Therapeutic focus - Promising therapies emerging for muscular dystrophy


Last week, GlaxoSmithKline licensed an RNA modulating therapeutic in phase II trials for Duchenne muscular dystrophy (DMD) from The Netherlands’ ProSensa. As a first stride into the world of niche medicines, this could certainly be described as a brave leap.

There is nothing on the market for the rare, inherited muscle wasting disease, current treatments only attempt to alleviate the symptoms; a definite unmet medical need. The reason for this absence can be explained by the complexity of the condition, only the relatively recent coding of the dystrophin gene allowed researchers to work on targeted, disease-modifying therapies. As the table below shows only a handful of products are in development, most following similar approaches. ProSensa’s PRO051 is not the most advanced, but the Glaxo deal provides strong endorsement and plenty of cash, so is certainly one to watch.

Faulty gene

Of the therapies in development for muscular dystrophy, most focus on the Duchenne type, one of the most common and devastating forms of muscular degeneration. Relatively speaking it is still a rare disease; there are only an estimated 30,000 sufferers in Europe and North America.

The disease is caused by a faulty X-linked gene so usually only affects males, who can develop symptoms as early as three years old. The average life expectancy for patients is 30 to 35 years.

DMD is caused by mutations or faults in the dystrophin gene, which encodes a protein also called dystrophin. In healthy individuals, this protein stabilizes the muscle cells during cycles of contraction and relaxation, its absence or presence of mutated forms result in progressive muscle weakness and wasting throughout the body. Sufferers normally become confined to a wheelchair during their teenage years.

Becker muscular dystrophy is a milder variant of DMD where the gene is less faulty and therefore the disease slower to progress; men with typical Becker DM become unable to walk in their 40s or 50s.

Helping the heart

The most advanced candidate in the clinic is idebenone, under development by Santhera Pharmaceuticals and Takeda, which entered phase III last month. The drug is targeted specifically at alleviating the symptoms of muscle wastage in the heart and respiratory system, life threatening complications of the disease.

Idebenone works by facilitating the transport of electrons within mitochondria. Santhera believes its candidate can help prevent cell damage and increase the production of energy within impaired nerve and muscle tissue in DMD patients.

The 12-month Delos study will enrol up to 240 patients in Europe and North America, primarily measuring change in respiratory function. Both the FDA and EMEA have agreed that this single pivotal study could suffice for approval, if results are positive.

Iplex, an insulin-like growth factor being developed by Insmed, is also not strictly targeted at the underlying mechanism of the disease. It is being trialled in another dystrophy, called myotonic dystrophy (MMD), which causes muscle weakness and wasting, but it is not always progressive, and affects individuals to varying degrees and at different ages.

Not very encouraging results were reported from an exploratory phase II trial of the product in MMD in June, although further work in MMD patients with severe insulin resistance might be carried out, if a research grant can be raised.

Clinical muscular dystrophy pipeline
Product Company Pharmacological Class Indication Summary
Phase III Sovrima/Catena (idebenone) Takeda/Santhera Pharmaceuticals Coenzyme Q10 Friedreich's ataxia [Phase III]; Muscular dystrophy [Phase III]
Phase II AVI-4658 AVI BioPharma Muscular dystrophy antisense Muscular dystrophy [Phase II]
Ataluren PTC Therapeutics/Genzyme Transcription modulator Cystic fibrosis (CF) [Phase III]; Muscular dystrophy [Phase II]
PRO-051 ProSensa Muscular dystrophy antisense Muscular dystrophy [Phase II]
Iplex Insmed/Roche/Ipsen IGF-1 Growth hormone disorders [Withdrawn]; Muscular dystrophy [Phase II];
Phase I SNT-317 Novartis/Santhera Pharmaceuticals GAPDH inhibitor Muscular dystrophy [Phase I]; Amyotrophic lateral sclerosis (ALS) [Abandoned - Unclassified]; Parkinson's disease [Abandoned - Unclassified]; Alzheimer's disease [Abandoned - Unclassified]
971086 GlaxoSmithKline Selective androgen receptor modulator (SARM) Muscular dystrophy [Phase I]
MyoDys Transgene Muscular dystrophy gene therapy Muscular dystrophy [Phase I]
ACE-031 Acceleron Pharma Myostatin (GDF-8) antagonist Muscular dystrophy [Phase I]; Amyotrophic lateral sclerosis (ALS) [Phase I]; Cachexia (wasting) [Phase I]
Biostrophin Asklepios BioPharmaceutical Muscular dystrophy agent Muscular dystrophy [Phase I]

Disease modifying

The remaining three phase II products are striving to modify the disease by directly interfering with the synthesis of the dystrophin protein. This approach is complicated by the fact that DMD is caused by more than one genetic mutation, and these targeted products are mutation specific. At the end of the day, this means that more than one drug will have to be developed to treat all DMD patients.

The collaboration between GlaxoSmithKline and ProSensa illustrates this challenge; the scope of the alliance includes four RNA-based compounds intended to treat specific, but different, sub-populations of patients suffering from DMD.

PRO051, an antisense oligonucleotide, is the first and most advanced compound, and works by a process known as exon skipping. Essentially, the molecule forces the cellular machinery to skip a specific mutated section of the dystrophin gene, in this case exon 51, and synthesise a fully functioning, or as near as possible, dystrophin protein. ProSensa believes PRO051 could treat 13% of DMD patients.

Glaxo has the option to license three more RNA-based compounds targeting additional DMD exons, should trials prove fruitful.

AVI BioPharma is pursing a very similar approach, which ultimately begs the question: if Glaxo was looking for a RNA-based DMD molecule, why did it chose PRO051 over AVI-4658?

AVI-4658 is a “splice switching oligomer” which also uses exon skipping. A phase I trial found that production of dystrophin was significantly increased in a series of DMD patients, and in February a phase II dose-escalation study was started in the UK. Results should be due mid-2010, when the company also hopes to start US trials.

Not nonsense?

Finally in phase IIb is PTC Therapeutics’ ataluren, which is targeted at a specific mutation on the dystrophin gene called the nonsense mutation; only 13% of Duchenne and Becker MD patients’ disease is caused by this.

Nonsense mutations prevent the generation of full-length proteins by stopping their transcription too early; ataluren overrides this premature stop signal, allowing fully functioning proteins to be created. Nonsense mutations are also found in cystic fibrosis; a phase III trial in this population was commenced last month.

This is certainly the most advanced potentially disease-modifying DMD compound; a pivotal trial completed enrolment of 174 patients in February of this year, two months ahead of schedule. The one-year study is determining whether walking, muscle function and strength in patients can be improved, and results could be available in the first half of next year.

Genzyme has already bought ex-US rights to the drug; if results from both cystic fibrosis and DMD trials are encouraging a takeout of the private company would certainly be a tempting prospect.

Still high risk

However, despite attracting a lot of interest the techniques behind these drugs, antisense and RNAi, are still very much in their infancy and have not yet generated any successfully commercialised product. Add to this the complexity of DMD and it is unlikely all of these products will make it to market.

However, these candidates are by far the most promising developments for DMD to date. With big players such as Genzyme and Glaxo now on board, the field is certainly looking promising.

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