Nomlabofusp: Research & Studies

Research Overview#

Nomlabofusp (CTI-1601) has been evaluated in a stepwise clinical development program for Friedreich ataxia. The published evidence includes Phase 1 safety, pharmacokinetic, and pharmacodynamic data, with Phase 2 dose exploration and open-label extension data reported via press releases and conference presentations. The compound represents the first protein replacement therapy for FA to reach late-stage clinical development.

The evidence level is classified as moderate based on consistent pharmacodynamic signals (frataxin restoration) across multiple studies and tissue types, supported by encouraging clinical outcome trends in the open-label setting. The key limitation is the absence of a completed randomized, placebo-controlled efficacy trial.

Phase 1: SAD and MAD Studies#

Clayton et al., Ann Clin Transl Neurol 2024 (PMID 38311797)#

The foundational clinical studies comprised single ascending dose (SAD, N=28) and multiple ascending dose (MAD, N=27) trials in adults with Friedreich ataxia aged 19-69 years.

Single Ascending Dose (SAD):

• Doses evaluated: 10 mg, 25 mg, 50 mg, and 100 mg subcutaneous
• Peak nomlabofusp plasma concentrations at 15 minutes post-injection
• Dose-proportional increases in plasma exposure
• Injection site reactions were brief, self-limited, and mostly mild (erythema, pruritus, pain)

Multiple Ascending Dose (MAD):

• Up to 100 mg administered daily for 13 days
• Plasma exposures increased with increasing doses and daily administration
• Frataxin increases observed in buccal cells, skin, and platelets
• 50 mg and 100 mg groups: greater than 2-fold frataxin increase, within the range of asymptomatic heterozygous carriers
• Well tolerated; most adverse events mild and self-limiting
• No serious adverse events or deaths

Key Pharmacokinetic Parameters#

Phase 2: Dose Exploration#

The Phase 2 dose exploration trial evaluated 25 mg and 50 mg cohorts in adults with Friedreich ataxia.

25 mg Cohort (n=13)#

• CTI-1601 generally well tolerated
• Frataxin increases observed in skin and buccal cells compared to placebo at day 14
• Median frataxin increase: 0.56 pg/mcg in buccal cells, 2.81 pg/mcg in skin cells

50 mg Cohort#

• Dose-dependent increases: median 0.72 pg/mcg in buccal cells, 5.57 pg/mcg in skin cells
• At Day 14, 100% of patients with quantifiable baseline levels treated with 50 mg achieved skin frataxin levels greater than 33% of healthy volunteer average
• 3 of these patients achieved levels greater than 50% of healthy volunteer average

Open-Label Extension Study#

The long-term open-label study provides the most extensive clinical experience with nomlabofusp. As of the most recent data cutoff (August 2025):

Enrollment and Exposure#

• 39 participants received at least one dose in the open-label study (65 total across program)
• 25 participants (19 adults, 6 adolescents) receiving daily dosing
• Treatment duration up to 527 days
• 14 participants treated for at least 6 months; 8 for over 1 year

Frataxin Restoration#

• 25 mg daily dosing: frataxin increased to 30% of healthy levels in buccal cells and 70% in skin cells after 90 days
• At 6 months: 100% of participants (n=10) achieved skin frataxin levels equivalent to asymptomatic carriers
• Sustained frataxin increases maintained with continued dosing

Clinical Outcome Trends#

• Median 2.25-point reduction in mFARS scores at 1 year
• In contrast, external matched natural history controls (FACOMS) showed mFARS worsening by median 1 point
• Trends toward improvement also observed on FARS-ADL, 9-HPT (nine-hole peg test), and MFIS (fatigue)

Important Caveats#

• Open-label, non-randomized design
• Clinical outcomes compared to external natural history data, not concurrent placebo
• Small sample sizes for long-term outcomes
• Selection bias inherent in extension study populations

Safety Across Clinical Program#

Anaphylaxis#

• 7 participants experienced anaphylaxis in the open-label study
• Most events occurred on the initial day of administration; all within first 6 weeks
• All participants recovered fully with standard treatment
• Modified starting regimen implemented: 5 mg test dose followed by 25 mg one hour later under observation

Injection Site Reactions#

• Most common adverse event across all studies
• Predominantly mild (erythema, pruritus, pain, induration, warmth)
• Median resolution time: 0.24 days (approximately 6 hours)
• Did not lead to any participant withdrawal

Overall Safety#

• No serious adverse events or deaths attributed to nomlabofusp in Phase 1 studies
• Long-term open-label study adverse events were predominantly mild to moderate injection site reactions
• No withdrawals due to injection site reactions

Evidence Quality Assessment#

Key Research Gaps#

1. Randomized controlled efficacy data: The Phase 3 confirmatory trial, planned as a post-approval requirement, will be the first adequately powered RCT with clinical outcome primary endpoints.

2. Cardiac outcomes: Cardiomyopathy is the leading cause of death in FA. Nomlabofusp's effect on cardiac frataxin levels and cardiac function has not been systematically assessed.

3. Pediatric data: While 6 adolescents are included in the open-label study, younger children (who may benefit most from early intervention) have not been studied.

4. Comparative efficacy: No comparison to omaveloxolone (the only approved FA therapy, which targets NRF2/antioxidant pathways rather than frataxin replacement).

5. Immunogenicity: Long-term exposure to a recombinant protein may elicit anti-drug antibodies. Full immunogenicity characterization is ongoing.

6. Optimal dosing: The dose-response relationship for clinical outcomes (beyond frataxin levels) remains to be defined. Whether higher doses (50 mg, 100 mg) provide additional clinical benefit over 25 mg is unknown.

Related Reading#

• Nomlabofusp overview and research guide
• Nomlabofusp dosing protocols
• Nomlabofusp molecular structure