Dr. Mathai Mammen knows well that a biotech company faces extremely high hurdles to bring a new drug to market. But to stand out among peers, this former head of R&D at Johnson & Johnson is leading his current company, Parabilis Medicines, not only to target difficult biological targets but also to go straight for those once labeled "undruggable."

This effort reflects what Mammen has learned over a decades-long career—from biotech startups to big pharma and back to startups: differentiation and persistence are the keys to surviving funding winters and intense competition.

Mammen's career began with co-founding Theravance, where five drugs were brought to market during his tenure; he then led multiple therapeutic areas at Merck & Co. and served as head of R&D at Johnson & Johnson, where he drove approvals of blockbusters such as Tremfya and Darzalex Faspro.

Drawing on this experience, Mammen realized that many biotech companies today are caught in a "follow-the-crowd" trap, chasing common targets. As CEO, President, and Chairman of Parabilis, he is attempting to leverage AI-based prediction anda highly adaptable platformto bring biotech back to its roots, tackling difficult pathways that have not been addressed before.

This biotech company, founded in 2015 and originally named FogPharma, wasrenamed Parabilislast year. Its lead candidate is in Phase 1/2 clinical trials, targeting the β-catenin:TCF complex—a protein that plays a role in multiple cancers, including colorectal cancer, and a pathway no other therapy has successfully targeted. Parabilis also has early-stage programs targeting drivers of prostate cancer, which Mammen says show promise.

"What distinguishes great drug hunters from ordinary people is the ability to connect the dots in a unique way."

—Dr. Mathai Mammen, CEO, President, and Chairman of Parabilis Medicines

Mammen says that tackling entirely new targets once thought beyond the reach of medicine not only addresses unmet medical needs but also allows the company to lead the industry in new directions and become a pioneer.

"You should develop drugs in a way that is unique and effective, while making it difficult for others to replicate," Mammen says. "If you focus on that and build a culture and team that knows how to execute and solve new problems from scratch—combining experience with novel thinking—you can build a great company."

Here, we spoke with Mammen about the current state of the biopharma industry, how a tight funding environment can make certain companies stand out, and why "undruggable" targets offer a window of opportunity for those willing to leap into the unknown.

This interview has been edited for length and style.

PHARMAVOICE: From your perspective, what is the current state of the pharmaceutical industry?

DR. MATHAI MAMMEN:From a macro perspective, my view starts in 1997, and I have watched this industry rise and fall—then rise and fall again. Having been through multiple cycles, I compare the current state to the late 1990s, when we were raising funds for Theravance—$5 million for the Series A and $20 million for the Series B. Even in the current downturn, those numbers are much smaller than what we see now, so I believe good ideas never lack funding. But since 2020, there has been a surge in the number of companies and an influx of generalist capital—I would say there are too many companies, leading to fragmented efforts. There are only so many good ideas worth pursuing, so we are seeing the industry contract.

That said, pharma's efficiency has improved because many old challenges have been solved. Now, everyone is focused on a few things like the "most-favored nation" policy or the Inflation Reduction Act, often forgetting that there are many extremely favorable factors right now that far outweigh those specific challenges.

When there is more money in the system but it is used less efficiently, where does the wasteful spending mainly occur?

I would not call it wasteful, but there may be many "shots on goal" for programs that may not necessarily become the most important drugs. Eight or ten companies might be doing very similar things, and all might produce decent data, but in the end perhaps only one or two will make an impact in the market. The results no longer have independent value because there may be no buyer.

Another aspect that is not necessarily wasteful but is certainly difficult is fully understanding biology to predict new mechanisms. Failure rates remain high because we do not clearly understand the relationship between biological fragments and the diseases we are trying to change. These are extremely hard problems, and the industry is investing effort along very narrow axes. The issue is an over-focus on incremental innovation.

When funding is difficult, what is most fundamental for biotech companies?

You need confidence that your biology can translate. What distinguishes great drug hunters from ordinary people is the ability to connect the dots in a unique way. You must have a differentiated drug—otherwise, in the end, you will not create value.

You also need to find the reason why that differentiation can be sustained. Today, with a flood of innovation from certain regions such as China, if you are developing small molecules or antibodies, the level of engineering is high enough that others can quickly follow such molecules. The concept itself should be contrarian to sustain long-term differentiation. At Parabilis, this model is so difficult to navigate that very few people know how to use it.

You said last year that you wanted to "break boundaries and shatter dogma." What boundaries and dogmas do you think are holding biotech back, and which can Parabilis overcome?

One important dogma has run through my career at Theravance, Merck, and Johnson & Johnson: many projects or biological targets you might want to pursue—those you gain confidence in through genetics or phenotypic approaches—often have to be shelved because existing tools cannot handle them. Our toolkit did not allow us to attack certain targets. I used to say, "Oh, some targets are just like that—too bad."

Some proteins appear "undruggable"—they have smooth surfaces with no cavities to accommodate small molecules. But at Parabilis, we have created special peptides called "Helicons" that are not limited to a single shape, containing thousands of amino acids and bringing the diversity of small molecules to a peptide backbone. This is a tremendous opportunity to address biological targets that were previously undruggable.

What is the commercial appeal of targeting targets once considered "undruggable"?

I am cautious about using that word—some cases seem undruggable but have simply not yet been successfully drugged. The commercial value, of course, lies in being able to attack targets others cannot and advancing all the way to clinical proof of concept and beyond. As a company, this is a huge barrier to entry, a wide moat. But it provides a durable advantage, especially in an era of intense innovation. In this "undruggable" space, if we can uniquely target the interface between β-catenin and TCF, that would be a major achievement, and the commercial advantage lies in that durable differentiation.