ORPHAN INDICATION: CHARCOT-MARIE-TOOTH DISEASE TYPE 1A
Charcot-Marie-Tooth (CMT) disease encompasses a heterogeneous group of inherited, progressive, chronic peripheral neuropathies. CMT type 1A (CMT1A), the most common type of CMT, is an orphan disease affecting at least 125,000 people in Europe and the U.S.
The genetic mutation responsible for CMT1A is a duplication of the PMP22 gene coding for a peripheral myelin protein. Overexpression of this gene causes degradation of the neuronal sheath (myelin) and is responsible for nerve dysfunction, followed by loss of nerve conduction. As a result of peripheral nerve degradation, patients suffer from progressive muscle atrophy in the legs and arms causing walking, running, balance problems and abnormal hand functioning. Patients with CMT1A end up in wheelchairs in at least 5% of cases. They might also suffer from mild to moderate sensory disorders. First symptoms usually appear during adolescence and will progressively evolve throughout life.
To date, no curative or symptomatic medications have been approved and treatment consists of supportive care such as orthotics, leg braces, physical and occupational therapy or surgery.
The proof of concept of the PLEOTHERAPY approach was obtained with PLEODRUG PXT3003 in Charcot-Marie-Tooth disease type 1A (CMT1A) through positive and consistent Phase 2 and Phase 3 results.
In preclinical studies in two different rodent models, PXT3003 inhibited the overexpression of the PMP22 gene, improved myelination of peripheral nerves and clinical / sensory impairments.
In a Phase 2 clinical trial in 80 adult patients with CMT1A, PXT3003, beyond stabilization, improved multiple efficacy endpoints, particularly the ONLS score (Overall Neuropathy Limitation Scale) which measures patient disability. The U.S. FDA suggested the use of ONLS as a primary efficacy endpoint in clinical trials in CMT. In addition, PXT3003 was safe and well tolerated.
In a Phase 3 clinical trial in 323 adult patients with CMT1A, PXT3003 confirmed the significant improvement in disability, particularly the ONLS scale and the 10-meter walk test. PXT3003 was still safe and well tolerated.
PXT3003 is a novel synergistic combination of baclofen, naltrexone and sorbitol formulated as an oral solution and given twice a day. PXT3003 has multiple main mechanisms of action: a synergistic inhibition of PMP22 gene overexpression associated with myelination improvement, direct nerve protection and additional positive effects on other cellular types: muscle cells, neuromuscular junctions and immune cells.
In 2014, the EMA and FDA granted orphan drug designation to PXT3003 for the treatment of CMT1A in adults.
TWO INTERNATIONAL PHASE 3 TRIALS WITH PXT3003
PLEO-CMT was a pivotal, multi-center, randomized, double blind, placebo-controlled, three-arm Phase 3 study that was initiated in December 2015 and has enrolled 323 patients with mild to moderate CMT1A in 30 sites across Europe, the U.S. and Canada. Over 15 months, Pharnext compared in parallel groups the efficacy and safety of two orally administered doses of PXT3003 to placebo. Efficacy has been assessed through one primary endpoint: change in the ONLS score at 12 and 15 months of treatment to measure improvement of patients’ disability with PXT3003. Additional secondary outcome measures has been assessed including functional and electrophysiological endpoints.
PLEO-CMT-FU is an international, multi-center, nine-month, Phase 3 follow-up extension study that was initiated in March 2017. PLEO-CMT-FU is designed to assess the long-term safety and tolerability of PXT3003. All randomized patients who have completed the primary PLEO-CMT trial (i.e. 15-month double-blind treatment with two active doses of PXT3003 versus placebo) will be eligible to continue or initiate treatment with PXT3003 in this nine-month extension study. Patients randomized to PXT3003 in the primary trial will continue in PLEO-CMT-FU at the previously assigned dose while those who received placebo will be randomized to one of two PXT3003 active doses.