Objective: To evaluate the pharmacodynamic (PD) and safety profiles of subcutaneous (SC) administration of multiple ascending doses of CTI-1601 in patients age ≥18 years with Friedreich’s ataxia (FRDA), the most common inherited ataxia.

Background: FRDA results from a deficiency of the mitochondrial protein frataxin (FXN). CTI-1601, a recombinant fusion protein designed to deliver human FXN into mitochondria, is in development as a FXN replacement therapy [Figure 1].

Method: In a Phase 1, double-blind, placebo-controlled multiple ascending dose trial (NCT04519567), patients with FA (n=27) received CTI-1601 (25, 50, or 100 mg; n=20) or placebo (n=7) SC. The 25-mg CTI-1601 cohort was dosed once daily (QD) for the first 4 days, then every 72 hours until Day 13. The 50-mg CTI-1601 cohort was dosed QD for the first 7 days, then every other day until Day 13. The 100-mg CTI-1601 cohort was dosed QD for 13 days. PD response was assessed by FXN concentrations measured by levels of the abbreviated n-terminal peptide segment for FXN in accessible tissue. Safety evaluations included incidence of treatment-emergent adverse events (TEAEs).

Results: Dose-dependent increases in FXN levels were observed in skin and buccal cells and in platelets with QD CTI-1601 administration. The greatest increases in buccal FXN levels from baseline occurred with 100 mg CTI-1601, but there was overlap in concentration ranges with daily dosing of 50 and 100 mg at Day 7. Between Days 7 and 13, buccal FXN levels were maintained with daily dosing of 100 mg. With the switch to alternate day dosing of 50 mg during Days 7 and 13, FXN levels decreased. Most TEAEs were Grade 1 or 2. Injection-site reactions were most commonly reported (100% of patients receiving CTl-1601; 43% for placebo).

Conclusion: In this first clinical study of CTI-1601, a therapy intended to increase FXN in patients with FRDA, increases in FXN levels were seen in multiple tissues. These observed increases in FXN after 7 days of QD dosing of 50 or 100 mg CTI-160 are potentially clinically relevant since 2- to 3-fold increases in FXN in patients with FRDA may achieve FXN levels observed in asymptomatic heterozygous carriers [1, 2]. CTI-1601 was generally well-tolerated. These data support the continued study of CTI-1601 as a treatment for patients with FRDA.

References: 1. Deutsch EC, Santani AB, Perlman SL, et al. A rapid, noninvasive immunoassay for frataxin: utility in assessment of Friedreich ataxia. Mol Genet Metab. 2010;101:238-245.

2. Saccà F, Puorro G, Antenora A, et al. A combined nucleic acid and protein analysis in Friedreich ataxia: implications for diagnosis, pathogenesis and clinical trial design. PLoS One. 2011;6:e17627.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/tissue-frataxin-increases-after-administration-of-cti-1601-a-frataxin-replacement-therapy-in-development-for-the-treatment-of-friedreichs-ataxia/