Partial clinical hold on nomlabofusp for Friedreich’s ataxia lifted

Larimar Therapeutics is expected to seek approval of the therapy next year

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by Andrea Lobo |

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The U.S. Food and Drug Administration (FDA) has removed the partial hold on the clinical development of nomlabofusp, an experimental treatment for Friedreich’s ataxia (FA).

The decision followed a review of data from a Phase 2 dose exploration trial (NCT05579691), which showed the treatment was well tolerated and increased frataxin, the protein that’s missing in FA, in skin and mouth (buccal) cells of adults. Previously known as CTI-1601, nomlabofusp is being developed by Larimar Therapeutics. A formal application to obtain the FDA’s approval is expected next year.

The agency placed a clinical hold on nomlabofusp’s development program in 2021 due to safety concerns with nonhuman primates. The hold was partially lifted in 2022 to allow clinical testing of the therapy at 25 mg, and of the 50 mg dose last year.

“We are now cleared to dose escalate to the 50 mg dose in our ongoing OLE [open-label extension]  study, which we plan to do following further characterization of frataxin … at the 25 mg dose,” Carole Ben-Maimon, MD, Larimar’s president and CEO, said in a company press release. “The OLE study is evaluating the long-term safety as well as frataxin levels following daily administration of nomlabofusp and we look forward to interim data in the fourth quarter of the year.”

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Nomlabofusp at 25 mg, 50 mg

FA is caused by mutations in the FXN gene that result in low frataxin levels, which impairs the ability of mitochondria, cells’ powerhouses, to produce energy. This primarily affects nerve cells and muscles that have high energy demands and causes a range of symptoms, including loss of muscle control and coordination, called ataxia, and neurological and heart issues.

Nomlabofusp delivers a lab-made version of frataxin to cells using a carrier peptide, that is, a small chain of amino acids, that helps the therapeutic frataxin get into mitochondria. Amino acids are the building blocks of protein.

In the Phase 2 trial, 28 adults with FA were randomly assigned to receive either 25 mg or 50 mg nomlabofusp, or a placebo, by injection under the skin, or subcutaneously, once daily for the first two weeks and every other day for two more weeks.

Skin cell results showed dose-dependent increases in frataxin levels, which increased by 2.81 picograms per microgram (pg/mcg) at the 25 mg dose after two weeks over the before-treatment baseline, and by 5.57 pg/mcg at 50 mg.

Baseline frataxin levels in skin cells were less than 17% of the levels in healthy adults for the patients who received 50 mg, but after two weeks with nomlabofusp, median frataxin levels were more than 33% of those in healthy average levels. Increases were also seen in buccal cells, though with more variability.

The treatment was generally well tolerated at both doses. The most common side effects were mild to moderate reactions at the injection site.

Nomlabofusp’s long-term safety and tolerability, pharmacokinetics, that is, how it moves into, through, and out of the body, and its effects on frataxin levels, are being evaluated in the OLE study in patients who enrolled in the Phase 2 trial or in earlier Phase 1 trials, NCT04176991 or NCT04519567.

The study is first assessing 25 mg daily doses, as administered by patients or their caregivers. After the initial characterization, the company plans to escalate to 50 mg. Further dose escalation would require FDA clearance.

“Helping patients with FA is our top priority and we appreciate the attention and thorough review by the FDA of all submitted data,” Ben-Maimon said.