Allergan is partnering with Heptares in an up-to-$3.3 billion R&D and commercialization collaboration to develop subtype-selective muscarinic receptor agonists for Alzheimer's disease and other major neurological disorders.

The deal comes just a day after the collapse of its $160 billion megamerger with Pfizer, following new Obama administration rules intended to discourage tax-slicing inversion mergers. Both Allergan and Pfizer had cited their neuroscience products and pipelines among the therapeutic areas they said they would focus on following a merger.

Under the new collaboration, Allergan agreed to license from Heptares exclusive global rights to the following compounds. The agreement covers first-in-class selective small molecule agonists targeting muscarinic M1 and M4 receptors in the brain, discovered using Heptares' StaR® technology platform.

Allergan agreed to pay Heptares $125 million upfront and up to approximately $665 million in payments tied to milestones associated with the successful Phase I, Phase II, and Phase III clinical development and launch of the first three licensed compounds for multiple indications—as well as up to approximately $2.5 billion associated with achieving annual sales thresholds over several years following launch.

Additionally, Allergan agreed to pay Heptares up to double-digit tiered royalties on net sales of all products resulting from the partnership. Allergan will also commit up to $50 million to an R&D program to be conducted jointly with Heptares aimed at advancing multiple candidates through Phase II studies. Allergan will oversee development of licensed compounds upon initiation of Phase IIb studies and for subsequent manufacturing and commercialization of the products.

In return, Allergan will receive exclusive rights to a broad clinical and preclinical portfolio of M1, M4, and dual M1/M4 agonists—including two selective M1 agonists now in Phase I clinical development, HTL9936 and HTL18318.

M1 selective compounds are being developed to treat symptomatic cognitive deficits in Alzheimer's patients, with the promise of better tolerability and a more pronounced effect compared with available treatments.

Allergan and Heptares reason that M4 selective compounds may provide a novel approach to treat the neurobehavioral symptoms (psychoses) associated with Alzheimer's disease and related neurological disorders through a different mechanism of action than available antipsychotics. Combined dual M1/M4 agonists may be capable of 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,” David Nicholson, evp and president, Global Brands Research and Development at Allergan, said in a statement.

HTL9936 was the subject of a recently completed Phase I study assessing the compound’s safety, tolerability, and pharmacokinetic profile. According to Allergan and Heptares, the data provided strong evidence of a therapeutic window for the selective M1 agonist mechanism in general and for the potential of HTL9936 and similar molecules to treat cognitive disorders.

According to the companies, HTL9936 exhibited good brain penetration and M1 selectivity with no adverse events typically attributed to stimulating M2 and M3 receptors. HTL9936 also exhibited robust and statistically significant changes in brain electrical activity measured using multiple electroencephalography biomarkers relevant to cognition. These effects were seen at low doses and low blood concentrations that were safe and well tolerated.

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