key: cord-1047057-czoehdl3 authors: Cummings, Jeffrey; Lee, Garam; Zhong, Kate; Fonseca, Jorge; Taghva, Kazem title: Alzheimer's disease drug development pipeline: 2021 date: 2021-05-25 journal: Alzheimers Dement (N Y) DOI: 10.1002/trc2.12179 sha: bbab7a44a3b914a574816f1b4885797eb472650c doc_id: 1047057 cord_uid: czoehdl3 INTRODUCTION: The number of individuals worldwide with Alzheimer's disease (AD) is growing at a rapid rate. New treatments are urgently needed. We review the current pipeline of drugs in clinical trials for the treatment of AD. METHODS: We interrogated ClinicalTrials.gov, the federal registry of clinical trials to identify drugs in trials. RESULTS: There are 126 agents in 152 trials assessing new therapies for AD: 28 treatments in Phase 3 trials, 74 in Phase 2, and 24 in Phase 1. The majority of drugs in trials (82.5%) target the underlying biology of AD with the intent of disease modification; 10.3% are putative cognitive enhancing agents; and 7.1% are drugs being developed to reduce neuropsychiatric symptoms. DISCUSSION: This pipeline analysis shows that target biological processes are more diversified, biomarkers are more regularly used, and repurposed agents are being explored to determine their utility for the treatment of AD. to warrant regulatory review and indicate increasing confidence in trials to demonstrate efficacy and safety of AD therapeutics. We conduct an annual review of the AD drug development pipeline with the intent of understanding the progress of the field in developing new therapeutics including new agents, targets, biomarkers, and trial design strategies. [9] [10] [11] [12] [13] Here we present the results of our analysis of the 2021 pipeline as represented on ClinicalTrials.gov. We used the FDA/US National Library of Medicine of the National Institutes of Health (NIH) clinical research registry, ClinicalTrials.gov, as the source of information for this review. The "common rule" governing ClinicalTrials.gov specifies that registration is required for studies that meet the definition of an "applicable clinical trial" (ACT) and were initiated after September 27, 2007 or initiated on or before that date and were still ongoing as of December 26, 2007 . ACTs, as defined in section 402(j) of the Public Health Service Act, include controlled clinical investigations of any FDA-regulated drugs, biological therapies, or devices for any disease or condition. ACTs generally include interventional studies (with one or more arms) of FDA-regulated products that meet one of the following conditions: the trial has one or more sites in the United States; the trial is conducted under an FDA investigational new drug application exemption; or the trial involves a small molecule drug, biological therapy, or device that is manufactured in the United States or its territories and are studied for research purposes. 14 Studies of ClinicalTrials.gov suggest that compliance with the common rule is high. 15, 16 The reporting of results of clinical trials is required, but trial sponsors are less adherent to this expectation. 17 The United States has more clinical trials than any other country, and ClinicalTrials.gov includes the majority of agents currently in clinical trials for AD; this review is therefore comprehensive but not exhaustive. There are other clinical trial registries and comparisons show that only a few agents registered in the European Union Clinical Trial Register, for example, are not found on ClinicalTrials.gov. 18 • There are 126 agents in clinical trials for Alzheimer's disease. • Most of the agents in the trial target disease modification. • More than 38,000 participants are required for currently registered trials; cumulatively they will contribute more than 2.5 million participant-weeks in trials. • Across all trials, biopharmaceutical companies sponsor 49% of trials and collaborate in another 14% of trials sponsored by public-private partnerships. company, NIH with academic medical centers, public-private partnership, or "other"). We included trials labeled as recruiting, active but not recruiting (e.g., trials that have completed recruitment and are continuing with the exposure portion of the trial), enrolling by invitation (e.g., open-label extensions of trials), and not yet recruiting. We did not include trials listed as completed, terminated, suspended, unknown, or withdrawn as information on these trials and reasons for their current status are often not publicly revealed. We do not include trials F I G U R E 1 Agents in clinical trials for treatment of Alzheimer's disease in 2021 (from ClinicalTrials.gov as of the index date of January 5, 2021). The inner ring shows Phase 3 agents; the middle ring comprises Phase 2 agents; the outer ring presents Phase 1 therapies; agents in green areas are biologics; agents in purple are disease-modifying small molecules; agents in orange are symptomatic agents addressing cognitive enhancement or behavioral and neuropsychiatric symptoms; the shape of the icon shows the population of the trial; the icon color shows the Common Alzheimer's Disease Research Ontology (CADRO)-based class of the agent ("Other" category includes CADRO classes that have three or fewer agents in trials). Agents underlined are new to the pipeline since 2020. Figure: J Cummings; M de la Flor, PhD, Illustrator of non-pharmacologic therapeutic approaches such as cognitive therapies, caregiver interventions, supplements, and medical foods. We do not include trials of biomarkers; we note whether biomarkers were used in the trials discussed. We include stem cell therapies among the interventions reviewed (they are not integrated into Figure 1 ). For mechanism of action (MOA), we classified agents using the CADRO 5 approach. Some agents have more than one mechanism of action and, in these cases, we noted both mechanisms and depended on the available literature to identify a dominant mechanism. We use the terminology of "symptomatic" treatments for agents whose purpose was cognitive enhancement or control of neuropsychiatric symptoms without claiming to impact the biological causes of cell death in AD, and we used the terminology of "disease-modifying" for treatments that intended to change the biology of AD and produce neuroprotection (often through a variety of intermediate mechanisms such as effects on amyloid or tau). 19 We used the features of the trials (e.g., clinical outcomes, trial duration, use of biomarkers, number of participants) to determine whether a trial was attempting to demonstrate disease medication or symptomatic benefit. We recognize that these definitions are arbitrary, and many therapies may have symptomatic and diseasemodifying effects. We divided disease-modifying therapies (DMTs) into biologics and small molecules. Biologics are generally derived from living organisms and include antibodies, vaccines, antisense oligonucleotides (ASOs), and therapeutic proteins. "Small molecules" refers to drugs typically taken orally that are <500 daltons in size and can regulate a biological process. AD has preclinical, prodromal, and There were 126 agents in 152 trials of treatments for AD (as of the In Phase 3 there are 28 agents in 41 trials ( Figure 1, Figure 2 , Table 1 ). 11.8%), oxidative stress (two agents; 11.8%), metabolism and bioenergetics (two agents; 11.8%), vascular factors (one agent; 5.9%), synaptic plasticity/neuroprotection (three agents; 17.6%), and gut-brain axis (one agent; 5.9%). Figure 2 shows the MOAs of agents in Phase 3. Four In Phase 2 there are 74 agents in 87 trials ( Figure 1 , Figure 3 , Table 2 ). Figure 3 shows the MOAs of agents in Phase 2. There are six trials in Phase 2 involving cell therapies (see Table 4 ). Twenty-six of the Phase 2 DMT agents are repurposed after approval for use in another indication. Since the 2020 review, 16 Phase 1 has 24 agents in 24 trials (Figure 1 , Across all trials, 49% are sponsored by the biopharma industry, 29% by academic medical centers (usually with funding from NIH), 14% are public-private partnerships, and 7% by others. In Phase 3, 61% of trials are sponsored by the biopharma industry, 20% by academic medical centers (with funding from NIH), 12% are public-private partnerships, and 7% by others. In Phase 2, 47% of trials are sponsored by the biopharma industry, 31% by academic medical centers (with NIH funding), 15% are public-private partnerships, and 7% by others. Table 5 shows the sponsor of agents in each phase of development. Repurposed agents are more likely to have academic medical centers/NIH sponsors (59%) and less likely to have industry sponsors (16%; Table 5 ). The rapid evolution of blood-based biomarkers may have a significant impact on patient screening and diagnosis and is expected to eventually act as entry criteria or outcomes in some 31 Repurposed agents are more common in trials in Phase 2 and more likely to be in trials sponsored by NIH/academic medical centers (Table 5) . Repurposed agents rarely progress to Phase 3; the Phase 2 trials of these drugs produce invaluable data on molecules that can be reengineered to have better intellectual property protection, pathways, and processes that may be promising therapeutic targets, and effects on biomarkers or novel clinical outcomes. These trials provide important educational opportunities for a variety of trainees who will comprise the clinical trial workforce of the future. 32 The total number of participants in trials and the total number of trial weeks they contribute is dramatic. Participants required for currently active trials total 38,826; when calculated in terms of participant-weeks in trials (Table 7) , the total number in all ongoing trials is 2,540,014. There are at least an equivalent number of weeks contributed by research partners, doubling the total participant-partner weeks to 5,080,028 weeks. This large number is a marked underestimate of total weeks because it does not include weeks spent in screening prior to randomization or weeks contributed by participants who are excluded during the screening period. A continuing challenge to trial conduct is the slow rate of recruitment. The average length of time required for recruitment of participants exceeds the duration of the treatment period in nearly all trials. There has been no trend toward shortening recruitment times over the past 5 years despite expanded efforts to improve recruitment. Although sponsors plan for slow recruitment, 66.7% of Phase 3 trials and 78.6% of Phase 2 trials took longer to complete than originally anticipated as recorded on ClinicalTrials.gov. The COVID-19 pandemic further exacerbated recruitment struggles with many clinics suspending research at least temporarily, delaying visits during this time, and experiencing attrition due to SARS-CoV-2 infections in patients and family members or an unwillingness to attend medical facilities. 33 These observations identify a gap in the trial system that requires remedy to accelerate trials and drug development. Many trials are conducted globally to increase the number of sites and accelerate recruitment. This is especially important for large Phase 3 trials. Global trials allow diversified participant exposures and improved understanding of effects of ethnicity, standard of care, body size, nutrition, and educational level on trial outcomes. Table 8 shows that most trials conducted have US representation either as the sole country in which the trials are conducted or as part of a world-wide global trial program. This is, in part, a reflection of the fact that Clinical-Trials.gov is a US trial registry (although note that most trials conducted by sponsors anywhere in the world are registered on ClinicalTrials.gov). Combined with the participant weeks in trials noted above, it is evident that participants and research partners throughout the world are making a remarkable contribution to AD drug development efforts through trial participation. Next generation biotherapeutics (NGBs) include cell, gene, and nucleotide therapies. 34 There are nine trials of cell therapies in AD (Table 4 ), one oligonucleotide targeting tau expression, and several epigenetic modulators. Technologies have advanced to facilitate trials of gene therapy in AD and trials are anticipated in the pipeline. 35 Stem cell interventions may promote nerve cell regeneration, adding a dimension to therapeutic response beyond the slowing of cognitive decline targeted by DMTs in current trials. 36, 37 Therapeutic concepts related to the larger universe of diseases of aging are beginning to influence the AD pipeline. Cell senescence occurs throughout the lifespan but plays a larger role with aging and is postulated to contribute to many diseases of aging including vascular disease, arthritis, and neurodegeneration. 38 Senolytic therapies directed at removing senescent cells are included in the AD pipeline. Three senolytics in current AD trials are metformin, rapamycin, and dasatinib plus quercetin; these therapies have shown benefit in nonclinical models of aging and AD. [39] [40] [41] A toolkit of biomarkers relevant to trials of senolytics suggests measures relevant to peripheral effects of treatment that may be useful in some AD trials. 42 Many questions remain unresolved concerning the relationship of cellular senescence and neurodegeneration/AD; 43 trials of senolytics will provide key insights into the value of these agents as treatments for AD and late-life cognitive decline. Clinical trials are the sole means by which new treatments for AD can be approved. Increasing the number of trials, enhancing trial efficiency, and improving trial success are critical to advancing new therapeutics for AD. Trials are being conducted in preclinical, prodromal, and AD dementia populations in an effort to prevent, delay the onset, slow the progression, or improve the cognitive and behavioral symptoms of AD. There are slightly more agents in the AD pipeline in 2021 compared to 2020. 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