“The State of Sepsis and Alzheimer’s Disease Research: Birds of a Feather” by Steven P. LaRosa, M.D.

I have spent the greater part of 20 years as a clinical trialist is sepsis. Recently I have become interested as an Infectious Disease Physician in the viral disease of Alzheimer’s disease. What has amazed me is how similar the situation is in both fields. Both illnesses afflict affect millions worldwide with the annual incidence growing rapidly as the population ages. Despite improvements in background care, the one month mortality from sepsis remains high at 20%. There are no adjuvant agents FDA approved to reverse the organ dysfunction seen in sepsis. The prognosis in those afflicted with Alzheimer’s disease is also poor, and currently FDA-approved therapies amount to what my colleague states as “giving the patient a cup of coffee”.

The history of clinical trials in the two disease entities is also remarkably similar. Thousands of patients and millions of dollars have been spent on clinical trials of experimental therapies. These two diseases are the “holy grails” or “Moby Dicks” of the pharmaceutical industry as a success would result in untold riches. Stupendous results in small Phase II clinical trials have been followed by complete and total flame outs in adequately powered Phase III clinical trials. Because of what is at stake both for the pharmaceutical companies and academic “thought leaders” associated with these trials, numerous statistical gyrations have been employed to claim “positive” trials. For example, in the recently completed trial of the Toraymyxin filter for septic shock a positive trial was claimed in a subgroup within a subgroup despite no clinical benefit in the entire ITT population. Recent trials of agents aimed at amyloid beta by Biogen and Eisai in Alzheimer’s disease employed tactics including changing the landmark time point for efficacy analysis, employing a “home-brewed” clinical trial endpoint and claiming efficacy in a subgroup with a clear imbalance in a baseline condition (APOE allele 4) that affects outcome in the disease.

In each field there is also a focus on expensive experimental therapies. One of the downfalls with Xigris for sepsis was its expensive price tag of 7500 dollars per course of therapy. Currently is sepsis the experimental focus is on recombinant proteins and devices for which a premium can be charged. This is also the case with the antibody therapies BAN 2401 and Aducanumab.

In both fields a relatively inexpensive therapy with biologic plausibility has been championed but met with significant resistance. In sepsis, Dr. Paul Marik has championed HAT therapy consisting of IV Hydrocortisone, Ascorbic acid (Vitamin C) and thiamine. This combination has multiple biologic effects that benefit vasoplegic shock, ARDS, multi-organ system failure and late sepsis-induced inflammation. This combination of these agents is anti-inflammatory and endothelial protective. They also aid in endogenous vasopressor production. Mitochondrial dysfunction, important to multiple organ system, is protected by this cocktail and immune function is bolstered. In a before and after study conducted at Dr. Mariks’ ICU, the mortality dropped from 40.4% to 8.5% after implementation of the HAT therapy.

In Alzheimer’s disease a similar phenomenon is occurring. Multiple groups have demonstrated that the virus HSV-1 is more apt to be found in the Alzheimer’s brain than controls. Patients with evidence of HSV-1 reactivation (anti-HSV-1 IgM) are 2.5X more apt to develop AD over time. In vitro HSV- 1 leads to amyloid Beta (the key component of the senile plaques and neurofibrillary tangles that cause Alzheimer’s. This effect can be blocked in vitro by acyclovir. In a > 33,000 patient study in Taiwan, patients with newly diagnosed had a 2.5X increased risk of developing Alzheimer’s compared to controls. In those with newly diagnosed HSV, anti-herpetic therapy was associated with a 90% reduction in the development of Alzheimer’s.

The Vitamin C/ HAT therapy for sepsis and anti-viral therapy for Alzheimer’s disease have faced significant cynicism by both industry and academia. There are likely a few good reasons for this. The pharmaceutical industry would be very unhappy to see relatively inexpensive solutions for such major indications when a premium can be designed for expensive biologics, For “thought leaders” in academics the reasons are monetary and non-monetary. Some are receiving significant consulting fees and grants on other experimental therapies. For some who have been toiling in the field for years they might look silly if this disease could be cured by relatively simple therapies that they did not think of. For others, they need to defend their “pet rock” therapy or ideas on pathogenesis to the death.

The good news is that there are a few RCTs going on with HAT therapy in sepsis. A proof on concept RCT study of anti-viral therapy could be performed in a 78 week trial looking for a clinically meaningful 1 point difference in decline from baseline in the Clinical Dementia Rating-Sum of Boxes score with as few as 250 patients. We eagerly await a determination of the efficacy of these agents.