Nomlabofusp (CTI-1601)

Dr. Mark Payne, physician and researcher at Indiana University, first described the possibility of frataxin replacement therapy via TAT-Frataxin and has been developing this as a treatment for FA. A recombinant fusion frataxin protein with a Mitochondrial Targeting Sequence (MTS) is partnered with a cell-penetrating delivery system (a protein fragment called a Trans-Activator of Transcription or TAT) to get the frataxin protein into the cell and to the mitochondria. Dr. Payne has tested TAT-frataxin in FA mice and demonstrated proof of principle and compelling results. (See publication below).

Dr. Payne demonstrated that TAT-frataxin increases the life span and weight of FA mice and improves their cardiac function. Dr. Payne formed a company, Chondrial Therapeutics, to further develop this approach and generate preclinical data. Chondrial is now Larimar Therapeutics.

January 13, 2016: Chondrial Therapeutics announces that the company’s lead drug candidate for the treatment of Friedreich’s Ataxia (FA), TAT-Frataxin (TAT-FXN) has been accepted for further development by Therapeutics for Rare and Neglected Diseases (TRND) program researchers at the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health. This support from the TRND program provides Chondrial with access to additional expertise and resources to complete IND-enabling studies and advance the program to Phase 1 human studies.

2025: Larimar published data demonstrating that frataxin delivered by nomlabofusp is detected in the mitochondria in cells in culture. Mature frataxin, which is thought to be an active form of the protein, was found in the cells. In addition, buccal swap samples from people in the Phase 1 clinical trial who received nomlabofusp, showed increases in mature frataxin levels along with changes in gene expression post-administration suggesting the drug was active in cells following dosing. Together, these results demonstrate that nomlabofusp enters the cell and localizes to the mitochondria. In a second publication, Larimar reported data on mouse studies aimed at understanding where the drug distributes in the body. The data suggest that following subcutaneous administration in mice, nomlabofusp distributes in a dose-dependent way to several organs including the dorsal root ganglion, heart, and skeletal muscle. Plasma nomlabofusp concentrations correlated with levels of human frataxin delivered by nomlabofusp into mouse tissues, and the increases in frataxin were correlated amongst tissues, especially with skin. Data from rats and monkeys were also included in the paper. These data are important because they support the use of skin frataxin levels following dosing with nomlabofusp as a way to understand the distribution of the drug in other parts of the body.

February 2017: Chondrial Therapeutics announced that it secured up to $22.6 million in Series A financing with plans to file an IND application for CTI-1601 (TAT-FXN) with FDA in order to initiate Phase 1 clinical trials of the compound. Chondrial Therapeutics also received Orphan Drug Designation for CTI-1601.

In November 2019, Chondrial Therapeutics began a first-in-human study of CTI-1601 (previously known as TAT-frataxin, now formally named nomlabofusp), a Phase I single ascending dose (SAD) study. As a phase I study, the primary goals were to evaluate safety and dose. The study enrolled cohorts of 6–8 participants who received single subcutaneous doses of nomlabofusp or placebo. The SAD was followed by a multiple dose study (MAD), and participants from both studies were eligible to participate in an open-label extension study.

In May 2021, Larimar shared top-line data from the Phase 1 placebo controlled single and multiple ascending dose (SAD and MAD) studies. Nomlabofusp was generally well tolerated at doses up to 100mg administered daily for 13 days. In the 50mg and 100mg dose groups, treatment resulted in more than a two-fold increase in frataxin levels in blood, buccal cells, and skin, which is in the range typically seen in in asymptomatic heterozygous carriers. The safety and pharmacokinetic data met the criteria for moving forward. This became the first time a frataxin replacement therapeutic approach has been tested in people with FA.

Between late 2024 and early 2025, Larimar Therapeutics advanced its pediatric development program for nomlabofusp by initiating a pharmacokinetic (PK) run-in study in an adolescent cohort with Friedreich’s ataxia (ages 12–17).

Participants were randomized 2:1 to receive either nomlabofusp or placebo daily for seven days, using weight-based doses equivalent to the 50 mg adult dose. On January 23, 2025, the company confirmed dosing of adolescents had begun, and by March 2025 dosing was completed, with results anticipated during a program update in September 2025.

In May 2021, the FDA placed a clinical hold on Larimar Therapeutics’ CTI-1601 (now known as nomlabofusp) when, in a long-term, non-human primate toxicology study, there were deaths at the highest dose levels. No patients had been dosed in the Phase II trial when the clinical hold went into effect. After data analysis and continued dialogue with the FDA, the hold was partially lifted in September 2022, allowing Larimar to initiate a Phase 2, placebo-controlled, four-week dose exploration trial in Friedreich’s ataxia (FA) patients, beginning with a 25 mg dose.

By May 2023, interim results showed that nomlabofusp was generally well tolerated and produced increases in frataxin levels in both skin and buccal cells. One participant at 25 mg had an allergic reaction that resolved with standard treatment. Injection site reactions were common, occurring in about half of placebo recipients and all nomlabofusp recipients, but were mild to moderate and resolved within 24 hours. These findings led to FDA clearance to escalate dosing to 50 mg and initiate an open-label extension (OLE) trial.

Top-line Phase 2 dose exploration results, released in February 2024, confirmed dose-dependent frataxin increases in skin:
• 33% increase at 25 mg
• 59% increase at 50 mg (measured after 14 days of dosing)
Buccal cells also increased, but results were more variable. There were injection site reactions and one person in the 25mg cohort withdrew due to a severe allergic reaction.

In March 2024, Larimar began dosing 25 mg daily in the OLE. The aim of this study was to understand the long-term safety of nomlabofusp, as well as the long-term changes in frataxin levels. The results may also support the US regulatory filing (the Biologics License Application or BLA submission) for approval of the drug. In May 2024, the FDA lifted the remaining partial hold, allowing use of 50 mg in the OLE.

On May 30, 2024, Larimar was selected by the FDA to participate in the START Pilot Program, a milestone-driven initiative to accelerate therapies for rare diseases. Nomlabofusp was selected based on its potential benefit in FA and the program’s readiness for late-stage development.

In November 2024, Larimar presented additional Phase 2 data supporting its dose selection. Analyses showed that daily 50 mg dosing is likely to achieve frataxin levels at or above 50% of healthy controls, comparable to levels seen in asymptomatic carriers.

In December 2024, data from the OLE showed that 25 mg daily dosing increased frataxin to 30% of healthy levels in buccal cells and 70% in skin cells after 90 days. Based on the safety and frataxin data, all OLE participants will now receive 50 mg daily. Larimar also reported trends toward improvement in early clinical assessments (mFARS, FARS-ADL, fatigue, and fine motor function), although these findings were based on a small sample (n=8) and a short duration (90 days).

In March 2025, the FDA indicated it is open to considering frataxin (FXN) concentration as a reasonably likely surrogate endpoint (RLSE), with a final decision pending review of the full data package. FDA recommended focusing on skin FXN levels over buccal cells due to more consistent sampling and lower variability and acknowledged that recent data support a relationship between increased skin FXN and key tissues affected in FA, including the heart, dorsal root ganglia, and skeletal muscle. The agency also agreed that the nonclinical studies were conducted at doses relevant to humans. Additional pharmacodynamic markers (e.g., lipid profiles, clinical measures) may be used to further support FXN as a surrogate endpoint.

In a June 2025 update, the company indicated that the FDA has provided guidance as to the quantity of data needed prior to submission of a BLA. The agency recommended a safety database that includes a total of at least 30 participants with continuous exposure for 6 months, and a subset of at least 10 with 1-year. Most of the participants should be on the 50 mg dose.

Larimar continues to enroll participants in the open-label extension (OLE) study, with all receiving 50 mg daily (or the weight-based equivalent). Due to observed risk of anaphylaxis, now deemed an adverse drug reaction likely associated with nomlabofusp, the OLE protocol has been amended to include premedication during the first month of treatment to mitigate allergic reactions. In the future, this study will be expanded to include participants who have never participated in any of their prior clinical studies and who are ineligible for the upcoming Phase III study.

Larimar has also received feedback from both the FDA and EMA on the design of its global Phase 3 trial, which remains on track to begin by late 2025 with planned sites in the U.S., Europe, U.K., Canada, and Australia.

In a September 2025 update, Larimar released additional data from the nomlabofusp clinical studies. In 4 completed studies and the ongoing open-label (OL) study, 65 participants received at least 1 dose of nomlabofusp, including 39 in the OL study, with 14 on treatment for at least 6 months and 8 for over 1 year in the OL study. Participants who completed treatment in a Phase 1 or Phase 2 study evaluating nomlabofusp were the first group of eligible patients to screen for the OL study. The OL study protocol has now been amended to include adolescent and adult patients who have not participated in a prior nomlabofusp study.

The data from the OL study showed increases in skin frataxin levels at six months that were similar to levels found in the skin of asymptomatic carriers. Data from clinical outcomes, including mFARS, FARS-ADL, 9-HPT, MFIS at 1 year may suggest potential for clinical benefit relative to a worsening in a FACOMS natural history study reference population.

Safety data were also reported. Anaphylaxis (a severe allergic reaction) has been reported in 7 participants in the OL study, with most events occurring on the initial day of administration and all occurring within the first 6 weeks of dosing. Following the 2 most recent cases of anaphylaxis, Larimar has modified the starting dose regimen. Larimar reported that the FDA agreed with the modifications of the dose regime.

Larimar is planning to submit a BLA by mid-2026.