This blog was written by Adam Rosenberg, CEO of Rodin Therapeutics, as part of the From The Trenches feature of LifeSciVC.
Disappointing results in Alzheimer’s clinical trials seem to be announced on an almost monthly, and sometimes weekly basis:
Unfortunately, these are just a few examples…there are many more.
If there is a silver lining to so much crushing disappointment, it’s this: We can learn from prior clinical development attempts, most of which were undertaken by highly qualified researchers and clinicians, based on good-faith data.
Further, new biology and chemistry ideas are moving forward, new preclinical and clinical tools are being developed and validated, and recent regulatory announcements suggest an understanding of the unique challenges in Alzheimer’s clinical development.
Translational Tools
Early and mechanistically relevant biomarkers are critical to breakthroughs in neuroscience, as I argued in my February 2016 blog post, Are We Poised for a Neuroscience Research Renaissance? Maybe.
That said, not all biomarkers are created equal, nor are they equally relevant. As an example, significant work went into developing brain amyloid PET tracers, which have been used to diagnose patients, enrich clinical trial populations and track drug response. That’s all very helpful to refine and assess an amyloid-directed approach. So far, however, reducing amyloid plaque has not translated to patient benefit.
To be sure, there is no official “validation” gold standard for biomarkers, and proponents of different mechanisms will often point to different markers as most relevant. Given the heterogeneity of Alzheimer’s disease and other forms of dementia, it is likely that a panel of markers will be required, rather than a single predictive marker.
To that end, NIH, academic and industry groups are collaborating to use new technology and analytical capabilities to advance and validate new biomarkers that will move beyond target engagement and show a functional, pharmacodynamic effect more closely tied to symptom and disease biology. Examples are numerous; here are just a few:
- NIH AMP-AD program
- Neurofilament light chain and Quanterix Simoa technology
- Neuroimaging, such as SV2a and mitochondrial complex-1
- CSF levels of synaptic proteins
My company, Rodin Therapeutics, is working toward this goal by sponsoring research on a novel PET scanning method to measure synaptic density in the human brain. These synaptic connections are critical to memory and learning; we are developing drugs to strengthen these connections and improve synaptic resilience, which we believe will significantly improve daily living for patients with neurologic diseases.
Today, we are also announcing a number of senior leadership additions to the Rodin team, who will greatly accelerate our ability to establish relevant translational tools and move into the clinic with our lead candidate.
Mechanistic Diversity
My January 2017 blog post, Alzheimer’s Research: Diversity Now, argued that the biopharmaceutical industry has for too long over-invested in the amyloid hypothesis, to the exclusion of other mechanisms. As I suggested then, “we need a more diversified, cost-effective approach, prioritizing therapeutic strategies that have the potential for meaningful and sustained patient benefit, without requiring quite so costly mega-trials.”
This belief still holds and has only been strengthened by recent failures to hit key clinical endpoints, across multiple mechanisms.
This is not just a Rodin-centric view. In addition to synaptic resilience, other approaches – such as targeting neuroinflammation or mitochondrial dysfunction – can leverage increasingly validated biomarkers, and show the potential to produce a durable effect while pursuing a “symptomatic” clinical development pathway.
Data (both real and anecdotal) support that researchers finally seem to be diversifying. BioCentury estimates that the vast majority of later-stage Alzheimer’s clinical trials address “much-exploited targets, including amyloid, tau or cholinergic pathway proteins”, but that at least half of the current crop of preclinical Alzheimer’s research programs target new mechanisms.
Industry and the venture capital community also seem to be responding. As just two examples:
- The Dementia Discovery Fund, launched in 2015 to invest in new dementia research, is only funding non-amyloid programs
- AbbVie’s Foundational Neuroscience Center, founded in 2016, is focused on tau, proteostasis, neuroinflammation and neuroregeneration
As with biomarkers, it is highly unlikely that a single therapeutic intervention will be the answer in all forms of dementia; different patients and different disease stages will require different treatments, often in combination. Mechanistic diversity is the only way that we can ultimately give neurologists the tool set they require to tackle such complex diseases.
Regulatory Initiatives and Other Indications
The FDA now seems to acknowledge the unique challenges in Alzheimer’s research and development, and recently signaled some flexibility: for example, the agency is considering accepting evidence that an experimental therapy is changing the biology of patients’ brains (for instance, reducing the build-up of toxic proteins, or perhaps improvement in synaptic health or neuroinflammatory markers) as a measure of efficacy.
The agency may also show flexibility, especially in early-stage populations, when applying the current approval requirement that experimental Alzheimer’s drugs hit two key endpoints – improving both cognition and daily function. The European Medicines Agency has followed the FDA’s lead and announced its own set of guidelines, scheduled to take effect on September 1, 2018.
Finally, while not directly bearing on Alzheimer’s disease, it is worth noting that clinical and regulatory successes in other disease areas should give the entire neuroscience sector a boost, especially given the co-morbidities in neurologic diseases. The recent NDA filing by Sage Therapeutics and the Johnson & Johnson Phase 3 esketamine data are good examples; both are indicated for the treatment of different forms of depression, which, like Alzheimer’s disease, has seen little therapeutic innovation in recent decades.
Moving Forward
All of this is not to suggest that we should stop development on Alzheimer’s proteinopathy-driven approaches, such as amyloid and tau. We should not. Finding the right patients or genetic carriers of disease mutations — and intervening early for an extended duration — may well delay symptom onset or progression. I very much hope that we can get there.
No matter how adept we become with early diagnosis and intervention, however, unfortunately there will always be patients with some form of symptomatic dementia. Clinical development disappointments are also likely to continue.
Despite the cascade of negative readouts, there are encouraging signs in neuroscience generally, and in Alzheimer’s research specifically, as demonstrated by greater mechanistic diversity, increasingly validated translational tools and new regulatory initiatives. Now we need to take the next step and translate this outpouring of fresh ideas and technologies into therapies that make a meaningful difference for the millions of patients, caregivers and families who urgently need our help.
