‘It’s been a fantastic journey’ — Dr Thomas Holm Pedersen, NMD pharma

‘Our company has its origins in the research I did for my PhD,’ says Dr Thomas Holm Pedersen, CEO of NMD Pharma, based in Aarhus, Denmark. ‘We’re developing a small molecule that inhibits a particular ion channel called ClC-1, a chloride ion channel that is only expressed in skeletal muscle. When you inhibit this ion channel, you enhance neuromuscular transmission.’ While setting up the company, Pedersen and colleagues came into contact with Prof. Geert Jan Groeneveld from CHDR, then head of the Neurology group. ‘Since then, we’ve been discussing with Geert Jan and his team how best to investigate this promising compound in humans.’

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Myasthenia gravis

The ClC-1 channel plays a role in balancing muscle strength and relaxation. When the motor nerve signals to a muscle to contract, this is accompanied by an influx of positively charged sodium ions at the interface between the nerve and the muscle fibre — the neuromuscular junction. In contrast, ClC-1 causes the influx of negatively charged chloride ions, and therefore has the opposite effect. Inhibiting the ClC-1 channel may be beneficial in conditions where the muscle does not contract hard enough because the muscle fibres fail to become activated at the neuromuscular junction.

Pedersen: ‘We chose myasthenia gravis as the first indication to investigate. It’s an area of significant unmet medical need, and recent therapeutic advances in this indication provide clear criteria to gauge the success of novel treatments, which in turn helps to guide the design of our development programme. In addition, the animal models of myasthenia gravis translate well to humans.’

Following single and multiple ascending dose studies in healthy volunteers, NMD Pharma and CHDR’s Neurology group (now headed by Dr Philip Kremer) started a crossover placebo-controlled single dose study in patients with myasthenia gravis. Hand grip strength was chosen as the main outcome measure. Additionally, patients were assessed using the quantitative myasthenia gravis (QMG) scale, which is a well validated instrument for quantifying the severity of muscle weakness. Pedersen: ‘The outcomes of the patient study were good — beyond expectations, in fact. Both hand grip and QMG scores visibly improved after a single dose of our drug, and compared well to placebo.’

Experimental biomarker

The first studies in healthy volunteers had already produced indications of a possible effect. ‘One of the volunteers experienced muscle stiffness at the highest dose level tested. For me, that was clear evidence that our drug had an effect,’ says Pedersen. ‘We know, for example, that people who lack a functional ClC-1 channel due to an inherited mutation are more likely to experience muscle stiffness.’

Corroborating evidence came from an experimental biomarker deployed by CHDR, called muscle velocity recovery cycles (MVRC). This technique, which uses electromyography (EMG), shows how easily the muscle can be excited again after a contraction. Pedersen: ‘The MVRC measurements, too, showed a clear difference between placebo and active compound in the first studies with healthy volunteers, and this finding was confirmed in the patient study.’

New indications

‘So it’s been a fantastic journey, but at the same time, the results also bring our company to a whole new chapter,’ says Pedersen. ‘We now see opportunities in a number of other neuromuscular indications, especially some rare diseases for which there are still few or no resources available. In the near future we want to investigate the efficacy of our compound in spinal muscular atrophy and Charcot-Marie-Tooth disease, in addition to myasthenia gravis. We’re all very curious to pursue these possibilities further and see what we can achieve in the coming years.’