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Spectrum wins early approval for Beleodaq; Akashi’s non-nonsense moves in DMD

By Michael Fitzhugh, Staff Writer

More than a month ahead of its scheduled PDUFA date, the FDA has approved Spectrum Pharmaceuticals Inc.'s in-licensed peripheral T-cell lymphoma (PTCL) therapy, Beleodaq (belinostat), triggering a $25 million payment to the drug's owner, Topotarget A/S.

The company said in a regulatory filing that accelerated approval of the pan-histone deacetylase (HDAC) inhibitor was based on tumor response rate and duration of response while noting that an improvement in survival or PTCL-related symptoms has not been established. Continued approval for Beleodaq's use in treating PTCL also could turn on verification and description of clinical benefit in a future confirmatory trial, Spectrum said.

Spectrum's December filing of a new drug application for Beleodaq followed news in August that Spectrum had to delay that application because the FDA wanted more analysis of pharmacokinetic data and had asked that Spectrum reformat the paperwork. (See BioWorld Today, Aug. 14, 2013 and Dec. 11, 2013.)

Beleodaq's safety and effectiveness was evaluated in a study of 129 participants with relapsed or refractory PTCL treated with the drug until their disease progressed or side effects became unacceptable. A little more than 25 percent of trial patients had their cancer disappear or shrink after treatment.

Beleodaq has shown similar efficacy in PTCL as the pair of drugs already approved in the indication, the HDAC inhibitor Istodax (romidepsin, Celgene Corp.) and Spectrum's own dihydrofolate reductase inhibitor Folotyn (pralatrexate), drugs approved in 2011 and 2009, respectively. However, it offers those benefits in a more convenient combined therapy. (See BioWorld Today, March 6, 2013.)

The most common side effects seen in Beleodaq-treated participants were nausea, fatigue, fever, anemia and vomiting.

PTCL comprises a diverse group of rare diseases in which lymph nodes become cancerous is a rare and fast-growing type of non-Hodgkin lymphoma.

“Today’s approval expands the number of treatment options available to patients with serious and life-threatening diseases,” said Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

 

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.  that 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 letting the cell make a full-length protein. Ataluren “should restore essentially a full-length dystrophin, by the nature of its mechanism,” Blaustein said, but it would only work 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 anti-parasitic 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 anti-fibrotic 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 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.