Ichor founder speaks out on some of the key challenges facing longevity drug developers and investors.
Longevity focused contract research organization Ichor Life Sciences recently revealed the expansion of its clinical services division, Ichor Clinical, to Australia, Europe, and the UK. The US-headquartered firm provides pharma and biotech companies with extensive clinical trial services, ranging from early preclinical studies to late-stage clinical trials and FDA approval.
From a longevity perspective, Ichor has developed a strong reputation for conducting lifespan and healthspan studies, and is currently engaged in running the LEV Foundation’s ambitious Robust Mouse Rejuvenation study. The company’s experience in the aging field has led it to provide venture capital to longevity companies, as well as operating a longevity biotech division, developing its own therapies to treat age-related diseases.
Longevity.Technology: Through its combined expertise as a CRO, drug developer, and venture capitalist, it’s fair to say that Ichor has a unique mix of perspectives on the longevity field. To tap into some of those views, we caught up with Ichor’s founder and CEO, Kelsey Moody, who began by sharing an interesting point regarding investor due diligence in the longevity field.
“It always surprises me how willing a VC firm is to write a $5 million check but will not run a $10k experiment to replicate key findings from a potential investee,” he says. “This is especially surprising given the reproducibility crisis that exists in the life sciences.”
Before making an investment in an early-stage biotech, Moody says Ichor first makes sure it can replicate the key preclinical findings of the company seeking funding.
“Importantly, this process also allows us to obtain a clear understanding of where the technical hurdles are for these companies, and this also serves to de-risk investments for our angel network when they syndicate on deals with us,” says Moody. “Unfortunately, in an effort to dazzle investors and get money, most companies cannot have a frank conversation about what their biggest development challenges are going to be.”
This, explains Moody, makes investments far riskier for both the company and the investor because cash outlays and expectations may not appropriately match the reality of how the science will progress.
“In many instances, we see these challenges are quite predictable (and therefore manageable) provided one is aware of them ahead of time,” he adds. “It also gives us a competitive edge. We see many ‘diamond in the rough’ deals that VCs will not touch, but we can move forward collaboratively with the investee very rapidly because of our knowledge on the bench and willingness to work through technical challenges.”
Challenges facing longevity biotech
Having worked with many biotech companies targeting one or more of the hallmarks of aging, Moody says that one of the biggest hurdles startups face early on is figuring out what indication to go after.
“If you successfully target a hallmark of aging, your molecule or biologic may be efficacious against many diseases at the same time,” he says. “But unless you’re targeting multiple hallmarks at once, that drug may only have a moderate effect in a specific disease. And that presents a lot of tactical challenges.”
It’s a fair point – until there are FDA trials for longevity and healthspan, companies still need to operate in the “one disease, one drug” landscape and first demonstrate that their therapeutic has an impact against a single indication.
“For a single disease, we’re probably not going to see longevity drugs beating standard of care by themselves,” says Moody. “We’re expecting them to augment standard of care in many circumstances. So, there are a lot of practical considerations when you’re designing your therapeutic strategy that you need to keep that in mind.”
Ichor now runs preclinical and clinical programs for more than 100 companies, and several of the company’s clients operate in the world of longevity biotech.
“Most companies that I see in the aging space are not drug developers,” says Moody. “There is a difference in skillset between the basic science researchers that are identifying and characterizing hallmarks of aging and their associated molecular targets, and groups that know how to build drugs that can go after those targets. We are the latter – we help these companies take tool molecules that they might have identified that had a relevant physiologic effect and turn them into drugs.”
“We have a clear understanding of what these things cost, where the developmental hurdles are going to be, and what pharma and VCs are looking for in terms of a partnership on developing assets.”
Aging as a disease?
While many in the field are calling for aging to be classified as a disease, Moody doesn’t see how that would necessarily help improve things for longevity biotech.
“It already takes decades to test Alzheimer’s drugs, so if you wanted to test drugs with aging as the indication, that’s not functionally useful, because it would take decades to get through different leads, and so on,” he says. “I still like the strategy of picking your first disease, and then picking multiple, completely unrelated diseases.”
Even though things didn’t work out, Moody applauds the efforts of resTORbio, a now-defunct longevity biotech that ultimately failed in a Phase 3 trial.
“They started out targeting an infectious disease and then planned to go after Parkinson’s disease,” he says. “Conventionally, those conditions have nothing to do with one another, and if they could have shown that the same molecule could have an impact on both, it would have been huge. Even though it didn’t pan out for them because the molecules weren’t where they needed to be, I thought the approach was very solid.”
Longevity drugs and the eye
An interesting aspect of Ichor’s specialization in longevity is the company’s expertise in ophthalmology. Diseases of the eye are favored by many longevity companies when it comes to their first indication.
“A lot of the very exciting emerging therapeutic modalities face a lot of problems in their development – half-life challenges, immune response and so on,” explains Moody. “So, if we’re developing an antiaging drug that targets a hallmark of aging, then those hallmarks should be present in the eye. We like the eye a lot, because we don’t have the half-life issues that are associated with systemic delivery.”
In addition, explains Moody, the eyes are an “immunologically privileged” area of the body, which means they are partially protected from the immune system and the destructive inflammation that may impair vision.
“Immune issues in the eye are significantly attenuated, plus it’s a very small area, so you only need small amounts of a drug to treat it,” he says. “And the eye can give you very quantitative assessments without invasive procedures, which is helpful when it comes to efficacy studies. So, it’s not surprising that the first pluripotent stem cell therapies and senolytics are being studied in eye indications.”
Senolytics’ reproducibility problem
When it comes to the specific challenges facing companies developing senolytics, Moody says that, in Ichor’s experience, “very few” senolytics reproduce literature findings and fewer still are “on mechanism.”
“As a biophysics-intensive company, we have also found numerous examples where the proposed mechanisms of action and associated biophysics reported in the literature are simply incorrect,” he adds. “Further, many compounds that have been identified from high-throughput screens are pan-assay interference compounds, which are compounds with characteristics known by drug developers to give false positives in this style of screening.”
“Collectively, we believe these observations account for the failure of many senolytics and senomodulators in development.”
However, despite these observations, Moody believes there is still a “significant opportunity” to identify and validate senescence-specific molecular targets and develop effective drugs for them.
Watch out for ‘phase separation’
Looking to the future of longevity drug development, Moody says that a big issue companies will need to address is a process called phase separation, which describes the dynamic formation and dissolving of membrane-less organelles, called condensates.
“The next generation of small molecule pharmaceuticals will function by modulating phase separation, but few organizations have biophysical tools and expertise required to drug proteins that phase separate,” he says. “In the longevity space, few people even know phase separation exists, much less think about how to modulate it. We are aware of at least a dozen longevity programs that have significantly stalled or failed because phase separation was not recognized as the mechanism of action of the target.”
“Further, we believe that many of the most exciting longevity drug targets undergo phase separation as their primary mechanism of action, and our ability to develop drugs for these targets will be essential for delivering on the promise of the space.”