Denovo Biopharma LLC has licensed ORM-12741 from Orion Corp., along with global rights to develop, manufacture and commercialize the alpha-2c adrenoceptor antagonist that has failed several previous clinical trials.
Denovo is eyeing the compound for treating neuropsychiatric indications such as Alzheimer's disease, schizophrenia and depression. The compound has been through more than 540 patients in 11 clinical studies. The trials show it is safe and well-tolerated, but that hasn't been enough to take it to market.
Taking on failed drugs is in Denovo's wheelhouse, according to its chief business officer, Michael Haller.
"We have four drugs now in our pipeline and all have failed," Haller told BioWorld. "When a drug fails, which happens once a week, we figure out why it failed and, most importantly, did it fail for a genetic reason or some other reason."
Acquiring a failed drug and attempting to redesign it for market success isn't a new idea. But Haller said he believes Denovo has a workable model, one that other companies don't have. San Diego-based Denovo uses archived patient plasma or other samples to identify genetic biomarkers to personalize the development by scanning the human genome, then conducting a proprietary data flow and data analysis algorithm. That, along with the clinical data from the previous studies, allows for the design of new, more focused clinical trials in a specifically targeted patient population.
"That sounds like a silly thing to do, to succeed when a first trial failed," Haller said. "But now we have genetic information which didn't exist before first trial that informs us which patients are expected to have a better response to a drug in the new trial."
Haller said Denovo doesn't see the failures as "bad drugs. We acquire drugs that are good drugs but were tested in the wrong population."
The platform can be applied to biomarker discovery in several areas, including oncology, metabolic, cardiology, immunology and neurology. With newly renamed compound DB-105, Denovo will target the alpha-2c adrenoceptor, differentiating it from many Alzheimer's disease programs that target beta-amyloid and tau, which regulates several brain systems, including its activity during stress.
A Cortellis search for alpha-2c adrenoceptor antagonists showed at least three drugs with an 85% or above chance of FDA approval for bipolar, agitation and suicidal agitation, including Sumitomo Dainippon Pharma Co. Ltd.'s lurasidone, H. Lundbeck A/S's brexpiprazole and Neurorx Inc.'s cycloserine/lurasidone.
There's a lot of patient data for Denovo to sift through. Seven phase I trials between 2008 and 2010 involved more than 200 volunteers in Europe. A phase IIa study completed in October 2012 compared flexible doses of 30 mg to 60 mg or 100 mg to 200 mg of the drug to placebo in patients with moderate Alzheimer's who were taking cholinesterase inhibitors or memantine. The study failed to meet the efficacy objectives, but the research showed an improvement in patients' memory and behavior. At three months, those who took ORM-12741 tested higher in memory tests compared to those taking placebo as memory scores for those who received the placebo pill had worsened by 3% while the scores improved by 4% for those who took ORM-12741.
In late 2013, Orion entered an agreement with Janssen Pharmaceuticals Inc. to develop and commercialize ORM-12741. That same year, a phase II trial of ORM-12741 evaluating its effectiveness in Raynaud's phenomenon was stopped at the request of the trial's data and safety monitoring committee. In mid-2015, the phase II study Nebula evaluated ORM-12741 for calming agitation and aggression in Alzheimer's patients.
All clinical testing was discontinued by May 2018.
Elsewhere in the pipeline, Denovo has DB-103 (pomaglumetad), which late last year, gained IND approval by Chinese regulators for international multicenter trials of the drug, designed to act on the glutamic acid mGlu2/3 receptor, setting it apart from current drugs used in the clinical treatment of psychosis, which mainly focus on dopamine D2 receptors in the central nervous system. The psychiatric drug was first developed by Eli Lilly and Co. to treat schizophrenia. But, in 2012, the pharma giant stopped development after the drug failed to meet the primary endpoint in the intent-to-treat population in its second phase III study. (See BioWorld, Nov. 21, 2018.)
In June 2018, Denovo entered a global license agreement with Stanford University School of Medicine. The deal allows Denovo to develop and commercialize DB-102 (enzastaurin), its lead compound, to treat pulmonary arterial hypertension (PAH) and emphysema. Stanford researchers found that DB-102 could prevent and reverse experimental PAH progression in preclinical models. The treatment modulates a pathway through a previously unknown drug target that is distinct from DB-102's targets for malignancies.
Denovo also is advancing DB-104, or liafensine, which is targeting treatment-resistant depression. Albany Molecular Research Inc. originally developed it and licensed it to Bristol-Myers Squibb Co. A number of phase II trials showed a high tolerance in patients.