The Opportunities Waiting on Big Pharma Shelves

Posted July 6th, 2023 by Mike Cloonan, in Business Development, Drug discovery, From The Trenches, Rare Diseases

By Mike Cloonan, CEO of Sionna Therapeutics

In 2016, following robust discovery efforts by Pfizer and others, the NBD1 domain of the CFTR protein was largely considered undruggable. They knew it was a key target – the most common genetic mutation in cystic fibrosis destabilizes NBD1, impairing function of the protein and leading to a buildup of mucus in the lungs and airways and other organ dysfunction. But they struggled to find a drug candidate that could bind to and stabilize it.

“Although these results cannot prove that there is no possibility of finding a high-affinity small molecule binder of NBD1, they are discouraging…”

It turns out the small molecules they were looking for are not only possible – they were ready for a dedicated team to push them ahead.

This isn’t uncommon in our industry. Many large pharma and biotech companies house wide ranges of preclinical compounds to support their R&D efforts, and some are kept highly secret. Some demonstrate their potential quickly and move rapidly ahead; others may take years to show their promise. Sometimes they don’t fit a strategic priority, or priorities change. Whatever the case – these hidden gems hold the potential to change treatment paradigms for patients with significant unmet needs. They just need the right team or company to come along and champion assets that may already be de-risked.

More than a decade ago, our co-founder, Dr. Greg Hurlbut, formerly the head of protein conformational and rare pulmonary diseases research at Sanofi Genzyme, developed a novel strategy to discover small molecules that directly address the key driver of molecular pathology of F508del, the most common cystic fibrosis-causing mutation. This unique approach, which aimed to identify small molecules that could directly stabilize the CFTR NBD1 domain, drew the attention of the Cystic Fibrosis Foundation (CFF), which made a significant investment to support work by Sanofi Genzyme to identify a special class of NBD1-directed small molecule “correctors” that would help the mutant CFTR protein function normally.

After years of steady progress and tens of millions of dollars invested, Sanofi Genzyme corporate strategy shifted, and eventually a strategic decision was made to suspend the program, focus resources on immunology/immuno-oncology, and out license these assets.

Fortunately, Sanofi Genzyme was willing to out license these assets to an internal team including Dr. Hurlbut and Dr. Mark Munson, who was the U.S. head of medicinal chemistry at Sanofi Genzyme, and they founded Sionna Therapeutics with a focused effort on NBD1. With Drs. Hurlbut and Munson, a strong scientific team joined them to advance these programs in a dedicated spin-off funded by RA Capital, TPG and the CFF. Atlas later joined that syndicate in an extension of the seed round.

The Sanofi Genzyme scientific team recognized the value and differentiation in the approach to stabilize NBD1, and Sionna was able to leverage the decade of significant Big Pharma investment and perseverance. Sanofi Genzyme had de-risked the science to a certain point, but to fully maximize the opportunity it required the laser focus of a company dedicated to improving the lives of people living with CF. Sionna Therapeutics was that company. If not for the significant investment made, followed by the strategic shift at Sanofi Genzyme, and the commitment of our scientific team and investors, we might not be conducting clinical trials with an NBD1-binding small molecule today and moving one step towards drugging the undruggable target.

Advancing this kind of research is especially important in rare diseases that have limited treatment options. Sionna benefited greatly from the years of deep research and dollars invested in a target that, until now, had been considered undruggable. With this science now in the hands of a small biotech, we have the dedicated focus and nimbleness needed to leverage this foundation and advance a robust pipeline with a sense of urgency, enabling the rapid development of treatments that may be transformational for patients.

Sionna is an example of how Big Pharma and small biotech can work together synergistically to advance medicines beyond what each individually can do on its own. We certainly are not alone – many of our industry peers are seeking the advantages of out-licensing from Big Pharma and generating significant value for patients and shareholders in the process. It’s a trend that has accelerated over the last decade with multiple success stories.

In just a few recent examples, Cerevel Therapeutics was created with a portfolio of pre-commercial neuroscience assets from Pfizer, Day One Biopharmaceuticals licensed its development programs from Takeda and Merck KGaA to target urgent needs in pediatric oncology, and Disc Medicine expanded their portfolio through licenses from each of AbbVie and Roche.

I hope that others in our industry maintain a similar focus on innovation. So many large, well-established pharma and biotech companies may have drug candidates waiting in the wings with differentiated, high-quality science and real potential. It is up to us to make those leaps of faith that can drive real change across generations.

Mike Cloonan

President and CEO of Sionna Therapeutics
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