This week’s highlights in the world of neurological diseases include Acadia receiving a CRL for its ADP drug, Sosei and Neurocrine’s schizophrenia drug study moving on to Phase II and MIT scientists finding microglia cells’ major role in Alzheimer’s disease progression. Details are discussed below.
Acadia Receives CRL For Proposed ADP Treatment
The U.S. Food and Drug Administration sent a complete response letter to Acadia Pharmaceuticals regarding its supplemental New Drug Application for Nuplazid (pimavanserin) as a potential treatment for hallucinations linked to Alzheimer’s disease psychosis (ADP).
The regulator said in its CRL that it could not approve the sNDA due to interpretability issues with the results from Study 019. Because the data is inadmissible in its present form, the FDA recommended that Acadia conduct another trial for the same indication. Pimavanserin is a selective serotonin inverse agonist and antagonist that targets 5-HT2A receptors, which play a key role in neuropsychiatric disorders.
In addition, the FDA noted that most of the positive results logged from using pimavanserin on dementia-related psychosis in Study 045 were associated with patients in the Parkinson’s disease dementia subgroup. The FDA said this condition is subsumed as Nuplazid was already approved in 2016 in the U.S. for Parkinson’s disease psychosis (PDP).
“We are disappointed with this outcome. The treatment of Alzheimer’s disease psychosis continues to be an area of high unmet need, for which there is no approved therapy,” Steve Davis, chief executive officer of Acadia, said while thanking the participants, their families and the researchers for their efforts.
Sosei, Neurocrine Move To Phase II On Schizophrenia Drug
NBI-1117568 is an oral, selective muscarinic M4 receptor agonist that is being developed for the treatment of schizophrenia and other related neuropsychiatric disorders. As an M4 orthosteric agonist, it may work to deliver targeted therapies while avoiding acetylcholine cooperativity versus using positive allosteric modulators.
“Muscarinic receptors are important drug targets in psychosis and cognitive disorders and through the application of our StaR technology platform and expertise in GPCR-focused structure-based drug design, we have discovered agonists selective to M4 and M1. These novel drug candidates have been designed to deliver improved therapeutic effects while avoiding the unwanted activation of M2 and M3 and its associated side effects,” Chris Cargill, the president and chief executive officer of Sosei Heptares, commented.
NBI-1117568 is Sosei’s most advanced candidate in its portfolio of M4, M1 and dual M1/M4 receptor agonists under development. With the FDA’s go-ahead, the company now stands to gain $30 million as a milestone payment from Neurocrine. Phase II is expected to start this year.
The two companies signed a collaboration and licensing deal in 2021, giving Neurocrine development and commercialization rights to Sosei’s portfolio. Sosei is also eligible to receive as much as $2.6 billion from present and future activities from this agreement.
Study Highlights Microglia Role In Alzheimer’s
Scientists from the Massachusetts Institute of Technology may have found a reason for the slowdown of neuron activity in people with Alzheimer’s disease by studying the activity of microglia cells that express the APOE4 gene.
Around 14% of people carry the APOE4 genetic variant, which has been associated with late-on-set, nonfamiliar AD. Those who have one copy of the variant are thrice more at risk of developing AD, while those who have two are at risk by tenfold. APOE4 affects the microglia cells’ ability to process lipids, leading to triglyceride and cholesterol buildup. This suppresses neuron firing, or neurons’ ability to communicate with each other.
In the MIT study, scientists tested if they could reverse the effects of lipid excess by treating the APOE4 microglia with Triacsin C, a drug that can interfere with lipid droplet formation. This is because they observed that the APOE4 microglia exposed to the drug experienced normal communication with neighboring neurons.
However, the problem is that Triacsin C can be toxic to cells, which means it will not be a sustainable solution for AD. For now, the researchers are looking into how microglia can be transitioned from being healthy to lipid-burdened and inflammatory, with the goal of understanding why and how it happens and then finding a way to block the change. Studies are ongoing.