On 3 November 1906, Dr. Alois Alzheimer, a German psychiatrist, described together the clinical symptoms of presenile dementia and the pathologic findings of amyloid plaques and neurofibrillary tangles, based on clinical records and autopsy of patient Auguste D. Four years later, in 1910, Dr. Emil Kraepelin, an influential German psychiatrist, coined the name “Alzheimer’s Disease” for this disease, in the eighth edition of his textbook “Psychiatrie”. It wasn’t until 9 September 1993, however, or 86 years and 10 months following Dr. Alzheimer’s initial presentation, that the first drug specifically targeting symptoms of Alzheimer’s Disease was approved, the acetylcholinesterase inhibitor Cognex (tacrine).
There have been a total of six drugs approved for the treatment of Alzheimer’s Disease, not including new formulations of previously approved drugs (click on Alzheimer’s Disease). The pharmacologic classes of the approved drugs for the treatment of patients with different stages of dementia of the Alzheimer’s type are only two, acetylcholinesterase inhibitors and NMDA antagonists:
- Acetylcholinesterase Inhibitors: 4 NME’s, i.e., Cognex (tacrine); Aricept (donepezil), Exelon (rivastigmine), and Razadyne (galantamine); registration interest spans 7 years and 5 months, from 1993 to 2001. Note that the first of these drugs, Cognex (tacrine), has been discontinued.
- NMDA Antagonists: 1 NME, i.e., Namenda (mematine); approval in 2003.
- Combination products: 1 non-NME, i.e., Namzaric (donepezil + memantine); approval in 2014. Note that this it not an NME, since both active components had been previously approved.
It should be noted that Hydergine (ergoloid mesylates), first approved on 18 January 1953, has been used in the past for treating patients with dementia or ‘age-related’ cognitive symptoms, although it has not been approved for the treatment of symptoms of Alzheimer’s Disease.
All three current acetylcholinesterase inhibitors (Aricept, Exelon, Razadyne) are approved for the treatment of mild to moderate dementia of the Alzheimer’s type, and one (Aricept) is also approved for the treatment of moderate to severe dementia of the Alzheimer’s type. The other two approved drugs (Namenda, Namzaric) are approved for the treatment of moderate to severe dementia of the Alzheimer’s type. The registration (Phase III) trials for these agents have used similar assessment scales, i.e., ADAS-cog (the cognitive subscale of the Alzheimer’s Disease Assessment Scale) and CIBIC-plus (Clinician’s Interview-Based Impression of Change with caregiver information) for mild to moderate, and ADCS-ADL (Alzheimer’s Disease Cooperative Study – Activities of Daily Living) and SIB (Severe Impairment Battery) for moderate to severe. In general, the therapeutic effects of these agents were modest, and both the active treatments and the placebo treatments showed a wide range of responses, but the active treatments were more likely to show the greater improvements.
Two issues are worth commenting on in the context of approved treatments for Alzheimer’s Disease. First, the most recent approval (Namzaric) involves a combination product of two previously approved drugs. Considering the current development challenges in this area (many failed development programs and failed mechanisms of action), the high unmet medical need, and that the effects of the approved drugs are not considered to significantly affect disease progression, although delaying cognitive decline, one wonders what other chronic diseases, where there has been limited development progress, might be ripe for new combination products of previously approved drugs. For example, for obesity, where there has been a paucity of new therapeutic approaches and high unmet medical need, two of the four drug approvals since 1999 (Contrave, Qsyma), have involved combination products of previously approved drugs (1). A systematic and comprehensive review of other therapeutic classes will undoubtedly identify several other diseases where similar situations exist, including for other Psychopharmacologic and Neurologic Therapeutics.
Second, if recent history of progression of modern therapeutics is any guide, it is not unlikely that will take many years until there are next generation(s) of new NME drug approvals for Alzheimer’s Disease, including more than one per each new pharmacologic class. We note that the average number of pharmacologic classes per therapeutic class for 25 therapeutic classes that have been looked at is 4 (ranging from 1 to 10), and that the number of new NME drug approvals per pharmacologic class ranges widely, from 1 to 14 (2). We also note that the length of registration interest, defined here as the length of time from the first approval to the latest approval within a give pharmacologic class, has varied tremendously, ranging from a year or two to over 40 years (2). Thus, based on recent NME approval history of 25 therapeutic classes, and assuming there are one or more new breakthrough pharmacologic classes in the pipeline, and assuming more than one new NME drug approval per pharmacologic class, unfortunately, it is likely to take many years until we have a markedly different therapeutic choices for Alzheimer’s Disease. One hopes meaningful progress will have occurred before the 120th anniversary of Dr. Alois Alzheimer’s initial presentation.
- Weight Reduction Drugs: Slow Progression and Innovation (https://tri-institute.org/?p=394).
- Progression of Modern Therapeutics (2014 version), pages 33-35 (Progression of Modern Therapeutics (2014 Report))
Refer to page 23 of Progression of Modern Therapeutics (2014 Report) available under Reports on this website; this Report also includes the methodology used.