An Open-Label Study of CTI-1601 in Subjects With Friedreich's Ataxia

Official title

An Open-Label Extension Study to Assess the Long-Term Safety, Efficacy, Pharmacodynamics, Pharmacokinetics, and Tolerability of Subcutaneous CTI-1601 in Subjects With Friedreich's Ataxia

Overview

An open label study designed to evaluate the safety, PK, PD, and clinical effects of long-term daily administration of CTI-1601 enrolling adolescent and adult patients with FRDA who have participated in a prior clinical study of CTI-1601 as well as children (age 2 years and older), adolescents and adults with FRDA who have not participated in a prior clinical study of CTI-1601.

Detailed description

An open-label study designed to evaluate the long-term safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical effects of subcutaneous (SC) administration of CTI-1601, also known as nomlabofusp, in subjects with Friedreich's ataxia (FRDA).

The objectives of this study are:

* To evaluate the safety and PK of long-term subcutaneous (SC) administration of CTI-1601 in subjects with FRDA * To evaluate the PD and clinical effects of long-term subcutaneous (SC) administration of CTI-1601 in subjects with FRDA on:

* Tissue FXN concentrations * Clinical evaluations of FRDA * Gene expression and select lipids

Interventions

• Drug CTI-1601
  CTI-1601 is a recombinant fusion protein and is intended to deliver human frataxin, the protein deficient in patients with Friedreich's ataxia

Primary outcome measures

• Number of subjects with treatment-emergent adverse events (TEAEs) by System Organ Class (SOC), Preferred Term (PT) and Maximum Severity [Time frame: Up to 24 months]
• Change from baseline in electrocardiogram (ECG) parameters including, but not limited to, HR, RR interval, PR interval, QRS duration, QT interval, and QTcF interval [Time frame: Up to 24 months]
• Change from baseline in left ventricular ejection fraction (LVEF) [Time frame: Up to 24 months]
• Change from baseline in left ventricular end-diastolic volume (LVEDV) [Time frame: Up to 24 months]
• Number of subjects with any suicidal ideation or behavior (Categories 1-10) of the Columbia Suicide Severity Rating Scale (C-SSRS) [Time frame: Up to 24 months]
• Change from baseline at each collection timepoint in tissue frataxin concentrations normalized to total protein observed in buccal cells collected from cheek swabs and skin cells collected from skin punch biopsies [Time frame: Up to 24 months]
• Change from baseline in motor function as assessed by 9-hole peg test (9-HPT) [Time frame: Up to 24 months]
• Change from baseline in motor function as assessed by the timed 25-foot walk test (T25-FW) [Time frame: Up to 24 months]
• Change from baseline in neurologic function as assessed by the modified Friedreich's Ataxia Rating Scale (mFARS) total score [Time frame: Up to 24 months]
• Change from baseline in neurologic function as assessed by the upright stability subscale examination of the mFARS [Time frame: Through study completion, up to 24 months]

Eligibility criteria

Inclusion criteria

• Subjects with FRDA who have or have not previously completed participation in a study of CTI-1601 are eligible to participate in this study unless the subject experienced one or more of the following in a previous CTI-1601 study: a) serious adverse event (SAE) related to study drug; b) significant AE, defined as Grade 3 or higher according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (or higher), related to study drug; c) some other event, related to participation in a previous study with CTI-1601, that supports the exclusion of the subject from participating in this study as determined by the Sponsor (i.e., an AE considered clinically significant by the Sponsor regardless of whether it met SAE criteria and regardless of CTCAE grade); d) Withdraw from participation in a previous study of CTI-1601 for any reason.
• Subject has a HbA1c less than or equal to 7.0%.
• Subject must demonstrate sufficient dexterity and visual acuity to prepare and self-administer SC injections of CTI-1601 QD or is able to identify a caregiver who will be trained and committed to prepare and administer the daily injections.

If 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 the initiation of Screening; however, subjects taking niacin and resveratrol must have been on a stable dose and frequency for 90 days prior to the initiation of Screening

\- Subjects who are currently receiving omaveloxolone or intend to receive omaveloxolone are permitted in the study but must either receive CTI-1601 for 3 months prior to their first dose of omaveloxolone or receive omaveloxolone for 3 months prior to their first dose of CTI-1601.

Exclusion criteria

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

• Subjects who are confirmed as compound heterozygous (GAA repeat expansion on only one allele) for FRDA.
• Subject has any condition, disease, or situation, including a cardiac condition or disease, that in the opinion of the PI, could confound the results of the study or put the subject at undue risk, making participation inadvisable.
• Subject used any investigational drug (other than CTI-1601) or device within 90 days prior to Screening.
• Subject requires use of amiodarone.
• Subject used erythropoietin, etravirine, or gamma interferon within 90 days prior to Screening.
• Subject use of biotin supplementation that exceeds 30 mcg/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 mcg/day is permitted if taken at a stable dose and frequency for at least 28 days prior to Screening and there is a commitment from the subject to maintain the biotin dose throughout the study (due to interference with assays).
• Subject uses more than 3 grams of acetaminophen daily.
• Subject receives medication that requires SC injection in the abdomen or thigh.
• Subject is unable to discontinue medications that have not been at a stable dose and frequency for at least 28 days prior to Screening.
• Subject has a Screening echocardiogram (ECHO) LVEF < 45%.
• Male subject has a QTcF > 450 milliseconds or female subject has a QTcF > 470 milliseconds on an ECG.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 8 centers

• University of California Los Angeles — Los Angeles
• Fixel Institute for Neurological Disease, University of Florida Health — Gainesville
• Morsani Center for Advanced Health Care, University of South Florida Health — Tampa
• University of Iowa — Iowa City
• Uncommon Cures — Chevy Chase
• Clinilabs Drug Development, Corp. — Eatontown
• Ohio State University United States — Columbus
• Children's Hospital of the University of Pennsylvania (CHOP) — Philadelphia

Publications

• Delatycki MB, Corben LA. Clinical features of Friedreich ataxia. J Child Neurol. 2012 Sep;27(9):1133-7. doi: 10.1177/0883073812448230. Epub 2012 Jun 29. PMID 22752493
• Deutsch EC, Santani AB, Perlman SL, Farmer JM, Stolle CA, Marusich MF, Lynch DR. A rapid, noninvasive immunoassay for frataxin: utility in assessment of Friedreich ataxia. Mol Genet Metab. 2010 Oct-Nov;101(2-3):238-45. doi: 10.1016/j.ymgme.2010.07.001. Epub 2010 Jul 8. PMID 20675166
• Fahey MC, Corben L, Collins V, Churchyard AJ, Delatycki MB. How is disease progress in Friedreich's ataxia best measured? A study of four rating scales. J Neurol Neurosurg Psychiatry. 2007 Apr;78(4):411-3. doi: 10.1136/jnnp.2006.096008. Epub 2006 Oct 20. PMID 17056635
• Fisk JD, Ritvo PG, Ross L, Haase DA, Marrie TJ, Schlech WF. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis. 1994 Jan;18 Suppl 1:S79-83. doi: 10.1093/clinids/18.supplement_1.s79. PMID 8148458
• Goodkin DE, Hertsgaard D, Seminary J. Upper extremity function in multiple sclerosis: improving assessment sensitivity with box-and-block and nine-hole peg tests. Arch Phys Med Rehabil. 1988 Oct;69(10):850-4. PMID 3178453
• Koeppen AH. Friedreich's ataxia: pathology, pathogenesis, and molecular genetics. J Neurol Sci. 2011 Apr 15;303(1-2):1-12. doi: 10.1016/j.jns.2011.01.010. PMID 21315377
• Guidelines MSCfCP. Fatigue and multiple sclerosis: evidence-based management strategies for fatigue in multiple sclerosis. 1998.
• Lazaropoulos M, Dong Y, Clark E, Greeley NR, Seyer LA, Brigatti KW, Christie C, Perlman SL, Wilmot GR, Gomez CM, Mathews KD, Yoon G, Zesiewicz T, Hoyle C, Subramony SH, Brocht AF, Farmer JM, Wilson RB, Deutsch EC, Lynch DR. Frataxin levels in peripheral tissue in Friedreich ataxia. Ann Clin Transl Neurol. 2015 Aug;2(8):831-42. doi: 10.1002/acn3.225. Epub 2015 Jul 1. PMID 26339677

Identifiers

NCT: NCT06447025 · CLIN-1601-201

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗