Scholar Rock picks SRK-181
CAMBRIDGE, Mass.—Scholar Rock has announced its selection of SRK181, a highly specific inhibitor of TGFβ1 activation, as the first product candidate in its TGFβ1 cancer immunotherapy program, based on the strength of its preclinical data and human translational insights. The company has initiated manufacturing and is progressing preclinical development, with plans to initiate a Phase 1 trial in patients with solid tumors in mid-2020.
“Given that a majority of cancer patients fail to respond to checkpoint blockade therapies, we are eager to advance the next product candidate from our pipeline of growth factor modulators to potentially address a key mechanism of pre-existing resistance,” says Dr. Nagesh Mahanthappa, president and CEO of Scholar Rock. “A growing body of evidence strongly implicates elevated TGFβ1 activity as a cause of immunotherapy failure, and we see tremendous potential for SRK-181 to expand the number of patients who could benefit from checkpoint blockade therapies by potently and selectively inhibiting the activation of TGFβ1.”
SRK-181 is a fully human antibody designed to bind to, and prevent the activation of, latent TGFβ1 with high affinity and high selectivity, with minimal or no binding to latent TGFβ2 and latent TGFβ3 isoforms. Several important factors led to the decision to advance SRK-181 as a clinical development product candidate for the treatment of tumors resistant to checkpoint blockade therapies (CBTs), such as anti-PD1 antibodies, including the fact that TGFβ signaling has been implicated as a culprit in primary resistance to CBTs in multiple peer-reviewed studies.
According to Mahanthappa, “SRK-181’s mechanism of action is rooted in Scholar Rock’s structural biology insights into the activation of the latent or precursor form of growth factors such as TGFβ1. Since the mature or active form of members of the same growth factor superfamily share considerable similarities, it is very challenging to achieve selective inhibition of the targeted growth factor without also targeting other closely related growth factors and thereby risking unintended side effects. However, the precursor forms of TGFβ superfamily members each present a structurally distinct ‘cage’ that holds what will be the mature growth factor in an inactive state. By targeting the structural differences in the precursor form of growth factors, Scholar Rock’s platform is designed to discover and develop monoclonal antibodies that have an unprecedented degree of specificity to achieve selective inhibition of growth factor activation and signaling.”
Translational data analyses by Scholar Rock have highlighted the prominent expression of TGFβ1 in many human tumor types, such as bladder cancer, non-small cell lung cancer and melanoma, for which CBTs have either been approved or demonstrated clinical activity in trials. Clinical correlation and preclinical model data suggest that TGFβ1 excludes effector cell entry into the tumor, limiting immune system access to tumor cells. Preclinical studies in syngeneic mouse tumor models resistant to CBT show that SRK-181-mIgG1 (the murine version of SRK-181), when combined with anti-PD1 antibodies, permitted effector T cell infiltration and expansion into the tumor microenvironment, and led to tumor regression or control as well as significant survival benefit.
“In a number of preclinical models of cancer immunotherapy that are otherwise refractory to CBT, we have observed that co-administration of SRK-181-mIgG1, the mouse version of SRK-181, with an anti-PD1 antibody renders these tumor models sensitive to the combination treatment. We identified mouse syngeneic tumor models that reflect the primary resistance to CBT observed in human cancers and results from these studies were presented at the SITC annual meeting last November,” Mahanthappa notes.
“These models, the MBT-2 bladder cancer model and the Cloudman S91 melanoma model, are poorly responsive or unresponsive to single-agent treatment with either anti-PD1 (a CBT agent) or to SRK-181-mIgG1 alone, with little or no effect on tumor growth. However, the combination of these two agents (anti-PD1 and SRK-181-mIgG1) resulted in either complete responses or tumor control, and led to significant survival benefit. Importantly, a 28-day pilot toxicology study of SRK-181 in adult rats also showed no observed drug-related toxicity up to a weekly dose of 100mg/kg for 4 weeks, with no observed valvulopathy as is commonly observed with TGFβ inhibitors that are not selective to TGFβ1 (i.e. also target TGFβ2 and TGFβ3).”
Detailed preclinical results for SRK-181-mIgG1 (formerly referred to as SRTβ1-Ab3) were presented at the Society for Immunotherapy of Cancer (SITC) 33rd Annual Meeting in November. The poster presented at SITC can be accessed by visiting the Scholar Rock website at http://www.scholarrock.com/platform/publications/. Additional preclinical data for SRK-181-mIgG1 were presented at the 2019 American Association for Cancer Research Annual Meeting in Atlanta.
“While advances in immunotherapy have transformed the treatment of patients with cancer, a majority still fail to respond to CBTs because they have what appears to be a pre-existing, or primary, resistance to immunotherapy,” adds Mahanthappa. “Other patients’ cancers appear to respond initially but subsequently progress. This has led to a deluge of efforts to evaluate these therapies in combination settings in order to overcome tumor resistance.”
“Given the growing body of evidence that implicates TGFβ1 activity as an important cause of immunotherapy failure, we believe that SRK-181 offers a rational path towards expanding the number of patients who could benefit from these cancer immunotherapies by potently and selectively inhibiting the activation of TGFβ1. In addition, we believe that SRK-181 has the potential to address unmet medical needs in other oncology indications, and we will endeavor to maximize the value of this product candidate for patients by exploring its potential in additional oncology indications,” Mahanthappa concludes.