Promising treatments for Charcot–Marie

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Charcot-Marie-Tooth disease (CMT) is a group of inherited disorders that cause nerve damage. While treatments exist to help manage some symptoms, there is no cure and patients have various unmet needs.

In this article, we explore the latest clinical developments that aim to address these unmet needs of people with Charcot–Marie–Tooth disease. From NMD Pharma’s promising phase 2 trials for NMD670 to promising gene therapies and innovative approaches targeting the disease at the molecular level, here’s a closer look at how science is working to improve patients’ quality of life.

NMD Pharma’s NMD670 launches phase 2 study for CMT patients

Last week, Denmark-based NMD Pharma began a phase 2a trial for NMD670, which scored Investigational New Drug (IND) clearance from the U.S. Food and Drug Administration (FDA) in June.

“Patients with Charcot-Marie-Tooth are very excited about entering into this study. This is the only clinical study with a clinically feasible treatment to address the muscle weakness and fatigue with a pharmaceutical therapy at the moment. The fact that this study enrols patients with all types of Charcot-Marie-Tooth 1 and 2 is also encouraging and motivating to the community. I am happy to be involved in this exciting clinical study,” said Yessar Hussain, neurologist at the Austin Neurological Center in Texas, where the trial is taking place.

Charcot-Marie-Tooth 1 (CMT1) is the most common form of the disease, with 60% of people with the disease being diagnosed with type 1. It is typically caused by mutations that affect the myelin sheath, which is the layer that protects nerves from damage. On the other hand, Charcot-Marie-Tooth 2 (CMT2) affects the axon – the part of the nerve cells that carry electrical signals.

The symptoms of Charcot-Marie-Tooth – named after the three doctors who first recognized the disorder – tend to be the same regardless of the cause. These include weakness and even paralysis in the legs, ankles, and feet, curled toes, difficulty lifting the feet, higher chances of tripping and falling, and numbness.

“Damage caused by Charcot-Marie-Tooth worsens slowly over time and as a result, the nerve connections to skeletal muscles are in various stages of being fully innervated, partially innervated or denervated,” said a spokesperson from NMD Pharma to Labiotech. “Muscles that are denervated or only partially denervated can result in substantial reductions in mobility, independence and quality of life due to muscle weakness, fatigue, and atrophy across skeletal muscle groups such as the legs, feet, arms, hands and potentially leading to diaphragm weakness and paralysis.”

NMD’s NMD670 is designed to improve muscle function to address these symptoms. The small molecule activates muscle fibers at the neuromuscular junction (NMJ) – the region where a neuron connects to a muscle fiber and electrical activity in the muscle is triggered. It does so by blocking the muscle-specific chloride ion channel (ClC) – a key therapeutic target. This helps the muscles to contract in order to enhance muscle strength. That’s why it’s also being tested for other neuromuscular disorders such as myasthenia gravis, spinal muscular atrophy, and sarcopenia.

Link between NMJ transmission and Charcot-Marie-Tooth disease found

The link between a process called NMJ transmission and Charcot-Marie-Tooth disease was first established in a study conducted by NMD last year. NMJ transmission is when the electrical impulses move from a neuron to a muscle fiber, which then leads to muscle contraction. The lack of NMJ transmission in patients has now been tied to how severe the disease is after the study measured muscle strength, fatigability, dexterity, and balance in participants.

Therefore, boosting NMJ transmission could relieve symptoms for the 126,000 Charcot-Marie-Tooth disease patients in the U.S., according to the National Institute of Neurological Disorders and Stroke.

NMD670 is the only clinical-stage program currently in development for Charcot-Marie-Tooth disease to address the muscle weakness and fatigue that are characteristic of the disease. While this is exciting for the company, NMD is excited to see other treatments progress in development, as NMD670 should be complementary or synergistic in use to provide even greater benefits to patients utilizing other treatments that can slow or stop the progression of nerve damage,” said NMD’s spokesperson.

Gene therapies: NT-3 and Engensis to tackle Charcot-Marie-Tooth at genetic level

Besides inhibitor drugs like NMD670, Charcot-Marie-Tooth could also be treated with a gene therapy since one of its main causes is genetic mutations. Massachusetts-based Sarepta Therapeutics – famed for its approved gene therapy drug Elevidys for Duchenne muscular dystrophy – has a gene therapy program focused on treating CMT1-A.

In CMT1-A, the PMP-22 gene is duplicated. This gene provides instructions for making peripheral myelin protein-22 (PMP-22). However, when there is a pair of them, it leads to the overproduction of abnormal myelin by Schwann cells present in the peripheral nervous system. This results in damage to the peripheral nerves.

So, altering this at a genetic level could curb the overproduction of abnormal myelin and allow the Schwann cells to support the normal growth of nerve cells instead. Sarepta and Nationwide Children’s Hospital in the U.S., are developing neurotrophin 3 (NT-3), which is made up of a transgene, a promoter that helps with the expression of the transgene, and a vector that carries it.

While much is yet to be disclosed about the gene therapy collaboration, it is hoped that NT-3 can help overcome these defects caused by mutations.

Like NT-3, Engensis is another gene therapy in development. South Korean biotech Helixmith’s therapy contains a plasmid DNA that contains a gene that codes for a growth factor to promote neuromuscular activity. However, a recent clinical failure in another nerve disease called diabetic peripheral neuropathy means that the candidate’s ability to treat Charcot-Marie-Tooth disease is still up in the air.

Gene and DNA-based therapies could really turn the tide for people with Charcot-Marie-Tooth disease. Researchers at the University of Miami have teamed up with the Charcot-Marie-Tooth Association to target CMT2 with the help of antisense oligonucleotides (ASOs). These are genetic materials that bind to RNA molecules to inhibit the production of certain proteins. Simply put, they are “like tiny pieces of genetic tape that can stick to faulty parts of a gene and fix them,” according to a report by the Charcot-Marie-Tooth Association.

As CMT2 affects axons, the scientists used biomarkers of axonal degeneration to measure how effective ASOs are in treating Charcot-Marie-Tooth. According to the Charcot-Marie-Tooth Association, the results were promising, “showing a significant decrease in clinically relevant biomarkers.” Although this was done in disease models, clinical studies would be needed to prove that the decline in biomarkers actually reduces symptoms.

ASOs hold promise in treating cancers and genetic disorders like Charcot-Marie-Tooth. That’s probably why the FDA granted IND clearance for Vanda Pharmaceuticals’ VCA-894A. The drug candidate targets a mutation in the IGHMBP2 gene, which is linked to neuron loss and the deterioration of the nervous system. This is an “important milestone” to be able to tailor treatments based on what kind of mutation a patient has, expressed Mihael H. Polymeropoulos, chief executive officer (CEO) of Vanda, in a press release, earlier this year.

DTx-1252 and Actio Biosciences’ candidate expected to enter clinic for CMT

Meanwhile, researchers are trying to bring their preclinical candidates to the clinic to treat the nerve disease. Like California-based DTx Pharma’s lead program DTx-1252. It had been sought after by pharma giant Novartis, which then bought the company for $500 million last year.

It is a small interfering RNA (siRNA) therapy that targets the overexpression of the PMP-22 protein, like NT-3. Preclinically, it has been found to encourage remyelination – when new myelin sheaths are created around axons – and increase muscle mass, grip strength, coordination, and agility.

The Swiss multinational has also placed its bets on the inhibitor drug CKD-510 after it signed a $1.3 billion licensing deal with South Korea-based Chong Kun Dang Pharmaceutical Corp. The drug blocks the HDAC6 protein to boost the normal growth of myelin, and phase 1 trials showed that it was safe.

Preclinical company Actio Biosciences also has skin in the game. Its lead program, which targets mutations that affect an ion channel, was assigned Orphan Drug and Rare Pediatric Disease designations for CMT2C in August.

Hope remains despite Pharnext’s PXT3003 phase 3 clinical trial setback for CMT

With all these candidates in development, up until recently, Pharnext’s PXT3003 was poised to be the first drug to downregulate PMP22 expression to hit the market. But a phase 3 flop last year says otherwise. While the trial with 387 patients saw “no deterioration” of the condition among those who were given the treatment, it was unable to improve motor disability.

Although Pharnext hasn’t announced that it is giving up on PXT3003 yet, not a lot of hope remains. NMD’s NMD670 seems to be ahead of the race at the moment, with other inhibitor drugs, gene therapies, and OSOs following closely behind. How these potential treatments do in the clinic, only time will tell.