Heavy ADME

Concert Pharmaceuticals will partner with Avanir Pharmaceuticals to develop and commercialize deuterium-modified dextromethorphan for nervous system disorders

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LEXINGTON, Mass.—Concert Pharmaceuticals Inc.—a six-year-oldcompany which is betting that replacing hydrogen molecules with deuterium willsignificantly and favorably alter ADME characteristics of many small-moleculedrugs—and Avanir Pharmaceuticals have entered into an exclusive licenseagreement that provides Avanir worldwide rights to develop and commercializeConcert's deuterium-modified dextromethorphan (d-DM) for the potentialtreatment of neurological and psychiatric disorders.
The agreement, announced last month, includes the rights tomultiple deuterium-modified dextromethorphan compounds. d-DM was developedusing Concert's proprietary Deuterated Chemical Entity (DCE) platform and is adeuterium-containing analog of dextromethorphan. The d-DM compounds are coveredunder U.S. patent 7,973,049, which was issued to Concert in July 2011, as wellas patent applications in other countries.
Per Avanir's regulatory filings, the company is obligated tomake milestone and royalty payments to Concert based on successful advancementof d-DM products for one or more indications in the United States, Europe and Japan.Individual milestone payments range from $2 million to $6 million, $1.5 millionto $15 million and $25 million to $60 million for clinical, regulatory andcommercial targets, respectively. In aggregate, the payments could total morethan $200 million. Royalty payments are tiered, beginning in the single-digitsand increasing to the low double-digits for worldwide net sales of d-DMproducts exceeding $1 billion annually.
Avanir will have overall responsibility for research,development and commercialization of d-DM. Concert will provide manufacturingsupport for investigational new drug-enabling studies.
"Concert's DCE Platform has produced severaldeuterium-modified dextromethorphan compounds that we believe may providetherapeutically effective levels of dextromethorphan, potentially without theneed for an enzyme inhibitor such as quinidine," says Greg Flesher, senior vicepresident of corporate development and chief business officer at AvanirPharmaceuticals. "As part of our portfolio strategy, we intend to explore theutility of d-DM in neurological and psychiatric disorders where dual NMDAantagonists and sigma-1 agonists may be beneficial."
Dextromethorphan, in a class of medications calledantitussives, is commonly known for its use to relieve cough. However,Nuedexta, (a combination of dextromethorphan and quinidine) is approved forpseudobulbar affect (PBA), or uncontrollable emotional outbursts of laughing orcrying. Avanir estimates there are 1.8 million people with moderate to severePBA.
The incorporation of deuterium into specific molecularpositions of dextromethorphan, resulting in d-DM, was done with two purposes,says Dr. Roger Tung, president and CEO of Concert Pharmaceuticals. The firstwas to slow metabolism to maintain the pharmacology of dextromethorphan; thesecond to provide significantly enhanced resistance to CYP2D6 metabolism andimproved plasma exposure in preclinical testing. As a result, d-DM has thepotential to be effective as a treatment for neurological and psychiatricdisorders for which dextromethorphan has shown pharmacological activity.
"We are very pleased to enter into this collaboration withAvanir, who we believe has the unique expertise to best maximize the broadclinical potential of d-DM. Avanir's knowledge of dextromethorphan-basedtherapeutics and their proven track record to bring drugs to the market makethem the ideal partner for this program," says Tung. "d-DM is a great exampleof how deuterium modification can, in favorable cases, create drug candidateswith the unique opportunity for both substantially improved therapeuticproperties over existing medicines, and lower development expense and riskcompared to typical new chemical entities."
Concert focuses its efforts in areas where there is a significantopportunity to improve the absorption, distribution, metabolism and excretion(ADME) profile of pharmacologically well-characterized compounds, and wheresuch an improvement has the potential to provide a clinical benefit. Concerthas investigated the effects of selective deuterium modification on dozens ofsuch compounds, including many validated drugs, and currently has 18 issuedU.S. patents. The company has executed on this approach to become aclinical-stage biotechnology company with its lead program in Phase II clinicaltesting: CTP-499 for chronic kidney disease. In addition, Concert is developinga pipeline of preclinical candidates in several therapeutic areas.

Concert Pharmaceuticals and Fast Forward sign deal for MSprogram
LEXINGTON, Mass.—Concert Pharmaceuticals Inc. also announcedlast month that it has been awarded funding by Fast Forward LLC, the NationalMultiple Sclerosis Society's subsidiary devoted to bridging the gap betweenresearch and drug development, to fund the preclinical advancement of apotential treatment for multiple sclerosis (MS).
Fast Forward will commit funding for the clinical-stagedevelopment of C-21191, a deuterium-modified subtype-selective GABAA modulatordeveloped by Concert with the therapeutic potential of treating spasticity andpain in multiple sclerosis (MS).
C-21191 is a deuterium-modified analog of L-838417, whichwas discovered by Merck & Co. Inc. and extensively profiled in preclinicaltesting by Merck and in numerous academic laboratories. L-838417 possesses anattractive pharmacological profile including minimal sedation and ataxia, buthas a poor pharmacokinetic profile, which prevented its progression to clinicalevaluation.
C-21191 has demonstrated significantly improvedpharmacokinetic characteristics in preclinical studies compared to L-838417,while maintaining its desired biochemical profile. In side-by-side studies,C-21191 demonstrated a threefold to fourfold increase in exposure compared toL-838417 in several preclinical species. This superior pharmacokinetic profileresulted in a prolongation of exposure and a corresponding extension ofpharmacodynamic effects.
C-21191 also demonstrated equivalent efficacy to gabapentinin a neuropathic pain model, with a superior duration of effect, at doses thatdid not cause sedation or ataxia as assessed by a rotarod model.
"We are pleased to partner with Concert on this new approachwith the potential to treat spasticity and pain, which are so challenging to largenumbers of people living with MS," says Dr. Timothy Coetzee, chief researchofficer at the National MS Society and Fast Forward. "This collaborationdemonstrates Fast Forward's commitment to pursue and fund innovative medicinesthat can address unmet needs and improve the quality of life for people livingwith this disease."

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