Expert Rev Clin Pharmacol. 2014 Mar;7(2):161-5. doi: 10.1586/17512433.2014.884923. Epub 2014 Feb 6.
Repackaging FDA-approved drugs for degenerative diseases: promises and challenges.
Cummings JL1, Zhong K.
Repurposing refers to the therapeutic use of a drug or drug candidate for a disease other than that for which it was originally intended. Repurposing is attractive as a drug development strategy since much is known about approved agents including their drug-likeness and pharmacokinetic features, dosing, safety, tolerability, formulation and manufacturing. Time savings are also robust accounting for several years of the drug development cycle. Tissue and cell-based assays, epidemiologic information and human studies identify approved drugs that might be repurposed from use in Alzheimer’s disease and other neurodegenerative disorders. The total number of compounds available for repurposing that are brain-penetrant is relatively small. Intellectual property and patent protection issues for repurposed drugs are hurdles for this approach to drug development. Repurposing may contribute importantly to development of new therapies for neurodegenerative disorders.
PMID: 24502586 DOI: 10.1586/17512433.2014.884923
Alzheimers Res Ther. 2016 Sep 20;8:39. doi: 10.1186/s13195-016-0207-9.
Drug development in Alzheimer’s disease: the path to 2025.
Cummings J1, Aisen PS2, DuBois B3, Frölich L4, Jack CR Jr5, Jones RW6, Morris JC7, Raskin J8, Dowsett SA9, Scheltens P10.
The global impact of Alzheimer’s disease (AD) continues to increase, and focused efforts are needed to address this immense public health challenge. National leaders have set a goal to prevent or effectively treat AD by 2025. In this paper, we discuss the path to 2025, and what is feasible in this time frame given the realities and challenges of AD drug development, with a focus on disease-modifying therapies (DMTs). Under the current conditions, only drugs currently in late Phase 1 or later will have a chance of being approved by 2025. If pipeline attrition rates remain high, only a few compounds at best will meet this time frame. There is an opportunity to reduce the time and risk of AD drug development through an improvement in trial design; better trial infrastructure; disease registries of well-characterized participant cohorts to help with more rapid enrollment of appropriate study populations; validated biomarkers to better detect disease, determine risk and monitor disease progression as well as predict disease response; more sensitive clinical assessment tools; and faster regulatory review. To implement change requires efforts to build awareness, educate and foster engagement; increase funding for both basic and clinical research; reduce fragmented environments and systems; increase learning from successes and failures; promote data standardization and increase wider data sharing; understand AD at the basic biology level; and rapidly translate new knowledge into clinical development. Improved mechanistic understanding of disease onset and progression is central to more efficient AD drug development and will lead to improved therapeutic approaches and targets. The opportunity for more than a few new therapies by 2025 is small. Accelerating research and clinical development efforts and bringing DMTs to market sooner would have a significant impact on the future societal burden of AD. As these steps are put in place and plans come to fruition, e.g., approval of a DMT, it can be predicted that momentum will build, the process will be self-sustaining, and the path to 2025, and beyond, becomes clearer.
2025; Alzheimer’s disease; Disease-modifying therapy
PMID: 27646601 PMCID: PMC5028936 DOI: 10.1186/s13195-016-0207-9
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Drug Des Devel Ther. 2016 Oct 3;10:3267-3279. eCollection 2016.
A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer’s disease.
Deardorff WJ1, Grossberg GT1.
Currently available therapies for the treatment of Alzheimer’s disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified.
Alzheimer’s disease; cholinesterase inhibitor; donepezil; fixed-dose combination; memantine
Alzheimers Res Ther. 2016 Nov 15;8(1):47.
Effect of concomitant use of memantine on mortality and efficacy outcomes of galantamine-treated patients with Alzheimer’s disease: post-hoc analysis of a randomized placebo-controlled study.
Hager K1, Baseman AS2,3, Nye JS4, Brashear HR4, Han J4, Sano M5, Davis B6, Richards HM4.
A large, prospective, 2-year, randomized study in patients with mild-to-moderate Alzheimer’s disease or mixed dementia demonstrated reductions in mortality and cognitive/functional decline in galantamine-treated patients. A post-hoc analysis was conducted to study the effect of (the presence or absence of) concomitant memantine use on treatment outcome.
Randomized patients (N = 2045) were divided into subgroups based on memantine use. Analyses included demographic and clinical characteristics (age, nursing home placement, Mini-Mental State Examination (MMSE) and Disability Assessment for Dementia (DAD) scores) and mortality endpoints.
Overall, 496 (24.3 %) patients were memantine users and were older (mean (SD), 74.0 (8.76) vs 72.8 (8.76), p = 0.008), with lower MMSE scores (18.2 (4.16) vs 19.2 (4.02), p < 0.0001) and DAD scores (58.0 (23.49) vs 62.5 (20.52), p < 0.0001) than nonusers. Mortality rates (per 100 patient-years) in memantine nonusers (n = 1549) were lower for galantamine (1.39) vs placebo-treated patients (4.15). In memantine users, mortality rates were similar for placebo-treated (4.49) and galantamine-treated patients (5.57). In memantine nonusers at 24 months, the decline in MMSE scores (effect size (95 % CI) 0.25 (0.14; 0.36)) and DAD scores (0.17 (0.06; 0.28)) from baseline was lower in galantamine patients vs placebo patients. The absence of these benefits in memantine users could not be explained by baseline age, MMSE, or DAD scores.
This post-hoc analysis shows that the beneficial effects of galantamine at 2 years post treatment were not observed in patients who had been placed on background memantine. The reasons for memantine treatment and the possibility of interaction between memantine and galantamine merit further investigation.
ClinicalTrials.gov NCT00679627 . Registered 15 May 2008.
Alzheimer’s disease; Baseline scores; Galantamine; Memantine; Mortality
PMID: 27846868 PMCID: PMC5111338 DOI: 10.1186/s13195-016-0214-x
Expert Opin Investig Drugs. 2016 Nov 25. [Epub ahead of print]
Pioglitazone for the treatment of Alzheimer’s disease.
Galimberti D1, Scarpini E1.
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. Pharmacological treatment of AD includes Anticholinesterase Inhibitors (AChEIs) for mild-moderate AD, and memantine for severe AD. These drugs provide mainly symptomatic short-term benefits without clearly influencing the progression of the disease. Pioglitazone (AD4833) is an insulin sensitizer of the thiazolidinedione class of nuclear Peroxisome-Proliferator Activated Receptor γ (PPARγ) agonists. It binds to PPARγ, affecting gene transcription and reducing inflammation. Areas covered: This review discusses the history of Pioglitazone, its pharmacokinetics and pharmacodynamics profile, and safety issues, together with an overview of clinical trials carried out so far. A literature search was made in Pubmed for pioglitazone, AD, trial, and on the ClinicalTrials.gov site for clinical trials with Pioglitazone. Expert opinion: A Phase II study in AD, and its previous indication for diabetes, showed that Pioglitazone is safe and well tolerated. So far, two large Phase III trials are ongoing, but there are no preliminary results yet on a possible beneficial effect on cognition in patients with AD.
AD4833; Alzheimer’s disease (AD); Mild Cognitive Impairment (MCI); clinical trial; pioglitazone
PMID: 27885860 DOI: 10.1080/13543784.2017.1265504
Expert Opin Investig Drugs. 2016 Oct;25(10):1181-7. doi: 10.1080/13543784.2016.1216972. Epub 2016 Aug 5.
Old and new acetylcholinesterase inhibitors for Alzheimer’s disease.
Galimberti D1, Scarpini E1.
To date, pharmacological treatment of Alzheimer’s disease (AD) includes Acetylcholinesterase Inhibitors (AChEIs) for mild-to-moderate AD, and memantine for moderate-to-severe AD. AChEIs reversibly inhibit acetylcholinesterase (AChE), thus increasing the availability of acetylcholine in cholinergic synapses, enhancing cholinergic transmission. These drugs provide symptomatic short-term benefits, without clearly counteracting the progression of the disease.
On the wake of successful clinical trials which lead to the marketing of AChEIs donepezil, rivastigmine and galantamine, many compounds with AChEI properties have been developed and tested mainly in Phase I-II clinical trials in the last twenty years. Here, we review clinical trials initiated and interrupted, and those ongoing so far.
Despite many clinical trials with novel AChEIs have been carried out after the registration of those currently used to treat mild to moderate AD, none so far has been successful in a Phase III trial and marketed. Alzheimer’s disease is a complex multifactorial disorder, therefore therapy should likely address not only the cholinergic system but also additional neurotransmitters. Moreover, such treatments should be started in very mild phases of the disease, and preventive strategies addressed in elderly people.
Acetylcholinesterase inhibitors (AChEI); Alzheimer’s disease (AD); clinical trial
PMID: 27459153 DOI: 10.1080/13543784.2016.1216972
Drugs Today (Barc). 2016 Apr;52(4):239-48. doi: 10.1358/dot.2016.52.4.2479357.
Memantine and donepezil: a fixed drug combination for the treatment of moderate to severe Alzheimer’s dementia.
Donepezil (and other cholinesterase inhibitors [ChEIs]) and memantine are the mainstays of treatment in Alzheimer’s dementia, addressing respectively, the cholinergic and glutamatergic dysregulation which underlies or results from its pathophysiology. To alleviate the pill burden and swallowing difficulties associated with the condition, a fixed drug combination of extended-release memantine and donepezil was developed. This combination was shown to be both bioequivalent to the components administered separately and could be administered sprinkled over soft food. The mode of action, pharmacokinetics, clinical efficacy and safety and tolerability of the combination are discussed together with the wider, often conflicting trial literature of combination versus monotherapy with memantine and ChEIs, their meta-analyses and treatment guidelines.
Copyright 2016 Prous Science, S.A.U. or its licensors. All rights reserved.
Alzheimer’s disease; Cholinesterase inhibitors; Donepezil; Memantine; Neurologic drugs
PMID: 27252988 DOI: 10.1358/dot.2016.52.4.2479357