Therapies in development for neurodegenerative diseases are looking beyond Alzheimer’s and Parkinson’s with novel mechanisms of action targeting newer pathways.
BioAge Labs, PTC Therapeutics, Biogen and others highlighted these approaches at the Cambridge Innovation Institute's recent Discovery on Target meeting.
The Broad Potential of NLRP3 Inhibitors
BioAge Labs focuses on the aging process itself to identify why and how people age, examining deep phenotypic data that includes cognition as well as lung capacity, body type, skin thickness and other factors.
“Data shows those with high levels of NLRP3 have poor survival levels (from all causes of mortality), as well as cognitive decline,” said Rusty Montgomery, Ph.D., VP biology at BioAge, in his presentation. Preclinical data suggest that knocking out NLRP3 extends the lifespan of mice and also helps their muscles resist atrophy.
“NLRP3 is a key protein in a multiprotein complex called the inflammasome, which drives inflammatory responses in the innate immune system,” said Kristen Fortney, Ph.D., BioAge's CEO and co-founder, in an interview with BioSpace.
“Because NLRP3 inhibitors have such broad potential, the whole field is trying to figure out which specific indications to tackle first. We’re going to learn a lot over the next two years as several programs across multiple companies advance into the early clinical stage,” Fortney predicted.
“We believe NLRP3 inhibition is a promising strategy for treating diseases of brain aging, as well as disorders driven by pathologic inflammation in other organ systems,” she continued. “This idea is supported by an extensive body of literature showing that in interventional animal models, decreasing NLRP3 pathway activity can increase longevity and prevent or reverse diverse diseases related to aging.”
Basically, NLRP3 brings proinflammatory signals under control and, Fortney said, may possibly “reverse the effects of diseases in which inflammation is actively disrupting normal function, and halt the progression of diseases driven by tissue destruction.”
This isn’t the first NLRP3 inhibitor to be developed, though. Fortney said BioAge’s version is “structurally and mechanistically differentiated from previously known NLRP3 inhibitors,” to minimize the safety issues that other molecules have encountered. BioAge’s preclinical studies show benefits in atherosclerosis, hypertension, neuroinflammation and other conditions.
The company is developing three classes of NLRP3 inhibitors: central nervous system penetrant, peripherally-selective molecules and an ocular eye drop.
The CNS penetrant compounds cross the blood-brain barrier and therefore may address conditions driven by inflammation in the brain. In the second program, the peripherally-selective molecules do not cross the blood-brain barrier.
“They accumulate at therapeutic levels in the systemic circulation,” Fortney said, and apply to non-alcoholic steatohepatitis (NASH), cardiovascular disease, arthritis and other conditions. Inhibitors for these programs may be delivered orally or by infusion.
The third program, an ocular NLRP3, is being developed as a topical eye drop. “We currently are evaluating our compounds to identify a lead candidate,” Fortney said. Indications may include dry eye, anterior uveitis and some forms of age-related blindness.
For all three programs, BioAge is currently optimizing its lead candidates. It plans to perform IND-enabling studies in the coming year to evaluate toxicity and identify dosing, Fortney said.
Splicing in Huntington’s Disease
In a different approach, PTC Therapeutics is harnessing splicing machinery to lower huntingtin (HTT) protein production. The company is conducting a two-part study involving PTC518, which is being developed to treat Huntington’s disease.
Part one showed a reduction of huntingtin protein levels in healthy volunteers. Part two, currently underway, is a global study that looks at huntingtin, RNA and protein levels in the blood, as well as levels within the brain.
“We identified splicing modifiers that cross the blood-brain barrier and uniformly lower huntingtin protein levels in the key affected areas of a Huntington’s disease mouse brain," said Anuradha Bhattacharyya, Ph.D., executive director, biology and nucleotide repeat diseases during the conference.
That finding represents a paradigm shift in terms of what is possible.
“Twenty years ago, most people thought splicing was something that happened that couldn’t be modulated,” said Stuart Peltz, Ph.D., co-founder and CEO of PTC. But, Peltz realized that RNA was a “primordial soup” type enzyme that could form into structures with catalytic activity. “Therefore, those structures, just like proteins, form pockets that small molecules can modulate.”
Digging deeper, he noted that the five- and three-prime sites mark the ends of the exon/intron boundaries and that the machinery that binds and ultimately leads to splicing has a specific sequence.
“Most (organizations) lack the molecules in their chemical libraries that are needed for a splicing modification approach to work well,” Peltz said, after an analysis of one big pharma company’s million compound library. Now, after 20 years, “We can look at every splice site in the gene and see if it's involved in a particular disease state.”
Spinal muscular atrophy is one example, and Huntington’s and familial dysautonomia are other diseases that can be affected by modulating gene splicing.
“We figured out how to both use this technology and, with a small molecule, increase or decrease the level of a protein (that’s produced) to treat a disease,” Peltz said.
Maximizing Success with a Multimodal Approach
Biogen is taking a multimodal approach to therapeutic discovery, as Anabella Villalobos, Ph.D., SVP, biotherapeutics & medicinal sciences outlined at the Discovery on Target meeting.
She reason, she told BioSpace afterward, is “to enable a focus on the right target (proteins and/or nucleic acids) to maximize our probability of success in identifying new medicines.”
By identifying the best targets, usually with genetic linkage, Biogen “can narrow the gap in the undruggable space, expand target space, leverage synergies across modalities and offer multiple investigational options to patients in high-value biological targets or pathways,” Villalobos said.
By leveraging multiple modalities, the company can better explore its combinations and address any limitations. “For example,” she said, “we can enhance tissue delivery into [the] brain or muscle after systemic administration with oligonucleotide-antibody conjugates.”
Biogen can also target a variety of biological hypotheses related to a given disease, regardless of the nature of the biological target, she explained. This not only improves the chances of success but also expands treatment options by “offering options with potential medicines that may show complementary therapeutic benefit when used in combination.”
For example, small molecules can reach the brain but have limited ability to modulate non-protein targets. Biogen, therefore, is pursuing small molecules that modulate RNA splicing. Biologics, in contrast, can achieve limited brain exposure.
So, Biogen is leveraging new technologies involving longer half-lives and high selectivities to access disease areas that previously were not tractable for particular therapeutic modalities, such as antibody-oligonucleotide conjugates, Villalobos said. The company is also expanding oligonucleotide therapeutics beyond rare diseases, accessing deeper brain areas.
New, more effective therapies for a wide swath of neurodegenerative conditions increasingly will be needed to address unmet needs for a global population that is living to advanced ages. These companies aim to help provide those solutions, tapping into what Mordor Intelligence predicts will be a $6.7 billion market by 2027, with a compound annual growth rate of nearly 7%.
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