#BrainHealth & #PreventiveNeurology: can we afford a biological therapy for Alzheimer's disease?

The costs of modifying the course of Alzheimer's disease with a biological therapy are mind-blowingly large. #BrainHealth #PreventiveNeurology

The perspective in this week's NEJM is a sobering reminder of why we need effective preventive strategies for Alzheimer's disease (AD). If we have to rely on Pharma to deliver expensive biological disease-modifying therapies (DMTs) to treat the disease it may end up costing society an extortionist amount of money. 

As most people with AD rely on the state for their healthcare can society afford expensive DMTs for symptomatic AD? I am not sure we can. People with symptomatic AD have already lost too much brain and slowing progression of their AD at this stage may be too late to have an impact on their, and their family's, QoL. The other issue is cost-effectiveness; most people with AD (pwAD) are aged and not economically active and hence any DMT will have to be relatively cheap to pass NICE's cost-effective thresholds. It is likely,  therefore, that only the wealthy will be able to access these treatments, further widening the gulf between the haves and have-nots. 

It is clear to me that we are going to have shift our attention and resources to prevention. The question is can we prevent AD? We think you can by simply maximising brain and cognitive reserve, which protects you from getting AD, or delays it long enough that you may die from another cause. This simple principle is what is underpinning our preventive neurology initiative. Can we do it? Yes, I think we can but it is going to take a massive effort. 

Sacks et al. The Failure of Solanezumab — How the FDA Saved Taxpayers Billions. N Engl J Med 2017; 376:1706-1708.

Excerpts:

.... The November 2016 announcement that Eli Lilly’s investigational drug solanezumab failed in a phase 3 clinical trial dashed hopes that it would be a long-anticipated disease-modifying treatment for Alzheimer’s disease.... 

..... the failure of solanezumab also offers a window into the U.S. drug regulatory system, particularly in the context of the recently signed 21st Century Cures Act and the ongoing national debate about the role of the Food and Drug Administration (FDA). The solanezumab story is an important case of a regulatory system that worked.....

..... Solanezumab is a monoclonal antibody designed to promote clearance of amyloid beta peptides that aggregate and deposit as plaques in the brain — a development long thought to be a cause of Alzheimer’s disease. Lilly had funded two prior phase 3, randomized trials, Expedition and Expedition, comparing solanezumab with placebo in patients with mild-to-moderate Alzheimer’s disease. The findings, announced in 2012 and later published,2 showed that the drug failed to improve cognitive or functional outcomes.....

..... However, in a prespecified analysis combining the two trials, there appeared to be a statistically significant benefit for the subgroup of patients with mild dementia. In a 2012 press release, Lilly reported a 34% reduction in cognitive deterioration in this population. For patients in Expedition2 who had mild disease, this result reflected a difference from the placebo group of 1.7 points, on a 90-point scale over 80 weeks. For comparison, one key study of donepezil (Aricept), a widely used treatment for Alzheimer’s disease that offers only modest clinical benefit, demonstrated a 3-point advantage over placebo on a 70-point cognitive function scale after 24 weeks of treatment.... 

.... Lilly’s decision to undertake Expedition, though logical, was not inevitable. The trial was undertaken after those reported discussions with regulators because the law requires manufacturers to provide the FDA with substantial evidence of a product’s efficacy before bringing it to market, and prospective, randomized trials are generally the best way to do so. In recent years, however, this standard has increasingly been criticized as overly stringent; some commentators have even suggested that the FDA should simply approve all drugs that are determined not to be toxic, letting “the marketplace” determine which ones work best......

.... Therefore, it is worth considering what might have happened if a more antiregulatory stance had been in place in 2012 and the pooled outcome assessments of Expedition1 and Expedition2 suggesting benefit in the subgroup of patients with mild Alzheimer’s disease had been enough to support FDA approval — particularly since no major safety concerns had been raised in those trials.....

..... Meanwhile, the costs of this new treatment would have been borne largely by Medicare (96% of people with Alzheimer’s dementia are 65 years of age or older), as well as by private insurers for patients with dual insurance and by patients subject to copayments..... 

.....Because Lilly never publicly indicated its target price in the event that solanezumab was approved, it is impossible to know for certain what that total cost might have been, but the prices of similar novel therapeutics suggest a plausible range. For example, the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors evolocumab (Repatha) and alirocumab (Praluent), monoclonal antibodies approved in 2015 for certain patients with another chronic condition, hyperlipidemia, carry a list price of about $14,000 per patient per year. For another monoclonal antibody, adalimumab (Humira), widely used to treat rheumatoid arthritis, inflammatory bowel disease, and psoriasis, the annual spending per Medicare patient, according to the 2015 Medicare Drug Spending Dashboard from the Centers for Medicare and Medicaid Services, was $29,278. With almost 57,000 Medicare patients receiving the medication, the total cost that year was $1.7 billion.....

...... Even conservative estimates suggest that the total costs of solanezumab would have been staggering. Of the more than 5 million people in the United States with Alzheimer’s disease, about half can be categorized as having mild disease, the subgroup initially thought to benefit from solanezumab. If the price had been set at $10,000 per patient per year and just one tenth of those patients had been treated, the cost would have been almost $10 billion over the past 4 years. Had the price been set higher, or had promotion yielded faster uptake and more prescriptions, the cost might well have been many times that amount. The graphRange of Potential Spending on Solanezumab during 4-Year Period from 2013 through 2016, with Varying Annual Drug Costs and Population Uptake. shows the range of potential spending on solanezumab, based on varying price and uptake.....