FA drug boosts frataxin protein, improves heart function in mice
Nomlabofusp benefits mirror those seen in clinical trials, researchers say
The investigational therapy nomlabofusp increased the levels of frataxin, the protein deficient in people with Friedreich’s ataxia (FA), in several tissues of animal models, and improved heart function and survival in an FA mouse model, a study showed.
The findings are consistent with benefits of the Larimar Therapeutics drug reported so far in clinical trials of people with FA, the researchers said.
“The consistency between our non-clinical findings and those of other researchers, as well as with our clinical data, underscores the ability of nomlabofusp to increase FXN [frataxin] levels across species, with dose-dependent effects observed in both animal models and patients with [FA],” they wrote.
The study, “Pharmacokinetics and Pharmacodynamics of Nomlabofusp in Non-clinical Studies of Friedreich’s Ataxia,” was published in the AAPS Journal.
Larimar has announced plans to launch a global Phase 3 clinical trial to confirm nomlabofusp’s benefits and to file a regulatory application next year seeking the therapy’s approval in the U.S.
Lab-made version of frataxin protein aims to ease symptoms
FA is an inherited neurological disorder characterized by reduced levels of the frataxin protein in tissues, correlating with FA symptom onset, severity, and disease progression. Low frataxin affects the function of mitochondria, the cell’s powerhouses, particularly in nerve and muscle cells, leading to a loss of muscle control and coordination.
Given daily through by under-the-skin injections, nomlabofusp (CTI-1601) is a lab-made version of the human frataxin protein that’s designed to better enter cells and boost mitochondrial function. The experimental therapy is expected to ease symptoms in people with FA.
After showing promising effects in adults with FA in a Phase 2 clinical trial (NCT05579691), the therapy is being tested against a placebo in up to 30 children and adolescents, aged 2-17, with FA in a Phase 1 trial (NCT06681766).
Adolescents and adults completing previous Phase 1 or 2 nomlabofusp trials may be eligible to enter an ongoing open-label extension (OLE) study (NCT06447025), where all will receive the therapy for up to two years.
The U.S.-based OLE trial, which started dosing last year, may also include FA patients who have participated in previous nomlabofusp trials.
Recently announced data from the OLE study showed that up to one year of nomlabofusp treatment resulted in sustained increases in skin frataxin levels and trends toward clinical improvement.
As with any experimental therapy, nomlabofusp underwent extensive preclinical testing in animal models before being evaluated in clinical trials with people with FA.
A team led by scientists at Larimar reported on nomlabofusp’s pharmacokinetics (movement into, through, and out of the body) and pharmacodynamics (effects on the body) in preclinical studies.
“The translatability of tissue-specific FXN levels between non-clinical models and humans is critical for evaluating therapeutic interventions,” the researchers wrote.
Results showed that a single 10 mg/kg dose of nomlabofusp, equivalent to the 50 mg human dose currently used in the OLE study, resulted in comparable mean drug levels in the bloodstream between healthy mice and an FA mouse model. Similar pharmacokinetics were observed in healthy rats and macaque monkeys.
Doses tested in animals “led to comparable [blood] exposure observed in [FA patients] who received doses in the intended therapeutic range (25-50 mg) in clinical studies,” the team wrote.
In both healthy and FA mice, a single nomlabofusp dose at 10 or 50 mg/kg resulted in a dose-dependent distribution of the therapy in several organs, including the brain, heart, liver, and skeletal muscle, which are known to be affected in FA. Similar results were observed when healthy rats received multiple nomlabofusp doses.
Treatment in mouse and rat models was also associated with a dose-dependent increase in mature human frataxin in the mitochondria within liver, heart, and skeletal muscle cells.
In heart and skeletal muscle mitochondria of mice with FA-like disease, the therapy restored the activity of succinate dehydrogenase, an enzyme activated by frataxin and involved in mitochondrial function.
Untreated FA mice developed heart problems at 4 weeks of age, which continued to worsen up to 8 weeks. In contrast, nomlabofusp treatment prevented heart function decline, resulting in no significant difference between nomlabofusp-treated FA mice and healthy mice by 8 weeks.
FA mice treated with nomlabofusp lived significantly longer than untreated FA mice (median 166 days vs. 98 days). By the end of the study (after about five months), no untreated mice were alive, while half of those given nomlabofusp remained alive.
“Nomlabofusp exposure results in a dose-dependent distribution of FXN to clinically accessible peripheral tissues as well as [FA-associated] tissues that is subsequently processed within the mitochondria into mature [human frataxin],” the team wrote. “These findings support the potential of nomlabofusp as a novel treatment for adults and children with [FA] that directly addresses FXN deficiency, the root cause of [FA].”
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