We believe SRK-181 has the potential to meaningfully increase the benefit as well as the number of patients who could benefit from immunotherapies by rendering resistant solid tumors vulnerable to immune checkpoint inhibitors such as anti-PD-1/PD-L1 therapies.
SRK-181 (Selective context-independent, anti-latent TGFβ-1)
While anti-PD-(L)1 therapies have revolutionized the treatment of patients with cancer, this therapeutic approach is only effective in a small subset of patients. This has led to a deluge of efforts to evaluate checkpoint inhibitors in combination therapy settings in order to overcome tumor resistance. This race to find the “right” combination therapy has been met with disappointing clinical results and failures as successes in preclinical models fail to translate to successful clinical trials.
True to the Scholar Rock way, we have taken a closer look and a different approach. We have applied knowledge gained from retrospective analyses of human tumors and therapeutic response data to our selection of preclinical models, which we believe, more appropriately reflect human tumor biology.
In preclinical studies, we demonstrated that targeting the precursor, or latent, form of the TGFβ1 growth factor can render tumors vulnerable to anti-PD1 therapy and drive tumor regression through combination therapy. This was demonstrated across multiple mouse models that reflect resistance to anti-PD-1 treatment, including melanoma, urothelial carcinoma, and breast cancer. By specifically targeting the TGFβ1 isoform and sparing the TGFβ2 and TGFβ3 isoforms, which are thought to be involved in functions such as cardiac homeostasis, we have also observed an improved preclinical safety profile compared to non-selective approaches.
We are investigating SRK-181, a selective inhibitor of latent TGFβ1 activation, in the DRAGON Phase 1 clinical trial in patients with locally advanced or metastatic solid tumors.
Immune Checkpoints: A Closer Look
A growing body of clinical and preclinical evidence has implicated TGFβ1 as a key culprit in driving primary resistance to anti-PD-(L)1 therapy. In one example, Genentech published the results of a study identifying an association between increased TGFβ signaling with impaired tumor responses and reduced survival from anti-PD-L1 antibody therapy in patients with metastatic urothelial cancer. We have further explored this topic by analyzing a database of thousands of molecularly characterized tumor samples and identified TGFβ1 as the predominant TGFβ isoform in many human tumors.
However, TGFβ has historically proved to be a challenging drug target. Traditional approaches broadly inhibit the signaling of all three TGFβ isoforms (TGFβ1, TGFβ2, and TGFβ3). The lack of selectivity amongst the different isoforms has resulted in on-target toxicities, most notably cardiovascular side effects. At Scholar Rock, we are developing SRK-181, a monoclonal antibody with high selectivity for specifically the TGFβ1 isoform, which we believe may lead to a more favorable safety profile (and potentially enable a wider therapeutic window) and therefore be better suited to combination therapy.
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