DMD: Reformulated Utrophin Upregulator Looks Good in Healthy Volunteers

SMT C1100, which increases levels of the protein utrophin, reached adequate blood levels in healthy volunteers; trials in Duchenne MD may be next

Summit PLC has reformulated SMT C1100 so that it now reaches adequate blood levels in humans.
Article Highlights:
  • The utrophin-upregulating drug SMT C1100, tested in a phase 1, dose-escalating trial in healthy human volunteers, appears to be safe and reaches blood levels considered adequate for a therapeutic effect.
  • Summit PLC, a U.K.-based drug development company, says the results, announced at the October 2012 meeting of the World Muscle Society, support moving forward with trials of SMT C1100 in Duchenne MD.
  • MDA has supported basic and clinical research related to SMT C1100 development.
by Margaret Wahl on October 10, 2012 - 4:15pm

Update (Nov. 7, 2012): In a Nov. 7, 2012, press release, Summit PLC announced that twice-daily oral dosing of SMT C1100 in healthy volunteers appears safe and well-tolerated, and results in blood levels of the drug that would be expected to increase utrophin production. Previously announced results were for single-dose administration of SMT C1100. A presentation will be made at the 2012 Action Duchenne Conference in London Nov. 9-10; a copy of it will be posted on the Summit PLC website after the event.
Protein Clusters

Note: Click on photo to expand.

Normally, the dystrophin protein helps protein clusters in the muscle-fiber membrane anchor to the inside of the muscle fiber. Utrophin can probably substitute for dystrophin in this role, animal studies suggest.

Summit PLC, a drug discovery company based in Oxford, U.K., has announced that SMT C1100, its experimental oral drug for Duchenne muscular dystrophy (DMD), appears safe and well-tolerated in healthy volunteers at all doses tested, and that it reaches levels in the bloodstream believed to be adequate for a therapeutic benefit.

SMT C1100 is designed to increase production of (upregulate) the muscle protein utrophin.These results support moving the drug into clinical trials in people with DMD.

MDA provided significant funding for both the development of SMT C1100 and the trial.

"We are very pleased by these encouraging results showing that SMT C1100 can reach plasma levels that might be expected to be effective," said Jane Larkindale, MDA's director of translational research. "MDA has been supporting the development of utrophin-increasing strategies for many years. We eagerly await the reporting by Summit of further data from this study and, hopefully, later-stage trials of SMT C1100 to see if this has a clinical benefit in patients."

Utrophin may substitute for dystrophin

SMT C1100 is formulated to increase production of utrophin, a muscle protein which has been shown in animal studies to partially substitute for dystrophin in muscle fibers. (See illustration.) Dystrophin is the muscle protein that is lacking in DMD.

Since utrophin is naturally produced by people with DMD, raising levels of this protein is expected to be well-tolerated by the body's immune system. Dystrophin, on the other hand, can sometimes elicit an unwanted immune response in DMD patients.

In addition, utrophin upregulation potentially could be of benefit in DMD regardless of the underlying genetic mutation that causes the disease. By contrast, strategies that focus on upregulating production of functional dystrophin (such as exon skipping and stop codon read-through) are necessarily targeted at specific DMD mutations.

Results support moving to DMD trials

The new and encouraging results were announced at the 17th Annual Congress of the World Muscle Society, held Oct. 9-13, in Perth, Australia.

"The positive outcome from this phase 1 trial is a significant step forward for DMD and our utrophin upregulator SMT C1100," said Glyn Edwards, CEO of Summit PLC in an Oct. 10 press release. "We are highly encouraged that the new formulation of SMT C1100 shows improved bioavailability, as we believe it supports the progression of this potential breakthrough treatment into DMD patient clinical trials."

Summit’s double-blind, placebo-controlled trial tested single and multiple increasing oral doses of SMT C1100 in 48 healthy volunteers.

When single doses were increased from 50 milligrams per kilogram to 400 milligrams per kilogram of body weight, blood levels of the drug increased for several hours. In separate experiments in cells taken from people with DMD, comparable SMT C1100 levels were enough to induce a 50 percent increase in utrophin.

Analysis of the multiple-dose groups is ongoing, with results expected later this year.

The presentation given at the World Muscle Society Congress is available at Summit PLC.

Drug development history

In May 2011, MDA-supported geneticist Kay Davies at Oxford University in the U.K., announced key findings showing that daily treatment with SMT C1100 reduced muscle abnormalities, increased overall strength, and improved the ability to resist fatigue after exercise in mice with a DMD-like disorder. The study was published in the journal PLoS One. MDA has provided Davies with $1.8 million since 1997 for utrophin-related research.

MDA Venture Philanthropy (the drug development arm of MDA’s translational research program) then awarded a $750,000 grant to Summit PLC in December 2011 to test SMT C1100 in humans.

At that time, Summit had produced a new formulation of SMT C1100 that it believed would result in high enough blood levels of the drug to increase utrophin production; an earlier formulation had proved inadequate in this respect.

In May 2012, the company announced that the first group of volunteers had begun receiving the drug in a phase 1, dose-escalating trial.

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