Neuromuscular disease treatments moving in the right direction
Skeletal muscles are essential for human movement and account for about 40% of the body mass. They enable various behaviors such as breathing, eating, walking, and speaking by contracting in response to electrical signals. These signals originate in the brain and travel through motor neurons to reach the target muscle. The motor neuron signals are then transmitted to muscle fibers in a process called neuromuscular transmission. Successful neuromuscular transmission is required to activate muscle contractions. However, if neuromuscular transmission is impaired, movement can become difficult.
Neuromuscular diseases are a group of disorders that affect approximately 14 million people globally and are characterized by progressive damage to muscle fibers. They can result in symptoms such as muscle weakness and excessive fatigue, which can occur at any stage in the activation of muscle fibers. Some neuromuscular diseases have a genetic basis or an autoimmune etiology, while others have no known genetic cause and develop during a person’s lifetime.
Spinal muscular atrophy (SMA) is an example of a genetic condition that affects the motor neuron and the neuromuscular junction (where nerves and muscle fibers meet). It is a progressive neurodegenerative disorder that affects the motor nerve cells in the spinal cord and impacts the muscles used for activities such as breathing, eating, crawling, and walking [1].
Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease that manifests clinically as muscle weakness and muscle fatigue. Although some patients only experience ocular symptoms, the majority have more generalized symptoms. An exacerbation of generalized muscle weakness can result in a life-threatening myasthenic crisis, requiring respiratory support. Beyond muscle weakness and muscle fatiguability, many patients also report central fatigue, experienced as a lack of physical and/or mental energy, which is associated with reduced quality of life [2].
Charcot-Marie-Tooth (CMT) is a group of inherited conditions that damage the peripheral nerves. The peripheral nerves are found outside the main central nervous system and control the muscles. CMT causes muscle weakness, and reduction in muscle size (atrophy), and some loss of sensation in the lower legs and feet. CMT also often causes contractures (stiffened joints due to abnormal tightening of muscles and associated tissues), and sometimes, curvature of the spine (scoliosis or kyphosis). There are no US Food and Drug Administration or European Commission approved therapies for CMT, but physical therapy, braces and other orthopedic devices, and even surgery can help individuals manage and improve symptoms [3]. Additional treatments are needed to help relieve symptoms, aid mobility, and increase independence and quality of life for people with the condition.
Neuromuscular conditions can have a profound impact on a person’s functional tasks. Those living with these conditions often struggle to live independent lives. Many of these conditions have no cure, but some treatments can help manage the symptoms and slow down the disease progression. Some prescription medications can alleviate muscle pain, cramps, stiffness, and weakness, while others can address nerve impulses and muscle strength. Additionally, if the disorder is caused by autoimmune issues, like MG, immunosuppressant or immunoglobulin therapies can be recommended. Other treatments include physical therapy and assistive devices. However, many neuromuscular diseases still lack effective therapies, with very few options approved that target the muscle, and this area represents one with a significant unmet need.
Yet, there is hope for patients living with these conditions as new treatment options are being explored.
NMD Pharma: An active future made possible by the power of science
NMD Pharma is discovering and developing novel therapeutics for neuromuscular diseases by developing new muscle-targeted approaches to improve the activation of the muscle fibers at the neuromuscular junction. The Company is currently developing this approach for three different neuromuscular disorders: spinal muscular atrophy, myasthenia gravis, and Charcot-Marie-Tooth disease.
NMD Pharma’s unique experimental platform focuses on ion channel function and electrophysiology of skeletal muscles. The Company is developing small molecules that block a specific type of ion channel (ClC-1) that is found only in skeletal muscles. These molecules could have a beneficial effect on various neuromuscular diseases where muscle activation is failing causing muscle weakness and excessive fatigue, which limit patients’ ability to move and live independently.
In November 2023, NMD Pharma announced it has raised €75 million in Series B financing to further progress the development of its lead programs. Proceeds from the financing will be used to complete three Phase 2 studies with NMD670, the Company’s lead ClC-1 inhibitor. The three studies will evaluate the novel mechanism of ClC-1 inhibition in AChR and MuSK antibody-positive myasthenia gravis (gMG), spinal muscular atrophy (SMA), and Charcot-Marie-Tooth (CMT) disease, respectively.
We spoke to NMD Pharma’s CEO and Co-Founder, Thomas Holm Pedersen, and Partner, Morten Graugaard Døssing of Novo Holdings, to find out about the Company, its recent financing, and plans for the future.
Thomas Holm Pedersen, CEO and co-founder of NMD Pharma
1. When you founded NMD Pharma in 2015, what was your vision?
NMD Pharma has of course changed a lot since it was founded in 2015. It is now more established and a clinical-stage company. However, our vision has not fundamentally changed. It remains all about creating a future in which patients with neuromuscular disease live better and more independent lives.
2. What advances does NMD Pharma bring to addressing this unmet medical need?
We have a unique experimental platform focusing on ion channel function and the ability to activate the skeletal muscle under conditions of weak or inconsistent signalling from the brain and neuron. With this platform we are developing small molecule inhibitors of skeletal muscle-specific CIC-1 ion channels that aim to enhance muscle force production, muscle quality, and ultimately to provide meaningful improvements in muscle function and mobility. We also plan to further explore the initial preclinical data that suggests the potential of our platform to add new neuronal connections to skeletal muscle or strengthen newly formed connections under dysfunction caused by disease.
3. How has NMD670 performed in Phase 1 trials?
In October 2022 we announced top-line results from a Phase I/IIa clinical trial of NMD670 in patients with myasthenia gravis. The data provided the first clinical proof of the mechanism of action of NMD Pharma’s ClC-1 chloride ion channel inhibitor in patients suffering from myasthenia gravis. NMD670 was found to be safe and well tolerated, with clinically significant improvements in the Quantitative Myasthenia Gravis Score in patients and changes in electrophysiological endpoints that demonstrated target engagement and restoration of neuromuscular transmission.
4. How will the recent funding be used?
We plan to accelerate the development of our lead drug candidate (NMD670) in already planned Phase 2 clinical studies for generalized MG and SMA and will also allow us to expand into a Phase 2 clinical trial for CMT. With this funding, we now have a higher probability of successfully helping even more patients suffering from rare neuromuscular diseases. Additionally, the funding allows us to advance additional assets in the pipeline from preclinical stages into the clinic, build our team and capabilities in Denmark, and establish a strong and growing presence in the United States.
5. What are the upcoming milestones we can expect to see from NMD Pharma in the next 12 months?
We plan to initiate three Phase 2 clinical studies of NMD670 in MG, SMA, and CMT over the next 12 months. We’ll also be able to recruit more employees in the organization in Denmark and the US.
Morten Graugaard Døssing, Partner at Novo Holdings
1. When you invested in NMD Pharma in 2016, what made the Company stand out?
We were attracted to the deep scientific understanding of the founding team as it related to the pathophysiology of a range of neuromuscular disorders and of the specific role of the ClC-1 ion channel in modulating muscle contractility. The team had really pioneered this field and had a well-thought-through therapeutic rationale for how to improve muscle function in areas of significant unmet medical need.
2. What was Novo Holdings’ role in the start of the Company?
Novo Holdings worked with the team while still at the University of Aarhus and provided pre-seed funding to validate the concept in an in-vivo model of myasthenia gravis. As part of the funding, we provided access to professional guidance and know-how, which has been critical for the successful development and transformation of NMD Pharma from a start-up to a fully integrated biotech company.
3. What excites you about NMD Pharma?
Almost 90% of neuromuscular diseases are classified as rare diseases and NMD is truly addressing a high unmet medical need with a unique experimental platform focused on the discovery of novel targets for developing first-in-class treatments.
4. How do you plan to continue to support the Company following its recent financing round?
As a board representative on behalf of Novo Holdings, I will continue to be a strong supporter of the company. We are highly active investors with a hands-on approach, and I have frequent catch-up calls with various members of the team on different topics — from introductions to other potential investors to pharma companies looking to understand more about NMD and our unique approach.
5. How will patients with Neuromuscular disorders benefit from the potential impact of NMD Pharma’s lead therapeutic?
The ultimate goal for NMD Pharma’s pipeline is to improve symptoms, increase mobility, and improve quality and length of life. In addition, we are exploring a potential disease-modifying effect of our treatment due to the prolonged function of the muscle fibers which seems to have a more longer-term effect and durable effect on patients.
