6:33 PM
 | 
Apr 18, 2019
 |  BC Innovations  |  Targets & Mechanisms

The next wave in neurodegeneration expands beyond neurons

Why modulating microglia could give drug developers a new handle on neurodegeneration

Working in the background, while amyloid therapies have floundered, has been a group of companies betting that the immune system can do for neurodegeneration what it is has done for oncology. The first wave of these companies is moving into early stage trials with therapies that modulate microglia, the brain’s immune cells, and the first data could come by year end.

As the immune system is increasingly implicated in all areas of disease, the neurodegeneration field is hoping for a paradigm shift analogous to the one that all but turned oncology into immuno-oncology.

The hope is pinned on genetic data, where the strongest evidence comes from Alzheimer’s disease.

“About 50% of genes discovered and linked to Alzheimer’s disease point specifically to glial biology and even more specifically to microglia,” said Ryan Watts, CEO of neurology-focused Denali Therapeutics Inc.

A major influence came from a 2012 paper that pinpointed TREM2 as a top genetic risk factor for AD, based on evidence tying it to a loss-of-function mutation in the gene.

The paper sparked a flood of venture and public capital into microglia-centric biotechs, with five companies, three of which were new, raising $1.3 billion since 2013 (see Figure: “Neuroinflammation Fundraising”).


Figure: Neuroinflammation fundraising

Companies focused on microglia and neuroinflammation have raked in cash in recent years, led by the $287 million IPO by Denali Therapeutics Inc. (NASDAQ:DNLI) in 2017. Alector Inc. (NASDAQ:ALEC) raised $175.8 million in its 2019 IPO. Below are annual total equity offerings for companies with a lead program against a neuroinflammatory target. The analysis excludes debt offerings. Source: BCIQ: BioCentury Online Intelligence

“The reason TREM2 was so striking was that TREM2 was only expressed in microglia,” said Third Rock Ventures’ Richard Ransonoff. The finding unambiguously tied the cell type to AD and gave drug developers a target that could be used to selectively manipulate it, he said.

TREM2 is one of at least 13 immune-related targets in development for a neurodegenerative disease, according to BioCentury’s BCIQ database (see Table: “Neuroinflammation Pipeline”).

Table: Neuroinflammation pipeline

At least 16 products targeting microglia or immune-related mechanisms are in development to treat neurodegenerative diseases. Some products are intended to inhibit inflammatory processes, such as complement, kinase and inflammasome inhibitors, while others are meant to stimulate microglial activation. Phases shown are for neuroinflammation indications; some products are more advanced in other indications. (A) Last year, vTv Therapeutics Inc. (NASDAQ:VTVT) halted two Phase III trials of azeliragon in mild Alzheimer’s disease for lack of efficacy, but plans to start a new Phase II/III trial this year specifically in diabetic AD patients. Source: BCIQ: BioCentury Online Intelligence, ClinicalTrials.gov, company websites

TargetCompanyProductIndicationStatus
Activators
Progranulin (PGRN; PCDGF)Alector Inc.AL001

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