Nomlabofusp may increase frataxin protein levels in FA: Analysis
Therapy predicted to boost frataxin to levels seen in carriers without disease
In adults with Friedreich’s ataxia (FA), treatment with nomlabofusp may increase levels of frataxin protein to at least half of what’s typically seen in people who don’t have the disease, according to new analysis of clinical trial data.
The analysis also predicted that use of the experimental therapy could boost frataxin protein among FA patients to levels seen in carriers — people with only one mutated gene, not two, who don’t develop symptoms but can pass the disease to their biological children.
Larimar Therapeutics, which is developing nomlabofusp, said treatment with the therapy candidate was found to modify gene activity in a clinical trial, “in addition to increasing frataxin … levels in study participants with Friedreich’s ataxia.”
The company presented its new data last week at the International Congress for Ataxia Research in London.
“As we move ahead with the development of nomlabofusp, it is important to consider the totality of the data observed to date. Nomlabofusp has shown dose-dependent increases in tissue [frataxin] levels as well as changes in gene expression [activity] and lipid [fat molecule] profiles,” Carole Ben-Maimon, MD, president, and CEO of Larimar, said in a company press release.
Larimar expanding nomlabofusp studies to include children with FA
Friedreich’s ataxia is caused by mutations in the FXN gene, which provides instructions to make the frataxin protein. That protein is critical for the activity of mitochondria — the so-called powerhouses of cells.
All people inherit two copies of the FXN gene, one from each biological parent; FA only develops if both copies are mutated. As a result, FA patients have reduced frataxin levels, leading to cellular dysfunction that ultimately drives disease symptoms.
Nomlabofusp, previously called CTI-1601, contains a lab-made version of the frataxin protein that’s designed to get into patients’ cells, boosting mitochondrial function to ease FA symptoms.
It’s been tested in two Phase 1 clinical trials — NCT04176991 and NCT04519567 — and in a Phase 2 dose exploration study (NCT05579691). An open-label extension study (NCT06447025) exploring nomlabofusp’s long-term safety and efficacy in adults is ongoing, and Larimar is planning another study to test the therapy in children and adolescents.
“Our studies have included a broad population of adults with FA and will be expanding study participants to include children and adolescents with the initiation of our pediatric pharmacokinetic (PK) run-in trial later this year,” Ben-Maimon said. PK refers to the movement of a medicine into, through and out of the body.
“With the ongoing open label extension study, we are collecting long-term safety, PK and [frataxin] data with the intent of supporting a potential accelerated approval using [frataxin] as a novel surrogate endpoint,” Ben-Maimon added.
If all goes well, Ben-Maimon said Larimar hopes to ask the U.S. Food and Drug Administration (FDA) to authorize the use of nomlabofusp for FA before the end of 2025. The company would seek accelerated approval, which is a pathway that the FDA can use to grant conditional approval to therapies that show early clinical evidence of likely being effective.
Therapy may boost frataxin levels to range typically seen in carriers
Larimar presented the findings from its analysis — which was based on levels of frataxin protein measured in adult patients’ skin cells after short-term studies of nomlabofusp — at the U.K. conference.
“As our nomlabofusp program advances towards potential registration, we are continuing to evaluate the characteristics and activity of nomlabofusp,” Ben-Maimon said.
Using modeling and simulation based on the data collected from our completed clinical studies, long-term daily administration of 50 mg nomlabofusp was predicted to achieve tissue [frataxin] levels in most patients similar to the average [frataxin] levels observed in asymptomatic [disease] carriers.
The results showed that, at a daily dose of 50 mg, nomlabofusp treatment is predicted to increase frataxin levels to within the range typically seen in people who have one mutated copy of the FXN gene and one healthy copy. These individuals are known as heterozygous carriers because they will not develop any disease symptoms but may pass the mutated gene to their biological children.
“Using modeling and simulation based on the data collected from our completed clinical studies, long-term daily administration of 50 mg nomlabofusp was predicted to achieve tissue [frataxin] levels in most patients similar to the average [frataxin] levels observed in asymptomatic heterozygous carriers,” Ben-Maimon said.
The deficiency of frataxin protein in FA leads to changes in cellular gene activity as well as abnormalities in levels of lipids, or fatty proteins, in the blood. An analysis of patients’ blood and buccal cells — those cells collected from inside the mouth — showed post-treatment values trending toward those observed in healthy volunteers. That suggests that nomlabofusp treatment affects cell signaling pathways involved in metabolism.
According to Rusty Clayton, Larimar’s chief medical officer, “the activity of nomlabofusp in participants from our Phase 2 study was encouraging.”
“It showed a trend towards normalization of dysregulated gene expression and lipid profiles identified by comparing profiles between patients with FA and healthy volunteers. We expect to build on these initial data with additional analyses of an expanded data set as we continue to advance our nomlabofusp development program,” Clayton added.
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