NEW YORK (GenomeWeb) – With an exclusive license for pomaglumetad methionil — a late-stage schizophrenia drug that Eli Lilly stopped developing due to poor efficacy in 2012 — San Diego-based Denovo Biopharma said it would apply proprietary testing methods to screen for genetic biomarkers and try to home in on which patients are likely to respond to the therapy.
In a deal announced this week, the drug developer acquired full rights to globally develop, manufacture, and commercialize pomaglumetad methionil. Additionally, Denovo has gained all intellectual property and data rights for the drug. However, if Denovo is successful in showing that the drug benefits a subset of schizophrenia patients, then Lilly can decide to re-acquire pomaglumetad methionil for a predefined but undisclosed sum.
"CNS diseases are usually very complex and the molecular mechanism underling the pathogenesis and drug action remains largely unknown," Michael Haller, Denovo's chief operating officer, told GenomeWeb. As such, Denovo is not entering this project with any predefine hypothesis, Haller noted, but will employ "an unbiased genome-wide scan to discover novel biomarkers based on the data generated from the clinical samples."
Privately held Denovo, which was known as Denovo Biomarkers until it changed its name last July to better reflect its focus, is in the business of using genomic strategies to help pharmaceutical companies resuscitate drugs that have shown lackluster efficacy or concerning side effects in late-stage trials. The company performs analysis on archived patient samples to retrospectively identify genomic biomarkers that can characterize the subset of patients most likely to benefit from a particular drug. With this data, Denovo aims to help pharma companies design new trials that employ companion diagnostics to identify a molecularly defined patient population that can garner more benefit or experience less side effects from a therapeutic.
With regard to the pomaglumetad methionil project, Denovo hasn't yet settled on a study design for seeking out best responder subsets. The most Haller could say was that Denovo would start off casting a wide net using a comprehensive genome-wide approach. "Unlike rapid advances in personalized medicine in oncology, where mutations in the tumor genes are the hot spots for a biomarkers study, germline polymorphisms may play an important role in [central nervous system] diseases and drug response," he said. "Thus, we would apply genetic DNA technology based on the biomarker identified from genome-wide scans to identify [a] responder population."
Most antipsychotics target the dopamine receptor, but pomaglumetad methionil is an agonist of the metabotropic glutamate receptor group II subtypes mGluR2 and mGluR3. The drug is thought to inhibit neurotransmitters that stimulate the brain and are dysfunctional in schizophrenia.
The three leading hypotheses underlying schizophrenia causation implicate dopamine, serotonin, and glutamate. The theory that has dominated schizophrenia research posits that the delusions and hallucinations symptomatic of the illness are due to an overabundance of the neurotransmitter dopamine, the chemical that neurons release to communicate with each other. The serotonin hypothesis holds that the dysfunction of systems regulating serotonin — a neurotransmitter critical for maintaining mood balance — is key to the development of disease.
And lastly, the glutamate hypothesis implicates this neurotransmitter necessary for forming memories, for learning, and for communicating between neurons. Glutamate activates various receptors involved in these tasks, and when the receptors malfunction, symptoms of schizophrenia emerge, the theory goes. Of course, schizophrenia is a complex, heterogeneous disease, and it has been challenging to parse out the extent to which all three neurotransmitters play a part in the illness.
In developing pomaglumetad methionil (previously dubbed LY-404,039), which selectively binds to certain glutamate receptors and activates them, Lilly explored a pharmacogenetic strategy and identified 16 SNPs in the serotonin 2A receptor that appeared associated with drug response.
Although Lilly attempted to replicate these early PGx signals in later studies, in 2012 the company reported that "pomaglumetad methionil did not separate from placebo in the primary efficacy endpoint [of a Phase II trial] in either the overall or predefined genetic subpopulation." Lilly subsequently announced that it would stop Phase III development of pomaglumetad methionil after independent analysis of another pivotal trial signaled that the study would not meet the primary efficacy endpoint.
Still in garnering the rights to further develop pomaglumetad methionil, Denovo will once again try to identify response-associated genetic biomarkers in the hopes of advancing the drug with a companion diagnostic. "Predefined subpopulation analysis and post-hoc analysis across multiple studies identified a meaningful subset of patients who showed significantly improved outcomes, although pomaglumetad did not meet the primary endpoint in the intent-to-treat population in Phase III studies," Denovo said in a statement announcing the deal. "Denovo will use its proprietary platform to identify genetic biomarkers as a companion diagnostic to screen for appropriate patient subsets in future clinical trials and eventual commercialization."
This is the second such deal between Denovo and Lilly. Last year, Denovo acquired the oncology drug enzastaurin from Lilly with the hope of similarly identifying a molecularly defined patient subset that responded to the agent.
In 2013 Lilly said it would stop developing enzastaurin as a treatment for diffuse large B-cell lymphoma after a Phase III study showed the drug didn't significantly increase disease-free survival in patients at high risk of relapse after treatment with rituximab-based chemotherapy. Regarding the enzastaurin program, Haller told GenomeWeb last year, Denovo and Lilly had calculated that the drug appeared to have a statistically significant impact on progression-free survival for approximately 20 percent of patients in the failed Phase III study.
These two deals with Lilly, according to Haller, represent Denovo's current pipeline. "We plan on doing several more [deals] in the future," he said. "[We] have started with those two."