Parkinson’s disease research has revealed insights into a particular protein that is now a hot target, drawing hundreds of millions of dollars in investment to support the research of drugs intended to stop it. Scientists at Neuron23 believe that their drug candidate can be the best in this emerging class of therapies, and the startup has raised $100 million, some of which will be used to bring the compound into human testing this year.
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The Parkinson’s target Neuron23 is pursuing is called leucine-rich repeat kinase 2 (LRRK2). This protein is found throughout various tissues and cell types throughout the body, including neurons. Research has found that mutated LRRK2 is toxic to neurons, and mutations of this protein are associated with an inherited form Parkinson’s disease. South San Francisco-based Neuron23 says there is also emerging evidence that activity of this mutated protein may play a role in a subset of those who have non-inherited forms of Parkinson’s.
Neuron23 aims to treat Parkinson’s by blocking LRRK2. Lead drug candidate NEU-723 is a small molecule designed to penetrate into the brain and stop the activity of the mutated protein. Neuron23 has some catching up to do to show how its LRRK2 inhibitor matches up against, and potentially bests, drug candidates from larger competitors.
An LRRK2-targeting drug is among the lead programs of Denali Therapeutics, a South San Francisco-based biotech company whose pipeline holds several brain-penetrating drugs for a range of neurological disorders. For Parkinson’s, the company’s most advanced program is BIIB122/DNL151, a small molecule in development under a partnership with Biogen that began in 2020. Biogen paid $560 million up front to begin the alliance on Denali’s brain-penetrating LRRK2 inhibitors, as well as those that do not penetrate the protective blood brain barrier. Denali has said that BIIB122/DNL151 was selected for further development due to properties that provide additional dosing flexibility. The company expects to begin a Phase 3 study testing BIIB122/DNL151 in patients who carry an LRRK2 mutation later this year.
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Cerevel Therapeutics is also pursuing LRRK2 with a drug candidate licensed from Pfizer. The Cambridge, Massachusetts-based biotech aims to treat address a particular LRRK2 variant called G2019S, which is the most common risk mutation for Parkinson’s, the company said in its 2021 annual report. The company’s LRRK2 inhibitor is in the discovery stage. Cerevel’s most advanced Parkinson’s program addresses a different target, the D1/D5 receptor.
Neuron23 acknowledges the LRRK2 competition it faces. In an email, CEO Nancy Stagliano wrote that her company’s drug has two features that differentiate its drug as potentially the best in the class of LRRK2 inhibitors. First, she said that not only is the drug highly potent and capable of penetrating into the brain, the Neuron23 molecule is also more selective in the way it hits its target compared to its competitors. Second, she said that the company is taking a precision medicine approach to Parkinson’s by using a companion diagnostic to select the patients most likely to respond to this treatment. In addition to treating patients with the LRRK2 mutation, Stagliano said Neuron23 will identify and treat a subset of those with sporadic Parkinson’s, whose disease is also driven by LRRK2.
“This should increase our chances of late-stage clinical success,” she wrote.
Neuron23 expects to begin clinical trials for NEU-723 by the end of 2022. The biotech has more in its pipeline. The new capital will also support development of a drug designed to block the immune signaling protein tyrosine kinase 2 (TYK2), part of the JAK family of proteins. These proteins are already targeted by drugs that treat a range of autoimmune disorders. Blockbuster JAK inhibitors from companies such as Pfizer, Incyte, and AbbVie are approved for treating conditions that include rheumatoid arthritis, atopic dermatitis, psoriatic arthritis, and ulcerative colitis.
TYK2 is an attractive target because hitting it does not limit immune function and cause immunodeficiency, which is a problem for many autoimmune disease drugs. Bristol Myers Squibb aims to block the enzyme as a way of treating a range of autoimmune disorders; last October, the pharma giant reported that its TYK2 inhibitor deucravacitinib failed a mid-stage clinical trial in ulcerative colitis. Unlike other TYK2-targeting drug candidates, Neuron23 said its preclinical drug can penetrate the blood-brain barrier, giving it the potential to address disorders characterized by neuroinflammation, such as multiple sclerosis. The entire class of JAK-blocking drugs is weighed down by stricter FDA warnings of cancer and cardiovascular risks. If Neuron23 can demonstrate its drug has a better side effect profile, the molecule would be able to further differentiate itself from the field.
Neuron23 launched in late 2020 backed by $113.5 million, which represented a combination of Series A and Series B financing. The company’s drugs were licensed from German company Origenis. Investors from Neuron23’s earlier funding rounds include Westlake Village BioPartners, Kleiner Perkins, Redmile Group, Cowen Healthcare Investments, Acorn Bioventures, HBM Partners, Perceptive Advisors, and Surveyor Capital. Those investors also participated in the Series C funding.
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