Grace Therapeutics, Inc. disclosed that the US FDA issued a Complete Response Letter (CRL) for the company’s New Drug Application (NDA) for GTx-104, an intravenous lipid nanoparticle formulation of nimodipine, under review as a treatment for aneurysmal subarachnoid hemorrhage (aSAH). The CRL represents a delay in GTx-104 FDA approval and requires the company to address outstanding items before the agency will consider approving the application.
The FDA’s CRL cited deficiencies related to chemistry, manufacturing, and controls (CMC) as well as non-clinical information. The agency did not identify efficacy or clinical safety concerns as the basis for the action. Under the CRL process, Grace Therapeutics must resolve the identified CMC and non-clinical deficiencies and submit a formal resubmission to the FDA before the application can be approved.
GTx-104 is a lipid-based nanoparticle formulation of nimodipine, a dihydropyridine L-type voltage-gated calcium channel blocker. Conventional nimodipine is administered orally for the reduction of ischemic deficits following aSAH, a condition in which blood accumulates in the subarachnoid space following rupture of a cerebral aneurysm. Cerebral vasospasm is a leading cause of morbidity and mortality in aSAH patients, and intravenous delivery of nimodipine has historically been limited by the risk of severe systemic hypotension associated with existing IV formulations. GTx-104 was designed to enable IV administration while mitigating that hypotension risk through nanoparticle encapsulation, potentially offering a route of administration more suited to critically ill patients who may not tolerate oral dosing.
The application was supported by the Phase III STRIVE-ON trial (NCT05995405), a prospective, randomized, open-label study comparing GTx-104 with oral nimodipine in 102 hospitalized aSAH patients. The trial’s primary endpoint was the incidence of at least one episode of clinically significant hypotension considered reasonably attributable to study drug, as adjudicated by an independent committee. GTx-104 met this endpoint, with 28% of patients in the GTx-104 arm experiencing at least one such episode versus 35% in the oral nimodipine arm — a 19% relative reduction. Secondary measures also favored GTx-104: 54% of patients receiving the IV formulation achieved a relative dose intensity of 95% or higher, compared with 8% on oral nimodipine. Patients on GTx-104 also showed a 29 percentage point higher rate of favorable functional outcomes at 90 days, along with fewer ICU readmissions, ICU days, and ventilator days. Adverse events were comparable between arms, and no deaths were attributed to either study drug.
Oral nimodipine, marketed as Nymalize and available in generic form, holds FDA approval for aSAH-related vasospasm prevention. No IV nimodipine formulation currently holds FDA approval in the United States, which represents the clinical differentiation GTx-104 was developed to address. The absence of an approved IV option for this indication defines the unmet need that the Grace Therapeutics drug application sought to fulfill.
Grace Therapeutics stated it is working to address the items cited in the CRL and intends to request a Type A meeting with the FDA to discuss the path forward. The company indicated it remains committed to the program, though no revised target action date or resubmission timeline was provided. The CRL’s focus on CMC and non-clinical items, rather than clinical data, may narrow the scope of work required for resubmission, though the complexity of manufacturing deficiencies in nanoparticle formulations can vary.