Lenalidomide [Revlimid ™], is a cancer drug that will be tested in early Alzheimer Disease (AD) / amnestic Mild Cognitive Impairment (aMCI), announced by Dr. M. Sabbagh, The Cleveland Clinic / Las Vegas. There is reason to think, based on animal studies of AD, that some of the drug’s “immunomodulatory” characteristics may help. Somewhat confusingly, lenalidomide does have action against that “other” amyloid, AL or Light-Chain Amyloidosis, which usually affects the heart and kidneys, but ironically usually spares the brain. Alzheimer amyloid is called A-beta.
There will be two Phase 1-2 trials, testing for safety and effect on biomarkers first, and then looking at safety and cognition in the second study. It’s not clear that they are recruiting subjects yet. Lenalidomide was approved about 15 years ago, and along with bortezomib, started to really improve survival in Multiple Myeloma (MM), a marrow cancer (expert opinion from R. Kyle, in the link), and is now part of many standard MM regimens.
“Chemo” is a term that can invoke negative ideas, but for oncologists, it’s part of a plan that can cure. Yeah, the drugs are imperfect, the side effects can be really bad (“poor therapeutic index”), but it’s usually the best shot we have. Cancer patients have volunteered for similar, ethically run Phase 1-2 studies, and we have dozens of new cancer drugs that have run that gauntlet [along with many agents that didn’t get approved].
Alzheimer’s disease is now one of the top six causes of death in the US, below heart disease, and cancer, but above diabetes and acute pneumonia. Since AD can be fatal, the rewards might be worth the risk.
Sabbagh’s group has already tested lenalidomide’s chemical cousin, thalidomide, but they found safety issues and many side effects. Does the name thalidomide ring a bell? It came to the US from Europe in the 1960’s, as a sleep and nausea drug for pregnant women, but it was found to be associated with dramatic birth defects (including arm and leg malformations). Dr. F.O. Kelsey at the FDA worked at keeping thalidomide out of the US market back then, a highlight of the FDA’s role in public safety. She won a President’s Medal from JFK.
Thalidomide was dramatic enough that a number of cancer researchers started wondering if the drug effect that caused devastating neurological and limb problems in developing fetuses could be used against proliferating cancer cells. Eventually, “repurposing” trials, if you will, showed that thalidomide could improve survival in MM. Later research showed that this class of drugs has many effects, some which might help a condition like AD.
Interestingly, a case report showed that a patient with dementia + MM had cognitive improvement after receiving chemotherapy. The improvement was documented with neuropsychological testing, but he later succumbed to his diseases. The brain autopsy (done by the Hulette group at Duke) confirmed the pathologic hallmarks of Alzheimer disease. The chemotherapy was conventional for the time; it did not include lenalidomide. The late author, hematologist R. Keimowitz, never received a query about the case (pers. comm, 2015); MM trials from that era did not report similar cases (pers. comm, R. Kyle, 2015), but trials many times exclude patients with cognitive / consenting issues.
Other chemo agents, including agents like bexarotene, imatinib, and others have been tested in dementia animal models or even in human subjects, measuring cognitive outcomes or biomarkers, with negative (bexarotene) or varying results. Another cancer treatment, therapeutic radiation, is being used in clinical trials.
An agent approved for chronic myelogenous leukemia is being studied for dementia in Parkinson disease patients. An early report on this agent, nilotinib, was positive, but it’s hard to tell from a follow up report how well it might be working.
Subjects who volunteer for such studies, and clinical investigators who enroll them, deserve much praise for participating, knowing that these agents can be hard (even at lower doses). With all the therapeutic failures over the last several years in AD (aducanumab decision pending), it seems to make sense to take a different, somewhat empiric approach, modulated by all the safety data already known about a repurposed agent, and with close safety and ethical IRB oversight. BRAVO!
[“TLP” = thalidomide-lenalidomide-pomalidomide in image above, from Wikimedia Commons public domain, cropped, author Hrodmar (2012), based on Kotla V et al, Mechanism of action of lenalidomide in hematological malignancies. J Hematology & Oncology 2 (1): 36, 2009. doi:10.1186/1756-8722-2-36.]
(AlzGadfly has been an institutional PI and administered Phase 1-2 agents to childhood cancer patients with parental consent and IRB oversight along with passing COG/NCI audits for safety and punctilious record management]