A Study to Evaluate the Efficacy and Safety of Subcutaneous Nomlabofusp in Subjects With Friedreich's Ataxia

A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Subcutaneous Nomlabofusp in Subjects With Friedreich's Ataxia

To evaluate the efficacy and safety of subcutaneous nomlabofusp in adult and pediatric subjects with Friedreich's ataxia

This is a global, randomized, multi-center, placebo-controlled study to investigate the efficacy and safety of nomlabofusp in subjects with Friedreich's ataxia

The main objectives of the study are to evaluate:

• The efficacy of subcutaneous (SC) administration of nomlabofusp compared to placebo at Week 72; 1) on the Upright Stability Score (USS) Subscale E of the Modified Friedreich's Ataxia Ratings Scale (mFARS), or 2) mFARS total score (Region specific objective)
• The efficacy of SC administration of nomlabofusp compared to placebo at Week 72 on the Clinical Global Impression of Severity (CGI-S) score
• The safety and tolerability of SC administration of nomlabofusp

Key Inclusion Criteria:

Subjects who meet all of the following criteria are potentially eligible for study participation:

1. Subject must provide genetically confirmed FRDA diagnosis report and is homozygous for GAA repeat expansions documented on the genetic diagnostic report, with repeat sizing (if available).

2. Subject must complete 1 trial at Screening and 1 trial at Day -1 of the T25-FW test, using their customary assistive device (e.g., cane, 2 canes/crutches [Canadian crutches], wheeled walker/rollator or canine assistance) if needed. Each trial must be completed within 3 minutes.

3. Subject must have the following at Screening and Day -1 per the following upright stability items from Module E of the mFARS:

   1. Item #E1, Sitting Posture - no more than a maximum score of 2
   2. Item #E2A, Stance Feet Apart - no more than a maximum score of 2 (average of 3 attempts)

4. Subject must have an mFARS score ≥ 20 and < 60 at Screening and Day -1.

5. Subject must have a Functional Staging for Ataxia score of 4 or less at Screening.

6. Subject demonstrates sufficient dexterity and visual acuity to prepare and self-administer SC injections of study drug daily (QD) or has an identified caregiver who will be trained and committed to prepare and administer the injections.

7. Subject has a Screening HbA1c ≤ 7.0%.

8. If the subject is taking permitted concomitant medication(s), subject must have been on a stable dose and frequency of medication(s) over the past 28 days prior to initiation of Screening. Subjects taking niacin and resveratrol must have been on a stable dose and frequency for 90 days prior to initiation of Screening and subjects taking omaveloxolone must have been on a stable dose and frequency for 1 years prior to initiation of Screening.

Key Exclusion Criteria

Subjects are excluded from the study if any of the following exclusion criteria are met:

1. Subject who is confirmed as compound heterozygous (GAA repeat expansion on only 1 allele) for FRDA.

2. Subject previously participated in a clinical trial involving nomlabofusp. Participation is defined as the subject having signed the informed consent for the study and received at least 1 dose of study drug (nomlabofusp or placebo).

3. The subject has any condition, disease, or situation that could confound the results of the study or put the subject at undue risk, making participation inadvisable in the opinion of the PI.

4. Women of childbearing potential who are pregnant (have a positive pregnancy test at Screening or Day -1), lactating, or planning to attempt to become pregnant during this study or within 90 days after the last dose of study drug (this includes male subjects with partners of childbearing potential who are attempting to become pregnant).

5. Subject used any investigational drug or device within 90 days prior to the initiation of Screening.

6. Subject previously received a gene therapy (investigational or approved) at any time in the past.

7. Subject requires use of amiodarone.

8. Subject used erythropoietin, etravirine, or gamma interferon within 90 days prior to the initiation of Screening.

9. Subject's use of biotin supplementation exceeds 30 μg/day, either as part of a multivitamin or as a standalone supplement, within 7 days prior to the first dose of study drug. Biotin supplementation ≤ 30 μg/day is permitted if taken at a stable dose and frequency for at least 28 days prior to the initiation of Screening and there is a commitment from the subject to maintain the biotin dose throughout the study (due to interference with assays).

10. Subject receives medication that requires SC injection in the abdomen or thigh.

11. Subject has a Screening ECHO left ventricular ejection fraction < 45%.

12. Subject has a QTcF on an ECG as specified below:

    1. For subjects ≥ 12 and < 18 years of age, a male or female subject with a QTcF > 460 ms.
    2. For subjects ≥ 18 years of age, a male subject with a QTcF > 450 ms or a female subject has a QTcF > 470 ms.

13. Subject has suicidal ideation as determined by a "yes" to item #2 on the C-SSRS at Screening (within the last 28 days) or at Day -1.