Dublin, Ireland-based global pharmaceutical company Allergan and Heptares Therapeutics, a clinical-stage pharmaceutical company whose proprietary technologies have created new medicines with the potential to transform Alzheimer’s disease, have entered into a global research and development and commercialization partnership for the treatment of Alzheimer’s disease (AD) and other neurological disorders.
With the partnership, Allergan will license exclusive global rights to the pipeline of novel subtype-selective muscarinic receptor agonists that Heptares has under development for Alzheimer’s and other major disorders.
Heptares is a wholly-owned subsidiary of Japanese multinational Sosei Group. Its proprietary StaR technology and structure-based drug design (SBDD) capabilities have enabled creation of new medicines targeting G protein-coupled receptors (GPCRs) — a “superfamily” of receptors linked to a wide range of human diseases. The ability of Heptares to engineer and develop medicines that address highly validated, yet historically undruggable, GPCRs has attracted multiple pipeline and technology partners, including Allergan, AstraZeneca, Morphosys, Pfizer, and Teva.
Under the agreement, Heptares will receive a payment of $125 million up front, and is eligible to receive milestone payments of up to approximately $665 million contingent on successful Phase 1, 2, and 3 clinical trial completion and commercial launch for multiple indications of the first three licensed compounds, and up to an additional $2.5 billion for achieving certain annual sales thresholds during a specified number of years following the products’ launch.
The agreement also specifies that Heptares is eligible to receive up to double-digit tiered royalties on net sales of any products developed under the partnership, with Allergan committing up to $50 million in funding for a research and development program to be conducted jointly by Allergan and Heptares with the objective of advancing multiple candidates through Phase 2 clinical trials. Allergan will be responsible for development of licensed compounds upon initiation of Phase 2b studies and for subsequent manufacturing and commercialization of such products.
Cognitive Impairment in Alzheimer’s Disease and Other CNS Diseases
In a joint release, Allergan and Heptares point to significant unmet medical needs and a heavy economic burden caused by cognitive impairment and dementia across multiple diseases, noting that currently available drugs for treating Alzheimer’s disease provide limited and transient effects on cognition. They cite projections of healthcare costs, including nursing home care, associated with Alzheimer’s and dementia (currently estimated to be in excess of $640 billion for North America, Western Europe, and Asia-Pacific), and continuing to grow based on data from the World Health Organization, Alzheimer’s Disease International, the National Institute of Mental Health, and the Lewy Body Dementia Association.
This puts a spotlight on an urgent need for development of new therapies capable of treating the estimated more than 45 million people worldwide suffering from dementia today — 4.8 million in North America, 7.5 million in Western Europe, and 3.6 million in Asia-Pacific — a number expected to increase to more than 130 million by 2050. Alzheimer’s disease is the most common cause of dementia, estimated to be associated with some 60 to 70 percent of cases. An additional estimated 1.4 million patients in the U.S. suffer from Lewy body dementia.
“Cognitive impairment and psychosis are progressive and debilitating symptoms associated with many CNS diseases, including Alzheimer’s disease, with few approved therapies available,” David Nicholson, executive vice president and president of Global Brands Research and Development at Allergan, said in the release.
Until now, attempts to develop medicines targeting M1 and M4 receptors have been unsuccessful due to unwanted side effects caused by the activation of M2 and M3 receptors. Selective M1 or M4 agonists that do not activate M2 or M3 are highly sought after and are expected to address blockbuster markets.
Included in the Allergan-Heptares agreement are first-in-class selective small molecule agonists discovered using Heptares’ proprietary StaR technology platform that target muscarinic M1 and M4 receptors in the brain. Allergan will be granted exclusive rights to Heptares’ broad clinical and preclinical portfolio of M1, M4 and dual M1/M4 agonists, including the selective M1 agonists HTL9936 and HTL18318, currently in Phase 1 clinical development.
In a 2014 review published in the journal Neuropsychiatric Disease and Treatment titled “Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer’s disease and schizophrenia,“ co-authors Daniel J. Foster, Derrick L. Choi, P. Jeffrey Conn, and Jerri M. Rook of the Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery in Nashville, Tennessee, observe that current clinical treatments for both Alzheimer’s disease and schizophrenia disorders have limited efficacy and are accompanied by dose-limiting side effects that result in failure to adequately address the broad range of cognitive impairment symptoms. They also said that novel therapeutic options for Alzheimer’s and schizophrenia are needed to better manage the spectrum of such symptoms with reduced adverse-effect liability.
The reviewers note that in order to maintain the clinical efficacy of drug treatments without the adverse-effect liability, efforts are focused on the discovery of compounds that selectively modulate the centrally located M1 and M4 muscarinic acetylcholine receptor (mAChR) subtypes. They note that in the past few decades, discoveries of small molecules capable of selectively targeting these subtypes have allowed researchers to describe the roles the receptors play in regulating cognitive and behavioral disturbances in preclinical animal models.
A 2005 study published in the journal Current Pharmaceutical Design, “Muscarinic receptor agonists and antagonists in the treatment of Alzheimer’s disease,” co-authored by
J.W. Clader and Y. Wang, notes that among the consistent findings in Alzheimer’s patients’ brains is loss of cholinergic function, and that a cholinergic approach to AD treatment involves counteracting the loss in cholinergic activity by pharmacological intervention to increase cholinergic transmission.
Clader and Wang observe that cognitive effects of acetylcholine are mediated via the muscarinic M1 receptor, and that direct stimulation of this receptor using muscarinic M1 agonists improves cognition in animal models and performance in cognitive tests in Alzheimer’s patients. Alternatively, antagonists of central presynaptic M2 receptors improve cognition by increasing central release of acetylcholine, but that both approaches require high selectivity for one muscarinic receptor sub-type both for efficacy and to avoid cholinergic side effects.
Heptares has M1 selective compounds in development for potential treatment of symptomatic cognitive deficits in Alzheimer’s patients, claiming potential for better tolerability and more pronounced efficacy compared with currently available treatments. The companies note that M4 selective compounds may provide a novel approach to treatment of neurobehavioral symptoms (psychoses) associated with Alzheimer’s disease and other neurological disorders through different pharmacological mechanisms of action than those of available antipsychotics, projecting that combined, dual, M1/M4 agonists may be effective in treating both cognitive impairment and neurobehavioral symptoms.
“The Heptares M1 compounds have shown promising results in early development in their ability to selectively target the M1 receptor without also activating the M2 or M3 receptors, which are associated with undesirable side effects,” Nicholson said. “We look forward to advancing these compounds into the next stages of development, and potentially adding new approaches to helping physicians treat patients suffering from the effects of Alzheimer’s disease, an area of medicine where Allergan remains committed to continued innovation.”
The safety, tolerability, and pharmacokinetic profile of the selective M1 agonist HTL9936 were assessed in a recently completed Phase 1 study, with resulting data providing “strong evidence of a therapeutic window for the selective M1 agonist mechanism in general, and for progression of HTL9936 and similar molecules as medicines to treat cognitive disorders.” Researchers report that HTL9936 exhibited good brain penetration and M1 selectivity, with none of the adverse events typically attributed to stimulation of M2 and M3 receptors observed.
The companies report that HTL9936 also exhibited “robust and statistically significant changes in brain electrical activity measured using multiple electroencephalography (EEG) biomarkers relevant to cognition,” noting that pro-cognitive effects were seen at low doses and low blood concentrations of HTL9936 that were safe and well-tolerated.
“We are delighted that the quality of our muscarinic agonist candidates, discovered and developed wholly in-house, and our translational capabilities have been recognized by Allergan, a global leader in the development and commercialization of treatments for CNS diseases,” said Malcolm Weir, CEO of Heptares and chief R&D officer at Sosei. “We have a highly committed and experienced partner in Allergan and look forward to working together toward the development of multiple new breakthrough medicines over the coming years.”
Shinichi Tamura, chairman and CEO of Sosei Group Corporation, said, “This new agreement with Allergan marks an important milestone in our journey to become a global biopharmaceutical company. This agreement further endorses our strategic decision to acquire Heptares in February last year, placing its GPCR-directed drug discovery and development capabilities at the heart of our business.”