Integrins were a big deal in the early days of biotech in the 1980s and 1990s. They looked like a promising class of receptors found on cells implicated in many diseases. Billion-dollar dreams were in the air. Then, thunderstruck by dangerous and surprising side effects, integrin-directed drugs were tossed in the trash.

But integrin biology is making a comeback with a big-name scientific entrepreneur from Harvard Medical School, and a healthy shot of cash from Big Pharma. Waltham, Mass.-based Morphic Therapeutic is announcing today it has raised $51.5 million in a Series A venture financing to build on new understanding from Tim Springer’s lab at Harvard Medical School about the shifting, not static, state of integrin receptors. GlaxoSmithKline’s SR One venture group and Pfizer Venture Investment co-led the financing, and were joined by Omega Funds, AbbVie Ventures, Tim Springer, Polaris Partners, Schrodinger, and Shangpharma Investment Group.

Integrins have long fascinated biologists as drug targets, because they are receptors commonly found on the surface of about 90 percent of human cells, and are thought to play a role in crucial cell processes—cell survival, differentiation, and migration. Acute coronary disease, autoimmune diseases, clotting disorders, and many more common ailments seemed to be in reach. Early targeted antibodies were made to specifically inhibit integrin targets, and a few are still around—Biogen’s natalizumab (Tysabri) is one famously potent integrin-directed antibody for multiple sclerosis that also comes with some serious warnings about side effects.

Praveen Tipirneni, CEO, Morphic Therapeutic

Early antibodies were good at specifically binding with these targets. The flaw, as is usually the case in biotech, was a lack of understanding of the underlying biology, said Morphic CEO Praveen Tipirneni. This time around, Springer’s lab has used advances in X-ray crystallography to obtain precise structural information on integrin targets. That led to the realization that the receptors don’t behave in a static way. They “morph” into specific shapes, including a closed one and an open one.

That’s a crucial insight. It means that if you make a specific antibody that inhibits an integrin in the closed state, and it does that job well, it can also have the opposite effect, by stimulating another activity. That can cause dreaded side effects, or even make a disease worse.

Armed with the vivid (and proprietary) crystal structure information of integrins from Springer’s lab, Morphic started working with the computational group at Schrodinger. The computational group runs calculations and simulations to find small-molecule chemical compounds, the kind which can be made into oral pills, that have the optimal binding characteristics to inhibit an integrin in its closed state, and keep it locked even in an open state, Tipirneni said.

Here’s what Springer said about the opportunity, in an email:

Almost every major pharma rode a wave of excitement on integrins as targets in the 1990s but the wave crashed when orally available small molecule antagonists failed to prevent thrombosis and even made patients worse. All this work was done without benefit of crystal structures or knowledge that integrins can morph from one conformational state (shape) to another. We now have extensive structural knowledge of integrins, much of it from my lab, and my lab also knows how to avoid the harmful effects of inhibitors that relate to integrin morphing and has licensed this knowledge to Morphic Therapeutic. Recent advances with biologicals as therapeutics have further proven the value of targeting integrins. With our structural knowledge of integrins, ability to solve structures of new drug-integrin complexes, ability to morph integrins into the desired conformational state, and Schrodinger’s expertise in computational design, we are in position to ride a new wave of integrin drug discovery all the way to FDA approval.

Springer is well-known for his scientific work that dates to the early days of integrin discovery, as well as his entrepreneurial ventures, especially LeukoSite, a company acquired by Millennium Pharmaceuticals. More recently, one of Springer’s angel investments, Selecta Biosciences, went public.

Morphic got started with Springer teaming up with Polaris Partners, an early-stage venture firm, and one of its partners, Kevin Bitterman (for more on Bitterman, see “12 VCs Who Matter, But You Never Read About” in TR). Bitterman helped bring in Tipirneni, a former sales and marketing executive at Cubist Pharmaceuticals, as the permanent CEO. The operation is still small, with just 15 employees, and at an early stage. It doesn’t yet have any drug candidates in clinical trials, or a publicly declared lead candidate.

By raising a lot of money early, Morphic will be able to move forward simultaneously on several fronts. Inflammatory bowel disease is a “high priority” of focus, given the recent success of Takeda Pharmaceuticals, which analysts expect will generate $2.5 billion a year in peak sales for vedolizumab (Entyvio), a drug aimed member of the integrin family. Fibrosis is another logical disease category for an integrin discovery shop, and there are potential novel strategies for cancer as well, Tipirneni said. About two dozen members of the integrin family are known, and about 15 appear to have good potential as drug targets, Tipirneni said.

Other companies are paying attention. Pliant Therapeutics, a Third Rock Ventures-backed fibrosis drug developer that I wrote about last year for Forbes, is one company working in an overlapping area of R&D, Tipirneni said. Cambridge, Mass.-based Nimbus Therapeutics is another company that leans heavily on a computational drug discovery approach in collaboration with Schrodinger, although against a different set of biological targets, Tipirneni said.

For a detailed review of the history of trials and tribulations with integrin-targeted drug development, see this 2011 review article in the journal Theranostics.

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