Aging and inflammation go hand in hand, so developing a drug to block the inflammation-causing multiprotein complex NLRP3 was a no-brainer for BioAge Labs. Since its inception, the biotech has targeted several indications tied to the “biology of human aging.”
“NLRP3 is implicated in a lot of different diseases,” said Kristen Fortney, CEO and co-founder of BioAge, pointing to its role in neurodegenerative conditions, cardiovascular disease and metabolic disorders.
That’s why Fortney sees “pipeline in a pill” potential for BioAge’s oral NLRP3 inhibitor, BGE-102, which recently showed positive results in a phase 1 study of cardiovascular risk factors.
But BioAge isn’t the only company with an eye on NLRP3’s potential. Earlier this month, Eli Lilly snapped up Ventyx Biosciences for $1.2 billion to gain access to its pipeline of NLRP3 inhibitors.
"There is increasing evidence that inflammation is a key driver of many chronic diseases," Dr. Daniel Skovronsky, chief scientific and product officer, and president of Lilly Research Laboratories, said in a statement about the acquisition.
In each indication BioAge is pursuing, an oral NLRP3 inhibitor could both provide a more convenient option than injectables or potentially improve the standard of care. In cardiovascular risk, for example, there are limited treatments to address inflammation. Oral NLRP3s could ultimately go toe-to-toe with the clinical-stage IL-6 inhibitors on efficacy in that indication while also complementing statin-lowering therapies.
The NLRP3 development pipeline is in early stages, and only a handful of candidates have entered the clinic.
Leading the pack is Ventyx, which is developing VTX3232 for Parkinson’s disease and obesity-associated cardiometabolic conditions. The drug also showed promise in Alzheimer’s disease, multiple sclerosis and amyotrophic lateral sclerosis.
A phase 2 study among patients with obesity and cardiovascular risk factors showed that within the first week of dosing with VTX3232 alone, patients achieved a roughly 80% reduction in high-sensitivity C-reactive protein (hsCRP), which can trigger future cardiovascular events when elevated. Patients with measurable drug levels maintained those results throughout the full 12-week dosing period.
Ventyx’s other NLRP3 inhibitor, VTX2735, is in phase 2 trials for recurrent pericarditis.
NodThera has also ushered an NLRP3 inhibitor into phase 2 trials. The candidate, dubbed NT-0796, is being investigated as a monotherapy and in combination with a GLP-1 in patients with obesity. The company is also testing the drug in Parkinson’s disease, and showed reductions of neuroinflammatory biomarkers in a phase 1b/2a study readout in August.
BioAge is hot on their heels with BGE-102, an internally developed and structurally novel NLRP3 inhibitor, which lowered hsCRP in patients with obesity and elevated hsCRP.
“We saw a very profound reduction [among participants] after being on our drug for two weeks,” Fortney said. After taking our drug once a day for two weeks, they got an 86% reduction in their hsCRP.”
In addition, 93% of people in the treatment group were corrected back to normal levels of hsCRP, Fortney said, which points to best-in-class potential for BGE-102.
“It’s the best anyone’s seen with this mechanism so far,” Fortney said.
Two additional companies started the year with NLRP3 announcements as well. Insilico Medicine and Hygtia Therapeutics entered into a license and co-development deal to advance ISM8969 for central nervous system disorders, starting with Parkinson’s disease. Meanwhile, Olatec Therapeutics, presented preclinical data showing Parkinson’s disease-modifying activity for its NLRP3 inhibitor, dapansutrile.
What’s next for BioAge
Just days after announcing positive interim phase 1 cardiovascular data for BGE-102, BioAge said it would expand its development program into ophthalmology, with an initial proof-of-concept study in patients with diabetic macular edema.
“One of the unique features of our drug is that it gets really well into the brain, and we would expect it to get really well into the retina as well,” Fortney said. “In patients with diabetic macular edema, we think this could be a superior drug to some of the [interleukin-6 targeting] injectables people are using.”
The biotech also plans to initiate another BGE-102 cardiovascular trial in the first half of this year, “giving our drug once a day for three months to a larger group of people who have elevated CRP at baseline, looking at CRP reduction over time and the durability of that.”
BioAge and others in the industry are also closely watching Novo Nordisk’s phase 3 ZEUS trial for an IL-6 drug called ziltivekimab, which also targets inflammation and could validate the link between hsCRP and major adverse cardiovascular events.
“It will be another data point showing that that can be the case,” Fortney said.
