President and CEO Tony Kingsley and CMO Yung Chyung, MD, tout the advantages of taking complementary therapeutic approaches in existing markets.

Scholar Rock drew headlines recently with positive 12-month data on a spinal muscular atrophy (SMA) candidate called apitegromab, the company’s selective inhibitor of myostatin activation. Those results supported six-month data released last October. The Boston-based company is now well positioned for a Phase III trial of this, its most advanced candidate, which is expected to be complementary to the products that already make up the approximately $2 billion market for SMA treatments.

The firm also has a TGF-β inhibitor that could help unlock at least part of the 80% of the $25-billion immunotherapy market, which comprises patients who don’t respond to these potentially life-saving drugs. These two leading programs are part of a broader view at Scholar Rock.

Scholar Rock CMO Yung Chyung, MD

“There are a lot of high-impact drug targets out there that are just waiting to be cracked,” said Yung Chyung, MD, the firm’s CMO. Notably, both of the company’s initial programs are additive, or complimentary, to existing regimens, not competitive.

Within the wide range of targets it aspires to address, Scholar Rock is currently pinning its hopes on these two growth factor-targeting therapies and betting on their novel approach—targeting latent forms to improve selectivity.


Scholar Rock was founded in 2012 by Leonard I. Zon, MD, and Timothy A. Springer, PhD—two distinguished researchers at Harvard Medical School. Zon is known for his pioneering research in stem cell biology, hematology, and cancer genetics. He is currently director of the Harvard Stem Cell Institute and his current research interests include identifying genes that direct stem cells to become cancers or more specialized blood or organ cells. The Zon lab is also developing chemical or genetic suppressors to cure cancers and other diseases.

Springer’s lab at Boston Children’s Hospital played a key role in discovering and characterizing adhesion receptors in the immune system, among many other things. He is also an active biotech entrepreneur whose investments have included Moderna. It was his research solving a high-resolution X-ray crystal structure of the precursor form of TGF-β1 that inspired Scholar Rock’s proprietary platform.

Tony Kingsley became CEO of Scholar Rock after the company’s founding CEO, Nagesh Manhanthappa, PhD, stepped down in 2020 after eight years at the helm. Kingsley was most recently the president and CEO of Taris Bio, which was acquired by Janssen Pharmaceuticals in late 2019.

The company netted its $75 million IPO at its midpoint asking price of $14 in 2018. Since then, the stock price has more than doubled, peaking above $68/share in mid-March before falling back. As of December 2020, the company had cash and other assets of approximately $341 million.

Complementary approaches

By focusing initially on SMA, Scholar Rock is entering a crowded marketplace. There are already several marketed products for this rare, fatal genetic disorder. Scholar Rock’s selective inhibitor of latent myostatin involves a different mechanism of action from current treatments.

Scholar Rock is planning a Phase III study of apitegromab that is set to start by the end of 2021. The company is also working to expand the drug’s use, and has plans to launch a proof-of-concept study in Becker muscular dystrophy (a milder form of Duchenne muscular dystrophy) next year.

The company’s second product is SRK-181, a fully human antibody that selectively binds to latent TGF-β1 and inhibits its activation. SRK-181 is being tested in the company’s DRAGON Phase I proof-of-concept trial in patients with locally advanced and metastatic solid tumors exhibiting primary resistance to anti-PD-(L)1 therapy. Company researchers published a recent paper in International Journal of Toxicology summarizing follow-up preclinical studies that support the drug’s safety profile and its favorable properties for “durable and sustained exposures.”

Preclinical programs include studies of TGF-β signaling to suppress pro-fibrotic signaling in multiple organs and targeting RGMc—a co-receptor of BMP6—to treat diseases associated with iron metabolism dysregulation. But Scholar Rock has plenty more targets to choose from: there are more than 30 protein growth factors in the TGF-β superfamily alone.

GEN Edge spoke to Chyung and Kingsley to get more insights into the company’s recent progress.

GEN Edge: Why did you pick growth factors as your first targets?

Scholar Rock president and CEO Tony Kingsley

Kingsley: Our focus on growth factors in the TGF-β superfamily is based on work by Springer’s lab at Boston’s Children’s Hospital, establishing that TGF-β is initially produced as a latent, or inactive form. [As noted earlier, Springer’s lab solved a high-resolution crystal structure of the precursor form of TGFβ1]. Selectivity is a particular problem with growth factors given the similarity between the structures of mature forms. The biology of many of these factors is well understood—sometimes it has been for decades. But because people couldn’t hit the targets selectively, there were all kinds of off-target effects. Thanks to our understanding and expertise in targeting the latent (precursor) forms, and validated biology, we can achieve selectivity where others have not in the past.

Chyung: Growth factors control much biology in the body and have an impact on a wide range of diseases. As a result, they are quite promising as drug targets. But the challenge is they are structurally quite similar, so it is very difficult to hit one target without hitting others. This fact causes unwanted toxicities and limits the ability to reach optimal dosing. Because, while you are aiming at one target, you may inadvertently hit another target with quite different biological effects.

GEN Edge: How does this give you an advantage?

Chyung: An important nuance here is about how some of these growth factors are produced in tissues. The ones we have been pursuing are made and secreted in an inactive latent state, which is structurally different. These precursor forms are then processed by enzymes and sometimes mechanical forces to turn them into the active mature forms, which go on to drive cellular signaling.

At Scholar Rock, we don’t go after the mature forms, like most companies do; instead we go after the latent forms, which are structurally more distinct. We then create antibodies that bind the latent forms, keeping them locked up and preventing their activation.

Beyond these growth factors, we think we can discover new molecules that provide a greater therapeutic window, in terms of dosing. There is a lot more to it than just finding the targets. The overall platform involves intellectual property, assay development, antibody discovery, protein expression, biological and translation expertise, as well as clinical development. Part of the hard work over the last eight years has been developing the assays to get exquisite selectively.

GEN Edge: How is your pipeline progressing?

Kingsley:  We have already applied apitegromab in a Phase II setting for SMA. These are patients with neuromuscular signaling problems. There are SMA correctors, such as [Biogen’s] Spinraza, but while those therapies correct the underlying problem, they still leave the patient with motor deficits. Our therapy is complementary. It works directly on muscle, so patients who have had some repair to neuronal signaling can also build muscle and add functionality. We now have human proof-of-concept with results from our Phase II trial that we are very excited about.

Our second candidate target is TGF-β. There is pretty hot science around this molecule. One reason is, checkpoint inhibitors are incredible but 80% of the patients who receive checkpoint inhibitors don’t respond. There is evidence, not just from us but from Genentech and other groups, that implicates TGF-β as a growth factor expressed in resistant tumors. There are three isoforms of TGF-β—types 1, 2, and 3. We think type 1 is the culprit, from a clinical efficacy standpoint related to resistance. But groups have seen significant toxicity if they target TGF-β, particularly types 2 or 3.

We have a molecule [SRK-181] that just hits the precursor of type 1. The application here is to address resistance to checkpoint inhibitors, which are already a $25-billion market. To be able to address more of that population, to help them respond, would be very exciting to the patients.

Both of these lead programs are complementary approaches playing into existing markets. We have more people rooting for our success than direct competitors.

GEN Edge: Where do you go from here?

Kingsley: The TGF-superfamily comprises more than 30 growth factors. Not all of them are equally interesting. We think we are onto some really interesting ones with this myostatin and TGF-β approach. Each of those has potential for expansion.

We have seen clinical proof-of-concept for apitegromab that suggests there may be other neuromuscular diseases that are tractable with our approach. We are also testing our oncology asset in patients who have demonstrated what is called “primary resistance to checkpoint inhibitors”—they took a checkpoint inhibitor and didn’t respond. That trial will see what happens if you re-dose them with SR-181 plus a checkpoint inhibitor. That could be the first step of unlocking resistance to checkpoint inhibitors.

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