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Heavy ADME
April 2012
by Lloyd Dunlap  |  Email the author


LEXINGTON, Mass.—Concert Pharmaceuticals Inc.—a six-year-old company which is betting that replacing hydrogen molecules with deuterium will significantly and favorably alter ADME characteristics of many small-molecule drugs—and Avanir Pharmaceuticals have entered into an exclusive license agreement that provides Avanir worldwide rights to develop and commercialize Concert's deuterium-modified dextromethorphan (d-DM) for the potential treatment of neurological and psychiatric disorders.  
The agreement, announced last month, includes the rights to multiple deuterium-modified dextromethorphan compounds. d-DM was developed using Concert's proprietary Deuterated Chemical Entity (DCE) platform and is a deuterium-containing analog of dextromethorphan. The d-DM compounds are covered under U.S. patent 7,973,049, which was issued to Concert in July 2011, as well as patent applications in other countries.
Per Avanir's regulatory filings, the company is obligated to make milestone and royalty payments to Concert based on successful advancement of 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 million to $15 million and $25 million to $60 million for clinical, regulatory and commercial targets, respectively. In aggregate, the payments could total more than $200 million. Royalty payments are tiered, beginning in the single-digits and increasing to the low double-digits for worldwide net sales of d-DM products exceeding $1 billion annually.  
Avanir will have overall responsibility for research, development and commercialization of d-DM. Concert will provide manufacturing support for investigational new drug-enabling studies.
"Concert's DCE Platform has produced several deuterium-modified dextromethorphan compounds that we believe may provide therapeutically effective levels of dextromethorphan, potentially without the need for an enzyme inhibitor such as quinidine," says Greg Flesher, senior vice president of corporate development and chief business officer at Avanir Pharmaceuticals. "As part of our portfolio strategy, we intend to explore the utility of d-DM in neurological and psychiatric disorders where dual NMDA antagonists and sigma-1 agonists may be beneficial."
Dextromethorphan, in a class of medications called antitussives, is commonly known for its use to relieve cough. However, Nuedexta, (a combination of dextromethorphan and quinidine) is approved for pseudobulbar affect (PBA), or uncontrollable emotional outbursts of laughing or crying. Avanir estimates there are 1.8 million people with moderate to severe PBA.  
The incorporation of deuterium into specific molecular positions of dextromethorphan, resulting in d-DM, was done with two purposes, says Dr. Roger Tung, president and CEO of Concert Pharmaceuticals. The first was to slow metabolism to maintain the pharmacology of dextromethorphan; the second to provide significantly enhanced resistance to CYP2D6 metabolism and improved plasma exposure in preclinical testing. As a result, d-DM has the potential to be effective as a treatment for neurological and psychiatric disorders for which dextromethorphan has shown pharmacological activity.  
"We are very pleased to enter into this collaboration with Avanir, who we believe has the unique expertise to best maximize the broad clinical potential of d-DM. Avanir's knowledge of dextromethorphan-based therapeutics and their proven track record to bring drugs to the market make them the ideal partner for this program," says Tung. "d-DM is a great example of how deuterium modification can, in favorable cases, create drug candidates with the unique opportunity for both substantially improved therapeutic properties over existing medicines, and lower development expense and risk compared to typical new chemical entities."  
Concert focuses its efforts in areas where there is a significant opportunity to improve the absorption, distribution, metabolism and excretion (ADME) profile of pharmacologically well-characterized compounds, and where such an improvement has the potential to provide a clinical benefit. Concert has investigated the effects of selective deuterium modification on dozens of such compounds, including many validated drugs, and currently has 18 issued U.S. patents. The company has executed on this approach to become a clinical-stage biotechnology company with its lead program in Phase II clinical testing: CTP-499 for chronic kidney disease. In addition, Concert is developing a pipeline of preclinical candidates in several therapeutic areas.

Concert Pharmaceuticals and Fast Forward sign deal for MS program
LEXINGTON, Mass.—Concert Pharmaceuticals Inc. also announced last month that it has been awarded funding by Fast Forward LLC, the National Multiple Sclerosis Society's subsidiary devoted to bridging the gap between research and drug development, to fund the preclinical advancement of a potential treatment for multiple sclerosis (MS). Fast Forward will commit funding for the clinical-stage development of C-21191, a deuterium-modified subtype-selective GABAA modulator developed by Concert with the therapeutic potential of treating spasticity and pain in multiple sclerosis (MS).
C-21191 is a deuterium-modified analog of L-838417, which was discovered by Merck & Co. Inc. and extensively profiled in preclinical testing by Merck and in numerous academic laboratories. L-838417 possesses an attractive pharmacological profile including minimal sedation and ataxia, but has a poor pharmacokinetic profile, which prevented its progression to clinical evaluation.  
C-21191 has demonstrated significantly improved pharmacokinetic 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 to L-838417 in several preclinical species. This superior pharmacokinetic profile resulted in a prolongation of exposure and a corresponding extension of pharmacodynamic effects.  
C-21191 also demonstrated equivalent efficacy to gabapentin in a neuropathic pain model, with a superior duration of effect, at doses that did not cause sedation or ataxia as assessed by a rotarod model.  
"We are pleased to partner with Concert on this new approach with the potential to treat spasticity and pain, which are so challenging to large numbers of people living with MS," says Dr. Timothy Coetzee, chief research officer at the National MS Society and Fast Forward. "This collaboration demonstrates Fast Forward's commitment to pursue and fund innovative medicines that can address unmet needs and improve the quality of life for people living with this disease."
Code: E041222



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