Nomlabofusp

What is Nomlabofusp?#

Nomlabofusp (CTI-1601) is a first-in-class recombinant fusion protein designed to deliver functional human frataxin to mitochondria in patients with Friedreich ataxia (FA). Developed by Larimar Therapeutics, it is the first disease-modifying protein replacement therapy that directly addresses the underlying cause of FA -- deficiency of the mitochondrial protein frataxin.

Friedreich ataxia is a rare, progressive neurodegenerative disease caused by a GAA trinucleotide repeat expansion in the FXN gene, which leads to reduced production of frataxin. This mitochondrial protein is essential for iron-sulfur cluster assembly, cellular energy production, and protection against oxidative stress. Without adequate frataxin, patients develop progressive ataxia, cardiomyopathy, and often diabetes, with most becoming wheelchair-dependent.

Nomlabofusp represents a pioneering application of cell-penetrating peptide (CPP) technology, using the HIV TAT protein transduction domain to ferry full-length human frataxin across cell membranes and into mitochondria.

Mechanism of Action#

Nomlabofusp employs a multi-step delivery mechanism:

• Cell-penetrating peptide (CPP): The TAT-derived sequence (YGRKKRRQRRR) at the N-terminus enables the fusion protein to cross cell membranes without receptor-mediated endocytosis
• Mitochondrial targeting: The native frataxin mitochondrial targeting sequence (MTS) directs the protein to the mitochondrial matrix after cell entry
• Enzymatic processing: Mitochondrial processing peptidase (MPP) cleaves the CPP and MTS, releasing mature human frataxin (14.3 kDa) from the full fusion protein (24.9 kDa)
• Functional frataxin delivery: The released mature frataxin is indistinguishable from endogenous frataxin and participates in iron-sulfur cluster assembly and mitochondrial function

This approach bypasses the genetic defect entirely, supplementing the deficient protein directly rather than attempting to correct the underlying gene expansion.

Clinical Development#

Nomlabofusp has progressed through a comprehensive clinical program:

• Phase 1 SAD/MAD: Published in Annals of Clinical and Translational Neurology (2024, PMID 38311797). Demonstrated dose-dependent frataxin increases in blood, buccal cells, and skin with good tolerability. At 50 mg and 100 mg, frataxin levels increased more than 2-fold
• Phase 2 Dose Exploration: 25 mg and 50 mg cohorts showed dose-dependent frataxin increases in skin and buccal cells. At 50 mg, all patients achieved skin frataxin levels greater than 33% of healthy volunteer levels
• Open-Label Extension: 100% of participants (n=10) on daily dosing achieved skin frataxin levels equivalent to asymptomatic carriers at 6 months. At 1 year, median mFARS improvement of 2.25 points vs 1-point worsening in natural history controls
• Regulatory Designations: FDA Rare Pediatric Disease, Fast Track, Orphan Drug; EMA PRIME, Orphan Drug
• BLA Submission: Planned for Q2 2026 seeking accelerated approval based on skin frataxin as a surrogate endpoint. Global Phase 3 confirmatory trial planned as post-approval requirement

Important Considerations#

Nomlabofusp is an investigational biologic not yet approved by any regulatory authority. Key considerations include:

• Anaphylaxis has been observed in 7 open-label study participants, all within the first 6 weeks of dosing. A modified starting regimen (5 mg test dose followed by 25 mg under observation) has been implemented
• Daily subcutaneous injection is required for sustained frataxin levels; treatment interruption leads to loss of frataxin restoration
• Injection site reactions are common but generally mild and self-limiting
• Long-term clinical benefit (mFARS improvement) is based on open-label data compared to external natural history controls, not a randomized controlled trial
• The FDA has indicated openness to skin frataxin concentration as a reasonably likely surrogate endpoint for accelerated approval

Key Research Findings#

Safety, pharmacokinetics, and pharmacodynamics of nomlabofusp (CTI-1601) in Friedreich's ataxia, published in Annals of Clinical and Translational Neurology (Clayton R et al., 2024; PMID: 38311797):

• Dose-dependent frataxin increases in buccal cells, skin, and platelets
• Greater than 2-fold frataxin increase at 50 mg and 100 mg doses
• Peak plasma concentrations at 15 minutes post-injection
• Generally well tolerated; most adverse events mild and self-limiting

Related Reading#

• Nomlabofusp research studies and evidence
• Nomlabofusp dosing protocols
• Nomlabofusp side effects profile
• Cerebrolysin research guide
• Davunetide research guide