Nimbus Therapeutics Reports Positive Phase 1/2 HPK1 Inhibitor Data at SITC 39th Annual Meeting

Nimbus Therapeutics, a biotechnology firm renowned for its innovative computational drug discovery technology, has announced notable clinical and translational findings from its ongoing Phase 1/2 trial of NDI-101150. This novel oral small-molecule inhibitor targets hematopoietic progenitor kinase 1 (HPK1) and is being assessed for advanced solid tumors. The data will be showcased in two poster presentations at the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting in Houston, Texas, from November 6-10, 2024.

The ongoing Phase 1/2 multicenter, open-label trial (NCT05128487) evaluates NDI-101150 both as a standalone treatment (50-200 mg daily) and in combination with pembrolizumab (200 mg every three weeks) in adult patients with advanced solid tumors. The clinical results being presented include updated safety data from 53 patients in the dose escalation cohorts (41 on monotherapy and 12 on combination therapy) and additional data from 35 patients in the dose expansion cohorts. Additionally, updated efficacy data from 17 response-evaluable patients with renal cell carcinoma (RCC) treated with NDI-101150 monotherapy are included. As of August 12, 2024, the findings are as follows:

**Safety Profile**

NDI-101150 was generally well-tolerated with immune-related adverse events aligning with the proposed mechanism of action of HPK1 inhibition, which activates the immune system. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 14% of all patients exposed to NDI-101150 (n=88). The most common TRAEs included nausea, diarrhea, vomiting, and fatigue.

**Efficacy and Target Engagement**

Treatment with NDI-101150 monotherapy led to objective responses in 18% (3/17) of response-evaluable RCC patients, including one complete response (CR) and two partial responses (PRs). A clinical benefit rate (CR + PR + stable disease [SD] ≥6 months) of 29% (5/17) and a disease control rate of 65% (11/17) were observed among response-evaluable RCC patients treated with NDI-101150 monotherapy. NDI-101150 effectively inhibited its target across multiple dose levels, providing robust pharmacodynamic evidence of its activity in patients.

**Supporting Mechanistic Evidence**

Analysis of tumor biopsies showed a more substantial presence of immune cells post-treatment, with increased numbers of tumor-infiltrating lymphocytes and dendritic cells in the tumor microenvironment. Comprehensive gene expression profiling revealed broad activation of immune-related pathways, including enhanced interferon response and T cell activation signals.

Nathalie Franchimont, M.D., Ph.D., Chief Medical Officer of Nimbus, remarked, "These clinical results of NDI-101150 are highly encouraging, particularly in the context of renal cell carcinoma patients who have experienced disease progression on prior checkpoint inhibitors. The objective responses and disease control rates seen thus far with NDI-101150 in heavily pretreated patients, as well as the current safety profile, support further evaluation of NDI-101150 in the clinic."

Jeb Keiper, M.S., MBA, Chief Executive Officer of Nimbus, added, "The clinical and translational data package being presented at SITC demonstrates both the therapeutic potential of NDI-101150 and the power of our computational drug discovery engine to design highly selective molecules against challenging targets like HPK1. The monotherapy activity we observed is particularly noteworthy, as many second-generation immunotherapy compounds have struggled to show clinical benefit on their own. Together with its safety profile and the immune activation signals we've observed, these data support NDI-101150's potential as a novel oral non-checkpoint immunotherapy option for patients who need new treatment approaches beyond current checkpoint inhibitors."

Nimbus Therapeutics is a clinical-stage company specializing in structure-based drug discovery, developing novel small molecule medicines targeting difficult-to-drug proteins implicated in various human diseases. The company advances research by integrating cutting-edge computational technologies with machine learning-based predictive modeling. Nimbus' pipeline includes a clinical-stage HPK1 inhibitor for cancer treatment, alongside preclinical programs focused on WRN for MSI-H cancers, autoimmune conditions, and metabolic diseases. The company is headquartered in Boston, Massachusetts.