Pathway To New Therapies

Article by Michael Rae about recent and forthcoming regulatory reforms required to support the testing of new therapies for Alzheimer's and other age-related diseases.

FDA Opens Pathway For Testing Rejuvenation Biotechnologies For The Prevention of Alzheimer's Disease

It’s often assumed that the fact that regulators like the FDA don’t recognize aging as a “disease” is a major challenge to the development of medical therapies targeting degenerative aging processes. In fact, as we’ve discussed before (scroll down to “Question of the Month”), this is not a major hurdle for rejuvenation biotechnologies, because of the specifics of the “damage repair” approach to rejuvenation biotechnology that we’re pursuing at SRF. That said, substantial regulatory reform is needed to create a pathway for investors and pharma to put the necessary time and money into researching and developing rejuvenation biotechnologies such that licensable therapies can come out the other end.

The most important regulatory reform would entail acceptance of novel biomarkers of the removal, repair, replacement, or rendering harmless of specific forms of cellular and molecular aging damage as sufficient basis to grant rejuvenation biotechnologies preliminary licensure. This would then be followed up by further monitoring of patients to ensure that the therapy actually does bend the curve on diseases of aging over the longer term. This standard would mark a break with regulators’ usual insistence (which has been getting more entrenched, rather than less, in recent years) that therapies prove an effect on “hard outcomes” to get approval: things like heart attacks, amputations, or blindness. But people should ideally begin to receive rejuvenation biotechnologies well before patients are in near-term danger of such acute threats to life and health, making it extremely expensive and time-consuming to run a trial.

In 2012, it looked as if significant progress had been made on this front and several others during major stakeholder meetings amongst Alzheimer’s disease (AD) patient and caregiver advocates, researchers, and FDA regulators. In particular, there was consensus on the need to work toward the development of new clinical trial designs and regulatory reforms to advance previously-untested combination therapies for AD into clinical testing. Shortly thereafter, FDA issued draft “Guidance for industry: Alzheimer’s disease: developing drugs for the treatment of early stage disease,” which acknowledged that therapies for AD are unlikely to have substantial effects in “full-blown” dementia, because by that point, the brain has suffered either irreversible damage, or too many kinds of damage for any one therapy to be useful anymore.

Recognizing that fact, they furthermore acknowledged that the industry focus should shift to testing therapies in people who, while they may be experiencing measurable cognitive deficits, are not yet even in the early stages of dementia per se. But the tests currently used in clinical trials to measure the progression of existing dementia are unlikely to be useful in assessing the effects of therapies designed to help people in these very early stages of the disease (let alone people who were aging, but still cognitively normal for their age). And therefore, FDA said, alternative outcome metrics will need to be developed instead.

Then, despite having climbed up to the top of the diving tower, with advocates and scientists cheering at every step, FDA and pharma seemed to hesitate. The same FDA leaders who had previously expressed their openness to bold initiatives instead adopted a more conservative stance on using biomarkers as outcomes for early-stage disease in the Guidance and a parallel New England Journal of Medicine article. Despite acknowledging beta-amyloid and aberrant tau as “leading candidates in this respect,” they hesitated: “Until there is widespread evidence-based agreement in the research community that an effect on a particular biomarker is reasonably likely to predict clinical benefit, we will not be in a position to consider an approval based on the use of a biomarker as a surrogate outcome measure in AD (at any stage of the illness).” However, they did, at least, express openness to the inclusion of favorable effects on biomarkers and imaging tests that reflect the pathological processes that set people on the path to dementia as supportive evidence for efficacy if combined with other preliminary evidence.

Meanwhile, at a research summit in 2014, major pharmaceutical companies also seemed to get cold feet, particularly on the key, related subject of cooperating on combination therapies capable of targeting multiple kinds of aging damage at once.

This February, however, FDA finally took the plunge with a revised Draft Guidance, which would represent a tremendous step in the right direction if finalized as official FDA policy. The results of imaging tests or relevant biomarkers could then be considered sufficient to identify so-called “Stage 1” Alzheimer’s patients as eligible candidates for clinical trials or new therapies, or to test existing therapies that had failed in people with frank AD. These “Stage 1” candidates are described in terms that identify people at an even earlier stage along the insidious path to dementia than the 2013 guidance: outwardly healthy but aging people without very-high-risk mutations or apparent cognitive or functional impairments, but who are nonetheless identified as being at higher risk than most. In short, these individuals would now be eligible to participate in trials of new and old therapies that might prevent them from ever tipping over into major cognitive impairments.

Even more boldly, FDA went on to say that since the march toward cognitive impairment in these “Stage 1” patients will be so hard to reliably pick up using any kind of cognitive tests, therapies that successfully move those biomarkers in the right direction would be granted accelerated approval, with a requirement for further followup to confirm the long-term benefit. In the case of “damage-repair” therapies, such movements would reflect the removal or replacement of the underlying cellular and molecular damage that the biomarkers pick up.

That said, the new Guidance is, surprisingly, a bit vague as to what those biomarkers would actually be, speaking instead of “biomarkers reflecting underlying AD pathophysiological changes;” at one point it even says that “there is no consensus as to particular biomarkers that would be appropriate to support clinical findings in trials in early AD.” It is unclear as to how these assertions would be justified; the leading candidates were not only disclosed in the 2013 Guidance, but are widely accepted in the field: levels of beta-amyloid and aberrant tau in the cerebrospinal fluid, imaging of plaques (and, potentially, aberrant tau) in the brain using radiolabeled tracers, markers of neurodegeneration, and impaired metabolism.

Scientific leaders and advocates hailed the new Guidance document, and will continue to push for more progress in this direction toward a more damage-repair-friendly regulatory climate. At SENS Research Foundation, we advocate for an even wider goal: that such new thinking should be extended to other diseases and debilities of aging. The use of biomarkers and imaging directly reflecting the key cellular and molecular damage driving AD and other neurodegenerative diseases of aging should be extended to testing of therapies in people who are in even greater danger, showing early signs of cognitive problems but still not suffering from full-fledged dementia. Analogously, biomarkers of the cellular and molecular damage that accumulates in our tissues as we age and that drives other age-related illness and debility should also be acknowledged as the best targets for new therapies that would prevent, arrest, and reverse those conditions. And because AD and other diseases of aging involve multiple kinds of cellular and molecular damage, it’s critical that regulators allow the testing of combination therapies potentially capable of attacking multiple kinds of cellular and molecular aging damage, without first needing the constituent therapies to be tested individually.

This step could unleash a new wave of testing of one of the most fearsome and stubborn of aging’s plagues, and finally give us a way to banish it into an indefinite future.

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