OUR CLINICAL PROGRAMME
- Amyotrophic lateral sclerosis (sometimes called motor neurone disease or Lou Gehrig’s disease) is a rapidly progressing neurodegenerative disorder
- Although rare, ALS is the most common neuromuscular disease, affecting around 3-4 in 100,000 individuals from all backgrounds
- The cause of ALS is not clearly understood, with genetic errors in at least 13 genes implicated in some (but not all) ALS cases – mutations in the SOD1 gene were the first discovered genetic link to ALS, but SOD1 mutations are only found in 1-2% of ALS patients. In fact, up to over 90% of ALS cases are sporadic, meaning there is no family connection to the disease
- People with ALS are usually diagnosed at age 40-60 and the prognosis is poor, with most patients dying within 3 years of diagnosis. Only ~20% of patients survive for 5 years after diagnosis
- There is no cure for ALS, and no new treatments have been approved in the EU/US since Riluzole that has a moderate effect on survival was approved in 1995
- Encouraging results have come from preclinical experiments and in particular from an investigator-led phase II trial into the effects of arimoclomol in SOD1-associated ALS. We are now meeting with regulatory authorities to agree on the next steps for the development of arimoclomol for SOD1-ALS
- Sporadic inclusion body myositis is marked by a progressive atrophy of the muscles, particularly in the legs, arms and neck
- Approximately 40 in 100,000 people are diagnosed with sIBM, but it is slightly more common in men than women
- sIBM generally presents in adulthood. Increasing muscle weakness leads to progressive disability and in the more severe cases to death is caused by respiratory or the inability to swallow
- The pathology involves inclusion bodies inside cells, which are caused by aggregations of a range of different proteins which clump together and cause the cells stress and toxicity Preclinical experiments and an investigator-led phase II study into the effects of arimoclomol in sIBM has produced encouraging results and we are moving forward with clinical research in this disease
Niemann-Pick Type C
- Niemann-Pick type C (NPC) is a lysosomal storage disease affecting around 1 in 150,000 newborns and is caused by mutations in the NPC1 or NPC2 genes which are inherited from both parents
- It is marked by an accumulation of lipid molecules in structures called lysosomes in the cells of internal organs and the central nervous system
- NPC results in a range of motor and cerebral impairments including progressive loss of muscle control and intellectual capacity
- NPC diagnosis is usually in childhood, and the prognosis is generally poor: the majority of NPC patients die before the age of 20 and very few live into middle age
- Currently there is only one approved therapy for NPC, and that has only been approved for use in the EU. It is called miglustat, and it extends life by a few months in a sub-group of patients
- Based on preclinical experiments indicating that arimoclomol may correct the underlying pathology of NPC we are currently conducting a phase II/III study in children and adolescents suffering with NPC to investigate the effects of arimoclomol on disease progression
- Gaucher’s disease is a lysosomal storage disease which affects around 1 in 100,00 newborns
- It is a recessive, autosomal genetic disorder, meaning both parents must be carriers of the mutation to pass on the condition, and is caused by mutations in the GBA gene
- There are three subtypes, but all are marked by an accumulation of lipid molecules in lysosomes of the cells in a number of different organs around the body, including the spleen, liver and central nervous system (types 2 & 3 only). White blood cells called macrophages are particularly vulnerable to lipid accumulation in Gaucher’s disease
- There are approved treatments for Gaucher’s disease, including enzyme replacement therapy and substrate reduction therapy, along with symptom management, however these therapies do not address the central nervous system manifestations of the disease
- Based on encouraging preclinical experiments with arimoclomol we are advancing our pre-clinical Gaucher’s disease programme and aim to advance our clinical programme in the near future
Lysosomal Storage Diseases
New Molecular Entities Programme
What is a clinical trial?
Clinical trials are investigations to evaluate new ways to prevent, diagnose or treat diseases in human patients or healthy volunteers. They test medical devices, products or techniques, or they explore new ways of using existing treatments, or combinations of different treatments. Based on the results of clinical trials, scientists can evaluate treatments in relation to both safety and effectiveness. Clinical trials are launched when there is good evidence from laboratory (or other preliminary) studies to suggest that the intervention being tested is an improvement on the current best practice.
Clinical trials are sometimes referred to as ‘clinical studies’, ‘medical research trials’ or simply ‘trials’. Almost all the pharmaceuticals that we use today can be traced back to the results of clinical trials conducted in the past.
Normally, there are four phases in the clinical trial process, referred to as Phases I-IV. Each phase of a clinical trial has a different purpose and helps scientists to find answers to various questions.
is to test the safety and possible side effects of a new treatment or intervention, and to identify the best dose to administer.
is to test if the treatment or intervention is effective against the disease and to find out more about the safety and dosage.
is to compare the new treatment with the current best practice and identify if it’s more effective. Phase III trials usually recruit large numbers of patients from many different sites because it can be difficult to compare the two categories of treatment with small groups. Patients are usually randomised, which means they are assigned to a treatment category (new treatment or current best practice) at random.
is usually carried out after an intervention has been approved for use. Phase IV trials are typically used to study if a treatment works for a wider range of uses, or to understand its long-term effects.
Arimoclomol is an ‘investigative medicinal product’, meaning it is not an approved medicine. We are conducting clinical studies to investigate how effective arimoclomol is as a treatment for a number of diseases. To be approved, all new therapies must be effective and must not cause undue harm. We have studied arimoclomol’s effects thoroughly in the laboratory and are now investigating its effects and safety in patients.
Arimoclomol is a small molecule, which readily distributes around the body, including crossing the blood-brain barrier. It is soluble, and has almost no taste or smell, which means it can easily be dissolved in a drink or suitable food.
Many lysosomal storage diseases are caused by mutations in a protein involved in lipid digestion and transportation. This causes an accumulation of lipid in compartments of the cell called lysosomes, which in turn leads to cell stress and toxicity. When stressed cells are treated with arimoclomol, they are stimulated to produce a natural chaperone called Heat Shock Protein 70 (HSP70), which helps to fold the digestive enzyme into a functional conformation, allowing the cell to process the accumulated lipid.
In rare circumstances, some proteins are vulnerable to aggregation, meaning they clump together and don’t get recycled properly. Aggregations of misfolded proteins cause cell stress, and eventually cell death. When stressed cells are treated with arimoclomol, they are stimulated to produce a natural chaperone called Heat Shock Protein 70 (HSP70), which helps to guide aggregated proteins into the recycling pathway and prevents newly-built proteins from aggregating.
The safety profile of arimoclomol has been extensively explored and confirmed in multiple pre-clinical and phase I clinical studies. The compound has been investigated in pre-clinical toxicity studies, in extensive Phase I studies in healthy adults as well as in Phase II studies in ALS. A total of more than 200 patients have been exposed to arimoclomol for up to a year. No major safety concerns were observed in any of the patients as a result of arimoclomol.