Today I'll point out an example of drug reuse and autophagy upregulation. The processes of autophagy are responsible for recycling molecular waste and broken cellular structures. Autophagy is upregulated in response to stress placed upon cells, whether by heat, cold, lack of nutrients, a toxic local environment, and so forth. This is beneficial to tissue function, health, and longevity, and thus there is considerable interest in the research community in producing therapies that boost the operation of autophagy. This hasn't made a great deal of progress towards the clinic, but nonetheless in any of the sizable databases of small molecule compounds there are some that result in increased autophagy - the question is always whether the side-effects are tolerable.
The cancer research community in particular tests a great many compounds and attempts to influence a great many core cellular processes, autophagy included. So when we see attempts at drug reuse, it is often the case that the drug in question is a small molecule that is either present used, used in the past, or was at least considered for chemotherapy. In the trial noted here, the drug is nilotinib. Researchers propose that it produces the observed reduction of toxic protein aggregates in the Alzheimer's disease brain by spurring increased autophagy, and can do so at low enough doses to avoid the worst of the side-effects noted to date. Of course, as is sadly standard in the mainstream of Alzheimer's development, no benefit to patients was observed to accompany improvements in biomarkers. The commentary provided by the trial administrators regarding the need more patients to see possible improvements is what is normally said by trial administrators about treatments that are expected to have only small and unreliable beneficial effects.
This is all par for the course. An entirely too sizable fraction of modern medical development centers not around the development of new therapies, based on new advances in science, but rather finding existing therapies that can be reused in new ways. This, I think, is one of the important underlying reasons as why most new treatments tend to be only marginally effective. The present regulatory structure makes it so costly and difficult to explore new approaches that funding entities are steered into the path of using whatever is already to hand, provided it can be shown to do at least a little good. The edifice of medical development is built of perverse incentives such as this, unfortunately.
Nilotinib is approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic myeloid leukemia. Nilotinib appears to aid in the clearance of accumulated beta-amyloid (Abeta) plaques and Tau tangles in neurons in the brain - hallmarks of Alzheimer's disease. Nilotinib appears to penetrate the blood-brain barrier and turn on the "garbage disposal" machinery inside neurons (a process known as autophagy) to get rid of the Tau, Abeta and other toxic proteins.
After careful screening, 37 people with mild dementia due to Alzheimer's were randomized to either the placebo or nilotinib groups for the 12-month study. A 150 mg daily dose of nilotinib or matching placebo was taken orally once daily for 26 weeks followed by a 300 mg daily dose of nilotinib or placebo for another 26 weeks. To prevent bias the study was blinded, meaning neither the study participants nor the investigators knew if the active drug or placebo were being administered until the end of the study. Nilotinib carries an FDA "black-box warning" because of cardiovascular issues that may lead to sudden death in cancer patients (typically treated with 600 mg daily), but no such incidents occurred in this study (maximum dose of 300 mg daily).
The amyloid burden as measured by brain imaging was reduced in the nilotinib group compared to the placebo group. Two forms of amyloid in cerebrospinal fluid were also measured. Aβ40 was reduced at 6 months and Aβ42 was reduced at 12 months in the nilotinib group compared to placebo. Hippocampal volume loss (on MRI scans of the brain) was attenuated at 12 months and phospho-tau-181 in spinal fluid was reduced at 6 and 12 months in the nilotinib-treated group.
This phase 2 trial was underpowered (as designed) to detect differences in clinical and cognitive outcomes and focused on evidence of nilotinib effects on safety and biomarkers, hence the incongruity between biomarker and clinical effects. Nevertheless, exploratory outcomes included efficacy of nilotinib versus placebo on the change from baseline to 6 months and 12 months. As expected, no differences were observed between the placebo and nilotinib groups on clinical, cognitive, functional, and behavioral outcomes, suggesting that a larger multicenter phase 3 study must be adequately powered to examine potential efficacy. The exploratory clinical outcomes in this phase 2 study will guide the design of an adequately powered larger and longer study to evaluate the safety and efficacy of nilotinib in Alzheimer's disease.