FDA Maintains Clinical Hold on Larimar’s Friedreich’s Ataxia Study

Larimar Therapeutics, a company focused on developing treatments for complex rare diseases, said that the U.S. Food and Drug Administration is maintaining the clinical hold on Larimar’s CTI-1601 program for the treatment of Friedreich’s ataxia.

Photo: Carole Ben-Maimon, president and CEO of Larimar

Friedreich’s ataxia is caused by a trinucleotide repeat expansion in the first intron of the frataxin gene, which encodes the mitochondrial protein frataxin. Pathogenic repeat expansions can lead to impaired transcription and reduced frataxin expression, which can result in mitochondrial iron overload and poor cellular iron regulation, increased sensitivity to oxidative stress, and impaired mitochondrial ATP production.

Patients with Friedreich’s ataxia experience symptoms in childhood, including progressive loss of coordination, muscle weakness, and fatigue that commonly results in motor incapacitation with patients requiring a wheelchair in their teens or early 20s. Patients with Friedreich’s ataxia may also experience visual impairment, hearing loss, diabetes, and cardiomyopathy. There are currently no approved therapies for the treatment of patients with Friedreich’s ataxia.

The FDA said it needed additional data to resolve the clinical hold. Larimar is further analyzing previously completed studies and is evaluating if additional studies are warranted. The company also intends to engage FDA to determine how best to provide these data. Larimar is reassessing guidance on the timing of the planned Jive open-label extension and pediatric multiple-ascending dose clinical trials as it works to meet the agency’s request.

“Our next step is to engage with the agency to determine how we can meet their request in the most efficient and expeditious manner,” said Carole Ben-Maimon, president and CEO of Larimar. “Based on all available clinical and non-clinical data, we continue to believe there is a path forward through the resolution of the CTI-1601 clinical hold. We have a robust phase 1 dataset, which demonstrates proof-of-concept for CTI-1601 as a frataxin replacement therapy and its differentiated mechanism of action.”

The company believes the mechanism of action leaves CTI-1601 uniquely positioned to address the need for disease modifying therapies in Friedreich’s ataxia, as it is designed to address the root cause of the disease. It said it is committed to CTI-1601’s further development and has a strong cash position that provides runway at least into 2023.

The company intends to operate under a cost reduction plan while resolving the clinical hold to manage burn and extend our cash runway if needed.

CTI-1601 is a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with Friedreich’s ataxia who are unable to produce enough of this essential protein. The CTI-1601 program was placed on a clinical hold in May 2021 by the FDA after Larimar notified the agency of mortalities that occurred at the highest dose levels in a 26-week non-human primate (NHP) toxicology study that was designed to support extended dosing of patients with CTI-1601. At the time of the notice, Larimar had no interventional clinical trials with patients enrolled or enrolling. The recent feedback from the FDA follows Larimar’s submission of a complete response including a comprehensive study report from the 26-week NHP toxicology study.

Data from the phase 1 single- and multiple-ascending dose (MAD) clinical trials indicated that repeated subcutaneous injections of CTI-1601 were generally well tolerated at doses up to 100 mg administered daily for up to 13 days. No serious adverse events, important medical events, or treatment-related severe adverse events were reported in the trial and the number and severity of adverse events did not increase with increasing exposure to CTI-1601. The most common adverse events were mild and moderate injection site reactions. Data from the MAD trial also showed that daily subcutaneous injections of CTI-1601 at doses of 50 mg or 100 mg resulted in frataxin levels in peripheral tissues (buccal cells) that were at or more than those that would be expected in phenotypically normal heterozygous carriers.

CTI-1601 has been granted Rare Pediatric Disease, Fast Track, and Orphan Drug designations by the FDA, Orphan Drug designation by the European Commission, and PRIME designation by the European Medicines Agency.

Author: Rare Daily Staff