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First-ever effective and safe treatment of CMT1A

Presented by
Dr Florian Thomas, Hackensack University Medical Center, New York, USA
AAN 2019
Phase 3, PLEO-CMT
PXT3003 is the first effective, safe, and well-tolerated treatment for Charcot-Marie-Tooth disease type 1A (CMT1A), a rare, inherited, chronic, peripheral neuropathy [1].

PXT3003 is a novel oral fixed-dose combination of 3 drugs: baclofen, naltrexone, and D-sorbitol. Two doses were evaluated in PLEO-CMT, an international, multicentre, double-blind, pivotal phase 3 trial. It assessed the efficacy and safety of 2 doses of PXT3003 given twice daily for up to 15 months versus placebo. The 323 participants were randomised 1:1:1 to placebo, dose 1 (D1: 3 mg baclofen, 0.35 mg naltrexone, and 105 mg sorbitol), or dose 2 (D2: twice D1). Primary endpoint was the effect on disability, measured by the mean change in Overall Neurology Limitations Scale (ONLS) score at month 12 and 15.

PXT3003 D2 met the primary endpoint. There was a 0.37-point reduction of ONLS (P=0.008) versus placebo. Dr Florian Thomas (Hackensack University Medical Center, New York, USA) explained a minimum 0.30-point reduction of ONLS had been deemed clinically meaningful. In addition, in group D2, a trend for improvement was observed compared to baseline with a 0.20-point reduction of ONLS (P=0.098). Dr Thomas: ā€œThe D2 group improved as much as the placebo group deterioratedā€. Also with D2, a reduction of 0.47 seconds was observed on the 10-meter Walk Test (10-mWT), the main secondary endpoint (P=0.016). The rate of treatment-emergent adverse events leading to withdrawal was low and similar between groups (D2 5.3%, D1 5.5%, placebo 5.6%). Dr Thomas said this was not surprising, since both D1 and D2 were low.

In another study, local muscle injections of ACE-083 were well tolerated in patients with CMT and resulted in increases in muscle volume and decreases in fat fraction [2]. ACE-083 is a locally acting protein therapeutic, consisting of a modified form of human follistatin that binds myostatin plus other negative muscle regulators. The ongoing, placebo-controlled part of the study will evaluate effects on function and quality of life.

1. Thomas FP, et al. AAN 2019, emerging science 001.
2. Thomas FP, et al. AAN 2019, S58.006.

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