Evolving clinical trial designs in Alzheimer’s - A double-edge sword?

by Decision Resources Group:

With repeated clinical-stage failures in the past 15 years, drug development in Alzheimer’s disease(AD) defines “hard.” Yet, pharmaceutical companies—large and small—persist in the hopes of succeeding where so many have failed and to reap the ultimate reward. Accordingly, trends in AD drug development continue to evolve. With each failure, new hypotheses emerge about how to achieve success, particularly when it comes to disease-modifying therapies (DMTs). For example, most companies with a DMT in active development have forgone proof-of-concept Phase II studies in favor of initiating better-powered, large-scale Phase III trials sooner, shortening development time and lowering costs. Notably, physicians interviewed question whether this strategy may perpetuate the high attrition rate among AD drugs owing to improper vetting.

The most discernible trend in AD trial design has been the move to recruit patients in the earliest symptomatic stages of AD or even presymptomatic patients (i.e., prevention studies, like A4), when DMTs theoretically can impart a greater effect on disease pathology (e.g., amyloid aggregation). Supporting this scientific shift, many DMTs (e.g., solanezumab, verubecestat) have failed in both moderate and mild disease. That said, the “pre-AD” phase (a proprietary DRG epidemiological category) presents its own challenges, first in identification: this is a population that is mildly symptomatic if they are symptomatic at all. What’s more, it is possible that even pre-AD may be too late to intervene and it is only through ongoing prevention trials that we will see emerging agents work—but that is a discussion for another day!At this point, most ongoing anti-amyloid DMT trials are enrolling only pre-AD patients (defined in various ways—e.g., prodromal AD, MCI due to AD). While this makes the most sense from a mechanistic point of view and may represent the best chance of demonstrating efficacy, we expect it may also present downstream commercialization challenges in labeling, diagnosis, and treatment initiation—all set against a complex backdrop of concerns regarding cost and perceived value. This cost-value conundrum is underlined in a recent study conducted by DRG which finds that DMTs may face a number of market access roadblocks in the EU5, despite the landmark achievement they are likely to represent and the dearth of effective current therapies. What follows is one of the more unique yet provocative findings linking back to trial design.Germany is one of the largest EU5 markets and is considered a bellwether for other EU countries when it comes to pricing and reimbursement. In DRG’s recent Alzheimer’s Disease Access & Reimbursement (EU5) study, surveyed German neurologists and interviewed German payers who influence reimbursement nationally or regionally answered questions about their views on the evolving market access landscape for AD agents (alongside their counterparts from the other markets covered). While German physicians surveyed indicate that 18% of their diagnosed patients are pre-AD, only approximately 20% of these pre-AD patients receive drug treatment. For neurologists, a treatment decision is complicated by, among other things, a (somewhat counterintuitive) belief that such patients are “too mild” to treat; in fact, greater than half of the neurologists surveyed who report prescribing drug treatment to less than 20% of their pre-AD patients, indicate that it is because the patient’s symptoms are too mild to justify treatment. This attitude could persist even as treatment evolves; the same German physicians indicate they will prescribe a future DMT to more mild AD than pre-AD patients. Meanwhile, German payers indicate that MCI is not considered a treatable disease in Germany. The rationale for this position is that not all MCI patients will go on to develop AD and there is no accurate way to diagnose AD so early—both fair points.This mindset presents a conundrum for DMT developers; they may be able to demonstrate that their drug delivers a statistically significant effect on key outcomes in pre-AD patients, but will they be able to convince German physicians and payers that pre-AD patients are a treatable population? One hope is that physicians and payers accept that amyloid-positive MCI patients (i.e., MCI due to AD) may be more likely to progress to AD dementia, but we envision heavy payer scrutiny of the data and precise population enrolled. Ultimately, it is our view that key stakeholders across the major markets will require educating on the latest thinking regarding the progression of AD, in addition to compelling evidence of the clinical and economic benefit of DMT treatment in pre-AD patients.As trials have moved earlier in the disease course, demonstration of amyloid pathology (either through amyloid imaging or CSF testing) has become a standard enrollment criterion for trials of anti-amyloid DMTs. We expect this requirement to remain in place post-approval and, as mentioned above, be critical to driving treatment in pre-AD patients. However, amyloid imaging is not reimbursed in Germany (or many other markets) at this time and most German physicians indicate that this requirement would be at least somewhat restrictive to their prescribing of DMTs. Meanwhile, German payers report that the G-BA is restrictive about reimbursing biomarkers and some contend that manufacturers should pay for biomarker testing rather than the health insurance funds, which would mandate extra investment and impose additional logistical challenges for developers.Most KOLs we interview agree that clinical trial design has come a long way in AD, but we must consider carefully the full implications of this evolution. On the surface, it’s tempting to think “it’s a DMT for AD, of course, it’s going to be covered.” But it is not that simple. Some fundamental questions need to be addressed first. A DMT for AD would be a landmark achievement, but will the benefits be judged as clinically meaningful? Are two-year trials long enough to prove benefit or, more importantly, convince payers and physicians of disease modification? Presuming a high price tag, will such a drug pass muster with nations’ (and individual regions’ within nations, in some instances) differing definitions of cost-effectiveness? Will healthcare systems even be able to afford it? As the baby boomers age and we await the results of numerous ongoing Phase III trials—hoping at least one succeeds—we continue to debate how this will all shake out, and at what cost….Source: http://bit.ly/2sZsDU8