Therapeutic focus – Sarepta success signals antisense progress in muscular dystrophy


Sarepta Therapeutics’ surge on the strength of 36-week phase IIb data for its Duchenne muscular dystrophy drug eteplirsen is a sign of the hopes laid in the antisense approach to treating this genetic disease. The leading candidate in the pipeline, GlaxoSmithKline's GSK2402968, is approaching pivotal data readout in coming months, and uses a similar approach to shut off a mutation that causes this form of the degenerative disease in boys.

Duchenne is one of the most severe forms of the disease, with onset apparent when a child begins walking and sufferers have a life expectancy of just 25 years. Current pharmaceutical treatments include use of steroids to improve muscle strength, but there are no disease-modifying therapies. Thus patients and specialists are awaiting new developments, not just in Duchenne but in the wider array of muscular dystrophies (see table below).

Better walking

Formerly known as AVI BioPharma, Sarepta reported statistically significant improvement in the six-minute walk tests of a small number of boys with Duchenne muscular dystrophy, following on 12 and 24-week data indicating significant improvements in levels of dystrophin, a protein that protects against destruction of muscle fibre.

Shares in the company rose 146% to $8.52 yesterday on the news, returning them to levels last seen in April, adjusted for a six-for-one reverse split implemented with the company’s name change earlier this month. In April, the Washington group released 24-week data from the trial that failed to demonstrate that increasing levels of dystrophin would lead to the clinical benefit seen with the six-minute walk test, leading to a massive sell-off. The 36-week trial results confirmed some analysts’ beliefs that longer dosing would yield positive results.

Duchenne affects about 1 in 3,600 boys, qualifying it for orphan disease status, which might help Sarepta secure a partner and speed regulatory review should the drug continue to perform in the clinic; a phase III trial might not be necessary. A share price boost could also set the stage for an equity fundraising should a partner not be forthcoming. The company had $30.6m at March 31, and analysts from Wedbush forecast a $25m cash burn for 2012.

Muscular dystrophy pipeline
Product Company Generic name Pharmacological class Trial ID
Phase III GSK2402968 GlaxoSmithKline/Prosensa drisapersen Muscular dystrophy antisense NCT01254019
Sovrima/Catena Takeda/Santhera Pharmaceuticals idebenone Coenzyme Q10 NCT01027884
Ataluren PTC Therapeutics ataluren Transcription modulator NCT01247207 
Phase II Increlex Roche/Ipsen mecasermin IGF-1 NCT01207908
PRO044 GlaxoSmithKline/Prosensa - Muscular dystrophy antisense NCT01037309
AVI-4658 Sarepta Therapeutics eteplirsen Muscular dystrophy antisense NCT01396239
Follistatin Program Milo Biotechnology follistatin Activin antagonist NCT01519349
CRD007 Cardoz pemirolast potassium Anti-inflammatory agent NCT01540604
Phase I GLPG0492 Galapagos - Selective androgen receptor modulator (SARM) NCT01538420
UC-MSC Shenzhen Beike Biotechnology mesenchymal stem cells Stem cell therapy NCT01610440
SNT-317 Novartis/Santhera Pharmaceuticals omigapil GAPDH inhibitor -
SMT C1100 Summit - Utrophin inducer -
HT-100 Halo Therapeutics halofuginone hydrobromide Muscular dystrophy agent -

Making antisense

However good the news from Sarepta, eteplirsen, also known as AVI-4658, is not the most advanced drug in Duchenne antisense. That honour belongs to GSK2402968, which GlaxoSmithKline licensed from the Dutch biotech Prosensa in 2009 for $25m and up to $655 in milestones (EP Vantage Interview - Prosensa’s antisense technology making sense to Glaxo, September 13, 2011).

Like eteplirsen, ‘968 silences a faulty exon in the gene coding for dystrophin, allowing production of a shorter, but functional protein. The specific exon being tested, 51, may may help treat 13% of Duchenne patients, according to the Muscular Dystrophy Campaign in the UK. Molecules are being developed that may address other faulty exons.

The GSK/Prosensa drug is nearing conclusion of a one-year trial in 180 boys, with the six-minute walk test the primary endpoint; it could read out by the end of this year.

Wedbush analysts believe eteplirsen will be a bigger success based on its safety profile – the Sarepta drug reported no adverse events, discontinuations, or changes in any laboratory safety parameters. By comparison, in phase I and II GSK’s ‘968 reported high levels of proteinuria, elevated urinary alpha1-microglobulin levels and injection site reactions, suggesting that long-term dosing “may not be feasible”, the Wedbush analysts write.

Also in phase III is PTC Therapeutics’ gene skipping drug Ataluren, which is also being trialled in cystic fibrosis. Two extension studies are under way, only one of which has efficacy endpoints, according to That trial may report sometime in the middle of 2013.

Pumping up

A look at EvaluatePharma’s data shows that the muscular dystrophy pipeline is directed toward the antisense approach, but not exclusively. The only other phase III candidate is Takeda and Santhera Pharmaceuticals’ idebenone, an antioxidant that has been marketed for Friedreich’s ataxia and skin damage.

In phase II, GSK and Prosensa again have PRO044, expected to report data later this year in a study of 18 patients, with muscular dystrophin levels a primary endpoint. Roche and Ipsen are testing Increlex, the insulin growth factor-1 product already prescribed for IGF-1 deficiencies; this has been tested in a different form of muscular dystrophy, the myotonic subtype, but did not show statistically significant improvements in the walking test or other clinical parameters.

In a more complex approach, it is hoped that Milo Biotechnologies’ gene therapy follistatin will stimulate muscle growth in Becker muscular dystrophy patients. A phase II study in Ohio is testing adenovirus delivery of follistatin genes to improve muscle strength and patients’ ability to walk. This trial will probably not read out until at least 2015.

Similarly, phase I candidates are taking the muscle-building approach. The Belgian biotech Galapagos has slated a selective androgen modulator, GLPG0492, as a hope in Duchenne muscular dystrophy along with cachexia. Shenzhen Beike Biotechnology is using umbilical cord-derived mesenchymal stem cells in a Duchenne trial to improve musculoskeletal function.

Finally, Santhera Pharmaceuticals believes that its glyceraldehyde 3-phosphate dehydrogenase inhibitor SNT-317 can prevent cell death in muscular dystrophy. As Novartis has abandoned this in Parkinson’s and Alzheimer’s diseases, it has much to prove.

The antisense approach, which has struggled to make headway in other clinical areas, is currently carrying the flag in the muscular dystrophy field, particularly for the difficult Duchenne type (Vantage Point - Clinical progress required to reignite RNAi field, May 20, 2011). If it fails, there is no shortage of innovation; however, as remaining technologies rely largely on building muscle rather than attacking underlying pathways, it will take a very effective agent to do more than just slow disease progression.

To contact the writer of this story email Jonathan Gardner in London at

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