Authored by Karl Simpson
One of the rare diseases currently gaining much attention is that of Duchenne Muscular Dystrophy (DMD), the most common fatal genetic disorder diagnosed in childhood and which only affects boys. This progressive muscle disorder causes progressive loss of muscle function. The prevalence of the disease is estimated at around 1 in 3500 boys. The condition is caused by the lack of the protein dystrophin. An estimated 30% of cases are due to spontaneous mutations owing to the large size of the dystrophin gene.
It is a rare and fatal disease for which patients have been given considerable hope for improved lives owing to a number of new products entering clinical development. In 2012, Sarepta and Prosensa gained particular attention for their exon skipping technology and the clinical development of new products to treat DMD.
In the build-up to rare disease day 2013, Liftstream decided to profile another innovative company addressing Duchenne Muscular Dystrophy – Summit Plc. Liftstream had the opportunity to interview the company’s management to bring you an in depth review of Summit.
Summit Plc. is an exciting company which spun out of Oxford University and has a lead programme in DMD. Last year, Summit appointed Glyn Edwards MBE as CEO, who had briefly filled the role of interim CEO of BIA and previously 13 years at the helm of UK biotech Antisoma.
Since his appoint to the CEO position at Summit, Edwards has set about refocusing the company around two assets, the SMT C1100 product for DMD and SMT 19969 being developed for C. difficile infections. This strategic realignment also meant the company moved away from its chemistry based platform, Seglin™ technology, resulting in the licensing of the technology to Bristol-Myers Squibb who will use it to screen new drug targets in multiple therapeutic indications. The deal could harvest Summit $30m in milestone payments per product developed.
Now Summit has realigned to focus on these development programmes, they are operating within the usual financial constraints of most small biotech companies and represent a far more virtual organisation today than a year ago. This has meant a reduction in staff by approximately 50% to around 15 people, having reduced the scientific research staff but retaining the skills and knowledge needed to progress both SMT C1100 and SMT 19969.
Summit is developing SMT C1100 as a disease modify drug which replaces dystophin with the naturally occurring protein called utrophin. The approach, called utrophin modulation, is capable of addressing the disease in all patients affected by the disease. When you look across clinical programmes being developed by Prosensa / GSK (exon skipping oligonucleotides), Sarepta Therapeutics (exon skipping) and PTC Therapeutics(nonsense mutation), these respective therapies have the potential to treat between 13% and 15% of the patient population, where Summit’s utrophin modulation programme can address the disease in all patients.
There are several distinct advantages to utrophin modulation, one of which is that it is a small-molecule production approach and therefore much more aligned to traditional drug production, allowing Summit to offer patients an orally administered flavoured solution which is advantageous in paediatric patients. Currently the products being developed by Prosensa and Sarepta are injectable products. This also offers distinct advantage to patients and their families because simple administration can greatly improve the therapeutic regime.
Apart from the range of production and delivery benefits from small-molecule production, utrophin is a naturally occurring protein which the body produces in foetal development and throughout the life of a DMD patient, as well in humans who do not suffer DMD, thereby expressing the protein to replace the dystrophin reduces the likelihood of triggering an immunological response.
The number of patients estimated to suffer from DMD is around 50,000 boys in the western developed world and around 250,000 in the rest of the world. While it is perhaps one of the more prevalent rare diseases, it is a considerably challenging disease and perhaps one of the more expensive rare diseases to society. In research conducted in Australia, the estimated medical and social cost of raising a boy with DMD to the age of 20 years is around A$3m. When you estimate the prevalence levels it is very easy to see this multiplies to a very considerable healthcare cost. Summit estimates the total value of the DMD market to be worth approximately $5bn globally, a market which is 100% addressable by their utrophin approach.
Following trials in the mdx mouse, Summit’s SMT C1100 showed encouraging results including significant improvement in the disease, retained or improved grip and muscle strength, improved survival of mature muscle fibres and reduced membrane damage and muscle fibre degeneration. Having seen such encouraging results, Summit conducted a Phase 1, Double-Blind, Placebo-Controlled, Ascending Single and Multiple Oral Dose, Safety, Tolerability and Pharmacokinetic Study in Healthy Male Subjects. They conducted this study with financial support in the form a $1.5m grant from a consortium of muscular dystrophy and DMD charities.
Liftstream was interested to know what Summit was planning for the Phase II trials and whether the company aimed to identify a partner for this phase of the SMT C1100 trials. Glyn Edwards responded by saying they were “reviewing a range of options for SMT C1100 which included looking at commercial partners, the opportunity of working further with the patient organisations and charities or seeking other strategic opportunities which would allow the company to advance the programme as well as maximise the long-term value for the company”. In looking for a partner, Glyn Edwards commented “they would look for the right combination of commercial reach, late stage clinical development know how and the right financial strength”.
These Phase II trials are expected to commence in early 2014, while in the meantime the company has plenty of work to do to address manufacturing, formulation, biomarker and regulatory toxicology, having so far only been in patients a total of 28 days. When considered in comparison to a company like Sarepta Therapeutics who have had eteplirsen in patients for 62 weeks as part of their recently announced trial results.
To assist with future trials and more accurately determining the effect of Summit’s utrophin modulation in DMD patients, the company has recently entered into a collaboration with the Children’s National Medical Centre to develop biomarkers in DMD, a relationship financially supported by the Foundation to Eradicate Duchenne. Dr. Hathout, a Principal Investigator at the Centre for Genetic Medicine Research at Children’s National, will apply his expertise in proteomics to develop assays which quantify utrophin protein levels in DMD muscle and will form a further part of a biomarker programme to measure biological endpoints.
As is often required in building any biotechnology or pharmaceutical company, you need to surround the company with advisors who can provide specialised input the development of the products and the company. Summit has only this past month announced a stellar line-up to their advisory board, bringing together six world-experts in neuromuscular diseases.
In our conversation with Summit, it is clear Glyn Edwards knows “how challenging it is to take their therapies from the MDX mouse testing and Phase I safety and tolerability studies through to the next stage of clinical trials and beyond.” The next stage will be the first time Summit undertakes activity in paediatric patients. They need to be able to demonstrate they can make utrophin in these patients and this is a key clinical test for this innovative approach which is based on over two decades of research.
Edwards also recognises the “invaluable contribution and support” the consortium of patient groups and charities provided in funding the phase I studies for SMT C1100. He added “These groups have an incredible understanding of the process of the disease and offer us access to patients via their active patient registries.”
DMD is a disease which has a massive impact on the patients living with the disease and those families who lose their loved ones because of its fatally destructive affects. Summit is highly optimistic of their innovative approach and they are inspired by these patients to work hard to advance the therapy and bring new hope to modify the disease in 100% of those patients affected. Liftstream will certainly be tacking very closely the activities of Summit to see if they can make a significant advance in treating DMD.