BioMarin has announced disappointing results from the Phase I clinical trial of 'BMN-195' and it has halted development of the compound. BMN-195 is an oral drug with the potential to increase the amount of the protein utrophin in the muscles. Utrophin is thought to be able to substitute for the missing dystrophin protein in boys with Duchenne muscular dystrophy.

The Phase 1 clinical trial administered BMN-195 to a small number of healthy volunteers. Increasing doses of the compound were given orally to the volunteers, but even at high doses (400mg/kg) only small amounts of BMN-195 entered the bloodstream. Furthermore, repeat doses resulted in even lower concentrations in the blood. The concentrations of BMN-195 in the blood were much lower than those expected to be able to have an effect on utrophin levels in the muscle. BioMarin therefore concluded that BMN-195 is highly unlikely to be effective for Duchenne muscular dystrophy.

What next?

Although BMN-195 appeared to be promising in pre-clinical tests in mice, in human volunteers the compound was not absorbed and distributed through the body as expected. However, all parties involved are still optimistic that this strategy of increasing levels of utrophin is a viable treatment approach for Duchenne muscular dystrophy and are working on alternative drug candidates which may be ready for clinical trial in the near future.

Jean-Jacques Bienaime, Chief Executive Officer of BioMarin said: "Duchenne muscular dystrophy remains a serious unmet medical need affecting approximately 40,000 patients in the developed world, and BioMarin remains committed to this disease area. Given the limitations of BMN 195, we believe that other approaches to up-regulation of utrophin may be more possible, and we continue to believe that utrophin upregulation is a viable approach for the treatment of DMD. We are currently working on additional candidates to take forward into early human studies, and the new compound we are working on appears to overcome the limitations of BMN 195."

Prof. Dame Kay Davies at the University of Oxford who has been funded for over 25 years by the Muscular Dystrophy Campaign and was involved in the initial development of BMN-195 said: "The failure of the BMN-195 is Phase I trials is obviously very disappointing as it looked so promising in the mdx mice. However, we have new screens coming along which should provide new and better candidates for increasing levels of utrophin. We, like BioMarin, remain committed to utrophin upregulation for the therapy of Duchenne muscular dystrophy."

Summit, the Oxford drug discovery company which initially developed BMN-195 in collaboration with Prof. Dame Kay Davies, has not ruled out further developing BMN-195. On their website they say: "Summit remains committed to working in DMD believing that use of an appropriate formulation has the potential to produce a viable medicine and is investigating commercial opportunities to support the future development of BMN-195."

More information about utrophin

Duchenne muscular dystrophy is caused by mutations in the dystrophin gene. This gene contains the instructions for making dystrophin protein which is an important structural component of muscle cells and acts as a shock absorber to prevent damage when the muscle contracts. Utrophin may be able to compensate for the lack of dystrophin in boys with Duchenne muscular dystrophy since both proteins are structurally similar and appear to have very similar functions. Increasing levels of utrophin could potentially be a treatment which would be applicable to all boys with Duchenne muscular dystrophy, regardless of their type of mutation.

Research on utrophin by Prof. Dame Kay Davies at the University of Oxford, has been funded by the Muscular Dystrophy Campaign for more than 25 years. The team used a mouse model for Duchenne muscular dystrophy to study utrophin function. By genetically modifying the mice to produce more utrophin, the muscular dystrophy symptoms in the mice were reduced. This was followed up with detailed analyses of how the gene for utrophin is controlled.

The knowledge gained from these studies on the utrophin gene was used to search thousands of chemicals for those that would increase the levels of utrophin in muscle cells (in collaboration with Oxford biotechnology company Summit plc). At Summit plc these chemicals were modified and improved until a final candidate- SMT C1100 (now also known as BMN 195), was chosen for further testing and eventual use in clinical trials. Summit plc signed a multi-million dollar deal with US pharmaceutical company BioMarin in July 2008 to take this chemical to clinical trials.

The Muscular Dystrophy Campaign continues to fund this important work on utrophin. Read about the utrophin upregulation project.

Further information and links:

Read BioMarin's press release.

Current clinical trials for muscle disease.

Muscular Dystrophy Campaign