FDA Clears IND for Novel Molecular Glue in Advanced Solid Tumors

Following the FDA’s acceptance of the IND application, investigators plan to assess the safety, pharmacokinetics, and preliminary efficacy of NST-628 in adult patients with advanced solid tumors harboring RAS-MAPK pathway mutations as part of an open-label, single-arm phase 1 trial (NCT06326411).

The FDA has cleared an investigational new drug (IND) application for NST-628 as a treatment for patients with advanced solid tumors harboring RAS-MAPK pathway genetic alterations, according to a press release from developers Nested Therapeutics.¹

Developers designed NST-628 as a fully brain penetrant non-degrading pan-RAF/MEK molecular glue targeting both RAF and MEK nodes in the RAS-MAPK pathway. Investigators previously reported preclinical data for NST-628 in October 2023 at the 2023 AACR-NCI-EORTC International Conference.²

Preclinical findings highlighted that NST-628 was capable of binding to CRAF-MEK, BRAF-MEK, and ARAF-MEK complexes; the agent induced stabilization of the CRAF-MEK complex, which was believed to contribute to decreased pathway reactivation in tumors driven by specific biomarkers. Additionally, treatment with the novel molecular glue correlated with efficacy and tolerability across various tumor models harboring RAS-MAPK alterations, including those with melanoma, lung cancer, and pancreatic cancer. Based on results from another presentation, dose-dependent NST-628 inhibited the MAPK pathway in murine brain tissue and elicited tumor regressions as part of a daily dosing schedule.

“Taken together, these superior preclinical data suggest that NST-628 could offer a potential first-in-class treatment in the current RAS/MAPK inhibitor space, supporting its advancement into first-in-human clinical trials,” Darrin Miles, chief executive officer at Nested Therapeutics, said in a press release on these findings.²

Following the FDA’s acceptance of the IND application, investigators plan to assess the safety, pharmacokinetics, and preliminary efficacy of NST-628 in adult patients with advanced solid tumors harboring RAS-MAPK pathway mutations as part of an open-label, single-arm phase 1 trial (NCT06326411). The study will consist of 2 parts, including a dose-escalation portion (Part A) and a dose-expansion portion (Part B).

“The significant majority of KRAS-, NRAS-, and BRAF-mutant tumors are not addressable by currently approved therapies, creating a pressing need for new medicines that provide superior, durable efficacy and tolerability for people living with these hard-to-treat cancers,” Philip Komarnitsky, MD, PhD, chief medical officer at Nested, said in the press release on the accepted IND application.¹

“We believe that NST-628 has the potential to provide a differentiated clinical profile, including a superior therapeutic index and prevention of pathway reactivation, for patients with advanced solid tumors harboring RAS-MAPK pathway alterations. The IND clearance for NST-628 is an important step in the advancement of our first clinical-stage program, and with clinical trial sites already activated, we look forward to dosing the first patients in this trial in the first half of this year.”

In Part A of the trial, investigators will determine the safety and recommended dose of NST-628 as a treatment for those with advanced solid tumors.³ In Part B, patients will be evaluated for objective tumor responses.

The trial’s primary end points include adverse effects (AEs) in Part A and Part B, dose-limiting toxicities in Part A, and the objective response rate (ORR) per RECIST v1.1 criteria in Part B. Secondary end points include progression-free survival, overall survival, and pharmacokinetics.

Patients 18 years and older with histologically or cytologically confirmed metastatic or locally advanced solid tumors who cannot derive benefit from standard-of-care therapy are eligible for enrollment on the trial. Additional eligibility requirements include having newly obtained or archived tumor tissue, an ECOG performance status of 0 or 1 or a Karnofsky performance status of at least 70 and an ECOG performance status of 0 or 1 if diagnosed with a glioma, and adequate organ function.

References

1. Nested Therapeutics announces FDA clearance of investigational new drug (IND) application for NST-628, a novel pan-RAF/MEK molecular glue. News release. Nested Therapeutics Inc. March 28, 2024. Accessed March 29, 2024. https://tinyurl.com/3b23wa8v
2. Nested Therapeutics presents first preclinical data for lead candidate, NST-628, a RAS/MAPK pathway inhibitor at 2023 AACR-NCI-EORTC Conference. News release. Nested Therapeutics, Inc. October 12, 2023. Accessed March 29, 2024. https://tinyurl.com/mrem43nm
3. A study to investigate the safety and efficacy of NST-628 oral tablets in subjects with solid tumors (NST-628). ClinicalTrials.gov. Accessed March 29, 2024. https://tinyurl.com/krdxj27n