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.
PXT3003, Pharnext’s lead PLEODRUG™, has shown positive results both in preclinical and Phase 2 studies. These results were published in the Orphanet Journal of Rare Diseases (OJRD) in December 2014.
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.
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. An international pivotal Phase 3 clinical trial is ongoing in 323 patients with CMT1A. Results are expected in the second half of 2018. Pharnext is also considering a study in pediatric patients.
Links to preclinical and Phase 2 results.
TWO INTERNATIONAL PHASE 3 TRIALS WITH PXT3003 ONGOING
PLEO-CMT is 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. Diagnosis of CMT1A has been confirmed genetically through detection of PMP22 gene duplication. Over 15 months, Pharnext will compare in parallel groups the efficacy and safety of two orally administered doses of PXT3003 to placebo. Efficacy will be 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 will be assessed including functional and electrophysiological endpoints. A nine month follow-up study is planned thereafter, where all patients who will have completed the first 15 months, will receive the active PXT3003 dose.
PLEO-CMT-FU is an international, multi-center, double blind, 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.