Therapy Areas: Respiratory
Scholar Rock Presents Data from Part A of the DRAGON Phase 1 Trial Evaluating SRK-181 as Monotherapy and in Combination with Anti-PD-(L)1 for the Treatment of Solid Tumors
12 November 2021 - - US-based clinical-stage biopharmaceutical company Scholar Rock (NASDAQ: SRRK) has presented initial clinical data from Part A of its DRAGON Phase 1 proof-of-concept trial (NCT04291079) at the ongoing 36th Society for Immunotherapy of Cancer annual meeting (November 10-14, 2021), which supported dose selection and advancement into Part B, the company said.

The DRAGON trial is investigating SRK-181, a selective inhibitor of TGFβ1 activation, in patients with locally advanced or metastatic solid tumors that have shown primary resistance to checkpoint inhibitor therapies.

The main objectives of DRAGON Part A are to evaluate the safety and tolerability of SRK-181 alone (Part A1) or in combination with anti-PD-(L)1 checkpoint inhibitor therapy (Part A2) and to determine the recommended dose for the Part B dose expansion phase.

Part A1 enrolled patients who have experienced treatment failure from available standard of care therapy, and Part A2 enrolled patients who did not respond to prior anti-PD-(L)1 therapy.

Based on the safety and pharmacokinetic data from Part A, Scholar Rock has initiated Part B, which is evaluating SRK-181 dosed 1500 mg every three weeks in patients receiving an approved anti-PD-(L)1 therapy dosed Q3W and 1000 mg every two weeks in patients receiving an approved anti-PD-(L)1 therapy dosed Q2W.

As of September 7, 2021, 29 patients have been dosed in Part A of the trial. The median number of prior lines of therapy was 4 (range 1, 9) for Part A1 and 4 (range 2, 6) for Part A2.

As of October 12, 2021, no dose-limiting toxicities were observed with SRK-181 in Part A. Doses up to 3000 mg Q3W and 2000 mg Q2W as a monotherapy in Part A1 and 1600 mg Q3W in combination with anti-PD-(L)1 therapy in Part A2 have been evaluated.

The most common treatment-emergent adverse events of any grade related to treatment were fatigue, decreased appetite, and nausea (Part A1) and rash maculo-papular (Part A2).

Preliminary data showed a pharmacokinetic profile of SRK-181 consistent with that which is generally observed for monoclonal antibodies.

The efficacy and safety of SRK-181 are being evaluated in DRAGON Part B. With early data anticipated to be available in 2022, Part B will enroll and dose patients in multiple proof of concept cohorts conducted in parallel, including urothelial carcinoma, cutaneous melanoma, non-small cell lung cancer (NSCLC), as well as a miscellaneous cohort of other solid tumors.

Another cohort focusing on patients with clear cell renal cell carcinoma (ccRCC) is being added based on emerging insights, including preliminary data from Part A.

Each cohort will enroll up to 40 patients with locally advanced or metastatic solid tumors who have demonstrated primary resistance to anti-PD-(L)1 therapy.

The ccRCC cohort will also explore the effects of SRK-181 in patients with relapsed response after anti-PD-(L)1 treatment.

Patients in the UC, MEL, NSCLC and ccRCC cohorts will be treated with SRK-181 in combination with pembrolizumab, and patients in the miscellaneous solid tumor cohort will be treated with SRK-181 in combination with any approved anti-PD-(L)1 therapy.

The selection of the Part B dose was based upon safety and PK results from Part A. Patients receiving an approved anti-PD-(L)1 therapy dosed Q3W will be dosed with SRK-181 dosed 1500 mg Q3W, while patients receiving an approved anti-PD-(L)1 therapy dosed Q2W will be dosed with SRK-181 dosed 1000 mg Q2W.

Drug exposures from these regimens are anticipated to exceed the levels hypothesized as needed for anti-tumor effects, as predicted from PK modeling and preclinical tumor model data.

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 tumor types. Based on analyses of various human tumors that are resistant to anti-PD-(L)1 therapy, data suggest TGFβ1 is a key contributor to the immunosuppressive tumor microenvironment, excluding and preventing entry of cytotoxic T cells into the tumor, thereby inhibiting anti-tumor immunity (1).

Scholar Rock believes SRK-181, which specifically targets the latent TGFβ1 isoform, has the potential to overcome this immune cell exclusion and induce tumor regression when administered in combination with anti-PD-(L)1 therapy while potentially avoiding toxicities associated with non-selective TGFβ inhibition.

The DRAGON Phase 1 proof-of-concept clinical trial (NCT04291079) in patients with locally advanced or metastatic solid tumors is ongoing.

The efficacy and safety of SRK-181 have not been established. SRK-181 has not been approved for any use by the FDA nor any other regulatory agency.
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