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Duchenne companies take steps along path to new therapies

Authored by James Sheppard

When Liftstream published its Special Report: The Pathway to New Therapies – Duchenne Muscular Dystrophy last month, we didn’t expect that merely a month later we’d need to provide a comprehensive update of all the new developments. However, it perhaps illustrates the considerable work which is being done to advance new therapies for this rare disease. There has been a lot of new information coming out and two of the main protagonists, Sarepta and Prosensa, have both reported positive clinical data for their exon skipping drugs, fuelling much debate among the industry scribes as to who might win out. Given all the news, we’ve provided here an overview of the main developments.

PTC Therapeutics started the spate of positive news by announcing they had closed a $60m round of private funding led by Brookside Capital. The funding brought in a number of new investors including Adage Capital Management and Longwood Fund. They join previous investors including corporates Novo A/S and Celgene. The proceeds of the funds will be used to continue the development of Duchenne drug Ataluren. PTC Therapeutics is initiating a phase 3 confirmatory study in patients with nonsense mutation DMD with the goal of commencing recruitment for the trial in H1 2013. CEO of PTC, Stuart Peltz, stated “This financing is critical to expanding our efforts to develop and commercialize novel therapies that may benefit patients with nonsense mutation Duchenne muscular dystrophy and cystic fibrosis.”  The successful funding news was quickly followed by the announcement that ARMGO Pharma has received $1m to develop ARM210 in DMD. The money was provided by the Muscular Dystrophy Association’s venture philanthropy arm.  Another major charity in the DMD community, CureDuchenne, announced they’d partnered with the University of Rennes to expand the eDystophin database.

To add to this wall of news, Halo Therapeutics announced on April 5th they had received FDA approval to commence a phase Ib/IIa study of HT-100 in 30 boys and young men (aged 6-20) at five sites in the USA. Halo Therapeutics was established to tackle Duchenne Muscular Dustrophy and is a subsidiary of DART Therapeutics who in the past month announced they’d obtained a drug from Belgium based biotech, Galapagos. The drug DT-200, is an oral SARM (selective androgen receptor modulator) with positive phase 1 clinical data that has broad potential for multiple neuromuscular diseases. It works by increasing muscle size and strength in patients living with neuromuscular diseases and the companies sees opportunities for the drug in treating DMD. DART Therapeutics also announced that they had signed a collaboration with Biovista’s Clinical Outcome Search Space (COSS) to identify novel repositioning candidates. DART Therapeutics will have the option to develop any promising drug candidates further.

More recently, Merck Serono EPP announcing they had donated €2.8m to EspeRare Foundation for the development of a novel DMD drug. The EspeRare Foundation is the first initiative of its kind in the framework of the EPP. The mission of the EspeRare Foundation is to uncover the potential of existing drugs to address severe therapeutic unmet needs in rare diseases, providing further evidence for drug-repurposing to address high unmet medical needs in rare diseases. EspeRare Foundation will be able to call on an established network of patient groups, pharmaceutical companies, biotechs, regulators and academic institutions across the world. Caroline Kant, founder of the foundation said ‘As a non-profit organisation, our priorities are not determined by commercial incentives or the size of a market, they are solely driven by the medical needs of patients suffering from rare diseases and the wealth of good science already available.’ EspeRare counts Sharon Terry of Genetic Alliance among its board members.

UK biotech, Summit plc, outlined the clinical development plans for their utrophin modulation therapy. Utrophin modulation therapy is of particular interest to the DMD community as it has the potential to work in 100% of patients, whereas more advanced exon-skipping drugs treat sub-populations of patients with specific mutations. Summit’sdrug SMT C1100 is now expected to enter clinical trials during H2 2013. The clinical study will consist of two parts: firstly a dose ranging safety trial and will be followed by a phase II trial that will include clinical markers of muscle health as well as levels of utrophin expression and other novel biomarkers. The biomarker programme has commenced in collaboration with Children’s National Medical Center of Washington DC.

However, the main news in the past few weeks has come from the two leading companies in exon skipping therapies, Sarepta and Prosensa. Sarepta announced the phase II data from their study of Eteplirsen. In the latest update on the 5th April 2013, Sareptaannounced 74 week results of a 6-minute walking test (6 MWT), showing a 65.2m benefit for 6 patients. Through 74 weeks, Sarepta announced there had been no adverse events or new safety issues. The company hopes that the results from this data will be used as qualifying evidence for a rapid pathway to approval for Eteplirsen in the USA.

Prosensa and their partner GSK followed Sarepta’s announcement a few days later with the presentation of data from their own phase II trial for Drisapersen. The Prosensa/GSKtrial is significantly larger than Sarepta’s trial which has 12 patients enrolled. The Prosensa trial has around 300 boys randomised in the trial. The data from GSK showed a mean improvement of 31.5m in the 6-minute walking test after 24 weeks. After 48 weeks of therapy there was a mean increase of 11.2m compared to a 24.7m decrease in the placebo arm.

Sarepta recently announced that they had signed an exclusive worldwide licensing agreement for exon-skipping programs in DMD with the University of Western Australia. The partnership is designed to apply Sarepta’s morpholino chemistry and the university’s ground breaking work with the Dystrophin gene to develop best-in-class drugs.

Much has been said of the need for increased use of conditional approval or adaptive licensing regulatory strategies and the use of real-world in-patient data to accelerate approvals and patient access. Chris Garabedian, CEO of Sarepta, recently made his pitch at the World Orphan Drug Congress in Washington D.C for open dialogue with the regulatory authorities regarding the exon therapies of Sarepta. He believes that if Sareptacan prove the clinical effectiveness of Eteplirsen as well as the safety and tolerance, then in effect they have proven the technology and the fact that it will have the same effect and safety profile in other exon indications, beyond exon 51 the mutation treated by Eteplirsen. Under the current regulatory approach, further toxicology and clinical studies would be required for each exon therapy, adding millions of dollars in expense and many years in development. Garabedian is calling for the regulatory authorities to work with them to consider the approval of the drugs as a ‘therapeutic class’, thereby allowing speedier development. Garabedian is clear that necessary measures and post approval commitments would need to be agreed, such as dose ranging studies and close clinical monitoring of the patients.

This is part of a broader assault on the existing regulatory framework in the rare diseases area, where more flexibility and creativity is being called for to expedite regulatory approval in rare diseases, something which gained further support among the community gathered at the International Rare Disease Research Consortium. The argument of whether you should need to prove your drug in each genetic mutation of the same disease is a debate which no doubt will gain momentum.

Last week also bought news from another company with a product in the DMD area,Santhera Pharmaceuticals. The company released news that the Phase III DELOS (DuchEnne Muscular Dystrophy Long-term IdebenOne Study) study of orally administered Catena® (Idebenone 150 mg tablets) in patients with Duchenne successfully passed a planned futility and safety analysis.

Santhera’s small molecule drug, Catena® is an orally available medication and therefore easily administered, which, is a distinct advantage in providing treatment for this disease. Because the drug is not dependent on any particular genetic mutation in Duchenne patients, it is potentially a product which could provide a treatment option for all patients living with Duchenne. Santhera is already partnered with Takeda for Catena® in Europe, however, in discussions with Liftstream, Santhera Pharmaceuticals’ CEO, Dr. Thomas Meier told Liftstream “the time has come to intensify efforts to find a suitable partner in the U.S who could co-develop the drug and ultimately commercialise it’. Dr. Meier will lead the partnering effort with support from Santhera’s advisors Piper Jaffrey.

Duchenne is a very active area of drug development and is illustrating some of the considerable opportunities but also challenges in advancing drugs along the path towards patients in rare diseases. It is an area which will continue to garner interest from many sections of the rare disease community and no doubt will provide some lessons for those stakeholders who care to observe.

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