Developing a brand-new drug takes an enormous amount of time, money and effort. Meticulous testing, delays and barriers mean that translation of a promising molecule into an approved drug often takes more than 14 years. If we are to develop treatments for this generation of DMD boys, it is crucial to advance strategies to reduce this time frame, decrease costs and improve success rates.

Drug repurposing or re-positioning is one such strategy. Repurposing is taking a drug which is already approved for one disease and using it to treat another. Drugs which have been developed or approved for other uses have already been tested in humans, so detailed information is available on their pharmacology, formulation and potential toxicity. Because repurposing/repositioning builds upon previous research and development efforts, new candidate therapies could be ready for clinical trials quickly, speeding their review by Regulatory Authorities and, if approved, their integration into treatment for Duchenne.

Tamoxifen

Duchenne UK is funding a clinical trial to assess the safety and efficacy of Tamoxifen as a potential treatment for Duchenne Muscular Dystrophy.

Tamoxifen has been used to treat breast cancer since the 1980s. It is also used for hormonal disorders in pre-pubescent boys. Preliminary data in the DMD mouse model (Dorchies et al. 2013) demonstrated that Tamoxifen reduced fibrosis, increased the thickness of muscle fibres, and resulted in a delay in disease progression.

Duchenne UK is contributing £575,000 to the study and will fund one European trial site and two in the UK, along with the project manager for the study, based in Switzerland. Duchenne UK is working with the DMD Hub to support the trial sites in the UK for the Tamoxifen study.

The trial is being jointly funded by Duchenne UK, E-Rare, Duchenne Parent Project in Holland, and the Monaco Association against Muscular Dystrophy. The first patient was dosed in June 2018 in Switzerland. The first and second trial sites in the UK for this study are Alder Hey Children’s Hospital in Liverpool and Leeds Children’s hospital, and they are aiming to start in 2019. 

In December 2018 we announced a further £780,000 funding to the Tamoxifen trial for an open-label extension study. This will ensure participants of the phase 3 trial continue to have access to the treatment when the trial is over. The open-label extension study will also help gather long term data on the effects of tamoxifen on patients with DMD.

Idebenone (Raxone®)

Idebenone (Raxone®) is being developed for a number of mitochondrial and neuromuscular indications by the pharmaceutical company Santhera. Raxone is currently approved in the EU for the treatment of visual impairment in adolescent and adult patients with Leber's Hereditary Optic Neuropathy (LHON).

In a phase III trial, Raxone significantly delayed the rate of lung function loss in Duchenne patients that were not taking concomitant steroids. In January 2018, Raxone received a negative opinion from the European Medicines Agency (EMA) for market authorisation. However, Raxone is available in the UK to patients under the MHRA’s Early Access to Medicine Scheme (EAMS). Sarepta is expected to re-submit to the EMA after collecting more data in a new Phase III study.

Simvastatin

Another example of a drug that has the potential to be re-purposed for Duchenne is simvastatin. In addition to cholesterol lowering effects, experiments in mice have shown that statins may also have potent anti-inflammatory, anti-fibrotic and anti-oxidant effects. In addition, they are already approved for treatment of familial hyperlipidaemia in children and a good safety profile has been established. Plans for a clinical trial to assess their effect in Duchenne are ongoing.

Rimeporide

Rimeporide was initially developed, up to clinical stage, as a treatment for congestive heart failure. It was not continued past phase I for strategic reasons, but was tolerated well by subjects. Comprehensive data on the pharmacology, formulation, dosing, pharmacokinetics and toxicity were obtained during this trial.  

EspeRare’s first clinical study for Rimeporide in patients with DMD (phase Ib) was completed in March 2018 and showed good safety and tolerability. EspeRare is preparing for a phase II cardioprotective study to evaluate the efficacy of Rimeporide in DMD.

Metformin

Metformin is an approved drug for the treatment of type II diabetes. Duchenne UK have been working closely with Professor Dirk Fischer at the Children's Hospital in Basel, Switzerland (UKBB), to help plan a clinical trial to examine the safety and efficacy of Metformin and L-Citrulline as a combination treatment for DMD. In March 2018 we received Orphan Drug Designation for Metformin/L-Citrulline for the treatment of DMD. 

Combination therapy

In 2018 we granted £200,000 to Dr Olivier Dorchies at the University of Geneva to run a 2-year pre-clinical study into a combination therapy for DMD. The study is investigating the effect of combining two repurposed drugs, tamoxifen and metformin, with L-Citrulline, a nutraceutical. The study is also looking at the effect of combining these drugs with prednisone, the most commonly prescribed steroid for DMD. Read more about this project here.

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