Fulcrum to Evaluate Losmapimod as Potential COVID-19 Treatment

Fulcrum Therapeutics has announced plans to evaluate losmapimod as a potential treatment for patients with COVID-19. Fulcrum has submitted an investigational new drug (IND) application to support initiation of a randomized, placebo-controlled, Phase 3 clinical trial in hospitalized patients in the United States following Pre-IND consultation via the Coronavirus Treatment Acceleration Program (CTAP).

“The decision to advance this development program is a reflection of the compelling science that supports losmapimod’s potential in COVID-19,” said Robert J. Gould, Ph.D., Fulcrum’s president and chief executive officer. “Prior clinical trials have shown its ability in other disease states to reduce acutely the inflammatory cytokines, such as C-reactive protein and IL-6 that are associated with poor prognosis. This new planned Phase 3 program adds to our robust development portfolio including potential treatments for facioscapulohumeral dystrophy (FSHD) and sickle cell disease. We are excited to apply our insights and understanding of losmapimod in COVID-19 as a potential differentiated treatment option in the global fight against this virus. I am proud of the work by our team and collaborators to rapidly advance this planned clinical program and look forward to collaborating with regulators and our outstanding team of clinical investigators to move this important effort forward as quickly as possible.”

“An extensive body of data in the literature suggests that inhibiting p38 MAP kinase may be beneficial for patients with COVID-19,” said Owen B. Wallace, Ph.D., Fulcrum’s chief scientific officer. “Poor prognosis for COVID-19 patients has been attributed to an exaggerated inflammatory response following SARS-CoV-2 infection. Losmapimod has been shown in preclinical and clinical studies to reduce proteins associated with acute inflammatory stress. Additionally, p38 inhibition has been reported to reduce pathophysiology associated with an activated renin-angiotensin system and positively impact the innate-adaptive immune system imbalance, both of which have been linked to increased morbidity and mortality in COVID-19. The p38 MAPK pathway has been implicated in other viral infections, and there may be the opportunity to explore losmapimod in additional serious infections.”

Several lines of preclinical and clinical evidence indicate that activation of the p38 mitogen-activated protein kinase (MAPK) significantly contributes to the pathogenesis of coronavirus infections including COVID-19. p38 MAPK is well known as an important mediator of acute response to stress, including acute inflammation.

In two clinical studies reported in the literature, an oral dose of 15 mg twice per day of losmapimod in older individuals restored the normal immune response to a viral antigen challenge and demonstrated resolution of acute inflammation, a relevant observation because the majority of severe and fatal cases of COVID-19 occur in older individuals. Additionally, in prior human clinical trials predominantly in chronic inflammatory conditions, losmapimod had an immediate effect on a number of inflammatory biomarkers that have been associated with poor prognosis in COVID-19, including C-reactive protein (CRP) and interleukin-6 (IL-6). In previous trials in more than 3,600 subjects, losmapimod exhibited favorable safety and tolerability not significantly different from placebo. These trials have also indicated that losmapimod had good exposure after oral dosing and robust target engagement.

The Company believes that losmapimod has the potential to treat COVID-19 by reducing the acute exaggerated pro-inflammatory responses to SARS-CoV-1 infection and restoring the antigen-specific immune responses needed for clearance of SARS-CoV-2, potentially leading to improved clinical outcomes. Additionally, p38 inhibition has been demonstrated to reduce angiotensin II (Ang II)-induced endothelial and organ damage in several experimental models and may address the renin-angiotensin system imbalance that is believed to contribute to key morbidities in COVID-19 patients.

Fulcrum’s clinical program in COVID-19 is not expected to impact the timing or prioritization of other key Company milestones, including the interim analysis of ReDUX4, a randomized, double-blind, placebo-controlled multicenter international Phase 2b clinical trial in 80 subjects with FSHD. The Company remains on track to report data from this interim analysis late in the third quarter of 2020. Additionally, Fulcrum believes that it has sufficient supply of losmapimod for ongoing clinical trials in patients with FSHD, as well as for the planned Phase 3 trial in patients with COVID-19. Fulcrum owns all worldwide development and commercialization rights to losmapimod.

FTX-6058 is an oral small molecule therapeutic discovered by Fulcrum and designed to induce expression of fetal hemoglobin (HbF) in red blood cells to compensate for the mutated adult hemoglobin in sickle cell disease. Fulcrum has completed IND-enabling studies including toxicology work with FTX-6058 and remains on track to initiate a Phase 1 trial by the end of 2020.