Nomlabofusp for Friedreich’s ataxia
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What is nomlafobusp for Friedreich’s ataxia?
Nomlafobusp, also known as CTI-1601, is an investigational therapy being developed for people with Friedreich’s ataxia (FA).
The therapy by Larimar Therapeutics is intended to help restore the normal functioning of mitochondria the energy-producing centers in the cell — which may help ease the symptoms of FA.
Therapy snapshot
| Treatment name: | Nomlafobusp (CTI-1601) |
| Administration: | Being tested in FA as subcutaneous injections |
| Clinical testing: | In an open-label extension of a Phase 2 trial |
How does nomlafobusp work in Friedreich’s ataxia?
FA is a rare, degenerative disease caused by a genetic defect that severely reduces the levels of the protein frataxin, which is coded by the FXN gene. Frataxin is key for the functioning of mitochondria and its deficiency affects energy production and increases oxidative stress in cells, which triggers inflammation and nerve cell death. Oxidative stress is a type of cellular damage that results from toxic reactive oxygen species outweighing the antioxidant molecules needed to counteract them.
Lack of frataxin eventually leads to symptoms that include loss of coordination, progressive muscle weakness, and diminishing eyesight.
Nomlafobusp makes use of a carrier peptide (a small chain of amino acids, the building blocks of proteins) to deliver a version of frataxin to cells. The so-called mitochondrial processing peptide then cleaves off the carrier portion in mitochondria so that frataxin is processed to become a functional protein and to help improve the functioning of mitochondria and reduce FA symptoms.
How will nomlafobusp be administered in FA?
In clinical trials with FA patients, nomlafobusp is being injected subcutaneously (under the skin). In a Phase 2 study, it was given daily over 14 days and then every other day for another two weeks. The trial first tested 25 mg of nomlafobusp, before winning clearance to test 50 mg.
An open-label extension (OLE) study is first assessing the effects of daily administration of 25 mg of nomlafobusp over a longer term. A higher (50 mg) dose may be tested pending clearance from the U.S Food and Drug Administration (FDA).
Nomlafobusp in clinical trials
In a Phase 1 clinical trial (NCT04519567), a multiple ascending dose study, 27 adults with FA were randomly assigned to receive multiple subcutaneous injections of nomlafobusp, at 25, 50, or 100 mg, or a placebo for 13 days. The dosing schedule was somewhat different among the groups, with daily injections given in the 100 mg group, and daily injections followed by every third or every other day injections in the other two groups.
The trial’s primary goal was to assess the therapy’s safety and tolerability. Secondary measures included pharmacokinetics — how a drug travels into, through, and out of the body — and changes in frataxin from baseline (start of the trial) in different tissues.
Results showed nomlafobusp was well tolerated. No serious side effects were reported. All treated participants experienced mild to moderate injection site reactions, the most common side effect, versus 43% of those given a placebo. A patient taking 50 mg of nomlafobusp discontinued the study after having mild to moderate nausea and vomiting. All others completed treatment.
The data also showed nomlafobusp was quickly absorbed, with a mean half-life of nearly 11 hours. Half-life means the time required to reduce the amount of a compound by half and indicates how long its potential benefits last.
Dose-dependent increases in frataxin were seen in all evaluated tissues, which included mouth cells, skin, and platelets (tiny blood cells involved in blood clotting).
Larimar sponsored a Phase 2 clinical trial (NCT05579691) comparing CTI-1601 with a placebo in adults with FA. In its first part, 13 participants were given 25 mg of the therapy or the placebo daily for two weeks then every other day for 14 more days.
Top-line results from the first group of patients showed nomlabofusp was well tolerated, with no serious side effects. One patient left the trial due to an allergic reaction to nomlabofusp that resolved with standard treatment. The most common side effects were mild or moderate reactions at the injection site.
As seen in Phase 1 testing, frataxin levels increased in the skin and mouth cells of those who received nomlabofusp after 14 days. No changes were found in those given a placebo.
These findings were supported by the trial’s top-line data. Among its 28 overall participants, frataxin levels showed a dose-dependent increase in skin and buccal cells after treatment with nomlabofusp. In the higher dose (50 mg dose), frataxin in skin cells was 17% of what’s seen in healthy adults at study start, which increased to 33% of healthy average levels after two weeks of treatment.
Again, no serious adverse events were reported. As in the results of the first group, the most common side effects were mild or moderate injection site reactions.
Ongoing trials
An OLE is assessing daily injections of nomlabofusp over a longer term. Eligible participants completed the Phase 2 trial or earlier nomlabofusp studies. The study seeks to assess how safe nomlabofusp is, how it moves into, through and out of the body, and changes in frataxin levels in the body.
Results will be compared to data from external controls taking part in the FA Clinical Outcome Measures Study (NCT03090789). Nomlabofusp will first be given at 25 mg.
Along with data from the completed studies, Larimar plans to use the results from this OLE study to request nomlabofusp’s accelerated approval in the U.S. For that purpose, the company intends to use frataxin levels as a surrogate endpoint, meaning a substitute measure that’s expected to predict that clinical benefit.
The nomlabofusp program has been under a clinical hold since 2021, as the FDA cited safety concerns and requested additional data due to the deaths of nonhuman primates given high doses of nomlabofusp in a six-month toxicology study. The FDA lifted the full clinical hold in 2022 and imposed a partial clinical hold after Larimar submitted detailed analyses from toxicology studies and Phase 1 clinical trials.
According to the hold, dose increases for both the Phase 2 or OLE studies, as well as the start of additional U.S. studies, are contingent on the FDA’s review of data from the Phase 2 trial’s 50 mg group.
Common side effects of nomlafobusp
Little data has been reported regarding the specific side effects of nomlafobusp in clinical trials, with mild or moderate injection site reactions being the most common events according to available trial data.
A single severe side effect event reported in the completed Phase 2 study was a case of allergic reaction that resolved with standard treatment.
Friedreich’s Ataxia News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about Nomlafobusp in Friedreich's ataxia
Nomlafobusp is in the early stages of clinical testing and is currently undergoing an extension study of a completed Phase 2 trial in people with Friedreich’s ataxia.
Nomlafobusp is an experimental therapy that is not yet approved for the treatment of Friedreich’s ataxia. It is designed to deliver a functional version of frataxin — a protein whose shortage causes Friedreich’s ataxia — to help improve the functionality of mitochondria, the so-called “powerhouses” of cells. This is expected to help ease FA symptoms.
Existing information from clinical trials does not mention a possible interaction between alcohol and nomlafobusp. However, clinical testing of nomlafobusp is still in early stages, so more information about treatment interactions and side effects is needed.
Efficacy results of nomlafobusp in clinical trials are still scarce, so more data will be needed to have an indication of how soon patients may see benefits with treatment. Data from Phase 1 (NCT04519567) and Phase 2 (NCT05579691) trials suggest consistent increases in levels of frataxin, the protein whose shortage is a hallmark of Friedreich’s ataxia, about two weeks into therapy, but whether and how that will translate into clinical benefits remains to be determined.
As nomlafobuspis still in Phase 2 clinical testing, information about potential side effects associated with this therapy is still scarce. Available trial data in people with Friedreich’s ataxia indicate that mild to moderate reactions at the injection site were the most common side effects reported to date.
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