Edinburgh Worldwide enlightenment: targeting cancer’s greasy ball

As with any investment, your capital is at risk.

Biotech has started to matter again in markets. The S&P Biotech ETF, an exchange-traded fund, was recently reported up by more than a quarter year-to-date and close to doubling over the prior 13 months.

More importantly, the move does not rest on sentiment alone. It has been supported by genuine clinical progress, including data from companies such as Revolution Medicines (RevMed), which has forced investors to reevaluate the area.

EWIT had not lost faith in the sector as a fertile hunting ground for the kind of companies it wants to own. We have remained consistently overweight in biotechnology, recognising how converging technologies and compounding scientific understanding can unlock treatments.

That has not always been comfortable, and the sector is unforgiving: biology is uncertain, raising capital has become harder and more costly and promising assets can be acquired by large pharma before long-term shareholders see the full benefit.

But the asymmetry remains powerful, as illustrated by our longstanding investment in Alnylam. Redwood City-based Revolution Medicines could also be one of those asymmetric outcomes.

But process and discipline matter enormously. That is why Brogan Harris’s extensive healthcare work last year was instrumental in consolidating our understanding of the sector. After meeting the management teams from more than 30 biotech companies across Boston and San Francisco, three lessons stood out. 

First, control matters. Pharma partnerships can provide capital, but they often dilute urgency and strategic direction. 

Second, cash is king because independence is only possible if the balance sheet allows it. 

Third, a lead asset capable of supporting a durable franchise is a better leading indicator than promises of a broad platform. 

Successful biotech companies usually scale based on one or two decisive assets – breadth comes later. Revolution Medicines, held in the EWIT portfolio since late 2025, was bought on the basis that it fits that framework unusually well.

The problem: RAS has been cancer’s greasy ball

RevMed is trying to solve one of oncology’s oldest problems: how to target rat sarcoma (RAS), a family of signalling proteins that help control cell growth. When mutated, RAS can drive cancer. RAS mutations are found in about one-third of human cancers, making it a key oncology target.

The challenge is that RAS was long considered ‘undruggable’. Scientists sometimes describe it as a greasy ball: a slippery protein with no obvious pocket for a small molecule to grab.

Among the most urgent test cases is pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer. About 90 percent of PDAC tumours are RAS-driven, and outcomes remain dreadful. Chemotherapy has remained the standard of care and the five-year survival rate is among the lowest of any common cancer.
 
Revolution says more than 90 percent of PDAC tumours harbour RAS mutations and that metastatic PDAC has a five-year survival rate of roughly 3 percent. If a company can meaningfully improve outcomes here, it is solving a real clinical problem.

The edge: targeting RAS when it is switched on

RAS is best thought of as a molecular switch. When it is ‘off’, it is largely inactive. When it is ‘on’, it sends growth signals through the cell. In many cancers, that switch is broken: RAS keeps signalling, and the tumour continues growing.

For decades, this was one of the hardest problems in oncology. The first successful Kirsten rat sarcoma viral oncogene homologue (KRAS) medicines made progress by targeting narrower mutations, particularly KRAS G12C, and often by binding RAS in its inactive state. That was a breakthrough, but it left much of the RAS cancer universe untouched.

RevMed’s approach is fundamentally different. Its drugs are designed to target RAS in the on state, where it is actively driving cancer growth. The company’s tri-complex chemistry uses another protein, cyclophilin A, as a molecular adaptor, helping the drug bind to active RAS and block the signal closer to its source.

This is technical, but the investment point is simple. By targeting active RAS, RevMed is not limited to one narrow mutation. Its approach has the potential to inhibit a much broader family of RAS-driven cancers, including the mutations most relevant to pancreatic cancer. Daraxonrasib, its lead drug, is therefore best understood as a broad RAS inhibitor rather than a single-mutation therapy.

Recent clinical data sharpen this thesis. In the phase 3 RASolute 302 trial, daraxonrasib doubled median overall survival in previously treated metastatic pancreatic cancer: 13.2 months versus 6.7 months for chemotherapy in the intent-to-treat population. Patients receiving daraxonrasib were 60 per cent less likely to die during the study period. In a disease as aggressive as pancreatic cancer, this is a striking result.

Daraxonrasib did have side effects, but discontinued use due to treatment-related adverse events was low: 1.2 percent for daraxonrasib versus 11.2 percent for chemotherapy. The standing ovation at the American Society Clinical Oncology conference announcement was a visible signal of how meaningful the oncology community considered the data.

The implication is that RevMed has begun to make progress against one of the largest unsolved targets in cancer. Daraxonrasib is the first step, but it may not be the whole story. 

Zoldonrasib, RevMed’s G12D-selective RAS drug, is now supporting two further pancreatic cancer strategies: an ongoing phase 3 trial alongside chemotherapy, and a planned phase 3 trial in combination with daraxonrasib. 

If RevMed is right, it may have found a repeatable way to target one of cancer’s most significant drivers, rather than a single setting in one cancer.

The opportunity: control, capital and commercial ambition

One of the most unusual features of RevMed is its desire to go alone. Many biotechs partner early because they have little choice. RevMed has deliberately retained control. Management argues that RAS biology is too complex to be handed to a committee, and that trial design, regulatory strategy and commercial priorities need to sit under one roof.

That ambition is credible only because the company is unusually well capitalised. Its recent financings give it the firepower to run multiple late-stage trials and prepare for launch giving up too much of the financial upside of its lead assets.

It is also no longer just a scientific organisation. RevMed is building large-scale commercial capabilities ahead of regulatory approval. That is a significant undertaking, particularly given the breadth of the drug pipeline. Still, it is exactly what we want to see if the company is serious about transitioning from a research-led to a commercially ambitious business.

The financial prize is large. Its lead asset alone could plausibly generate multi-billion-dollar annual sales if it becomes the standard of care for pancreatic cancer and expands into other RAS-mutant tumours. 

Sell-side forecasts vary, but several now contemplate daraxonrasib generating sales of more than $10bn, before considering the company’s other candidates. The valuation already reflects some of the opportunity, but the scale of the opportunity still leaves room for substantial upside if execution holds.

Too good to be true?

The risks are obvious and important. This is still clinical biotechnology. Further data must confirm durability, tolerability and benefit across broader populations and earlier lines of therapy. 

RAS inhibition can cause on-target side effects, including rash and stomatitis, that require careful management in the real world. In RASolute 302, the most frequent Grade 3 or higher treatment-related adverse events on daraxonrasib were rash and stomatitis.

Execution risk is also high. RevMed is attempting to run several global trials, prepare regulatory filings and launch commercially without a large pharma partner. That is precisely what makes the company interesting, but it also introduces risk. There are competitors too, including companies pursuing different ways to target the same cancer-causing process.

Finally, success may make the company an attractive acquisition target. Large pharma companies approaching patent cliffs need new growth franchises, particularly in oncology. RevMed has already attracted reported takeover interest, although nothing officially transpired. We remain aware of the possible outcome.

Why it fits EWIT

From our experience investing in this sector, RevMed stands out as one of the most exciting opportunities we have encountered. It is a late-stage, well-capitalised company with control over its assets, a franchise-worthy lead programme and clinical data that are beginning to validate the core thesis.

That aligns closely with the lessons from Brogan’s healthcare work: prefer control, insist on capital, look for a defining asset and focus on companies that are seriously preparing for commercial scale. 

RevMed remains high risk, but the upside could be equally significant. If active-state RAS inhibition becomes a new foundation in oncology, RevMed could be much more than a trade that predicts clinical trial outcomes. It could go on to become one of the rare companies that crosses the chasm from clinical promise to a durable healthcare franchise.

For EWIT, that is the attraction. We are not trying to own biotechnology broadly because the sector is having a better year. We are trying to own a small number of companies where science, management ambition, capital and asymmetry line up. RevMed may be one of them.

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