Multiple Sclerosis (MS) is a long-term, degenerative disease that affects the central nervous system in which the immune system attacks the myelin sheath that protects nerve fibers, causing neuroinflammation and neurodegeneration. Without the protection of myelin, nerves lose functionality, become damaged and are ultimately destroyed, which leads to the formation of scar tissue (sclerosis). Symptoms tend to vary depending on the nerves affected and the damage caused.
MS is most commonly diagnosed between the ages of 20 and 30, however most patients will have evidence of prior, inflammatory CNS damage at diagnosis, as seen via Magnetic Resonance Imaging (MRI). In 85% of the cases, MS presents itself at the original diagnosis in a form called relapsing-remitting MS (RRMS), which will usually degenerate after 10-20 years into a more aggressive form of the disease: the secondary progressive form (SPMS) during which the loss of neuronal function increases. Approximately 10% of patients present from the outset with a form of the disease called primary progressive MS (PPMS).
There is currently no cure for MS. Treatment options interfere at the level of the patient’s immune system, reducing partially or almost completely the number of inflammatory relapses (one of the manifestations of the disease). However, there is no treatment presently available that has shown a determining impact on the progression of long-term disability resulting from the disease.
Despite these challenges researchers at GeNeuro, a Geneva, Switzerland based clinical stage biopharmaceutical company has completed a MS Phase 2 clinical trial with encouraging results.
GeNeuro CEO Jesus Martin-Garcia believes that GeNeuro’s ground-breaking approach can ultimately lead to an effective treatment. The company’s lead drug, temelimab, centers on the causal factors of MS rather than treating the symptoms. In a new MS series WuXi AppTec Communications discussed the causes of MS and how GeNeuro’s drug can make a real impact for MS sufferers.
Martin-Garcia began his career in 1983 at the World Economic Foundation, and later at McKinsey & Co where he led studies in the pharmaceutical and food industries. By 1993, he chose the entrepreneurial path by creating, investing and leading start-ups in Switzerland and the United States. In 2003 he created Eclosion, a public-private partnership for translating scientific discoveries in the field of life sciences into innovative drugs with disruptive potential. This unique structure was instrumental in the creation of GeNeuro, which Martin-Garcia has led since its founding in 2006. Martin-Garcia holds a bachelor’s degree in industrial sciences, a master in law from Geneva University and an MBA from Harvard Business School. He serves on the board of several biotech companies and industrial and business associations.
WuXi AppTec: Are there any major differences between developing drugs for multiple sclerosis (MS) compared with other diseases? Are there unique regulatory and business challenges?
Jesus Martin-Garcia: As with any other neurological disorder, the development of medicines to treat MS remains cumbersome, as access to target tissue in situ is literally impossible. Therefore, development relies on surrogate biomarkers, such as imaging or fluid biomarkers. In addition, the different clinical manifestations of MS and the variable long-term evolution of clinical disability make it difficult to develop therapies for MS. Today we have an arsenal of approved drugs that are very effective against relapses. The effectiveness of these drugs can be measured over two years, i.e. relatively short periods of time compared to the duration of the disease.
What we lack are solutions to slow underlying neurodegeneration that drives disability progression over the long term. Anti-inflammatory and immunosuppressive drugs, which are very effective against relapses, have unfortunately been demonstrated to have limited impact on long-term neurodegeneration. As disability progression is a long-term phenomenon, developing drugs against neurodegeneration is certainly challenging.
WuXi AppTec: Many MS drugs started out as cancer drugs. Why did you decide to target MS directly?
Jesus Martin-Garcia: You make an interesting observation, which is right. Most drugs effective against MS relapses were initially developed for oncology and organ transplant, where immunomodulation and/or immunosuppression can have benefits. Some of these drugs have also been utilized in treating other autoimmune diseases, with varying success and efficacy.
In GeNeuro’s case, it’s probably more accurate to say that MS chose us! GeNeuro was founded based on 25 years of research conducted on human endogenous retroviruses (HERVs), including 15 years within Institut Mérieux and the French National Institute for Health (INSERM). These HERVs are the remnants from viral infections in our primate ancestors that, over the millennia, have integrated themselves into our genome. In fact, the DNA from these ancient viruses make up about 8% of the human genome!
This HERV research showed that there is a link between these viral genes and certain diseases, paving the way for us to uncover and understand the action of a potential causal factor of multiple sclerosis, an envelope protein (Env) that is produced by a pathogenic member of the human endogenous retrovirus-W family (pHERV-W). pHERV-W Env is systematically found post-mortem in the brain lesions of MS patients, but neither in the normal appearing white matter of MS patients, nor in the brains of patients with other neurological disorders.
WuXi AppTec: How do you overcome patient recruitment challenges in MS research?
Jesus Martin-Garcia: Treatment of MS has been well established over the past several years – a positive consequence of the advances in treatment options. There are specialist clinics and centers around the world that treat MS patients. By collaborating with these we are able to reduce the challenge of recruitment. Yet, as most patients experience increasing disability despite their MS treatment, there is an aspiration by those patients for experimental drugs that hold promises to slow down the underlying neurodegeneration.
WuXi-AppTec: How much progress has been made in MS drug research and development over the last 20 years?
Jesus Martin-Garcia: Over the past 20 years, there has been significant progress in our ability to treat the symptoms of MS; however, treating the underlying cause and stopping the progression of the disease has proven to be much more difficult.
Today there is a good understanding of the immune mechanisms of relapses, with T and B cells penetrating into the brain and causing a local edema. The clinical manifestation of this edema will depend on its localization in the brain, and can take many forms, such as muscle weakness, loss of muscle coordination, pain, loss of vision, etc. But these symptoms will generally disappear with the resolution of the edema. This knowledge has been the basis for the development of the very effective drugs available today to reduce the frequency and severity of relapses, which is a great benefit for the patients.
We have also made very good progress in understanding some of the mechanisms that lead to long term neurodegeneration and disability. Among those, two interesting areas of research on progression in MS are the potentially damaging role of pro-inflammatory microglial cells and the impaired function of oligodendrocyte precursor cells (OPC), the latter being key for myelin repair.
There are also a number of new biomarkers being developed to be able to measure disease progression over time, such as the measure of brain atrophy, myelin density, and the differentiation of lesions that appear to be specific to long-term progression. Neurofilament light chain biomarkers in the periphery and the CSF are also an interesting new avenue to measure the inflammatory state of MS patients.
But slowing down and hopefully stopping disability progression over time remains an unmet medical need in MS, and there is still much more research to be done to help these underserved patients, and GeNeuro is playing its part!
WuXi AppTec: We have been talking about MS research in general. I would like to switch to your specific drug program. What phase is it in? What is its MOA? and what results have you seen so far? And will it treat all stages of the disease?
Jesus Martin-Garcia: GeNeuro is currently evaluating temelimab, a monoclonal antibody designed to neutralize the pathogenic envelope protein, pHERV-W Env. This protein, which is specific to MS in the brain of patients, has been shown to activate microglial cells into an aggressive phenotype, causing direct damage to brain tissue, and to inhibit the differentiation of oligodendrocyte precursor cells, which are key to myelin repair. Neutralizing pHERV-W Env is thus expected to stop these two key mechanisms that are involved in fueling long term neurodegeneration and disability.
GeNeuro has completed a 1-year Phase II on 260 remitting MS patients followed by a one-year extension study. The two-year results, announced in March 2019, showed a continued, positive impact on key MRI measures of disease progression in MS patients, confirming and extending the data reported at year one. This includes reductions in brain atrophy, particularly in the cortex and thalamus, and maintenance in myelin integrity, as measured by magnetization transfer ratio (“MTR”) imaging. Also, for the first time, encouraging dose-dependent effects were seen on clinical measures of disease progression. The study also showed that temelimab had only a modest effect on B and T-cell driven neuroinflammation, indicating that the positive results observed on MRI measures associated with disease progression maybe specific to neurodegeneration mechanisms independent of relapse-associated inflammation.
GeNeuro announced on November 20, 2019 an agreement with the Karolinska Institutet / Academic Specialist Center (ASC) of Stockholm to launch a new Phase II clinical study specifically targeting patients whose disability progresses without relapses. It will document the safety and tolerability of temelimab following higher doses as well as measures of efficacy based on the latest biomarkers associated with disease progression. The study aimed to start enrolling patients in Q1 2020, with last patient out and expected top line results in H2 2021; however, due to the COVID-19 crisis, we announced on March 19, 2020 that we were temporarily postponing this trial to prioritize healthcare resources against the pandemic. Assuming recruitment can still be completed by the end of 2020, the company expects that results would still be communicated in H2 2021.
WuXi AppTec: When do you think it may be available to patients?
Jesus Martin-Garcia: If the results of the trial at the Karolinska Institutet confirm temelimab’s activity against disability progression in the absence of relapses, we would expect a rapid development based on the results of this trial through Phase III pivotal trials. Temelimab may be developed as a monotherapy for “non-active” progressive patients, or as an adjunctive therapy for remitting patients in combination with existing immunomodulatory drugs addressing neuroinflammation, such paths being non-exclusive.
WuXi AppTec: Why do you think your approach can be more successful than other companies’ drug programs in this disease?
Jesus Martin-Garcia: Today, there are many drugs that are effective against relapses in MS through modulating and/or suppressing key parts of the immune system of the patients. But long-term disease progression, which is the focus of GeNeuro, remains a very urgent unmet medical need. GeNeuro’s approach is very unique as it tries to neutralize a causal factor fueling disability progression. We do know that temelimab is very well tolerated, with no safety flags thus far, and we do need to continue our evaluations in larger clinical studies to confirm its unique potential.
WuXi AppTec: Do you see a time when we will have a cure for this disease? What scientific advances would be required to reach this goal? Any predictions when this might happen?
Jesus Martin-Garcia: Our knowledge of MS and other neurological diseases is expanding every day. The research into HERVs shows that they could be one of the key missing links that scientists have been seeking for many years. Whether they result in a cure remains to be seen, but they are certainly a step in the right direction. As with many other diseases, we still don’t know enough about MS to predict when there will be a cure, but we have made great progress in our ability to help support and treat patients in the meantime.
WuXi AppTec: Anything we haven’t touched on that you would like to add?
Jesus Martin-Garcia: The role of HERVs and their effect on human health are still being explored. Despite the accumulation of mutations and various mechanisms to silence their genetic expression, HERVs are still contributing to the human transcriptome. A growing number of studies suggest that HERV expression products may play pathogenic roles in a number of diseases. As well as MS, GeNeuro has research programs in Type 1 diabetes, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s Disease), in partnership with the US National Institutes of Health, and chronic inflammatory demyelinating polyneuropathy (CIDP), a rare neurological disorder.
We believe that our pioneering work in MS will open a new avenue for the effective treatment of many other poorly understood diseases.