key: cord-0739120-adfxwcl9 authors: Cummings, Jeffrey; Lee, Garam; Nahed, Pouyan; Kambar, Mina Esmail Zadeh Nojoo; Zhong, Kate; Fonseca, Jorge; Taghva, Kazem title: Alzheimer's disease drug development pipeline: 2022 date: 2022-05-04 journal: Alzheimers Dement (N Y) DOI: 10.1002/trc2.12295 sha: 2be746b0709f85c08f079907d2367ad326eff46a doc_id: 739120 cord_uid: adfxwcl9 INTRODUCTION: Alzheimer's disease (AD) represents a global health crisis. Treatments are needed to prevent, delay the onset, slow the progression, improve cognition, and reduce behavioral disturbances of AD. We review the current clinical trials and drugs in development for the treatment of AD. METHODS: We searched the governmental website clinicaltrials.gov where are all clinical trials conducted in the United States must be registered. We used artificial intelligence (AI) and machine learning (ML) approaches to ensure comprehensive detection and characterization of trials and drugs in development. We use the Common Alzheimer's Disease Research Ontology (CADRO) to classify drug targets and mechanisms of action of drugs in the pipeline. RESULTS: As of January 25, 2022 (index date for this study) there were 143 agents in 172 clinical trials for AD. The pipeline included 31 agents in 47 trials in Phase 3, 82 agents in 94 trials in Phase 2, and 30 agents in 31 trials in Phase 1. Disease‐modifying therapies represent 83.2% of the total number of agents in trials; symptomatic cognitive enhancing treatments represent 9.8% of agents in trials; and drugs for the treatment of neuropsychiatric symptoms comprise 6.9%. There is a diverse array of drug targets represented by agents in trials including nearly all CADRO categories. Thirty‐seven percent of the candidate agents in the pipeline are repurposed drugs approved for other indications. A total of 50,575 participants are needed to fulfill recruitment requirements for all currently active clinical trials. DISCUSSION: The AD drug development pipeline has agents representing a substantial array of treatment mechanisms and targets. Advances in drug design, outcome measures, use of biomarkers, and trial conduct promise to accelerate the delivery of new and better treatments for patients with AD. HIGHLIGHTS: There are 143 drugs in the current Alzheimer's disease (AD) drug development pipeline. Disease‐modifying therapies represent 83.2% of the candidate treatments. Current trials require 50,575 participants who will donate 3,878,843 participant‐weeks to clinical trials. The biopharmaceutical industry sponsors 50% of all clinical trials including 68% of Phase 3 trials. Sixty‐three percent of Phase 3 trials and 46% of Phase 2 trials include non–North American clinical trial site locations indicating the global ecosystem required for AD drug development. Alzheimer's disease (AD) is increasing as the size of the aged population grows. 1 In the United States there are currently 6.2 million individuals with AD dementia and the number will reach 12.7 million by 2050. In addition to those with AD in the dementia stages, there are ≈10 million individuals in the United States with mild cognitive impairment (MCI), half of whom (5 million) have MCI due to AD. The total number of persons in the United States with symptomatic forms of AD-MCI due to AD and AD dementia-is 11.2 million. 1 The estimated 2021 cost of caring for those with Alzheimer's disease and related dementias (ADRD) was $355 billion. The world-wide prevalence of AD dementia will triple from its current 50 to 150 million by 2050 with most of those affected living in low-and middle-income countries. 2 The need for therapy to prevent, delay the onset, slow the progression, and improve the symptoms of AD is compelled by the rising number of those with AD and the growing public health crisis posed by the disease. Advances in therapy are being achieved; aducanumab, the first disease-modifying therapy (DMT) to be approved for AD, became available on the market for those with MCI due to AD and mild AD dementia in 2021. Aducanumab is an anti-amyloid monoclonal antibody, and two more monoclonal antibodies (donanemab and lecanemab) are under review by the US Food and Drug Administration (FDA). [3] [4] [5] Additional new treatments for AD may become available in the foreseeable future. We review the drugs in current clinical trials for AD. We present data from analyses of the clinicaltrials.gov registry, noting agents in Phase 1, 2, and 3; we describe their mechanism of action (MoA) and major trial characteristics. Our goal is to provide an update on agents being developed for AD and to present information on progress in the field of AD therapeutic development. The report follows the strategy developed in previous annual reviews of the AD pipeline. [6] [7] [8] [9] [10] [11] The current report used more advanced analytic tools than previously applied including artificial intelligence (AI) and machine learning (ML) to automate our interrogation of clinicaltrials.gov. We used the 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. Beginning in 2007 the "Common Rule" governing clinicaltrials.gov required registration for studies that meet the definition of an "applicable clinical trial" (ACT). ACTs include controlled clinical investigations of any FDA-regulated drugs, biological therapies, or devices for any disease or condition. 12 Review of studies of clinicaltrials.gov indicate that compliance with the common rule is high and most ACTs are registered appropriately. 13, 14 The United States has more clinical trials than any other country, and clinicaltrials.gov includes most but not all therapies currently in clinical trials for AD globally. 10 A recent review showed that this registry includes far more trials than any other of the 18 registries reviewed. 15 Based on this information, the current review can be regarded as a comprehensive but not exhaustive analysis of clinical trials of therapies for AD. The index date for this review is January 25, 2022, and the tables and text apply to the information available on that date. We include all trials of agents in Phases 1, 2, and 3. We collect information on the trial agent; trial title; trial number assigned on clinicaltrials.gov; start date; projected end date; actual end date, if completed or terminated; primary completion date; calculated trial duration; duration of treatment exposure; calculated recruitment period; number of subjects planned for enrollment; number of arms of the study (usually a placebo arm and one or more treatment arms with different doses); whether a biomarker was described as an entry criterion or an outcome; whether the agent was repurposed; subject characteristics (e.g., allowable Mini-Mental State Examination [MMSE] range); and sponsorship (a biopharmaceutical company, NIH with academic medical centers, public-private partnership, or "other"). We included trials labeled as recruiting, active but not recruiting (e.g., trials listed as terminated, suspended, unknown, or withdrawn unless the specific reasons for their status were publicly revealed. We do not include trials of non-pharmacologic therapeutic approaches such as cognitive-behavior therapies, caregiver interventions, supplements, medical foods, or devices. We do not include trials of biomarkers; we note whether biomarkers were used in the trials for inclusion or as outcome measures. We include stem cell therapies among the interventions reviewed (they are not integrated into Figure 1 ). We use the National Institute on Aging and the Alzheimer's Asso- unknown target, and other. Some agents may have more than one MoA and, for these we reviewed the available literature to identify the putative predominant mechanism. "Symptomatic" was used for treatments whose purpose was cognitive enhancement or control of neuropsychiatric symptoms without claiming to impact the underlying biological causes of AD. "Disease-modifying" was used for treatments intended to change the biology of AD and produce neuroprotection (often through a variety of intermediate mechanisms such as effects on amyloid or tau). 16 To generate the tables and data used in the pipeline, we designed a sentinel system to collect the needed data automatically from clinicaltrials.gov and store it in a relational database system. In this system, charts and graphs can be generated to provide insight into the data and illustrate trends. We identified 143 agents in 172 trials of treatments for AD (as of the There are 31 agents in 47 Phase 3 trials (Figures 1 and 2 , Table 1 ). There are 82 agents in 94 Phase 2 trials (Figures 1 and 3 , Table 2 ). There are five trials in Phase 2 involving cell therapies (Table 3) . Four (4%) of the trials in Phase 2 are prevention trials enrolling cognitively normal participants known to be at risk for AD (preclinical AD); three (3%) trials enroll both preclinical participants and participants with MCI to mild AD dementia; 49 (52%) trials enroll early AD defined as prodromal AD and mild AD dementia; 34 (36%) trials are with participants with mild to moderate AD dementia; two (2%) trials include participants with mild-to-severe AD dementia; and two (2%) trials enroll healthy volunteers. There are 30 agents in 31 Phase 1 trials ( Figure 1 , Table 5 shows the biomarkers used as entry criteria or as outcome In Phase 2, 12 (14%) DMT trials used amyloid PET as an entry criterion, five (6%) used CSF amyloid or amyloid ratios, and 12 (14%) used either amyloid PET or CSF amyloid assessments. Six (7%) of the Phase 2 DMT trials used CSF-amyloid/tau ratio as an entry criterion, four (5%) used either CSF-amyloid/tau ratio or amyloid PET, three (4%) used tau PET, and one trial (1%) used either amyloid PET or CSF-tau. Thirty-nine (47%) of Phase 2 trials did not require biomarker-based diagnostic confirmation for study entry. Of Phase 3 DMT trials, 19 (61%) used biomarkers as supportive outcomes. Ten (32%) used amyloid PET and seven (23%) used tau PET in support of clinical outcomes. In Phase 2, 46 DMT trials (55%) have biomarkers as supportive outcomes (11 amyloid PET; 10 tau PET). Including all currently active trials, the total number of partici- Across all trials, 50% are sponsored by the biopharma industry, 28% by academic medical centers (usually with funding from NIH), 17% are funded through public-private partnerships, and 5% are funded by other entities. In Phase 3, 68% of trials are sponsored by the biopharma industry, 15% by academic medical centers/NIH, 11% are public-private partnerships, and 6% are sponsored by others. In Phase 2, 41% of trials are sponsored by the biopharma industry, 36% by academic medical centers/NIH, 19% are public-private partnerships, and 3% are funded by others. Table 7 shows the sponsor of agents in each phase of development. Repurposed agents are more likely to have academic medical center/NIH sponsors (56%) and less likely to have industry sponsors (21%; Table 7 ). Development of new therapies for diseases of the nervous system is challenging with high failure rates and long development times forcing some major pharmaceutical companies to stop investing in this area of drug development. 18 Of the 49 novel drugs approved by the FDA in 2021, seven were for treatment of disorders of the central nervous system (CNS) and two were for the peripheral nervous system disorders (Duchenne muscular dystrophy, myasthenia gravis; fda.gov). 19 The Aducanumab is the first DMT approved by the US FDA for the treatment of AD. It is the second DMT approved in the United States for any neurodegenerative disease, the other is edaravone used in the treatment of amyotrophic lateral sclerosis. 20 The approval of aducanumab used an accelerated regulatory mechanism based on demonstration of amyloid plaque lowering considered reasonably likely to predict clinical benefit. 21 The accelerated pathway may be used for other antiamyloid plaque-lowering antibodies currently under review by the FDA (donanemab and lecanemab). [3] [4] [5] The trials of gantenerumab will be completed in 2022 and may lead to a request for marketing approval based on conventional clinical outcomes. 22, 23 Other biomarkers may eventually be qualified as surrogate outcomes predictive of clinical benefit. Surrogate outcomes facilitate drug development. 24 MCI due to AD and mild AD dementia comprise the most common population included in current clinical trials accounting for 36% of Phase 3 trials and 52% of Phase 2 trials. 25 These trials may be most impacted by the approval of aducanumab for this same population. Trial patients eligible for aducanumab may wish to begin active therapy rather than remain in a placebo-controlled trial that will last many months; patients appropriate for treatment with aducanumab and eligible for trial participation may prefer active treatment to trial enrollment; or patients on aducanumab may wish to continue this treatment and be included in trials of potential new AD therapies in addition to their ongoing treatment. Trial design will require reconsideration to account for the presence of aducanumab in the market. 26 and illness, death, and resignation of trial site staff. 30 The FDA provided guidance of Good Clinical Practice of trial conduct during the pandemic. 31, 32 The FDA also provided guidance on statistical and analytic considerations for data from trials affected by the COVID pandemic. 31 Many AD trial outcomes were successfully administered using telemedicine without compromise of data reliability. 33 Statistical modeling and trial simulation of AD trials indicated that stopping trials usually resulted in substantial loss of power and prolonging or enlarging trials were strategies to preserve trial integrity. 34 Despite the many challenges posed by the SARS-CoV-2 pandemic, the AD trial ecosystem proved to be resilient with few trials stopped during the pandemic and a substantial number of new trials initiated. The increased use of composite outcomes is apparent in this review. This trend is especially evident in trials in early AD (MCI due to AD and mild AD dementia) in which a significant drug-placebo difference on a single primary outcome measure may be the basis for regula- Biomarkers play increasingly informative roles in AD trials. The Phase 2 trial of donenemab used tau PET to define the population, requiring the presence of tau but without a high level of tau abundance suggesting advanced disease. 4 Nearly all the participants meeting the tau PET criteria had positive amyloid imaging; the discordance was 0.9% of individuals who met the tau PET criteria and not the amyloid PET criteria. This supports the observation that the presence of moderate levels of tau are highly predictive of the amyloid plaque burden. 38, 39 Plasma p-tau is highly correlated with amyloid PET 40, 41 and is being used to identify participants for some AD trials (e.g., Trailblazer 3). If confirmed, use of p-tau to identify individuals for AD trials is anticipated to simplify and accelerate AD trial recruitment. Other notable observations from this pipeline review include the of-concept and are more likely to be funded by NIH (56%) than biopharmaceutical sponsors (21%). 42 Global participation in drug development is evident in this review. Sixty-three percent of Phase 3 trials and 46% of Phase 2 trials include non-North American sites. This review is based on data from the clinical trials registry, clinicaltrials.gov. Recent studies support the use of this data source. Venugopal and Saberwal showed that clinicaltrials.gov is more comprehensive than any other of the 18 worldwide registries they reviewed. 15 The FDA Amendments Act of 2007 requires reporting of trial results within 1 year of trial completion and the FDA and NIH are increasingly vigilant about enforcement of this mandate, further strengthening the data available from the registry. 43 The registry and our search strategies are imperfect, and some agents may have been omitted in this review. Clinical trials for AD target a robust array of biological processes and clinical trial methodology increases confidence that more and better treatments will emerge from the AD drug development pipeline. 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Strengthening the FDA's enforcement of ClinicalTrials.gov reporting requirements How to cite this article Alzheimer's disease drug development pipeline Alzheimer's Dement