SRK-181 for Immuno-Oncology

Scholar Rock has selected SRK-181, a potent and selective inhibitor of the activation of latent TGFβ1, as the first product candidate in its cancer immunotherapy program based on the strength of its preclinical data and human translational insights. We believe SRK-181 has the potential to overcome primary resistance to anti-PD-(L)1 therapies and expand anti-tumor responses to immunotherapy.

In the first quarter of 2020, Scholar Rock initiated the DRAGON Phase 1 dose escalation and dose expansion clinical trial evaluating SRK-181 in patients with locally advanced or metastatic solid tumors. The two-part DRAGON trial consists of a dose escalation portion (Part A) for SRK-181 as both a single-agent and in combination with an approved anti-PD-(L)1 therapy, followed by a dose expansion portion (Part B) evaluating SRK-181 in combination with an approved anti-PD-(L)1 therapy in patients with solid tumors exhibiting primary resistance to that anti-PD-(L)1 therapy. Part B will encompass multiple cohorts that are expected to include urothelial carcinoma, cutaneous melanoma, non-small cell lung cancer, and other solid tumors. Patients will be administered SRK-181 IV every 3 weeks (Q3W), and additional dosing regimens may be explored in the future.

Key objectives of the trial include evaluating the efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of SRK-181 in adult patients with locally advanced or metastatic solid tumors enrolled across multiple sites in the U.S.  An update on dose escalation of SRK-181 as a single agent as well as in combination with anti-PD-(L)1 therapy is expected in the fourth quarter of 2020, subject to the pace of enrollment as impacted by the COVID-19 pandemic. Clinical response and safety data are anticipated in 2021. Timing of data read-outs may be further impacted by the COVID-19 pandemic.

Selective Inhibition of TGFβ1 Could Be Key in Unlocking Immune Exclusion

Despite the clinical breakthroughs achieved by cancer immunotherapy, there remains significant unmet need with a majority of patients failing to respond to checkpoint inhibition. Immune checkpoints are cellular mechanisms that act as a brake on the immune system, and tumors express these proteins in the tumor microenvironment to create an immunosuppressive environment to evade the host’s immune system. Immune checkpoint proteins, such as PD-1 and PD-L1, have therefore become key therapeutic targets in the tumor microenvironment. By inhibiting these proteins, the brakes on the immune system are released, allowing the T cells to kill the cancer cells. There are currently multiple approved immunotherapies that target the PD-1/PD-L1 pathway. However, a significant proportion of patients fail to respond to checkpoint inhibition therapy because their cancers have pre-existing resistance to immunotherapy. Or in some cases, patients’ tumors initially respond to checkpoint blockade but subsequently acquire resistance.

Multiple peer-reviewed studies have implicated TGFβ signaling as a key driver in primary resistance to checkpoint blockade. Our analysis of publicly available human tumor data has identified TGFβ1 as the predominant TGFβ isoform in many human tumors, particularly for those cancers, such as bladder, lung and melanoma, where checkpoint therapies are already approved. Preclinical and translational data suggest that TGFβ1 works to exclude effector cell proliferation and entry into the tumor, thereby preventing the immune system from exerting anti-tumor activity. By specifically inhibiting the activation of latent TGFβ1, our antibodies may allow effector cell entry and access to their target, after which the brakes on the immune system can be released and potentially lead to tumor regression.

Conventional TGFβ antagonists do not discriminate among the three isoforms of TGFβ. We have hypothesized that this lack of isoform selectivity may at least in part underlie the toxicities observed in both preclinical and human studies. To achieve improved safety (and a therapeutic window enabling higher levels of dosing), our antibodies are designed and aimed at selectively targeting the latent TGFβ1 complex, without meaningfully affecting the other isoforms.

We have published our preclinical data in the peer-reviewed journal Science Translational Medicine that established the therapeutic rationale for evaluating a potent and highly selective inhibitor of transforming growth factor-beta 1 (TGFβ1) activation to overcome primary resistance to checkpoint inhibitor therapy. In addition, Scholar Rock presented these preclinical data at the Society for Immunotherapy of Cancer’s (SITC) 33rd Annual Meeting in November 2018 and at the American Association for Cancer Research (AACR) Annual Meeting in April 2019 demonstrating the ability of SRK-181-mIgG1 (the murine version of SRK-181) to render tumors vulnerable to anti-PD1 therapy across multiple syngeneic mouse models of primary resistance to checkpoint blockade therapy (CBT).

Science Translational Medicine publication:  Selective inhibition of TGFB1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape.

SITC poster titled: “Defeating checkpoint resistance: Highly specific inhibition of latent TGFβ1 activation renders resistant solid tumors vulnerable to PD-1 blockade” (Poster #550)

AACR poster titled: “Defeating primary checkpoint resistance: SRK-181 is a first-in-class, fully human antibody that renders resistant tumors sensitive to anti-PD-1” (Poster #4090)

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