even greater weight loss? The second: can we get even better tolerability — particularly GI tolerability? The third: can you make these things even more durable? The fourth: can we, wherever there’s an injectable option, develop an oral option? And the fifth: can we work around some unwanted effects — particularly muscle loss — that happen sometimes with these agents.

What about brenipatide, Lilly’s GLP-1/GIP receptor agonist? It works in a similar way to tirzepatide but Lilly are focused on neuroscience indications — things like depression, schizophrenia, bipolar disorder. Why is it that that particular drug is focused on neuroscience?

There has been some observations made largely using clinical data in patients receiving these medicines. People have shown that these medicines seem to decrease cravings, cravings for food of course but also alcohol and substance abuse — suggesting that these may have broader neurologic benefits, neuropsychiatric benefits. And this has been confirmed in a series of observational studies. Probably among the best was in the American Veterans Administration System database. These are all observational data, so of course could be due to confounding. The best way to get around and prove that the medicine that it’s cause and not correlation mere correlation is actually test a medicine in a randomized way — and that’s really what Lily is intending to do with brenipatide.

What about retatrutide, Lilly’s triple agonist — the next generation after tirzepatide, that causes a lot of weight loss. Anecdotally when people take it they say they get some tachycardia (fast heart rate). To me it seems like it’s going to be a more specialized, focus drug, for very overweight people, but maybe not for everyone given that it seems like it’s a little uncomfortable to take. Is that a fair assessment?

Reta is in late-phase development right now. And you just saw some of the phase three results this year. The most dramatic finding is the weight loss, the degree of weight loss. We’re getting to bariatric surgery-levels of weight loss with an injection, without having to go through that dramatic procedure of bariatric surgery. So, that’s the most striking finding in my my view. It is an agonist of three hormones GLP1, GIP and glucagon. And it has some of the profile that you mentioned of an increase in heart rate and other items that come from the glucagon component.

When I started my medical career there were no options for obesity. This was a graveyard of medicine development. Every medicine attempted failed and it was pretty hopeless actually.

We now have a sea change in the last five years. Now we have a plethora of approved medicines and ones in development that all seem to work. What’s going to happen, I think, over the years it’s going to be like the blood pressure space or the cholesterol space where a physician is going to have probably a range of mechanisms they could turn to — four or five different mechanisms. It’ll segment the market into people with different needs, and we’ll have different medicines that address those needs. You can see a future, not too far from now, where there will be four hormones that can be agonized for weight loss. One is GLP-1, the other would be GIP, the third would be glucagon, the fourth is amylin. You can imagine all the different permutations of those four — onesies, twosies, threesies, maybe even four.

The other day Novo Nordisk had a big trial so for an IL6 inhibitor, Ziltivekimab, in chronic kidney disease, patients with existing cardiovascular disease and high inflammation. The trial was a negative. Lilly have an NLRP3 inhibitor in trials. I wonder what your thoughts are on the IL6 trial, because it was also based in genetic evidence and then what your thoughts are on NLRP3 and its chances of preventing cardiovascular events, given the failure of IL6 inhibition.

Inflammation has been a very challenging pathway to target. There’s very good observational data that high levels of blood CRP correlate with increased risk of atherosclerotic cardiovascular disease, but one of the biggest challenges in medicine, when it comes to therapeutics, is confusing correlation with cause. This literally is the biggest problem I think, and we’ve gone down blind alleys many many times because we confuse correlation with cause. HDL cholesterol is a great example of this. I think for inflammation here it’s been challenging to come up with therapies that decrease inflammation and also decrease rate of heart attacks.

I think this IL6 inhibitor is a good example — very good pre-specified hypothesis that people with CKD who have high CRP and high IL6 would be at particularly high risk, and you’re targeting specifically the driver of inflammation — and it was a very null result.

So, what happened? It very well could be that inflammation plays a role, but the ability to target it and have a therapeutic benefit, particularly in advanced disease, is just not there. You’re not going to get a big bang for your buck by targeting this pathway, even though it may play a causal role.

And then you have to be a little careful here on the human genetics. It’s typically said that the human genetics supports IL6. It actually supports IL6 receptor and it’s pretty different from IL6. The gene variant that supports IL6 receptor has this pattern: the allele that lowers risk of disease has lower blood CRP level but higher blood IL6 level. How’s that happening? So if you truly wanted to generate a medicine that mimic the genetics, you would need to find a medicine that lowered blood CRP while simultaneously raising blood IL6. I’m being a bit silly, but that’s just to say that we don’t we may not truly understand what that variant is doing, in which tissue, at what time point — to actually get that benefit in patients.

I think that the jury is still out on other targets like NRLP3, and I think it’s worth testing. But I’m fairly sceptical for atherosclerotic cardiovascular disease. Inflammation has been hypothesized to play a role in a range of cardiovascular conditions, not just atherosclerosis, so I’m open that it may play a role in these other conditions beyond atherosclerosis, but I think for atherosclerosis I think the prior probability of success is quite low, given the Zeus results.

Thank you very much to Sek for the fascinating and insightful conversation!

This post is sponsored by Consensus, the AI agent that helps me with the research for these articles. Consensus now has >2.5 million monthly users. If you’re a doctor, try Medical Mode to query guidelines and the top medical journals. If you’re doing research, Consensus has access to 220 million peer-reviewed papers, and has deals with 6 top publishers to access full texts (even behind paywalls). You can use my link for a free trial!

1. A new drug target for metabolic syndrome

I actually thought we’d exhausted our discovery of targets for metabolic syndrome, but researchers from the Regeneron Genetics Center this week have proved me — happily — wrong.

They found a new target: FNIP1 (folliculin-interacting protein 1). People carrying loss-of-function FNIP1 variants have lower triglycerides, lower liver fat, better glycaemic control and less visceral fat — plus a much lower risk of coronary artery disease, type 2 diabetes, metabolic liver disease or cirrhosis.

They used the ratio of triglycerides: HDL as a biomarker to make this discovery. Such a continuous biomarker gives a measurable number for every person in the study (unlike a binary marker like cardiovascular events), which gives much more statistical power. This has actually been done before, in a study of 170,000 people, but loss of function FNIP1 variants are extremely rare. They occur in only about 1 in 7,000 people, so a huge dataset was needed, which Regeneron built from 1,032,116 people in America, Europe and Asia, complete with exome sequencing and blood samples, and annotated with clinical data (like diabetes diagnoses).

An siRNA might be the best route to target FNIP1 — and it’ll need to be liver-targeted (GalNAc-conjugated) because systemic loss of FNIP1 causes immunodeficiency and heart problems. I checked the Regeneron pipeline, by the way, and they do not seem to have this in trials yet — so if you’re quick you can beat them to it!

Source: Regeneron Genetics Center in Nature.

2. The first medicine that targets the underlying biological cause in narcolepsy

The sleep disorder, narcolepsy type 1, is caused by the loss of neurons that produce the neuropeptide, orexin. There are a few drugs approved here (modafinil, solriamfetol, pitolisant, oxybates) all of which boost wakefulness but none of which target orexin.

Takeda’s oveporexton — an orexin receptor agonist — was FDA-approved this week; in trials, it reduced daytime sleepiness, cataplexy, sleep paralysis and hallucinations, and improved night-time sleep. It seemed to improve cognition and function, too. The main side-effect? Insomnia.

Source: Takeda in NEJM and FDA.

3. Eli Lilly starts a GLP1 trial in irritable bowel syndrome

Lilly provided an update to their pipeline this week, with a new indication for brenipatide: irritable bowel syndrome (IBS). Brenipatide is Lilly’s dual GLP1/GIP agonist, being investigated mainly for addiction/psychiatric conditions (rather than obesity/metabolic conditions). They’re also testing it in depression, alcohol use disorder, opioid use disorder, bipolar disorder, smoking cessation, and schizophrenia.

IBS is a gut-brain disorder caused partly by visceral hypersensitivity (hypersensitivity of the nerves supplying the gut). Lilly are trialling brenipatide in both subtypes of IBS: IBS-D, where diarrhoea is the main symptom, and IBS-C, where constipation is the main symptom.

I think this is interesting because the main side-effects of GLP1s are also the symptoms of IBS (constipation and diarrhoea) — but there are actually some anecdotal reports that GLP1s help in IBS and some trial data, too.

Lilly have only said that brenipatide has “optimal properties for neuroscience indications” — so the reason behind this focus for brenipatide isn’t clear yet.

Source: Lilly Q2 earnings deck.

4. Targeting RAS G12D with combination therapy in lung cancer

The current standard of care for first-line advanced non-small-cell lung cancer is pembrolizumab and chemotherapy, which reaches an objective response rate (ORR) of ~48%. About 2–5% of these cancers is driven by the KRAS G12D mutation, for which we currently have no targeted therapy.

Revolution Medicines presented new data for zoldonrasib this week — their oral inhibitor of active KRAS G12D — combined with pembrolizumab and chemotherapy.

In a small group of 28 patients, the ORR was 82%, with a quite beautiful waterfall plot, and ~little extra toxicity beyond the chemotherapy–immunotherapy backbone. These data come from a phase 1/2 trial, so it’s still early, but represents a response rate substantially higher than the current precedent, by targeting a specific biomarker.

Source: Revolution Medicines’ August 2026 corporate presentation.

5. A new map of cancer’s genetic vulnerabilities

When I posted about using Codex to discover new cancer drug targets with the Depmap resource, some people were critical because this resource isn’t very good. Fair enough — Depmap uses data from cancer cells grown flat in petri dishes, which really doesn’t represent real human biology.

Two papers in Nature this week aim to solve this, with a much more realistic atlas — built using patient-derived organoids and three-dimensional cancer models — to preserve more of the architecture and biology of real tumours. They used CRISPR dependency screens like Depmap, and discovered a series of new vulnerabilities in cancer, including:

A) KRAS-amplified oesophageal/gastric cancers are unusually dependent on SCD, an enzyme required for monounsaturated-fat synthesis — suggesting KRAS amplification could be a biomarker for SCD inhibition.

B) Mucinous, ‘classical’ gastrointestinal tumours are dependent on FZD5 and other components of the WNT pathway — suggesting these tumours may be selectively vulnerable to WNT-pathway inhibition.

C) Glioblastomas with a glial transcriptional state and CDKN2A loss are particularly dependent on CDK6 — suggesting CDKN2A loss could identify tumours vulnerable to CDK6 inhibition.

Source: Two papers in Nature, from the Wellcome Sanger Institute and the Broad Institute.

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This post is sponsored by Consensus, the AI agent that helps me with research for these pieces. Consensus now has >2.5 million monthly users. If you’re a doctor, try Medical Mode to query guidelines and the top medical journals. If you’re doing research, Consensus has access to 220 million peer-reviewed papers, and has deals with 6 top publishers to access full texts (even behind paywalls). You can use my link for a free trial!

1. Blocking chronic inflammation (via IL6 inhibition) did not prevent cardiovascular events

The inflammation hypothesis of atherosclerosis — that chronic, low-level inflammation is an independent, targetable risk factor for cardiovascular disease — has actually been proven before: here, with colchicine and here, with IL1 blockade. Colchicine is now approved for this indication, though its use isn’t widespread, and IL1 blockade was never approved. Novo Nordisk tried a different approach: IL6 inhibition, in people with atherosclerotic cardiovascular disease, chronic kidney disease and inflammation (high levels of hsCRP).

The trial was huge: 6,300 people, and IL6 blockade had absolutely no effect on cardiovascular events. And it caused more serious infections too — yikes. This is a big hit to the thesis, but Novo has two other trials ongoing with IL6 blockade (one in patients with heart failure, the other in patients hospitalized with myocardial infarction) and inhibition of the pathway upstream — by hitting NLRP3, a constituent of the inflammasome — is being tested by many teams, too.

2. A non-opioid painkiller

Latigo Biotherapeutics published data for their new non-opioid painkiller — an oral inhibitor of the pain-sensing sodium ion channel, NaV1.8, which showed opioid-level — or better — pain relief. It reduced postoperative pain in a phase 2b trial, and reduced the need for opioid rescue medicines. At the high dose, it was about 50% better for pain relief than the hydrocodone/acetaminophen control used.

This drug (LTG-001) binds the NaV1.8 channel in a different way to today’s only approved NaV1.8 inhibitor (Vertex’s suzetrigine) — it’s designed specifically for higher potency and better penetration into peripheral nerves. Next up, phase 3.

3. Two steps forward for vitiligo

First, Pfizer’s oral JAK3/TEC inhibitor, ritlecitinib, met its endpoints in vitiligo (where the immune system destroys the pigment-producing melanocytes in skin).

Second, Argenx agreed to acquire Forte biosciences. Their drug is a first-in-class antibody against CD122, the subunit shared by IL2 and IL15 — so it inhibits T cells and NK cells (but spares T-regs). In vitiligo, it can re-pigment the skin:

4. A GLP-1/glucagon agonist helps treat alcohol use disorder

In a phase 2 trial, Altimmune’s GLP-1/glucagon receptor co-agonist, pemvidutide, reduced heavy-drinking days and increased abstinence in patients with alcohol use disorder. This adds to the trial data that shows semaglutide reduces alcohol consumption, and to the developing body of evidence that GLP1s could help treat addiction.

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To test this I asked Codex to look for new cancer drug targets, focusing on synthetic lethality, which describes the phenomenon where combined loss or inhibition of two genes or pathways is deadly, but loss of only one is tolerable.

The canonical synthetic lethal interaction, discovered in 2005, is between mutations in BRCA1/2 and inhibition of PARP, an approach that’s now approved for 8 indications in 4 cancer types: ovarian, breast, pancreatic and prostate. Cancers deficient in BRCA1/2 are exquisitely sensitive to PARP inhibition, because PARP inhibition generates deadly DNA double strand breaks that can’t be repaired in BRCA1/2-deficient cells.

PARP inhibition in BRCA-deficient tumors is still the only synthetic lethal interaction approved for the treatment of cancer, but recent data for the PRMT5-MTAP interaction, which generated unprecedented 92% objective response rate (on top of RAS inhibition) in pancreatic cancer has brought new light to the field.

The context I gave Codex was DepMap, a huge genetic database of many different genome-wide CRISPR screens, as well as individual papers that did genome-wide synthetic lethality screens (like this one). These experiments systematically delete genes using CRISPR to discover essential pathways that cells can’t live without, and, since cancer cells naturally lose tumor suppressors, the data can also reveal synthetic lethal pairs. Codex compared 115 tumor suppressors against 18,443 CRISPR targets, for a total of 2.12 million combinations, and found three genuinely interesting, novel synthetic lethal interactions:

1. Inhibition of the histone chaperone, ASF1B, should kill cancer cells deficient in the DNA methyltransferase, DNMT3A (DNMT3A is often lost in adult myeloid cancers).

2. Inhibition of the membrane-bound transcription factor, MYRF, should kill cancer cells deficient in the chromatin regulator, BAP1 (BAP1 is often lost in kidney cancer, mesothelioma, and uveal melanoma).

3. Inhibition of the transcriptional regulator, HCFC1R1, should kill cancer cells deficient in the DNA repair master regulator, ATM (ATM is often lost in endometrial cancer and melanoma).

These interactions are shown in the following table, alongside established synthetic lethal pairs as positive controls. A score of 0 is the median effect for non-essential genes; -1 is the median score for a pan-essential gene. The key number is the delta, which shows the fitness difference between target loss in wildtype vs. mutant/deleted cells. A good synthetic lethal interaction is one with a wide delta, where target inhibition spares normal cells while killing cancer cells. The new interactions uncovered by Codex have deltas that are comparable to established interactions.

BRCA-PARP is actually not a good positive control here, because the interaction depends on PARP inhibition (and consequent trapping) rather than genetic loss — which highlights a drawback of this approach.

What about the plausible mechanisms by which these synthetic lethal interactions might occur?

For DNMT3A-ASF1B, since DNMT3A deficiency disrupts chromatin, and since ASF1B regulates histones during replication, it might be that ASF1B becomes essential for maintaining DNA replication forks in DNMT3A-deficient cells.

For BAP1-MYRF, since loss of BAP1 can hyperactivate MYRF and its transcriptional network, BAP1-null cancers might become reliant on MYRF’s target genes.

For ATM-HCFC1R1, since ATM-deficient cells suffer chronic replication stress, inhibition of HCFC1R1 might disrupt the HCFC1R1-dependent transcriptional program needed for healthy S phase progression.

This analysis is imperfect — experts tell me that DepMap doesn’t have the best data for target discovery (though I don’t think there’s a better one). The next steps would be validation of these hits in the lab using cell lines and pharmacological inhibition (none of the targets have inhibitors yet, either). But with the rate of progress in AI and the rise of labs that can do experiments like these autonomously — like Ginkgo Bioworks — it might not be long before we have 1-person biotech companies.

This post is sponsored by Consensus, the AI agent that helped me with the research. Consensus now has >2.5 million monthly users. If you’re a doctor, try Medical Mode to query guidelines and the top medical journals. If you’re doing research, Consensus has access to 220 million peer-reviewed papers, and has deals with 6 top publishers to access full texts (even behind paywalls). You can use my link for a free trial!

Thank you for reading, let me know what you think!

started Entelo Bio to solve this, with a novel biobank and an obsessive focus on patients.

03:20 Origination of Entelo Bio
08:30 The focus on muscle, atrophy, and intrinsic capacity
13:48 Make something patients want
17:00 Drugs need to be safe, selective, and simple
19:10 Entelo’s biobank, platform and the focus on function
24:13 The musculoskeletal system is >40% of bodyweight and <1% of data
25:35 Figuring out the heterogeneity of disease
28:30 Bimagrumab
30:50 GLP1s
36:13 Peptides, BPC-157 and the ne1study
41:38 The diseases that piss people off
43:50 Surrogate endpoints for long-term trials
47:15 High-quality bio data in the AI era
54:54 Automated labs
1:01:54 Exciting future companies and ideas

This post is sponsored by Consensus, the AI agent for research that now has >2.5 million monthly users (me included!). If you’re a doctor, try Medical Mode to query guidelines and the top medical journals. If you’re doing research, Consensus has access to 220 million peer-reviewed papers, and has deals with 6 top publishers to access full texts (even behind paywalls). You can use my link for a free trial!

Thank you for listening! Please reach out to Peter or me to discuss anything further.

This post is sponsored by Consensus, the AI agent for research that now has >2.5 million monthly users (me included!). If you’re a doctor, try Medical Mode to query guidelines and the top medical journals. If you’re doing research, Consensus has access to 220 million peer-reviewed papers, and has deals with 6 top publishers to access full texts (even behind paywalls). You can use my link for a free trial!

1. A step towards cure for type 1 diabetes

Functional cure in type 1 diabetes would require two things: first, no requirement for exogenous insulin injections, and second, no need for systemic immunosuppression. For the first, there’s been recent progress, with stem cell-derived islet transplants. But the second is harder.

Sana Biotech is working on this. Their approach depends on islet transplants that are gene-edited, in two ways: B2M and CIITA are disrupted (they are required for expression of HLA class I and class II, respectively) so that T cells don’t attack the transplanted cells, and the ‘don’t eat me’ signal, CD47, is overexpressed, so that macrophages and natural killer cells don’t attack them.

Just over a year ago, Sana transplanted these edited islets into a single patient. They chose the forearm muscle(!) as the transplant site, which has a good blood supply, is easy to monitor, and is easy to access if something goes wrong. This week they released longer-term follow-up data, up to 14 months. This image shows the islets, visualized by PET-MRI of the GLP1 receptor.

The islets produced durable, meal-responsive insulin for at least a year — without any immunosuppression (which is unprecedented). A low, proof-of-concept dose was used, so the patient did not achieve insulin-independence, but HbA1C came down a bit, as did glucose levels — though it’s not possible to say this was because of the transplanted islets.

Even the current islet transplants we do today (which are donor-derived) don’t usually allow patients to achieve durable insulin-independence — their main aim is to improve awareness of hypoglycaemia, which can be dangerous in type 1 diabetes. There’s no data from Sana on hypoglycaemia awareness yet.

The islets in Sana’s experiment came from donors, so the next step is a scalable trial using the same tech — at higher doses — with stem cell-derived, gene-edited islets.

With the (controversial) news this week that Kalshi will launch prediction markets on clinical trials, it’s only right to highlight the market they have on FDA-approval of a cure for type 1 diabetes before 2033, which is pricing in a 43% chance (tiny market though!).

2. Approval of an oral PCSK9 inhibitor

Inhibition of PCSK9, the protein that degrades the receptor that removes LDL cholesterol from blood, has turned out to be (probably) the most effective mechanism to lower LDL cholesterol. The idea is built on an amazing natural experiment: people born with inactivating mutations in PCSK9 have low cholesterol from birth, and up to 10 x lower risk of coronary heart disease.

There are already three medicines in this class — Inclisiran (an siRNA), Alirocumab and Evolocumab (monoclonal antibodies) — all of which are injectables. Merck (the American one) have a new, oral PCSK9 inhibitor, enlicitide, which is a macrocyclic peptide that mirrors the mechanism of the antibodies: it blocks the PCSK9-LDL receptor interaction, and was just FDA-approved this week.

I am no chemist, but my understanding is that the chemical synthesis of this thing is enormously complicated — Merck’s first attempts to make it took 63 steps, meaning that a 100 kg batch would need >170 tonnes of material. After that, they were able to cut this to 43 steps, improving yield by about 1000-times. This year, they went much further: engineered enzymes now assemble and cyclise the peptide in a shorter, more efficient process.

In the main phase 3 trial (in a secondary prevention population with LDL ≥ 55 mg/dL, or a primary prevention population with LDL ≥ 70 mg/dL) enlicitide cut LDL by an average of ~60%, on top of baseline statin therapy.

In a second trial, with enlicitide head-to-head against other cholesterol drugs — bempedoic acid, ezetimibe, or the bempedoic acid-ezetimibe combination — enlicitide was more effective than either (or both) for cholesterol-lowering.

It’s worth noting that there are no cardiovascular outcome data for enlicitide yet, but its efficacy on LDL-lowering is ~similar to evolocumab, which I think is likely to be reflected in cardiovascular benefit.

An interesting tangential idea with PCSK9 is that, as well as promoting degradation of the LDL receptor, it also helps to degrade MHC-1 (which presents cancer-associated antigens on the cell surface) — so PCSK9 inhibition stimulates anti-cancer immunity in pre-clinical models. For this reason, PCSK9 inhibitors are being tested against cancer in trials, too.

3. Early stages of a vaccine to intercept pancreas cancer

Pancreas cancer develops from normal tissues via well-established precursor lesions (PanINs and cysts — IPMNs and MCNs). These precursors usually express the dominant driver in pancreas cancer (mutant KRAS), are often (though not always) visible on imaging — and present for many years before progression.

This means the case for a vaccine against mutant KRAS — to intercept pancreas cancer before progression from precursor to cancer — is a compelling one.

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What does the future of medicine might look like, and what are the companies building it? I make some predictions here, looking for companies at the start of the S curve, before potential exponential growth. This is for information only and not investing advice!

This post is sponsored by Consensus, the AI agent for research that now has >2.5 million monthly users (me included!). If you’re a doctor, try Medical Mode to query guidelines and the top medical journals. If you’re doing research, Consensus has access to 220 million peer-reviewed papers, and has deals with 6 top publishers to access full texts (even behind paywalls). You can use my link for a free trial!

1. Remission rates in autoimmune disorders will reach new highs.

Discovery of the pathways underpinning autoimmune conditions — and the biologics that target them — have dramatically improved the care of these conditions. But there’s still a long way to go.

To illustrate that, this chart shows how effective the best-in-disease therapies are where remission (or a remission-like state) is used as an endpoint. In Crohn’s disease and rheumatoid arthritis, only about 50% of patients reach remission with today’s best medicines; for lupus and ankylosing spondylitis, it’s even less.

To show this in more detail, a good example is ulcerative colitis (inflammation of the colon). Drugs here have got a lot better over time: the anti-TNFs in the early 2000s and 2010s achieved placebo-adjusted clinical remission rates of less than 20%; JAK inhibitors, anti-integrins and S1P modulators improved this, and with today’s best-in-disease medicine, Obefazimod, about 40% of patients achieve clinical remission.

I think, in the future, we can get to unprecedented levels of remission in three ways.

First, with combinations of advanced therapies. This is far from the standard-of-care today, but it has been tested before. Some combinations of immunosuppressive therapies have been tried, which (unsurprisingly) failed due to increased risk of infections. Others were successful though — for example, the combination of the IL23p19 inhibitor, Guselkumab, and the TNF inhibitor, Golimumab, achieves better remission in ulcerative colitis than either medicine alone.

The key here will be using medicines with independent modes-of-action (or indeed, using multi-specific drugs that hit multiple pathways — more on that later) and making sure there’s no synergy in immunosuppression. A clear opportunity here, using the ulcerative colitis example, would be the combination of the miR-124 inducer, Obefazimod (Abivax), and the IL23 receptor antagonist, Icotrokinra (J&J)— these have distinct modes-of-action, (probably) no synergistic immunosuppression, and are both oral pills.

Second, using combinations with weight loss medicines. By cutting adiposity, the GLP1 receptor agonist, Semaglutide, reduces systemic inflammation (measured by high sensitivity CRP) by ~45%, the dual GLP1/GIP receptor agonist Tirzepatide by ~55%, and the triple GLP1/GIP/GCGR agonist Retatrutide by ~65%.

There’s already phase 3 precedent that this can translate to better clinical outcomes in the autoimmune disorders plaque psoriasis and psoriatic arthritis, with the combination of Tirzepatide and an IL17A inhibitor. We are likely to see much more of this — in ulcerative colitis, Crohn’s, rheumatoid arthritis, ankylosing spondylitis and more. The big players (Eli Lilly and Novo Nordisk) will benefit from this, but so might the up-and-comers like Viking Therapeutics and Structure Therapeutics, both of whom have competitive, differentiated GLP1s.

Third, through better personalization. I think autoimmune disorders will learn from the treatment of cancer, where, for example, we test for mutations before using targeted medicines. Autoimmune disorders still lack this level of personalization, but there are interesting emerging companies working on it. For example, Palisade Bio are innovating not only on the route of their medicine (it’s oral rather than injectable), and its mode-of-action (a gut-restricted PDE4 inhibitor — it’s for inflammatory bowel disease) but also by co-developing a companion, personalized diagnostic — a test to find the patients most likely to respond to PDE4 inhibition.

Companies that could be at the start of the S curve: Abivax ($ABVX), Viking Therapeutics ($VKTX), Structure Therapeutics ($GPCR), Palisade Bio ($PALI).

2. Therapeutics will get more precise.

Given the complexity of medicine and the heterogeneity of disease, it is not surprising that multispecific drugs — drugs with more than one target — are starting to beat monospecifics in head-to-head trials. For example, the GLP1/GIP receptor agonist, Tirzepatide, beats the GLP1 receptor agonist Semaglutide for weight loss. The anti-PD1/VEGF bispecific antibody, Ivonescimab, beats anti-PD1 alone in lung cancer. And the biparatopic HER2 antibody Zanidatamab (which binds two sites in the same molecule) beats the HER2 monospecific, Trastuzumab, in gastroesophageal cancer.

Approvals of these multi-specific molecules, and clinical trial initiations, are already ticking up, and it’s likely to continue in the future — not just bi-specifics but also tri-specifics, quadra-specifics… quinque-specifics?

Here are some examples.

Sanofi is taking us straight to the future with a monster in development for osteoarthritis. It’s a trispecific nanobody that anchors to cartilage (via a cartilage anchoring peptide, CAP) and inhibits two cartilage-degrading enzymes, MMP13 and ADAMTS5.

Pfizer are working on Tilrekimig, which builds on the established anti-IL4 x anti-IL13 foundation for eczema treatment, but bolts on anti-TSLP — to tailor this more for individual patients.

ModeX are trialling antibodies that bind both CD3 and CD28 on T cells — to provide both the T cell activating (CD3) and co-stimulation signal (CD28) — as well as two targets: in this case, both CD19 and CD20 for broad, deep B cell depletion in autoimmunity or B cell cancers.

CStone pharma have a bispecific antibody for inflammatory bowel disease, that blocks two independent pathways — TL1A, to reduce mucosal inflammation and fibrosis, and α4β7, to stop trafficking of immune cells into the gut.

Sinocelltech have SCTB-41, a trispecific targeting PD-L1, to release T cell inhibition, VEGF, to improve immune infiltration, and TGF-beta, to help the immune response in ‘cold’ or fibrotic tumours.

Companies that could be at the start of the S curve:

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1. The first approved medicine to prevent pancreatitis

I’m fascinated by the idea of new medicines based on genetic evidence. This week another was approved, to prevent pancreatitis. Pancreatitis is severe inflammation of the pancreas. Most patients fully recover, but about 10% need intensive care, and the case fatality is still about 5%.

~10% of cases are caused by high levels of triglycerides, which can clog pancreatic vessels — but this is still not really respected (in my experience) as a serious cause of pancreatitis. This is probably because we don’t have any medicines that can actually prevent pancreatitis in those with severe hypertriglyceridemia — which affects ~1 in 100 people, and carries a ~4-5% annual risk of acute pancreatitis.

People with severe hypertriglyceridemia tend to be those with metabolic syndrome: obesity, diabetes, and liver disease, which disrupts triglyceride metabolism.

The genetic evidence is that people born with loss-of-function APOC3 variants have low triglyceride levels — mechanistically, this is because of increased activity of lipoprotein lipase, an enzyme that breaks down triglycerides.

Based on this, Ionis Pharma developed Olezarsen, an antisense oligonucleotide that reduces triglycerides by silencing the APOC3 mRNA. Olezarsen was just approved this week, based on the trial where it cut the risk of pancreatitis by 85% in those with severe hypertriglyceridemia:

Beyond pancreatitis, high triglycerides also contribute to arterial plaques, so can cause cardiovascular disease: the next question is whether APOC3-targeting therapies can reduce that risk, and those trials (for example, from Arrowhead Pharma) are ongoing.

2. An emerging new mode-of-action to treat ulcerative colitis

Another emerging target based on genetic evidence is TL1A, the TNF-superfamily ligand, in inflammatory bowel disease (ulcerative colitis and Crohn’s disease). Genetic variants in TL1A increase the risk of ulcerative colitis — it sits upstream of several inflammatory pathways, which means that blocking it might result in remission in a broader range of patients than blocking the individual pathways (like TNF or IL-23).

TL1A also directly activates the fibroblasts that drive fibrosis — so it might be particularly helpful to treat fibrostenotic Crohn’s, where there are still no therapies.

This week, Merck announced positive phase 3 data for their TL1A inhibitor, Tulisokibart, in the induction phase of ulcerative colitis. They’ve said it met the primary endpoint... but haven’t actually told us the numbers.

To see how it looks in context, I put the clinical remission with Tulisokibart — from its previous phase 2 trial — together with its competitors from phase 3. Tulisokibart’s 25% placebo-adjusted remission is not far from best-in-disease, in this cross-trial comparison:

This chart shows that, even with the most effective therapies, most people still do not achieve remission. I spoke to an inflammatory bowel disease specialist about this, who confirmed to me that, to solve this, (at least) two things are needed: 1) more drugs, with differentiated mechanisms-of-action 2) better understanding of disease heterogeneity and subgroups — and better diagnostic tests to pinpoint them — so we can tailor medicines to the right patients.

3. A KRAS G12D inhibitor in pancreatic cancer

Next week is the gastrointestinal cancer conference (ESMO GI) in Munich. I will be there! Arguably the most interesting abstract is from Revolution Medicines, with an inhibitor of KRAS G12D, the most common mutation in pancreatic cancer.

It’s not only the commonest, but the G12D mutation also correlates with worse survival than some of the other KRAS mutants:

The trial tests Zoldonrasib, which works in a similar way to Daraxonrasib. It’s an oral, RAS(ON) tri-complex inhibitor, that uses cyclophilin A to inhibit the active form of KRAS G12D.

This week, RevMed announced the data from the phase 1/2 trial. Combined with the current standard-of-care chemotherapies, mFOLFIRINOX or Gemcitabine/nab-Paclitaxel (whose objective response rate, ORR, in this setting is ~23-43% and ~32-42%, respectively) addition of Zoldonrasib achieved 82% and 61% ORR, respectively:

It’s notable that grade 3 adverse events (which are severe enough to consider hospitalisation) were above 60% in this trial, though much of this is from the chemotherapy.

One of the potential benefits of using a G12D-specific inhibitor (Zoldonrasib) over a multispecific RAS inhibitor (Daraxonrasib, which also inhibits the wildtype RAS that normal cells express) is reduced toxicity. Indeed, in this trial, incidence of rash was 18% with Zoldonrasib, compared to ~ 90% in previous Daraxonrasib trials.

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1. The best year for progress against pancreatic cancer in decades

Daraxonrasib

Many trials have been done in metastatic pancreatic cancer, all of which have failed to improve (or only incrementally improved) the standard of care. This year we saw the first step change in survival, with Daraxonrasib.

Daraxonrasib is a ‘molecular glue’ that locks RAS — the oncogenic driver in pancreatic cancer — into an inactive trimer with a third molecule, Cyclophilin A. This works for multiple RAS isoforms — both wildtype and mutant — and Daraxonrasib inhibits active, GTP-bound RAS(ON), which is more potent than RAS(OFF) inhibition.

As second-line therapy, Daraxonrasib doubled median overall survival, improved quality of life, and reduced pain associated with pancreatic cancer.

RAS inhibition as the backbone

Just a couple of weeks after those data, Tango Therapeutics revealed results that layer a new therapy on top of the Daraxonrasib foundation. Tango’s approach depends on a concept called synthetic lethality between an epigenetic enzyme, PRMT5, and the metabolic enzyme MTAP, which is deficient in about 40% of pancreatic cancers. In a small phase 1/2 trial, this combination achieved 6 month progression-free survival of ~90%, compared (cross-trial) with ~50% for Daraxonrasib alone (and ~30% with the current standard-of-care chemotherapy).

Early detection

These therapies are both for metastatic disease, which is the stage where most patients present — earlier detection is a key problem to solve too.

One way to do this is with blood tests, and the one we currently use is CA19-9. In February, the first independent validation of Immunovia’s PancreaSure blood test was published, which measures 5 pancreatic cancer proteins. Compared to CA19-9 alone, Pancreasure had higher sensitivity and specificity, including for early-stage disease.

Early pancreatic cancer is often missed on CT scans, so the other way is to improve detection on imaging. There were two new AI models trained to solve that, PANORAMA and REDMOD. The image below, on the left, shows a pancreatic tumor missed on CT imaging, 1.8 years before eventual diagnosis. On the right, the same tumor was detected with the REDMOD AI system:

Tumor-treating fields for locally-advanced pancreatic cancer

If we can solve the early detection problem, outcomes are likely to improve — partly because more therapies are available. One of those, newly approved this year, is Novocure’s tumor-treating field device — the first new therapy for locally-advanced pancreatic cancer in >30 years.

Tumor-treating fields deliver low-intensity electric fields that disrupt mitosis to cause death in dividing cells — and impair DNA repair too, so can sensitize cells to DNA-damaging chemotherapy.

2. First-in-class medicines for cardiovascular disease

LDL cholesterol

A fortunate set of people are born with inactivating variants in PCSK9, which means they have low LDL cholesterol and low cardiovascular risk for life. Based on this, PCSK9 has emerged as probably the most effective target for lowering cholesterol — and we’re hitting it from every angle, including, now, a pill.

Merck’s Enlicitide cut LDL cholesterol by >60% in phase 3 trials on top of statin therapy — that’s almost twice as much as combination therapy with two other non-statins, Bempedoic acid + Ezetimibe:

Treatment-resistant hypertension

The other major cardiovascular risk factor is high blood pressure (hypertension). Treatment-resistant hypertension is common, affecting ~7-10 million adults in the US. AstraZeneca’s Baxdrostat, which was approved in May, uses an established mechanism — aldosterone inhibition — but in a differentiated way to circumvent side-effects: blocking the synthesis of aldosterone altogether.

Reducing pathological clotting (with lower bleeding risk)

Another target built on genetic evidence is clotting factor XI. Humans born with factor XI deficiency have a reduced risk of ischaemic stroke, but no increased hemorrhagic stroke risk. This finding was replicated pharmacologically this year, with Bayer’s factor XI inhibitor, Asundexian, which reduced the risk of (non-atrial fibrillation-related) stroke in a phase 3 trial.

Non-obstructive hypertrophic cardiomyopathy

The most common genetic heart condition is hypertrophic cardiomyopathy, which affects about 1:200-500 people. It causes thickening of the left side of the heart, due to a range of mutations — most commonly, in the proteins that help heart muscle contraction, like myosin. About 30-50% of these patients have non-obstructive disease, where we still have no disease-modifying therapies. The cardiac myosin inhibitor, Aficamten, from a small biotech called Cytokinetics, became the first drug with positive phase 3 data in this condition.

3. GLP1s charge on

Oral GLP1s

At the start of the year, the first oral GLP1 launched in obesity, Novo Nordisk’s oral Semaglutide, which was later followed by Lilly’s Orforglipron. Oral Semaglutide — the Wegovy pill — has been the fastest-launching (non-infectious disease) drug of all time.

GLP1s for inflammatory conditions

Anecdotally, GLP1s help reduce inflammation, but this year we saw the first clinical trial proof of this, in patients with overweight/obesity and psoriatic arthritis. Tirzepatide improved disease activity in psoriatic arthritis by an extra ~25% on top of the IL17-A inhibitor, Ixekizumab.

This is really only the beginning of this story: Lilly’s pipeline shows there are many more studies like this running, testing GLP1s in Crohn’s, ulcerative colitis, and psoriasis.

GLP1s for addiction

Observational data show that GLP1s are associated with reduced risk of addictive disorders: alcohol, cannabis, cocaine, nicotine, and even opioids. This year we saw the first real clinical trial proof that GLP1s — in this case Semaglutide — can reduce heavy alcohol consumption, in people with coincident obesity and alcohol use disorder.

Again, Lilly is the innovator here — their drug Brenipatide, a GLP1/GIP receptor agonist, is in dedicated development for psychiatry and addiction indications, with ongoing trials in smoking cessation, bipolar disorder, schizophrenia, opioid use disorder, depression, and alcohol use disorder.

Muscle-sparing GLP1 combinations

Rapid weight loss with GLP1s can cause muscle loss. Phase 2 trials this year have shown that muscle-sparing antibodies like Bimagrumab, when added to GLP1s, can reduce loss of lean mass — in addition to more fat loss, and bigger reductions in inflammation.

GLP1s of the future

To much anticipation, Lilly’s triple agonist, Retatrutide, presented its phase 3 data in obesity:

Other new GLP1s presented data too: Novo’s triple agonist UBT251. AstraZeneca’s oral GLP1, Elecoglipron, Structure Therapeutics’ oral GLP1 Aleniglipron and Zealand Pharma’s GLP1/glucagon co-agonist, Survodutide.

I think it’s likely we’ll see GLP1s used as a backbone therapy in metabolic medicine. In line with this, there were pre-clinical data for an agonist with 5 different targets — GLP-1, GIPR, PPARα, γ, and δ. This adds anti-inflammatory effects, burns more liver fat, and increases insulin sensitivity on top of baseline GLP1 therapy.

4. Cancer therapies with new mechanisms

The first approved PROTAC drug

Some proteins are inherently hard to make a drug against, and an alternate solution is ‘proteolysis-targeting chimeras’ — PROTACs. PROTACs degrade, not inhibit, targets. This means they could drug ‘undruggable’ targets, lead to more potent inhibition, and circumvent some resistance mechanisms.

In May, the first PROTAC was approved — it’s called Vepdegestrant, and it works by recruiting an E3 ligase to potently degrade the estrogen receptor in breast cancer (specifically, it’s for ER-positive, HER2-negative, ESR1-mutated metastatic breast cancer after progression on endocrine therapy).

Relacorilant to suppress resistance to chemotherapy

Cancers often develop resistance to chemotherapy, and it turns out a major driver of resistance is the glucocorticoid pathway, which suppresses chemotherapy-induced apoptosis. To resolve this, Corcept therapeutics’ Relacorilant, a glucocorticoid receptor blocker, was approved for platinum chemotherapy-resistant ovarian cancer — only the second drug approved specifically to restore or increase sensitivity to chemotherapy.

5. New genetic therapies

Lipids

One-and-done cholesterol-lowering

It feels very futuristic to imagine a world with one-and-done therapies that lower LDL cholesterol for life, but... it might not be far off. This year saw new phase 1 data for Verve/Lilly’s PCSK9 base editor: one single intravenous infusion reduced LDL cholesterol by as much as 60%.

One-and-done lipoprotein(a)-lowering

Lipoprotein(a) is an LDL-like particle that also contains a protein component — apolipoprotein(a) — which means it’s unaffected by diet, exercise, or statins. It’s genetically determined, and it’s implicated in about 10% of cardiovascular disease as well as aortic stenosis (age-related narrowing of the heart’s aortic valve). CRISPR therapeutics made an apolipoprotein(a)-targeting genetic therapy, which, in a first-in-human trial, reduced lipoprotein(a) by as much as 73%.

The first in vivo CRISPR therapy

CRISPR therapies today (like Casgevy for sickle cell) usually remove cells, edit them ex vivo, and reinfuse them. This year Intellia Therapeutics presented the first positive phase 3 trial for an in vivo CRISPR therapy — where DNA was edited directly inside the body.

It’s for hereditary angioedema, which causes swelling attacks that are unpredictable, painful, and — if airway swelling occurs without treatment — can be even be fatal. The therapy inactivates KLKB1, the gene encoding plasma prekallikrein in the liver, in a single dose, dramatically reducing bradykinin-driven swelling attacks.

6. Hair loss drugs

Reformulated minoxidil for pattern hair loss

The most common form of hair loss is pattern hair loss, which affects… pretty much everyone eventually. VeraDermics presented phase 3 results for an oral, gel-matrix, extended-release minoxidil, which means minoxidil diffuses out slowly, so the peak is lower and the exposure is longer. This should keep its levels high enough for continuous hair growth, but not high enough to be toxic.

In cross-trial comparisons, it looks to be more effective than anything else on the market:

Rezpegaldesleukin for alopecia areata

A less common — but still very important — form of hair loss is alopecia areata, an autoimmune condition where the immune system attacks hair follicles. Nektar therapeutics are working on turning the discovery that won the 2025 Nobel Prize in Medicine — T regulatory cells — into a medicine for it.

Their drug is ‘Rezpegaldesleukin’, an IL2 receptor agonist which expands anti-inflammatory T regs without broad immunosuppression. In phase 2 data so far, it looks to be effective.

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Here it is!

This post is sponsored by Consensus, the AI agent for research that now has >2.5 million monthly users. If you’re a doctor, try Medical Mode to query guidelines and the top medical journals. If you’re doing research, Consensus has deals with 6 top publishers, to access full texts that’re behind paywalls. You can use my link for a free trial!

Here’s the transcript from the episode:

[1:39] Tiff: How was ASCO? You went to the biggest cancer conference of the year. It happens annually and is run by the American Society of Clinical Oncology. It was your first ASCO. How was it?

[1:53] Sam: I loved it. I love science, so if you are like me, it is like crack cocaine. Everywhere you go, there is science: posters, talks, and Big Pharma. Eli Lilly is right in the middle, and you can just go and talk to them. It is the latest groundbreaking science, presented for the first time by the researchers themselves. At the posters, you can speak directly to the person who did the work. That person might be the chief executive officer, an academic, or someone else entirely. Chicago is beautiful, by the way.

[2:34] Tiff: That is amazing. Did you go to the Bean?

[2:43] Sam: The mirror thing?

[2:44] Tiff: Yes, the Bean.

[2:45] Sam: Is that what it is called? I should have known that.

[2:47] Tiff: No, it is fine. I think it was being renovated until recently, so you went at a good time.

[2:53] Sam: Yes. You have to go really early, otherwise there are a lot of people and a huge queue.

[2:59] Tiff: In this episode, we thought it would be good to go over some of the highlights from ASCO: the biggest groundbreaking studies, China, and future directions for these therapies.

[3:23] Sam: Exactly. To kick off with the themes of the conference, I thought there were five major themes at ASCO this year. The first was pancreatic cancer. The major news was daraxonrasib. I can say that now that it has been talked about so much.

[3:48] Tiff: Daraxonrasib. I love the name, because “on” refers to the on state, “RAS” is the target, and “-ib” means it is a small-molecule drug.

[4:00] Sam: Exactly. Daraxonrasib was the major news. It increased overall survival in second-line metastatic pancreatic cancer compared with chemotherapy. It also improved quality of life, reduced pain, and did this with almost half as many serious adverse events.

[4:19] Tiff: It got a standing ovation from the crowd. I saw your tweet. It went viral.

[4:26] Sam: Super viral. Very exciting. I loved it. That was the main news, but pancreatic cancer had more than one breakthrough. Daraxonrasib stole the show, but there were many other therapies: antibody-drug conjugates, and a really nice bispecific T-cell engager. There is an antigen that pancreatic cancer sometimes expresses called claudin 18.2.

[4:55] Tiff: Very specific.

[4:57] Sam: Yes. It is also expressed in some gastric cancer cells. If you target claudin 18.2 and CD3 to recruit T cells, and give that to pancreatic cancer patients, that also looks like quite an effective approach.

[5:10] Tiff: That is amazing. There was not only one breakthrough in pancreatic cancer. There were several. For years, even decades, there have only been incremental improvements in pancreatic cancer, which has a very poor five-year survival rate of around 10%. Suddenly, there has been a lot of progress announced within one year. I thought that was really interesting.

[5:45] Sam: It is. Revolution Medicines is the company behind daraxonrasib, but now there are many companies with RAS inhibitors, and they are approaching it from every direction. Big Pharma is there, small biotech is there. They are developing pan-RAS inhibitors, KRAS G12C inhibitors, KRAS G12D inhibitors, on-state inhibitors, off-state inhibitors, and different combinations.

[6:08] Sam: This week, there was an impressive combination of daraxonrasib plus another new drug in pancreatic cancer, and it improved survival even further on top of what daraxonrasib does.

[6:23] Tiff: That is incredible.

[6:24] Sam: What I think we are going to see is daraxonrasib becoming the foundation, or bottom layer, of therapy, and then being combined with other therapies.

[6:32] Tiff: For that specific mutation or subgroup.

[6:36] Sam: Exactly. I did not think we would see this layering of therapy so quickly, given that it has only been two weeks since we saw the data in the first place. But this week we are already seeing it start. The company I am talking about is Tango Therapeutics. They are working with Revolution Medicines to build this combination therapy.

[6:56] Tiff: That is so exciting. They waste no time.

[6:59] Sam: They do not. For those who missed it, daraxonrasib doubled survival in PDAC, which is the most common form of pancreatic cancer, with a hazard ratio of 0.4. It decreased pain and side effects, and it is a daily oral pill.

[7:31] Tiff: That is important. People talk about the time burden of cancer therapy. If you are having chemotherapy as an intravenous treatment, you have to go to the clinic.

[7:44] Sam: Exactly. You have to go to the hospital, sit there, and have the intravenous chemotherapy treatment. With daraxonrasib, it is a pill. You take it at home. It reduces the time burden and time toxicity, as well as other toxicity. It does not mean it is completely without toxicities. There were rashes, stomatitis, and one patient in the trial died because of lung inflammation. It is not completely without adverse events, but it is cleaner than chemotherapy.

[8:14] Tiff: That is huge. It is also a cool paradigm shift from the last generation of RAS inhibitors, which tried to target the off state of RAS. RAS is an oncogenic driver of cell division. It is like a gas pedal that is being pressed down all the time, and we have to find a way to stop it.

[8:40] Tiff: The issue with RAS, as we covered in a previous episode before the phase 3 data came out, is that it was considered an undruggable target because there is no pocket in the molecule for a drug to bind to. Revolution Medicines became creative and developed a molecular glue that binds to the chaperone protein cyclophilin A. That creates a complex that can target the on state of RAS rather than the off state. The on state is more susceptible to inhibition, because most of the time RAS is on in human cancer cells rather than off. So you might as well target the on state.

[9:36] Sam: Exactly. If you target the off state, your drug is waiting around for RAS to switch itself off, bind, and then inhibit. But the RAS protein spends hardly any time in the off state. It spends most of its time in the on state, so ideally you target on, not off.

[9:55] Tiff: It is clever. The craziest thing is that this is a pan-RAS inhibitor. In oncology, KRAS is the most common mutated form of RAS, but there are also NRAS and HRAS. Even within KRAS, there are different mutations. There have been developments before in G12C mutations, which means the glycine at codon 12 is replaced by cysteine. In pancreatic cancer, people care a lot about G12D.

[10:37] Sam: Yes, where it is replaced by aspartic acid.

[10:40] Tiff: Now they do not have to worry as much about which type of mutation is occurring in the tumour.

[10:46] Sam: Exactly. That is also one of the future directions. RAS is mutated in pancreatic cancer, but also in colorectal cancer, lung cancer, and other cancers. The big three are pancreas, colorectal, and lung.

[11:02] Tiff: Lung is what Revolution Medicines is going after next in one of their trials.

[11:06] Sam: Exactly. It may not only revolutionise the treatment of pancreatic cancer, but also lung, colorectal, and other cancers. One future direction in cancer is RAS inhibition as a therapeutic foundation.

[11:22] Tiff: That is exciting. Revolution Medicines is a Californian company founded in 2014, and they IPO’d in 2020. Did you look at the stock price afterwards?

[11:34] Sam: Yes. I am in the stock. I think most biotech people are in the stock. Why would they not be?

[11:45] Sam: The market cap is now around $35 billion. People start to think about acquisition: is this going to get bought by Big Pharma? But if the market cap is $35 billion, Big Pharma has to pay a premium, so they would have to pay $40 billion or $50 billion.

[11:59] Tiff: They use the current stock price as a benchmark.

[12:03] Sam: Exactly. As Big Pharma, how do you spend $35 billion, $40 billion, or $50 billion on one company? That probably means it is too big to get taken out now, which is interesting.

[12:15] Tiff: The biggest deals we have seen in the past year have been around $10 billion.

[12:20] Sam: This is much bigger. Some companies could technically take it out, but it would be a huge swing.

[12:27] Tiff: I can see smaller deals being made. Maybe not the whole company, but licensing one asset or one indication to another Big Pharma company.

[12:38] Sam: Exactly. There is another company called Erasca with a molecule that is basically identical to Revolution Medicines’ daraxonrasib. If you look at the chemical structures, they are almost the same, so there is a patent concern. If you are Big Pharma and want to buy something similar more cheaply, maybe you take out Erasca.

[13:02] Tiff: Then they have to deal with the patent disputes, not Big Pharma.

[13:09] Sam: That was the first theme: progress in pancreatic cancer.

[13:15] Tiff: The second theme was other innovative therapies. What else did you see?

[13:21] Sam: Daraxonrasib was definitely the most important one, but there were lots of others. One was ivonescimab, a bispecific antibody.

[13:29] Tiff: PD-1 and VEGF.

[13:30] Sam: Exactly. It is a PD-1/VEGF bispecific made in China, with trials done in China. In lung cancer, it beat PD-1 immunotherapy on its own. PD-1 immunotherapy is one of the biggest drug classes in the world, but if you use a bispecific that also blocks VEGF, it improved overall survival in lung cancer.

[13:53] Tiff: That is incredible. It is good synergy. PD-1 is the checkpoint inhibitor part of the drug, and the VEGF part is supposed to promote a more normalised vasculature. Then immune cells, especially T cells, can reach the tumour and kill tumour cells. When VEGF is overexpressed by cancers, the chaotic vasculature can prevent immune cells from getting to the tumour.

[14:25] Sam: Exactly. The trial format at ASCO is fascinating. In the plenary session, the lead investigator presents the trial, and then someone else puts the trial in context and criticises it. So the lead investigator is sitting there while someone else says, “Yes, but...”

[14:49] Tiff: It is like a lab meeting in front of thousands of people.

[14:53] Sam: Exactly. The main criticism was that all of the data were from China. The data are strong, but from that perspective, it only really applies to the Chinese population. If we want to show that ivonescimab can beat Keytruda, or pembrolizumab, in a broader population, we have to do the trial in the US. That is happening.

[15:22] Tiff: It has to be tested across different ethnicities. The same statement can be reversed as well. American therapies that want to enter the Chinese market, which is obviously huge, also have to do trials in China. That is happening too. It goes both ways.

[15:42] Sam: It does. But it was interesting that this was the main criticism. Ivonescimab is definitely a major breakthrough. We might actually be able to beat PD-1.

[15:55] Tiff: I hope they are working with MD Anderson or another major centre to test it in a Western population.

[16:00] Sam: They are running at least 15 massive global trials with that compound.

[16:08] Tiff: Amazing.

[16:09] Sam: Another innovative therapy I liked was for cancer cachexia. We talked about this in our first pilot episode. This is one of your favourite proteins: GDF-15.

[16:22] Tiff: Exactly.

[16:23] Sam: Cancer cachexia is a wasting syndrome in advanced cancer. Patients lose muscle and weight, lose appetite, and feel miserable. There are no good drugs. It seems to be driven by a stress-induced cytokine called GDF-15.

[16:42] Sam: This new study, also from China, tested a GDF-15 antibody as a bispecific with an IL-6 blocking antibody. It reduces inflammation and blocks the cachexia-driving factor GDF-15. I spoke to the person presenting the poster, and they told me that the main complaint from patients in the trial was that they were gaining too much weight.

[17:08] Tiff: That sounds like a champagne problem.

[17:14] Sam: With this bispecific antibody, they were gaining too much weight. Some gained around 25% of their body weight.

[17:20] Tiff: That is amazing.

[17:23] Tiff: That is such a cool synergy: block GDF-15 and block IL-6. What does blocking IL-6 do here? Does it just reduce inflammation? Is that because blocking GDF-15 might increase inflammation?

[17:46] Sam: I think one of the mechanisms by which GDF-15 is induced is probably systemic inflammation.

[17:53] Tiff: So you block GDF-15 directly, but also suppress its induction by suppressing systemic inflammation. To be honest, I do not know. It is just cool. I wonder how they make these decisions about what to pair in a bispecific.

[18:11] Sam: As we have discussed many times, suppressing chronic systemic inflammation is generally a good idea. People with advanced cancer have high inflammation. If you suppress it, you probably make them feel better. They also say it increases appetite, increases muscle, increases weight, and improves quality of life. It is generally good to control inflammation.

[18:32] Tiff: We could have a whole other episode on inflammation. I know it is one of your theses.

[18:40] Sam: It is definitely a thesis.

[18:43] Tiff: What else was there apart from this cachexia drug?

[18:48] Sam: Antibody-drug conjugates were everywhere. They are so hot now. The biggest one is sac-TMT. I think they are running 17 phase 3 trials with sac-TMT.

[19:05] Tiff: It is American now. It is Merck. But it was produced in China.

[19:10] Sam: It was developed in China and acquired by Merck. They are running 17 phase 3 trials. It is a TROP2-targeted antibody-drug conjugate with a topoisomerase I inhibitor payload.

[19:22] Tiff: So it is an antibody-drug conjugate delivering a topoisomerase I inhibitor payload.

[19:31] Sam: Exactly. It also improved overall survival in lung cancer compared with standard of care.

[19:40] Sam: If you add daraxonrasib plus those three innovative therapies, that is the second major theme. The third theme was prevention. I was at ASCO trying to discover what was happening in prevention, because prevention is the best cure.

[20:00] Tiff: Or early intervention.

[20:05] Sam: Exactly. There was a lot on GLP-1s: many observational studies showing that GLP-1s seem to reduce the risk of many different cancer types.

[20:15] Tiff: That is cool.

[20:16] Sam: Basically everything you can think of: breast cancer, colorectal cancer, blood cancers, and lung cancer.

[20:22] Tiff: Somehow, it does not come as a surprise that they could have those effects.

[20:26] Sam: Obesity is a risk factor for cancer, so GLP-1s obviously reduce that risk factor. But there must be something else going on as well.

[20:37] Tiff: Maybe inflammation. I do not know the effects of GLP-1s on inflammation.

[20:44] Sam: Systemic inflammation definitely drives cancer, so suppressing inflammation is likely to be one mechanism.

[20:55] Tiff: So far, these are observational studies, because there is now so much data on GLP-1s and researchers can correlate them with other datasets. The next step is randomised trials to support this.

[21:12] Sam: What is amazing about the conference is that Eli Lilly’s oncology team is just standing there. Lilly makes tirzepatide, so you can go and ask them what they think. I asked whether they were going to run randomised trials with GLP-1s to prevent cancer. They said no, but if you look deeper, Lilly actually is running relevant trials.

[21:39] Sam: There is a randomised trial with tirzepatide where liver cancer is at least a readout. There is another trial with retatrutide and tirzepatide, the dual and triple agonists, looking at whether all-cause cancer risk is reduced. Cancer is not the primary endpoint, but it is an exploratory endpoint.

[22:03] Tiff: There is another trial happening in breast cancer for primary and secondary prevention with a GLP-1. These are already underway.

[22:13] Sam: Yes. We will have readouts in a few years.

[22:17] Tiff: It feels like everyone is going to be on a GLP-1 soon, for one reason or another.

[22:25] Sam: What is fascinating is that everyone knew overweight and obesity were bad, but GLP-1s have shown us they are worse than we thought. Obesity contributes to so many diseases, and when you suppress it, many things improve.

[22:42] Tiff: It feels like a holy grail, with obvious caveats and side effects.

[22:52] Sam: Do not worry about side effects.

[22:53] Tiff: Pancreatitis, which you disproved.

[22:55] Sam: Yes. No pancreatitis, actually. That was the third theme. The fourth theme was cancer vaccines.

[23:03] Tiff: One of my favourites. The big Moderna and Merck vaccines are personalised vaccines in phase 2. The phase 2 trial took five years to finish. It was in resected melanoma, using the vaccine plus pembrolizumab. It was around 72% versus 49% progression-free survival.

[23:50] Sam: It is definitely bullish. There is also a Chinese company running a trial in oesophageal squamous cell cancer with a personalised vaccine. Oesophageal cancer has miserable survival, and they got strong results. I was happy because Infinitopes is running a trial too.

[24:18] Tiff: A different kind of trial. You are an investor, obviously. We are doing ours in oesophageal adenocarcinoma. Oesophageal adenocarcinoma and oesophageal squamous cell carcinoma overlap, but they have distinct profiles. Squamous disease mainly affects Asian and Chinese populations, while adenocarcinoma mainly affects Western populations.

[24:45] Sam: That is a good point. It is useful that they are running the squamous trial in China, where it is more relevant. It would be interesting to see whether any antigens overlap between the two types. Their trial is personalised, whereas Infinitopes is doing semi-personalised, off-the-shelf vaccines. It is a different approach, but as proof of concept showing that you can improve survival in a difficult cancer with a vaccine, it is very bullish for Infinitopes. That is why I was happy to make that discovery.

[25:17] Tiff: Watch his face, everyone.

[25:21] Sam: That was the fourth theme. The fifth theme is that, with the exception of daraxonrasib, a lot of the most innovative work we discussed came out of China.

[25:35] Tiff: China biotech is on the stage.

[25:40] Sam: China biotech is doing amazing work.

[25:45] Tiff: I was surprised. China is no longer just doing me-too therapies. They are innovating and coming up with their own ideas. You said you had some stats to back that up.

[26:04] Sam: Some criticism of China is that it is doing me-too therapies and fast follows. That is happening, and China is also the pharmacy of the world. But they are also doing innovative things: ivonescimab, sac-TMT, and the cachexia bispecific we discussed.

[26:21] Sam: Last year, there were 5,000 new trials started worldwide for innovative therapies. Half of them started in China. In 2015, it was about 10%. There were about 2,000 trials started globally and 200 in China. In 2025, it was 5,000 globally and 2,500 in China. China went from around 10% of innovative trial starts to 50%.

[26:53] Sam: Not only is the number of innovative trials increasing rapidly, showing that science is speeding up, but China is also playing a bigger and bigger role.

[27:07] Tiff: How many of these do you think are sponsored by American or European Big Pharma companies? A lot of them partner with Chinese pharma because they get access to the Chinese population, which is a major market.

[27:27] Sam: That is a good question. This year so far, for the first time ever, most biotech deal value is going to China. Around 70% of biotech deal value is going to Chinese companies. In 2021, it was 4%.

[27:50] Tiff: That is huge.

[27:52] Sam: It has gone from 4% to 70%, stepping up over time.

[27:59] Tiff: Why do you think that is? Is it because the companies are cost-effective, the trials are cheaper, and the trials are faster?

[28:07] Sam: Exactly. It is cheaper and faster. The cost per patient in a trial in the US is around $65,000. In China, it is around $20,000 to $25,000. It is also much faster to recruit patients, about three times as fast. It is roughly a third of the cost and much faster.

[28:30] Tiff: Those are basic business fundamentals. What is faster and cheaper gets you to the end goal faster.

[28:39] Sam: Exactly. If we want to reverse the trend of all this money going to Chinese companies, we have to fix the fundamentals in the US and Europe. I think that is doable. We need to lean more on artificial intelligence.

[28:55] Tiff: We also need to look at the architecture of the regulatory bodies. Part of the speed of running trials in China may come from the NMPA enabling cross-border trials to happen quickly. I wonder whether it gets criticised as being less stringent than the FDA. Is that why trials can be run so fast? Is that why people are going there? Is the data reliable? These are questions some founders have asked. As a founder myself, I do not see an obvious reason to stop me from going to China and running a trial there.

[29:56] Sam: To prove the concept quickly, China is an amazing place to do it. But to get your product approved in Europe, the US, or both, you still have to run the trial in those regions as well. You still need to show that the results apply to the relevant broader population.

[30:20] Tiff: Now it feels like China is becoming a proof-of-concept ground for proving therapies quickly. Once the proof of concept has been shown in China, companies can bring the therapy back to the West. It swings both ways and uses the best of both worlds.

[30:44] Sam: Exactly. In general, as I said on TBPN this week, if you are on the side of new medicines and patients, more competition is better. Competition is good for patients. If China is just as good as the US, or arguably even better, at doing this, that is great. We will get more medicines faster, which is better for patients, saves more lives, improves lives, and helps eradicate disease.

[31:17] Tiff: That is the end goal. One good thing about medicine and science is that they are cross-border. As you saw at ASCO, researchers fly in from many different countries. That is a beautiful thing about science.

[31:36] Sam: It is like music. It is not contained within one country.

[31:43] Sam: That was the China theme. I also wanted to say something about the future, given what we have discussed.

[31:52] Tiff: I am excited.

[31:56] Sam: These are basically syntheses of what we have already said. First, RAS inhibition is going to become a foundation of therapy in several cancer types: pancreatic cancer, colorectal cancer, and lung cancer.

[32:19] Sam: Second, we are going to see many more antibody-drug conjugates. When I spoke to some of the pharma teams and asked what the most exciting product in their pipeline was, the Lilly team told me about a new antibody-drug conjugate. It does not only target topoisomerase I, like many antibody-drug conjugates do, but also targets ATR.

[32:44] Sam: That takes me back to our PhD days. It inhibits both ATR and topoisomerase I. If you do that, you disrupt DNA replication, which is disastrous for the cell and can kill it.

[32:57] Tiff: That makes sense. Remember the problem we had in our PhDs? This is a niche reference. ATR is not essential for the cell to live.

[33:10] Sam: Is that right? Do you mean in terms of inhibition?

[33:14] Tiff: No, I am confusing it with ATM. ATM is not essential. My morning coffee has not kicked in. Does targeting both make it more specific?

[33:30] Sam: I think so. To be honest, the product is preclinical. They acquired it. If you inhibit topoisomerase I, ATR helps repair the topoisomerase I lesions.

[33:44] Tiff: So they are synthetic lethal.

[33:48] Sam: Exactly. It is a synthetic lethal or synergistic relationship.

[33:53] Sam: The second future theme is many more antibody-drug conjugates. The third is radiopharmaceuticals. When I asked what they were most excited about in the pipeline, they also mentioned radioisotopes.

[34:07] Tiff: Targeted radiopharmaceuticals.

[34:10] Sam: Exactly. It is similar to an antibody-drug conjugate, but instead of using chemotherapy, you use a radioisotope, such as an alpha or beta particle. You link it to a tumour antigen and use it to kill cancer cells.

[34:25] Tiff: That is a creative payload. There have been a few more biology-physics convergence therapies coming out.

[34:34] Sam: The third future theme is radiopharma. The fourth is prevention.

[34:41] Tiff: That is your job. I am working on it.

[34:46] Tiff: Thank you for being an investor in both companies.

[34:54] Sam: The fifth theme is that daraxonrasib has shown that things we thought were undruggable are not necessarily undruggable. There will now be a wave of supposedly undruggable things being drugged. My two top examples are MYC and p53. Both have companies focused on drugging them, and I think we will see them drugged.

[35:24] Tiff: I completely agree. It is about being creative. You do not have to drug the target directly. You can drug its interaction partners.

[35:38] Sam: Exactly. That is one way people are trying to target MYC. Another is degraders, such as PROTACs. You do not need a little small molecule. You can use a PROTAC.

[35:51] Tiff: We now have much more context around disease biology. With RAS, we now know to go for the on state and not the off state. The same principle will apply to MYC, p53, and other previously undruggable targets.

[36:10] Sam: I am really excited.

[36:13] Sam: Whenever we talk about therapies, we also have to say that prevention is best. Early detection and prevention are much better than treating metastatic disease. We have to combine these approaches.

[36:22] Tiff: That is why we have early detection technologies. They make existing therapies work better.

[36:30] Sam: Exactly. You have to jump in before the disease becomes metastatic.

[36:38] Tiff: You are working on that, and we will keep people updated on the progress.

[37:59] Sam: One last thing. There was an interesting All-In Podcast episode this week. They had someone from EcoR1 Capital, which is a biotech hedge fund.

[38:17] Tiff: Very nerdy name.

[38:21] Sam: He gave a stock pitch for a company called Aktis Oncology. Do you know what they work on? Radiopharmaceuticals. Radiopharma is definitely one of the major up-and-coming themes.

[38:37] Tiff: Now that cancer vaccines have matured, the next new shiny thing is radiopharmaceuticals.

[38:46] Sam: There are already two approved radiopharmaceuticals, including one in prostate cancer. But there are only two, so it is still very early. It is definitely a direction for the future.

[38:57] Tiff: Exciting. I am glad you had a good time. Let’s go next year.

[39:01] Sam: Come next year and we will do some chatting, interviewing, or something like that.

[39:08] Tiff: More standing ovations.

And the Youtube video:

1. The RAS revolution continues

After decades of minimal progress, a couple of weeks ago we saw the first step change in survival for metastatic pancreatic cancer — with the RAS inhibitor, Daraxonrasib.

This week a Boston company, Tango Therapeutics, revealed new data that layers a new therapy on top of Daraxonrasib. Their approach depends on a concept called synthetic lethality.

Tango’s approach is rooted in a couple of discoveries from 2016 (the first and the second). About 40% of pancreatic cancers are deficient in the metabolic enzyme MTAP, which clears a metabolite called methylthioadenosine (MTA). This means MTA accumulates, partly suppressing an epigenetic enzyme, PRMT5, and making tumor cells hypersensitive to pharmacological PRMT5 inhibition (with Vopimetostat). PRMT5 is an essential gene; without it, cancer cells die.

I am comparing cross-trial here — and this is only a phase 1/2 trial — but the numbers look good. In MTAP-deficient pancreatic cancer, the objective response rate and 6-month progression-free survival were 92% and 90%, respectively, with the Vopimetostat-Daraxonrasib combination, compared with 20-32% and 41-56% with Daraxonrasib alone (and 11% and 33% with the current standard-of-care chemotherapy).

The synthetic lethality itself is independent of RAS, but it looks like PRMT5 inhibition (in MTAP-deficient cancers) might also be synergistic with RAS inhibition.

This layering of therapy is likely to continue, and could continue to improve outcomes, with RAS inhibition as the foundation. Since most pancreatic cancer still presents as metastatic, what we need alongside this is better early detection.

2. A potentially best-in-class ulcerative colitis drug

Last July, a small French biotech company dropped some data that led to the biggest stock price jump in Nasdaq history. That company is Abivax, who have an experimental new drug for inflammatory bowel disease.

Trials in inflammatory bowel disease happen in two stages: first, induction of remission, and then maintenance of remission. Last July’s data were for induction, and this week (actually it was last week, I am a bit late) Abivax dropped new maintenance data.

Their drug is Obefazimod, a daily oral pill, and the indication here is ulcerative colitis (though they’re also running a trial in Crohn’s). The mode-of-action is a bit up in the air, but it seems to work by inducing expression of miRNA-124, an anti-inflammatory miRNA. The way Obefazimod probably does this is through modulation of the aryl hydrocarbon (AH) receptor. Strangely enough, this was discovered not by Abivax, but by another company with a similar drug, Equillium.

Here are the data, looking at clinical remission (stool-frequency score, rectal-bleeding score, and Mayo endoscopic subscore). Efficacy looks like it might be best in class — better even (cross-trial) than the injectable biologics:

Endoscopic remission is a more objective endpoint, which measures remission on colonoscopy. Here, the data are arguably even better:

Clearly safety is essential here. The safety endpoint I’m most interested in is opportunistic infections, which can happen with some of the other ulcerative colitis drugs, given their immunosuppressive nature. With Obefazimod, the risk of opportunistic infections was 1% with placebo, 1% with low-dose Obefazimod, and 0.5% with high-dose Obefazimod: no clear concerns — the drug is not immunosuppressive.

Listening to gastroenterologists discuss this, Obefazimod has potential first-line use as well as later-line use — indeed, patients in this trial had typically failed 1, 2, 3, or even 4 prior therapy classes before Obefazimod.

The next landmarks here are submission to the FDA this year, and the Crohn’s phase 2 trial next year.

3. Discovery of a defined subtype of inflammatory bowel disease

In inflammatory bowel disease (Crohn’s disease and ulcerative colitis) there is a small amount of therapy tailoring, but it’s really limited to a few things — disease severity, prior biologic exposure, drug safety profile. Choice of therapy itself is pretty much based on trial and error: try one drug, and move to the next if it doesn’t work.

This is partly because the causes of inflammatory bowel disease are still poorly defined, and no established, common molecular mechanisms exist. This study, from the New England Journal this week, changes that.

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1. A standing ovation for Daraxonrasib

The story of the meeting was Revolution Medicines’ full phase 3 dataset, for Daraxonrasib vs. chemotherapy in metastatic pancreatic cancer. This was greeted by a standing ovation (in the middle of the talk!) which I recorded here:

Here’s the full Kaplan-Meier curve:

There are two reasons this is so important. First, many trials have been done in this setting, all of which failed to improve (or only incrementally improved) the standard of care. Daraxonrasib inhibits the oncogenic driver in pancreatic cancer, RAS, producing this step change in survival and laying the new foundation of therapy:

Second, RAS was king of the undruggable, and it took some serious creativity to inhibit it. Daraxonrasib is a 'molecular glue' that locks RAS into an inactive trimer with a third molecule, Cyclophilin A. This works for many species of RAS — both wildtype and mutant forms — and Daraxonrasib binds RAS in its ON state (which produces more potent inhibition than OFF state inhibition). This also gives rise to the name: Darax-ON-RAS-IB.

As well as doubling average survival, Daraxonrasib improved quality of life and reduced pain associated with pancreatic cancer:

What's next for Daraxonrasib? More trials! 1st line in metastatic pancreatic cancer, and after surgery in resectable disease. RAS is also a major driver in lung cancer and in other solid cancers, like colorectal, so Revolution Medicines are running trials there, too:

Daraxonrasib is far from the only RAS inhibitor moving through trials — these are some of the other ongoing phase 3 trials. There are many others in earlier phases, too – the more the merrier!

2. Innovative therapies

There were trials presented for new, innovative therapies — antibody-drug conjugates (ADCs), vaccines, bispecific and even trispecific(!) antibodies.

A bispecific antibody in cancer cachexia

One that caught my eye was this trial in cancer cachexia (weight and muscle loss in advanced cancer). There are no targeted therapies approved for this condition, but it’s become pretty well-established that a stress-induced cytokine, GDF15, drives it, and recently were recently positive phase 2 data on a GDF15-blocker from Pfizer.

This approach from ASCO builds on that idea with a bispecific antibody that inhibits both GDF15 and IL6 — blocking the driver of cachexia (anti-GDF15) and suppressing inflammation (anti-IL6).

In patients with advanced cancer and cachexia, the antibody increased bodyweight (up to 25% for high dose vs. low dose), increased muscle mass, and increased appetite. The presenter of the poster told me that patients’ main complaint was... gaining too much weight.

Cancer vaccines

These new, final, 5-year phase 2b data were presented for Moderna/Merck’s personalised cancer vaccine (plus the standard of care, Pembrolizumab, a PD1-blocking antibody) in resected melanoma. Melanomas were removed by surgery, personalised vaccines built based on specific cancers’ mutations, with the aim to prevent recurrence — and it worked: there was less recurrence and less metastasis.

Based on a similar idea, these data, from a Chinese biotech, dropped in esophageal squamous cell carcinoma. This condition has huge unmet need, with average disease-free survival of about 22.4 months with the best standard-of-care (PD1 blockade). This personalised neoantigen vaccine looks like it might extend disease-free survival, when used after surgery:

Beyond this, there were new data on a trispecific anti-PD1/CTLA4/VEGF antibody in lung cancer, new data on CEACAM5-targeted CAR-T cells in colorectal cancer, and data on a neoantigen vaccine in glioblastoma, where there’s been minimal progress for decades.

3. Pancreatic cancer progress beyond Daraxonrasib

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