March 26, 2019

Trio of new medicines originate from Scripps Research discoveries

March 26, 2019

La Jolla, CA - While billions of investment dollars pour into pharmaceutical development in the biotechnology and pharmaceutical industry sector each year, centers of academic excellence remain the birthplace of innovative discoveries that enable novel treatment strategies addressing the world's most dire unmet medical needs.

Scripps Research is doubling down on its legacy of discovery biology that is translated into much-needed new medicines within the boundaries of Scripps Research, a track-record exemplified by a trio of new drugs making their way to the marketplace.

The pharmaceutical company Celgene announced Monday that it filed an application with the U.S. Food and Drug Administration seeking approval to treat multiple sclerosis (MS) with ozanimod, a drug invented by Scripps Research professors Hugh Rosen, MD, PhD, and Edward Roberts, PhD.

In January, the FDA also accepted a drug application from Pfizer for the treatment of cardiomyopathy with tafamidis, a medicine invented by Scripps Research professors Jeffery Kelly, PhD, and Evan Powers, PhD. And in May of last year, individuals with a rare genetic disorder called phenylketonuria (PKU) received new hope with the FDA's approval of BioMarin's drug Palynziq , which was developed in collaboration with the Scripps Research laboratory of Raymond Stevens, PhD.

These three new drugs continue a long history of translating groundbreaking discoveries made at Scripps Research into new drugs used in the clinic, said Matt Tremblay, PhD, chief operating officer of Scripps Research and its drug discovery division, Calibr. They underscore the ability of our researchers to play a major role in creating new medicines.

Scripps Research has originated a total of nine approved drugs, from surfaxin, which helps premature babies take their first breaths, to humira, an inflammation-blocking antibody used to treat rheumatoid arthritis and other conditions.

Over the past two years, Scripps Research has greatly expanded its own in-house translational research capacity with the aim of advancing its medicines through clinical studies in patients and reinvesting revenues from those drugs back into research. Under the leadership of Peter Schultz, PhD, president and CEO, the institute has assembled a unique infrastructure by merging with two other entities: Calibr, a nonprofit drug discovery center with a pipeline of new medicines founded by Schultz in 2012; and the Scripps Research Translational Institute, founded by Eric Topol, MD, that focuses on personalizing medicine with the power of genomics, wireless digital technologies and artificial intelligence.

This new business model for nonprofit research institutes simultaneously fuels fundamental biomedical discoveries and speeds their translation into medicines by re-investing licensing revenues into ongoing basic and translational science. Ozanimod, tafamidis and Palynziq demonstrate how scientific insight into the biology underlying disorders are essential to developing therapies, and how that insight can be effectively paired with drug development expertise to have a significant impact on patients living with disease.

The seminal discovery that led to ozanimod was reported by Rosen and his team in Science in 2002. They showed that altering the activity of certain cellular receptors could dampen the effects of the immune system. Working with Roberts and other researchers, Rosen developed ozanimod, which binds to these receptors and inactivates immune system cells involved in MS and inflammatory bowel disease (IBD).

Celgene acquired the rights to ozanimod in 2015 and the application filing announced this week seeks approval to market the drug for relapsing and relapsing-remitting MS. At the same time, Phase 3 studies for ulcerative colitis, a form of IBD, are on track to be completed by mid-2020, resulting in a subsequent filing for approval in 2021.

The story of ozanimod and these other new therapies highlights the uniqueness of Scripps Research, Rosen says. There are hardly any other academic institutions in the world that have the multidisciplinary expertise to discover a new disease-modifying compound and generate clinical data in support of its development.

Tafamidis, conceived and synthesized in Kelly's lab and now exclusively licensed to Pfizer, has been approved in 40 countries for the treatment of familial amyloid polyneuropathy (FAP), a rare neurodegenerative disorder that results from transthyretin aggregation. Pfizer has also recently completed a tafamidis Phase 3 clinical trial in individuals with the heart disorder transthyretin amyloid cardiomyopathy, which affects a much larger population. Tafamidis demonstrated a significant reduction in the risk of all-cause mortality and cardiovascular-related hospitalizations. The FDA has granted fast track designation for considering approval of tafamidis for this condition, which leads to congestive heart failure and death within about five years of diagnosis if untreated.

The approval of Palynziq marked a watershed moment for people with PKU, a disorder that occurs in 1 in 10,000 to 15,000 births in the United States.

The therapy replaces a critical enzyme, phenylalanine hydroxylase (PAH), which breaks down phenylalanine, an amino acid found in most proteins and in ubiquitous artificial sweeteners resulting in significant dietary restrictions and life-threatening consequences for PKU patients, who lack the enzyme.

Stevens' research on the three-dimensional structure of the PAH enzyme alone or bound to drug candidates enabled a collaboration with BioMarin that ultimately led to Kuvan , the standard of care for mild PKU patients. By activating the metabolism of phenylalanine, Kuvan expands dietary options for about 40 percent of

LINK:	https://www.scripps.edu/news-and-events/press-room/2019/20190326-crava...
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