Current status: clinical studies did not reach primary endpoints; preclinical studies to identify new compounds to upregulate utrophin

Utrophin upregulation

Aim:
To increase the levels of the dystrophin homologue utrophin in muscle.

Background:
Utrophin is a protein that is very similar to dystrophin and forms the same link between cell skeleton and connective tissue dystrophin does, but primarily in non muscle tissues. During muscle development or regeneration, utrophin is located at the membrane of muscle fibers. However, when dystrophin production is initiated, dystrophin will replace utrophin. In adult muscles utrophin is expressed at very low levels and mainly located at the transition of nerve to muscle (neuromuscular junction). In Duchenne patients and animal models, however, utrophin is expressed at the muscle fiber membrane as well. In patients these increased levels are still too low to be beneficial. Mouse studies have revealed that 300-500% increased levels of utrophin can functionally compensate for lack of dystrophin and delay disease progression.

Genes have a volume switch, which is regulated by special proteins that can turn a gene off, or set it to low or high in different tissues (resulting in low or high levels of protein, respectively). The utrophin gene switch is set to a very low volume in muscle. Thousands of drugs are screened in order to find those that can increase the volume of the utrophin gene.

Ezutromid (discontinued)

Clinical trials:
Drugs to enhance utrophin expression in cultured cells and animal models have been identified by Summit PLC (John Tinsley and Kay Davies, UK) and BioMarin Pharmaceutical Inc.. BioMarin has completed a phase 1 clinical trial where ezutromid (then named BMN-195) was tested in healthy volunteers. Unfortunately, the amount of ezutromid that ended up in the blood of the volunteers was considered too low to lead to utrophin upregulation. BioMarin therefore stopped the development of this compound. Meanwhile, Summit produced an optimized formulation that should allow improved uptake.

Clinical trials 2:
Summit has tested the new formulation of ezutromid in healthy volunteers and observed that uptake was sufficient to enable utrophin upregulation when taken with a meal. This formulation was tested in DMD patients in 3 different doses and uptake resulted in sufficient levels in blood for two of the 12 patients. A follow up trial has been performed where the formulation was tested with a high-fat meal. This improved uptake with 6/12 Duchenne patients having drug levels expected to increase utrophin expression by 30-50% based on mouse data. A phase 2 trial to assess efficiency in ambulant Duchenne patients is currently ongoing (and fully recruited) in the UK and the USA. For an interim analysis, a biopsy was taken after 24 weeks of treatment showing a 7% increase in utrophin levels. A phase 3 confirmatory study is being prepared. Analysis after 48 weeks revealed that the primary endpoint and secondary outcomes were not met (i.e. the drug had no therapeutic effect) and Summit announced that the development of ezutromid will be discontinued for Duchenne.

Additional approaches to enhance utrophin levels are in the preclinical phase. Biglycan from Tivorsan aims to increase both utrophin and nNOS. Laminin-111 from Prothelia aims to increase utrophin and integrin (another protein that links muscle fibers to connective tissue and thus provides stability).