I have been inundated with headlines ranging from announcing the promise of a cure to the arrival of the cure itself as Biogen Phase 1B trial data findings are sparingly reported. Although it seems that the news is optimistic there are a few things you need to know about clinical trials before you decide on the impact of the latest findings. In a nutshell, when they are evident in a very small population and powered to only examine safety and tolerability, other claims are premature.
A Randomized, Double-Blinded, Placebo-Controlled Multiple Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB037 in Subjects With Prodromal or Mild Alzheimer's Disease
That mouthful is the title of the study. What this means exactly is that this was a randomized control trial and neither the researchers or participants knew who was actually receiving the investigative drug (double-blinded). In summary, Phase 1 B studies are often dose escalation studies where researchers are looking to evaluate the safety and tolerability by measuring the pharmacokinetics (how the drug is absorbed, distributed, and eliminated) and pharmacodynamics (the dose and response--the drug's effects on the body). Because these are the main objectives of a phase 1B study this represents the primary outcome or what the study was actually powered to measure--safety and tolerability.
Discussions following the presentation at the 12th International Conference on Alzheimer’s and Parkinsons’s Diseases in Nice, France were optimistic but continued to highlight the complexity of both the failed trials of similar compounds and the small size of the clinical trial and if the rate of amyloid-related imaging abnormalities (ARIA) would signal an association with higher doses. Clinical trials of therapeutics that target amyloid deposits have revealed MRI signal changes in patients, thought to be vasogenic edema (abnormal movement of fluid in the brain) and cerebral microhemorrhages.
For outcomes, the study set safety and tolerability as the primary, and six-month change in amyloid PET as the secondary endpoints. Exploratory endpoints included this formidable list: one-year amyloid PET; MMSE; CDR-sum of boxes; a version of the NTB neuropsych battery; the FCSRT (which doubled as an inclusion criterion); the NPI-Q neuropsychiatric inventory; and small sub-studies on fluid biomarkers, FDG PET, as well as volumetric, resting-state functional, and ASL spin labeling MRI. On top of that came a quarterly surveillance MRI to monitor ARIA-E.
The suspicion is that if the worst responders drop out from a treatment but not placebo arm—in this case, for example, the ApoE4 carriers with symptomatic ARIA-E from the high dose—it could make the drug look better than it is. Common ways of analyzing such datasets include:
We can dive back into these findings when we discuss the historical trials and more of the conflicting mechanisms theorized to be causative of Alzheimer's Disease that have preceded the latest research findings.
There is also a lack of consensus in measurements of cognitive function, etc that make this post perhaps a bit too simplistic as the discussions surrounding the clinical trial design will evolve more organically in coming months. I just wanted to pull in these early clinical trial results to contextualize the enthusiasm and investor interest exhibited in spite of far from conclusive evidence of efficacy at the approved dose for the next phase of research, Phase III. The data for this clinical trial will continue to be collected through 2016 according to clinicaltrials.gov
Alzheimer-Munich: Cerebral Cortex On an Unusual Illness of the Cerebral Cortex
What is your name?
In spite of these remarkable findings the case presentation received lukewarm attention and little to no discussion following the conference for quite some time--in spite of the symptoms characterized in a woman significantly younger than a typical patient with dementia. Questions to explore include the questionable naming of the disease after Alois Alzheimer and the disappearance and reappearance of Auguste Deter's brain many years later...
Congress enacted the Prescription Drug User Fee Act (PDUFA) in 1992 to provide a mechanism to charge fees to industry on each new drug application (NDA) filed. The revenues from these “user fees” were used to hire 600 new drug reviewers and support staff. These new medical officers, chemists, pharmacologists, and other experts were tasked with clearing the backlog of NDAs awaiting approval. Consequently, the FDA was able to reduce review times of NDAs to 12 months for standard NDAs and to 6 months for priority applications that involved significant advances over existing treatment. As a result of PDUFA, the timing of U.S. drug approvals began to mirror that of the rest of the world. Congress clearly likes PDUFA as the act has been renewed five times since 1992. PDUFA-V was approved in 2012. Undoubtedly, this legislation helps to support the FDA and fuel needed growth. In 1995, The actual user fee charged to each company filing an NDA in 1995 was $208,000. In 2014, the user fee will be $2,169,100. If you assume that as many as 50 NDAs are filed in a year, Congress is passing on $100 million of FDA funding costs to the industry.--Forbes
Of the top ten leading causes of death in the United States, Alzheimer’s disease — which ranks sixth — is particularly devastating in that there is no cure, no way to prevent it and no proven way to slow its progression. And with at least 11 million Americans expected to have the disease by the middle of the century (see ‘Degeneration generation’ figure) — boosting the annual costs of health care to more than US$1 trillion — the US government is anxiously looking to researchers to improve the prognosis.--Forbes
The complexity of debates around what constitutes Alzheimer's Disease are of interest because there is a lack of consensus regarding the clinical and neuropathic determinants. Are the behavioral and cognitive manifestations a disease entity in and of themselves or just a natural complication of aging? These issues continue to resonate and influence the development of elusive effective treatments. Perhaps the futility of attempting to find a cure is muted due to the substantial investment in funding.
A medical writer and insight analyst focuses the lens on the evolution of Alzheimer's Disease as a diagnosis into a billion dollar healthcare juggernaut
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