On March 22, 2021 Scholar Rock (NASDAQ: SRRK), a clinical-stage biopharmaceutical company focused on the treatment of serious diseases in which protein growth factors play a fundamental role, reported the publication of preclinical development data for SRK-181 in the peer-reviewed journal International Journal of Toxicology (Press release, Scholar Rock, MAR 22, 2021, View Source [SID1234576973]). SRK-181 is a product candidate that has been shown to be a potent and highly specific inhibitor of latent growth factor-beta 1 (TGFβ1) activation in preclinical studies. SRK-181 is being developed to overcome primary resistance to checkpoint inhibitor therapy and is currently being studied in the two-part DRAGON Phase 1 trial in patients with locally advanced or metastatic solid tumors exhibiting primary resistance to anti-PD-(L)1 therapy.
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"This publication provides a comprehensive preclinical assessment of the pharmacology, pharmacokinetics, and safety of SRK-181, which support its evaluation in the DRAGON Phase 1 trial," said Gregory Carven, Ph.D., Chief Scientific Officer of Scholar Rock. "The initial clinical response and safety data from the DRAGON trial, which we anticipate by end of year, will provide an early look into SRK-181’s safety and tolerability profile and the potential for a specific inhibitor of latent TGFβ1 to overcome the immune exclusion that we believe, for many patients, is responsible for primary resistance to checkpoint inhibitor therapies."
Targeting the TGFβ1 Pathway
Greater understanding of the role of TGFβ signaling in promoting cancer progression has led to heightened interest in the development of therapies that inhibit the TGFβ pathway. However, most of the approaches to date have been non-selective and target at least two of the three TGFβ isoforms, which may limit the therapeutic window and potentially result in a lack of efficacy, an unfavorable safety profile, or a combination of the two. Examples of dose-limiting toxicities observed nonclinically for nonselective anti-TGFβ therapies include cardiovascular abnormalities, skin lesions, epithelial oral hyperplasia, and gingival bleeding.
Scholar Rock’s approach to targeting the TGFβ pathway is fundamentally different. SRK-181 is a highly specific inhibitor of the latent TGFβ1 isoform with minimal or no binding to latent TGFβ2, latent TGFβ3, or any of the active TGFβ growth factors based on in vitro studies. Based on preclinical evaluations of SRK-181’s pharmacologic and safety profiles across multiple animal species, SRK-181 may offer an improved safety profile and a wider therapeutic window than non-selective TGFβ inhibitors.
About the Preclinical Data
The International Journal of Toxicology publication, "Nonclinical Development of SRK-181: An Anti-latent TGFβ1 Monoclonal Antibody for the Treatment of Locally Advanced or Metastatic Solid Tumors," provides a comprehensive preclinical assessment of the pharmacology, pharmacokinetics, and safety of SRK-181. (Welsh et al., Int J. Tox, March 19, 2021). Key findings include:
Selective inhibition of latent TGFβ1 activation by SRK-181 was shown to avoid dose-limiting toxicities associated with pan-TGFβ inhibitors in preclinical pharmacology studies.
In-vitro studies showed that SRK-181 had no effect on human platelet aggregation, activation, or binding and that SRK-181 does not trigger a proinflammatory cytokine response in peripheral blood mononuclear cells (PBMC).
Four-week toxicology study showed that weekly intravenous administration of SRK-181 achieved sustained serum exposure and was well-tolerated in rats and monkeys with no treatment-related adverse findings.
No observed adverse effect level (NOAEL) of 200 mg/kg and 300 mg/kg were achieved in rats and cynomolgus monkeys, respectively.
Preclinical pharmacologic and pharmacokinetics assessments provided support for the dose-selection strategy for the ongoing DRAGON Phase 1 trial in patients with solid tumors.
About SRK-181
SRK-181 is a selective inhibitor of TGFβ1 activation and is an investigational product candidate being developed to overcome primary resistance to checkpoint inhibitor therapy, such as anti-PD-(L)1 antibodies. TGFβ1 is the predominant TGFβ isoform expressed in many human tumors, particularly for those tumors where checkpoint therapies are currently approved. Based on profiling of human tumors that are resistant to anti-PD-(L)1 therapy, data suggests TGFβ1 is a key contributor to excluding immune cell entry into the tumor microenvironment, thereby preventing normal immune function. Scholar Rock believes SRK-181 has the potential to overcome this immune cell exclusion and induce tumor regression when administered in combination with anti-PD-(L)1 therapy. By specifically targeting the latent TGFβ1 isoform, Scholar Rock hypothesizes that SRK-181 can increase the therapeutic window by potentially avoiding toxicities associated with non-selective TGFβ inhibition. A Phase 1 proof-of-concept clinical trial in patients with locally advanced or metastatic solid tumors is ongoing. The effectiveness and safety of SRK-181 have not been established and SRK-181 has not been approved for any use by the FDA or any other regulatory agency.