Scholar Rock Announces Publication of Preclinical Pharmacology, Pharmacokinetics, and Safety Profile of SRK-181 in the International Journal of Toxicology
“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
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
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.
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.
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This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the potential of SRK-181, Scholar Rock’s future expectations, plans and prospects, including without limitation, Scholar Rock’s expectations regarding its growth, strategy, progress and timing of its clinical trials, the potential of its proprietary platform, and its intellectual property protection. The use of words such as “may,” “might,” “will,” “should,” “expect,” “plan,” “anticipate,” “believe,” “estimate,” “project,” “intend,” “future,” “potential,” or “continue,” and other similar expressions are intended to identify such forward-looking statements. All such forward-looking statements are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include the possibility that data from the DRAGON clinical trial will be inconsistent with the data observed in preclinical studies, the data generated from Scholar Rock’s nonclinical and preclinical studies and clinical trials, competition from third parties that are developing products for similar uses, Scholar Rock’s ability to obtain, maintain and protect its intellectual property, Scholar Rock’s dependence on third parties for development and manufacture of product candidates including to supply any clinical trials, Scholar Rock’s ability to manage expenses and to obtain additional funding when needed to support its business activities and establish and maintain strategic business alliances and new business initiatives, and the impacts of public health pandemics such as COVID-19 on business operations including its DRAGON clinical trial, as well as those risks more fully discussed in the section entitled "Risk Factors" in Scholar Rock’s Annual Report on Form 10-K for the year ended