On March 26, 2020 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 in the peer-reviewed journal Science Translational Medicine of preclinical data 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 (Press release, Scholar Rock, MAR 26, 2020, View Source [SID1234555882]).
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"With this publication, we are sharing the strong body of preclinical evidence we have built supporting the clinically-derived rationale for evaluating TGFβ1’s key role in primary resistance to checkpoint inhibitor therapy and the potential of a highly specific inhibitor of TGFβ1 activation to overcome this challenge. In the second half of this year, we may gain early insights from our Phase 1 proof-of-concept trial in patients with solid tumors on SRK-181’s potential to overcome the immune exclusion that we believe leads to primary resistance to anti-PD-(L)1 therapy," said Alan Buckler, Ph.D., Chief Scientific Officer of Scholar Rock. "Moreover, these published data provide further validation of Scholar Rock’s proprietary platform to develop antibodies that locally and selectively target the precursor form of growth factors with the aim of avoiding the dose-limiting toxicities that have hindered traditional approaches to targeting growth factors."
The introduction of immunotherapy, including checkpoint inhibitor therapy, has revolutionized the treatment of a wide variety of cancers, delivering profound and durable responses for many patients. Unfortunately, this therapeutic approach is only effective in a small subset of patients; even at the outset of treatment, some tumors show primary resistance to anti-PD-(L)1. Human tumor profiling and several preclinical studies have implicated TGFβ signaling activity as a potential point of intervention to overcome primary resistance to checkpoint inhibition. However, the development of therapies targeting TGFβ signaling has been hindered by dose-limiting cardiotoxicities, potentially due to non-selective inhibition of multiple TGFβ isoforms.
As detailed in the Science Translational Medicine publication "Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape," SRK-181 inhibits TGFβ1 activation with high selectivity and has demonstrated in preclinical studies the potential to overcome primary resistance and meaningfully expand the number of patients who could benefit from checkpoint inhibitor therapy. (Martin et al., Sci. Transl. Med. 12: 25 March 2020)
Based on RNAseq data from the Cancer Genome Atlas (TCGA), TGFβ1 is the most prevalent isoform expressed in the majority of human cancer types, with the exception of breast cancer, mesothelioma, and prostate cancer, where TGFβ3 is also expressed. This finding was also observed in examination of individual samples.
TGFβ1 is likely expressed by multiple cell types within the tumor microenvironment and each cell type produces TGFβ1 in different large latent complexes (LLCs). This is supported by TCGA data, which indicates essentially all tumor types express mRNA encoding all four LLC-presenting molecules, namely LTBP1, LTBP3, GARP, and LRRC33. By targeting the precursor form of TGFβ1, SRK-181 achieves exquisite isoform specificity, inhibiting latent TGFβ1 activation in all known molecular contexts without binding to latent TGFβ2, latent TGFβ3, or any of the three active TGFβ growth factors.
Scholar Rock identified three syngeneic mouse tumor models that recapitulate key features of human primary resistance to checkpoint inhibitor therapy: MBT-2 (bladder cancer), Cloudman S91 (melanoma) and the EMT-6 (breast cancer) mouse models. Combination treatment with SRK-181-mIgG1 and an anti-PD-1 therapy resulted in tumor regression or control and survival benefit across these three identified cancer models. This tumor response was also shown to be durable, where mice with no measurable tumor at treatment cessation remained tumor free.
MBT-2 bladder
cancer model
(Response**: %, N)
Cloudman S91
melanoma model
(Response***: %, N)
EMT-6 breast
cancer model
(Response*: %, N)
Control
0% (0/12)
0% (0/11)
0% (0/9)
Anti-PD1 monotherapy
0% (0/13)
25% (3/12)
0% (0/9)
SRK-181-mIgG1 monotherapy
0% (0/12)
0% (0/12)
0% (0/10)
Anti-PD-1/SRK-181-mIgG1, 3 mg/kg
29% (4/14)
75% (9/12)
NT
Anti-PD-1/SRK-181-mIgG1, 10 mg/kg
57% (8/14)
44% (4/9)
50% (5/10)
Anti-PD-1/SRK-181-mIgG1, 30 mg/kg
NT
73% (8/11)
NT
* For EMT-6: Response is defined as animals that achieved a tumor volume at study end of less than 25% of the 2,000mm3 survival threshold.
** For MBT-2: Response is defined as animals that achieved a tumor volume at study end of less than 25% of the 1,200mm3 survival threshold.
*** For Cloudman S91: Response is defined as animals that achieved a tumor volume at study end of less than 25% of the 2,000mm3 survival threshold.
NT: Not tested
The tumor regression and control demonstrated in the EMT-6 breast cancer model, which expresses both TGFβ1 and TGFβ3, suggest TGFβ1 is the key isoform contributing to checkpoint resistance and highlights the possibility that selective TGFβ1 inhibition may have therapeutic potential in overcoming primary resistance across a broad spectrum of cancers, irrespective of the expression of other TGFβ isoforms.
Dose-limiting cardiotoxicities have challenged the therapeutic development of TGFβ pathway inhibitors. Selective inhibition of latent TGFβ1 activation with SRK-181 has demonstrated an improved safety profile as compared to pan-TGFβ inhibitors. In a 4-week repeat-dose rat toxicology study, the no-observed-adverse-effect-level (NOAEL) was the highest dose tested of 100 mg/kg once weekly, which is well above the doses necessary to elicit robust anti-tumor responses when combined with anti-PD-1 antibody.
Following combination treatment with SRK-181-mIgG1 and anti-PD-1, there were significant increases in intratumoral effector T cells and decreases in immunosuppressive myeloid cells, suggesting TGFβ1’s multiple contributions to primary resistance to checkpoint inhibition.
Overall percentage of the CD45+ immune compartment did not change.
Ten-fold increase in CD8 T cell representation (average of 34% vs. control average of 3.5%). Single-agent treatment with anti-PD-1 or SRK-181-mIgG1 only resulted in modest increases that did not reach significance in the study.
Significant reduction in immunosuppressive M2-like macrophages (14% vs. control average of 47%) and myeloid-derived suppressor cells (MDSC; 1.4% vs. control average of 10.9%).
About SRK-181
SRK-181 is a potent and highly 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 analyses of human tumors that are resistant to anti-PD-(L)1 therapy, TGFβ1 is implicated as a key contributor to exclude immune cell entry into the tumor microenvironment, thereby preventing normal immune function. By overcoming this immune cell exclusion, Scholar Rock believes SRK-181 has the potential to induce tumor regression when administered in combination with anti-PD-(L)1 therapy. 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.