BioWorld Today – July 7, 2014 (VOLUME 25, NO. 129)
PLENTY OF ‘PATIENTS’ Akashi makes no- nonsense moves in DMD with group backing
By Randy Osborne, Staff Writer
With fast track FDA status for its lead compound against fibrosis in Duchenne muscular dystrophy (DMD) and new financial support from the main disease association through a philanthropy program based on promising preliminary phase Ib/IIa data with oral HT-100 (delayed-release halofuginone), Akashi Therapeutics Inc. takes its place in the race for a new DMD therapy.Small-molecule halofuginone, designed also to reduce inflammation and promote healthy muscle fiber regeneration in DMD patients, has been granted orphan designation in the U.S. and European Union. “It’s going to take a cocktail of drugs to treat DMD,” said Marc Blaustein, CEO of Cambridge, Mass.-based Akashi, who called HT-100 “a mini-cocktail for DMD in and of itself.” Other compounds in development target mutation-specific forms of DMD, whereas Akashi’s candidate is “relevant for all boys, no matter what the mutation,” he added.
Blaustein mentioned ataluren, the oral small molecule from South Plainfield, N.J.-based PTC Therapeutics Inc., which won a recommendation for conditional approval in Europe, where it would be marketed as Translarna for nonsense-mutation DMD in ambulatory patients 5 years and older. (See BioWorld Today, May 27, 2014.)Nonsense mutations create a premature stop signal in the translation of the genetic code contained in mRNA, which prevents full-length, functional proteins from growing. Ataluren apparently interacts with the ribosome, letting it read through the stop signals on mRNA and allowing the cell to make a full-length protein. Ataluren “should restore essentially a full-length dystrophin, by the nature of its mechanism,” Blaustein said, but it would work only in the 10 percent of cases where the nonsense mutation is a factor.
Not so with HT-100. The drug’s active ingredient, halofuginone, “is a derivative of one of the basic building blocks of Chinese medicine,” Blaustein told BioWorld Today, which is found in the root of a hydrangea plant called chang shan. Synthesized “quite a while ago by the U.S. Army,” it’s used in China to treat malarial fever and approved in the U.S. for veterinarian use as an antiparasitic therapy, but it has never reached the market for humans because of poor gastrointestinal tolerability. “We developed HT-100 to address that issue,” Blaustein said, and side effects have been minimal so far.Akashi bought assets and intellectual property related to halofuginone, which blocks Th17 cells, from Collgard Biopharmaceuticals Ltd., of Petah Tikva, Israel. Collgard had been investigating the drug’s value in sclerodoma, an indication that Akashi also intends to explore further. As an oral systemic antifibrotic agent, the compound holds potential in “a large number of indications, orphan and non-orphan,” Blaustein said. But first, the company is working on DMD, the most common and most aggressive form of muscular dystrophy, affecting about one in 3,600 boys worldwide. “It’s the leading genetic killer of children,” he said.Akashi intends to “generate the data we need to design the next study, which we anticipate will be a registrational study,” that will enroll “somewhere in the range of 40 to 120 patients,” depending on how the experiment is set up, Blaustein said. He acknowledged that other studies are enrolling in DMD, but said “the fact that our drug is not mutation-specific, and we’re exploring it for younger and older boys, means that there’s a relatively large patient pool from which to draw.”The early data in the first two DMD patient cohorts (with six patients each) from the phase Ib/IIa study were presented at the New Directions in Biology and Disease of Skeletal Muscle 6th Biennial Conference in Chicago this week. HT-100 turned up a favorable safety profile in dosing cohorts ranging from 0.3 mg/day to 1.2 mg/day for up to 92 total dosing days with no serious adverse events and no clinically significant adverse events. Researchers found significant biologic activity, too, and positive trends in serum biomarkers of muscle tissue remodeling in DMD, including biomarkers of collagen formation (fibrosis) and collagen degradation, as well as positive effects on a biomarker of muscle damage.
GOING SOLO, IF NECESSARYEnrolling up to 30 boys and young men, ages 6 through 20, with DMD (ambulatory and non-ambulatory), the dose-escalating, multicenter trial should enable investigators to evaluate HT-100 in a broad patient population. The study has been designed to assess trends in a range of exploratory biomarkers and efficacy endpoints. Such biomarkers include plasma-derived measures of fibrosis formation and degradation in muscle that have been validated in other disease states. The clinical outcome endpoints include motor function and muscle strength tests, as well as measures of pulmonary and cardiac function.“We are building a portfolio of compounds to address the disease, to be part of this cocktail and make DMD a chronic, manageable disease,” Blaustein said, adding that another clinical asset is “prepared to move forward, and we’ve done some work on trial design.” That asset is DT-200, an oral selective androgen receptor modulator that has yielded positive phase I data. “It’s basically a muscle-building drug,” he said, reciting the three main ways to attack DMD: go after the underlying defect by replacing dystrophin; take aim at pathologies such as fibrosis (HT-100’s role); and “do what you can to strengthen the remaining muscle,” which is DT-200’s job.
“We expect later on during the summer to announce in-licensing of another preclinical compound that will be the third component of our portfolio,” Blaustein said, noting that the company would “like to have the resources to see multiple compounds move forward, so we are interested in partnering in the near term.” If the right partner doesn’t materialize, Akashi has “the resources we need to continue to move HT-100 forward at a rapid pace,” he said.
The company was founded through patient associations, and all of its funding has come from them, which means a “unique and very close relationship” with those afflicted, who make up “a community that is incredibly active and very effective at pursuing policy goals and helping to provide resources to move important therapies forward,” Blaustein said.Most recently, the Muscular Dystrophy Association made an investment to boost HT-100 through the MDA Venture Philanthropy program, bringing the collective funding to $1.5 million that Akashi has collected from 15 other nonprofit organizations. //