Pfizer’s announcement early this year that it was ceasing its own early clinical development efforts in neuroscience caused severe disappointment among stakeholders involved in Alzheimer’s disease (AD) research. The impact of this withdrawal led some to wonder whether this is a sign of things to come, and that developing a disease-modifying drug (DMD) is unviable. Is this true?
For this pharmaceutical giant, their statement indicates the difficulties involved: “after our internal programs faced continual setbacks, we had to come to terms with the fact that our research efforts were simply not making the progress necessary to translate into truly transformational therapies for patients.” Others in industry are also feeling the pain, with Eli Lilly and Merck among the larger players suffering costly failures when their candidate therapies stumbled at Phase 3 in recent years.
With this seemingly unrelenting bad news, what does the future hold for drug development for AD? This post provides a brief overview of the landscape of trials for AD and why there is optimism that DMDs for this devastating condition will be a case of when they will be developed not if.
What we know now
Approximately 55 million people worldwide are living with dementia (of which those with AD constitute 60-70%) and this number is projected to increase to ~150 million by 2050. With a patient population larger than those of many countries, the unmet need is unquestionable. Despite the failures so far, it is an exciting time for the field. Researchers and industry are learning lessons from the past, and new findings are providing valuable tools for increasing the rigor and applicability of trial designs.
A few publications last year provided rich data regarding the status of clinical drug development and how to increase the chance for success in AD trials. Figure 1 provides a summary from an insightful paper that describes 12 lessons learnt from past trial failures to enhance future success, from ensuring that the drug actually crosses the blood–brain barrier and works in the brain to ensuring that population heterogeneity is minimized in trials.
Meanwhile, two groups accessed data from ClinicalTrials.gov in 2017 (one in January, the other in July) to assess trends in the AD drug pipeline. The January analysis identified 105 agents, of which 25 were in Phase 1, 52 were in Phase 2, and 28 were in Phase 3. Encouragingly, 70% of these agents are DMDs, and 65.5% of all trials are sponsored by biopharma, with academic medical centers constituting the second-largest sponsors (16.6%). In the report by the Alzheimer’s Drug Discovery Foundation (ADDF), their research identified 126 potential DMDs, of which 33 drugs were in Phase 1, 68 in Phase 2, and 25 in Phase 3. The differences in numbers are likely due to the different criteria applied during the searches; nonetheless, the broad trend is that ~50 of candidates are in Phase 2 (the ADDF report didn’t discuss specifics regarding trial sponsors).
Current barriers to success
These data indicate that candidate DMDs are coming through; however, the papers also discussed some of the immediate challenges facing AD trials. Most striking is the monumental challenge of the length of time and the number of patients needed for recruitment. Indeed, for Phase 3 trials, the anticipated recruitment period is often longer than the treatment period, and recruitment numbers are often not met. Based on the Jan 2017 data, it was calculated that 54,073 participants would be required to complete all the AD trials identified at that time point.
Moreover, with the knowledge that neurological changes can occur up to 20 years before symptoms appear in patients with AD, the move toward preventive AD trials is adding another layer of complexity. For instance, how to enroll patients who don’t even know they have the disease?
The future shows promise
The good news is that these issues and others are being actively addressed, and upcoming trials are more rigorous and informed. For example, the advent of PET imaging-based biomarkers in recent years is helping to ensure that the appropriate patient population is enrolled. In addition, the vast numbers of participants needed and the prevalence of AD means globalization of AD trials is inevitable. So, strategies for ensuring timely recruitment and minimizing variability among centers in different countries are ongoing, as is an increased awareness of the influencing factors that might affect results.
Meanwhile, the US FDA has recognized that it needs to change its criteria regarding the selection of patients and endpoints for trials of early AD, and recently published draft guidance on this topic. There are still plenty of players in AD drug development and together with the positive buzz coming from the latest Clinical Trials on Alzheimer's Disease meeting, the possibility of developing a genuine DMD for patients is high.
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