Nomlabofusp (CTI-1601)

Dr. Mark Payne  who first described the possibility of frataxin replacement therapy via TAT-Frataxin, has been developing this exciting prospect for FA therapy. A recombinant fusion frataxin protein is partnered with a unique delivery system (a protein fragment called a Trans-Activator of Transcription or TAT) to get the frataxin protein 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’s approach 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.

February 2017: Chondrial Therapeutics announces that it secured up to $22.6 million in Series A financing led by Deerfield Management. Also, Chondrial expects to file an Investigational New Drug (IND) application for CTI-1601 (TAT-FXN) with the U.S. Food and Drug Administration (FDA) and, upon acceptance of the IND by the FDA, initiate Phase 1 clinical trials of the compound.

August 2017: Chondrial Therapeutics announces that it has received Orphan Drug Designation for CTI-1601, a novel investigational therapy for FA. In its press release, Chondrial reports that the IND-enabling studies are ongoing.

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 CTI-1601 or placebo. Eligible participants were adults with FA who were able to travel 25 feet independently or while using a self-propelled assistive device or manual wheelchair. The SAD was followed by a multiple dose study (MAD), and participants from both studies were eligible to participate in an open-label (Jive) extension study.

In 2020, Chondrial Therapeutics did a reverse merger with Zafgen, Inc. The combined, publicly traded clinical-stage biotechnology company began operating under the name Larimar Therapeutics, Inc.

In May 2021, Larimar shared top-line data from the Phase 1 placebo controlled single and multiple ascending dose (SAD and MAD) studies. CTI-1601 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.

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).

As of March 2025, Larimar is targeting submission of a BLA to the FDA by the end of 2025 to seek accelerated approval for nomlabofusp. The FDA has 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.

Larimar continues to enroll participants in the adult open-label extension (OLE) study, with all receiving 50 mg daily. 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.
The FDA has agreed to Larimar’s plan to introduce a lyophilized formulation—intended for commercial use—into the clinical program by mid-2025. (The current formulation used in trials is a frozen solution.)

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 mid-2025 with planned sites in the U.S., Europe, U.K., Canada, and Australia.

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.

Larimar plans to initiate a similar PK study protocol in cohort of children ages 2–11 in the first half of 2025, following review of adolescent data.

After safety and PK data are reviewed for each cohort, participants become eligible to transition into an open-label extension (OLE) study.

In parallel, Larimar reaffirmed plans to launch a global Phase 3 trial in 2025 to support future regulatory submissions.