Scholar Rock Aims to Hit Disease-Causing Proteins in a “Niche”

Xconomy Boston — 

For the better part of a year, Scholar Rock has worked behind the scenes mapping out an approach to hit well-known disease targets in an unusual way. Now, the nascent Cambridge, MA-based startup is ready to discuss what it’s found.

Scholar Rock is emerging from stealth mode today to make two announcements: First, it’s licensed intellectual property from Boston Children’s Hospital related to what it calls “niche” activators—the new drug candidates it wants to develop against certain types of growth factors. Second, it’s filling out its board of directors with some well-known Boston biotech entrepreneurs: Katrine Bosley, the former CEO of Avila Therapeutics, and Michael Gilman, the former head of Stromedix. They’ll join chairman Amir Nashat of Polaris Partners, co-founder Timothy Springer, and president and CEO Nagesh Mahanthappa (the former vice president of corporate development and operations at Avila).

The two bits of news mark the first time Scholar has come up for air to tell its story since it was co-founded just over a year ago. It’s still an infant company, with about 10 employees (including a few consultants), no drug candidates in clinical trials, a Kendall Square office/lab and seed funding from Polaris and Springer to show for its efforts.

Scholar was formed in January 2012 out of the work of Springer and Leonard Zon, a fellow researcher at Boston Children’s Hospital and Harvard Medical School. Springer is perhaps best known as the founder of Cambridge-based LeukoSite, which was sold to Millennium Pharmaceuticals for $635 million in 1999, though he’s also been involved in more recent biotech startups in town, like Selecta Biosciences and Moderna Therapeutics.

Scholar Rock CEO Nagesh Mahanthappa

Scholar Rock CEO Nagesh Mahanthappa

The concept behind Scholar is to seek out certain specific, seemingly dormant growth factors, and create a drug that indirectly and selectively either turns them on, or keeps them switched off. By doing so, according to Mahanthappa, Scholar could create drugs with higher potency, or fewer side effects (or both), than those with a more “broad” effect on growth factors as a whole.

Growth factors are, of course, very well known in the biotech world. They’re proteins that mediate a number of normal physiological processes like cell growth and differentiation, and are also known to go haywire in the case of various diseases. As such, they’re often used or targeted for therapeutic reasons. Sometimes, for example, the growth factor is made through genetic engineering and given as the drug itself, like in the case of interferons. Other times, growth factors are themselves the biological targets that scientists seek to shut down with targeted antibodies or small molecule chemical compounds.

Mahanthappa says, however, that the vast majority of growth factors have a “wide variety” of roles and exist throughout the body. This means that broadly shutting down those growth factors—with an antibody, for instance—might hit the desired biological target, but might also interfere with other, normal physiological processes.

This is where Scholar comes in. Mahanthappa says all that growth factors aren’t just freely floating around in the body. Most of them are sitting “latently in depots” waiting to be activated. Springer, over the past few years, has been working to identify the mechanisms by which this happens. As it turns out, these growth factors can be switched on sometimes by other molecules, or “cofactors,” that are either on the surface of nearby cells, or floating in the extracellular matrix (the fluid between cells), he says.

Scholar’s plan, then, is to engineer drug candidates to “tweak” certain dormant growth factors—wake them up, or keep them sleeping—indirectly, by targeting these complexes of proteins. If a disease is caused by a deficiency of a specific growth factor, for instance, Scholar would try to switch it on. If a growth factor is inappropriately activated in a certain disease, Scholar would try to preemptively keep it dormant. These experimental drugs—likely initially antibodies, though Scholar may later try small molecules as well—would be Scholar’s so-called “niche” activators or inhibitors.

Scholar isn’t saying specifically which growth factors it’s looking at as of yet. It’s homing in on areas of disease biology where specific growth factors have a “very clear and known role,” but where systemically activating or inhibiting those growth factors hasn’t worked out well—either because of side effects at potent doses, or ineffectiveness at tolerable doses.

“That’s what creates the window of opportunity for [us], where we can come in with our therapeutic candidates and get a very potent and selective advantage in areas where the biology is well known,” he says.

For now, Scholar is narrowing that down to fibrotic, autoimmune and musculoskeletal diseases, though it won’t say which ones.

Still, it’s very early in the game. Scholar has worked in stealth over the past year figuring out which specific growth factors it’s interested in and exactly which complexes of proteins it should target to affect them, and making sure it can engineer those protein groups to test its scientific hypotheses. It’s also been developing assays to help it see if it can get the results it’s looking for. Just now, Scholar is moving on to the drug discovery phase.

Even so, Mahanthappa is talking boldly. Over the course of the year, Scholar plans to roughly double the size of its team—chiefly adding R&D positions— and gather initial proof-of-concept data. It’ll likely raise a Series A round to take its next step, but Mahanthappa wants to ink a partnership to validate the company’s approach before then.

“That’s the goal,” he says. “We have some very exciting discussions ongoing and I expect that some near-term partnering activity, in conjunction with the work that we’ve done with the seed funding, is going to create a very strong foundation for us before we actively seek the next round of financing.”