Ep209: Mathai Mammen on Developing Drugs Against Undruggable Targets

Mattai Mammen traces his path from being born in India and raised in Halifax, Nova Scotia, where his parents worked in biomedical fields, through his chemistry and physics studies at Dalhousie University. He pursued an MD-PhD at Harvard in George Whitesides' lab, focusing on multivalency in molecular interactions—how repeated binding elements in nature could be harnessed therapeutically. After cold-sending his business plan to Roy Vagelos, Mammen co-founded TheraVance in 1997 based on multivalency principles, where he spent 14 years building a platform that ultimately produced five FDA-approved medicines and trained numerous future biotech CEOs.

Mammen's trajectory then took him to Merck, where he led research in oncology and other therapeutic areas, building organizational capabilities and recruiting exceptional talent. He moved to J&J as head of R&D, overseeing 14,000 people and driving a portfolio transformation that included novel approaches like CAR-T cell therapy, nasal spray ketamine (Spravato), and targeted radioligand therapies. During this period—between 2010 and 2014—Mammen lost two daughters, Mia and Laney, both at age six. Rather than abandoning his career, he deepened his commitment to developing impactful medicines, viewing his work as a way to honor their memory and reduce suffering for other families.

Mammen joined Parabolus (formerly Fog Pharma) as CEO to build a company around Greg Verdine's alpha-helical peptide platform. The core innovation addresses a fundamental limitation in drug discovery: approximately 80% of intracellular proteins lack the drug-binding pockets that small molecules and traditional biologics require. Parabolus's technology uses stabilized alpha-helical peptides incorporating thousands of unnatural amino acids (versus the 20 naturally occurring ones) to bind flat protein surfaces. The lead program, Zolocatetide, targets the beta-catenin-TCF complex, which had eluded all previous drug discovery efforts despite decades of attempts by major pharma companies.

In clinical trials, Zolocatetide demonstrated a 74% objective response rate in desmoid tumors—aggressive soft tissue cancers causing chronic pain and dysfunction—with manageable safety profiles. The company strategically pivoted from colorectal cancer, where patients carried multiple mutations, to indication-specific approaches starting with genetically pure diseases driven primarily by beta-catenin alterations. Parabolus conducted the largest venture-backed biotech IPO in 2026, raising $770 million to expand Zolocatetide into multiple indications (FAP, adenomatous cranial pharyngeoma, hepatocellular carcinoma) and pursue additional undruggable targets in oncology and beyond through a Regeneron collaboration.

Mammen emphasizes that his hiring and organizational philosophy—prioritizing intellectual curiosity, genuine hunger to achieve, and mission-driven motivation—proved critical across all his roles. He advocates for choiceful project selection, only pursuing medicines addressing truly unmet needs rather than incremental improvements. The company leverages AI and machine learning both in peptide discovery (using reinforcement learning on proprietary datasets of helical peptides) and in clinical development (analyzing patient biopsies, PDX models, and genetic signatures to identify responsive populations and optimize trial design).