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New Trials, New Targets: New Hope for Alzheimer's
New Trials, New Targets: New Hope for Alzheimer's

Medscape

time2 days ago

  • Health
  • Medscape

New Trials, New Targets: New Hope for Alzheimer's

After decades of frustration and failure, the landscape of drug development for Alzheimer's disease (AD) is starting to shift beyond anti-amyloids. Fueled by a growing pipeline of investigational agents, a broader range of therapeutic targets, and a record number of active clinical trials, a growing, but cautious, optimism is taking hold. The Alzheimer's Drug Development Pipeline 2025 reported there are currently 138 novel drugs under evaluation in 182 clinical trials — up 9% from 2024. Initiated by Jeffrey L. Cummings, MD, and colleagues in 2016, this year's annual report showed these clinical trials are being conducted at more than 4500 sites worldwide and included more than 50,000 participants. 'There's great reason for optimism. It's not just the increased amount of clinical trials, but the targeted therapies being studied,' said Cummings, Department of Brain Health, Kirk Kerkorian School of Medicine, University of Nevada, Nevada, in a statement. Howard Fillit, MD, cofounder and chief science officer of the Alzheimer's Drug Discovery Foundation, agreed. 'What's going on is really quite remarkable. We have the first disease-modifying drugs on the market, which is amazing, and I think the portfolio of drugs in development has changed dramatically from even 5 years ago,' Fillit told Medscape Medical News . James Rowe, PhD, professor of cognitive neurology, University of Cambridge, Cambridge, England, was equally impressed by the latest report. 'What strikes me is not just the number of new drugs but their range of targets in which they work, giving us multiple shots on goal,' Rowe commented during a media briefing on the report. The Next Big Thing? Currently 12 phase 3 trials are expected to report results this year. In an interview with Medscape Medical News , Cummings noted that 'one of the most interesting and probably most influential of the readouts that will occur this year' involves two trials evoke and evoke+ of the GLP-1 receptor antagonist semaglutide in patients with mild cognitive impairment (MCI) or mild AD dementia. 'Semaglutide is a drug approved for diabetes and obesity, and it has epidemiologic and laboratory support for testing in Alzheimer's disease. And what's important is that this is an oral medication and it would just be fabulous if we had an oral alternative for treatment,' said Cummings. Phase 3 data on the combination of xanomeline plus trospium, a medication approved for schizophrenia in adults, which is being tested for psychosis in AD, is also highly anticipated, Cummings said. 'There are no approved treatments for psychosis in Alzheimer's disease, so this is going to be a particularly interesting readout,' he noted. Cummings also highlighted BIIB080, Biogen's investigational antisense oligonucleotide targeting tau, as another promising compound for early-stage AD. The therapy received Fast Track designation from the FDA in April. In early testing, BIIB080 reduced soluble tau protein in cerebrospinal fluid (CSF), decreased aggregated tau pathology in the brain and showed favorable trends in exploratory clinical outcomes. New data on BIIB080 is expected in 2026. Hopes are also high for trontinemab (Roche), a modified version of the anti-amyloid monoclonal antibody gantenerumab. The therapy uses brain shuttle technology to improve its ability to cross the blood-brain barrier. 'This so-called brain shuttle technology is exciting because they've found a way to get much more of the antibody across the brain barrier and into the brain and engage the target. And this technology could be used to get other drugs into the brain,' Cummings said. The Big Picture There are currently 48 trials assessing 31 drugs in phase 3; 86 trials assessing 75 drugs in phase 2; and 48 trials assessing 45 drugs in phase 1. Of the 182 trials, 16 are long-term extensions of agents in prior trials. Since the beginning of 2024, 56 new trials entered the pipeline across all phases, including 10 new phase 3 trials. A total of 12 therapeutic agents are expected to complete phase 3 trials and 29 are scheduled to complete phase 2 in 2025. Disease-targeted therapies (DTTs) continue to dominate the AD drug pipeline. Biological DTTs comprise 30% of the pipeline and small molecule DTTs account for 43%. Drugs targeting cognitive enhancement make up 14% of the pipeline and drugs aimed at ameliorating AD neuropsychiatric symptoms comprise 11%. Repurposed agents represent 33% of the pipeline agents. In addition, biomarkers are among the primary outcomes of 27% of active trials. Beyond Amyloid: New Targets Anti-amyloid agents, lecanemab and donanemab, became the first disease-targeting medications for AD and represented a 'huge leap forward in our understanding and ability to treat AD,' Sheona Scales, PhD, director of research, Alzheimer's Research UK, told reporters attending the press briefing. Scales noted that a key focus of ongoing anti-amyloid research is to find ways to increase brain exposure and reduce the side effects of these agents. Beyond anti-amyloids, the latest pipeline report showed not only numerical growth but also increased biological diversity among the agents under investigation. 'Research is revealing even more complexities around how Alzheimer's disease starts and progresses, and this goes beyond amyloid. The current therapeutic pipeline has more diverse targets than in previous years,' Scales said. Similar to 2024, this year only 18% of drugs in the pipeline target amyloid-related pathophysiology, whereas 11% target tau-related processes. 'Neuroinflammation, in particular, is a highly active area of therapeutic development,' Emma Mead, PhD, interim chief scientific officer, Oxford Drug Discovery Institute, told reporters. 'Neuroinflammation is the brain's response to injury, infection or disease, and research has suggested that in neurodegenerative conditions, microglia, the immune cells of the brain, become dysregulated and this contributes to the damage associated with Alzheimer's disease,' Mead explained. Thirty drugs (22%) in the pipeline target neurotransmitter receptors, 24 (17%) address neuroinflammation/immune processes and 6% address synaptic plasticity/neuroprotection. Combination Therapies and Prevention Given the complexity of AD, it's become clear that targeting a single pathway may not be sufficient for effective treatment. Combination therapy targeting multiple complementary pathologic mechanisms will be necessary to maximize therapeutic effects. The 2025 AD drug pipeline includes 20 trials of combination therapies, comprising 11% of all current trials. Ten of these trials target aspects of both inflammation and amyloid. For example, two trials are testing dasatinib, in combination with quercetin, as a senolytic therapy for dementia. Senescent cells accumulate with age and are believed to contribute to age-related diseases like dementia. Six trials are assessing combinations of dextromethorphan and a CYP2D6 inhibitor for reducing agitation associated with dementia. Four trials are assessing the combination of xanomeline plus trospium. 'Because Alzheimer's disease is so complex and different pathologies develop at different times across the disease course, it's likely that in the future, patients are going to be offered specific treatments that target distinct mechanistic pathways depending on their disease stage,' Mead said. Rowe said one of the most compelling findings in the latest pipeline reported as the notable increase in late-phase trials focused on prevention. These AD prevention trials aim to intervene before symptoms appear — targeting individuals at high risk due to genetics, biomarkers, or early pathological changes — to delay or even prevent clinical onset. 'The aspiration to prevent, not just treat, is starting to be seen in the figures and that's very exciting,' he told the briefing. Repurposing Current Medications? About a third of the agents currently under investigation are repurposed medications — drugs originally approved for other conditions — which may offer a faster path to patient access. They include the GLP-1 receptor agonists (RAs) used to treat diabetes and obesity. In addition to semaglutide, another GLP-1 RA, liraglutide, demonstrated a 50% reduction in brain atrophy and 18% slower cognitive decline in the phase 2b ELAD clinical trial of adults with mild to moderate AD. The diabetes medication metformin is also in phase 3 testing for AD with results expected in 2026. Antihypertensive medications — including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs) — are also being studied for their potential neuroprotective effects. A randomized trial of the ARB candesartan showed positive neurocognitive effects independent of, and in addition to, their blood-pressure lowering effects. Further, a low dose formulation of the antiepileptic levetiracetam has also shown potential in the treatment of MCI and early AD by targeting hippocampal hyperactivity, a hallmark of AD. Research has also hinted that antibiotics, antivirals, some vaccines, and anti-inflammatory medications may protect against dementia, possibly by mitigating pathogen-induced neuroinflammation. Closer to a Cure? 'Trial innovation' is also evident in the 2025 AD drug development pipeline, the report's authors noted, with plasma biomarkers playing a greater role in AD diagnosis. Recent studies have suggested that plasma p-tau 217 measures are equivalent in diagnostic accuracy to CSF biomarkers of AD pathology. Several trials entering the pipeline this year are using plasma p-tau 217 to confirm AD diagnosis and serve as an eligibility criterion for clinical trial participation. In one trial, eligibility was based on Aβ 42/40 plus the ratio of p-tau 217/nonphosphorylated tau 217; a separate trial used 'blood biomarkers' or past CSF or PET evidence of Aβ abnormalities for eligibility. CSF levels of microtubule-binding region tau243 have been shown to correlate with insoluble tau detected by tau PET imaging and are being used as a primary outcome measure in an anti-tau antibody trial. 'The use of biomarkers to determine eligibility and as outcomes in clinical trials shows the increasingly important role that biomarkers play in AD drug development,' Cummings and colleagues wrote. Summing up, they said the 2025 AD drug pipeline report demonstrates 'robust' momentum toward identifying new therapies for the treatment of AD. 'Seeing the broad range of scientific research that's taking place, I am extremely hopeful that we are closer than ever to finding a cure for Alzheimer's,' Cummings said in the news release.

The Alzheimer's drug pipeline is healthier than you might think
The Alzheimer's drug pipeline is healthier than you might think

Mint

time04-06-2025

  • Business
  • Mint

The Alzheimer's drug pipeline is healthier than you might think

Of all the medical challenges that scientists have faced, Alzheimer's disease, the most common form of dementia, has been one of the trickiest. Between 1995 and 2021 private money spent on Alzheimer's research totalled $42.5bn, but more than 140 trials failed to deliver a single drug capable of slowing the disease. Yet the tide may be turning. There are two working drugs, offering modest benefits, on the market. A new review paper suggests more could soon follow. There are 182 clinical trials for Alzheimer's treatments under way in 2025—an 11% increase on the previous year—testing 138 different drugs, of which 12 are set to complete their final 'phase 3' trials this year. Moreover this pipeline includes medicines aimed at a diverse range of targets in the brain, reflecting an increasingly sophisticated understanding of the molecular processes behind Alzheimer's and dementia more broadly. For decades, the theory that has dominated Alzheimer's research, and drug pipelines, is known as the amyloid hypothesis. It argues that the primary cause of the disease is the accumulation of plaques of beta-amyloid proteins in the brain. These would lead to a cascade of negative effects including neuronal dysfunction, brain-cell death and neuroinflammation. The amyloid hypothesis was supported by genetic evidence, which showed mutations in key genes within families to be linked to early onset of the disease. The success of the two drugs already treating Alzheimer's—lecanemab and donanemab, which arrived on the market in 2023 and 2024, respectively—proves that a connection exists. Both help to clear amyloid from the brain, and offer modest help to a subset of patients for whom the drug is thought to be safe and useful. They slow the progression of the disease by about one-third, according to clinical trials, meaning patients can retain their quality of life for longer. The excitement generated by these drugs was tinged, however, with a feeling that they were not much to show for decades of effort. The singular focus on amyloid was probably misplaced. James Rowe, a professor of cognitive neurology at the University of Cambridge, says that although amyloid accumulation is a critical 'early trigger' for the disease, by the time patients arrive at his clinic there are other neural processes accelerating the illness. These include the accumulation of a misshapen version of a protein called tau; increased metabolic stress on brain cells; neuroinflammation; and degeneration of the brain's blood supply. A more nuanced understanding of Alzheimer's is at last being reflected in drug development. That is the conclusion of Jeffrey Cummings at the University of Nevada, Las Vegas, and colleagues in a review published on June 3rd in the journal Translational Research & Clinical Interventions. Academic experts, and investors, agree. Dame Kate Bingham is the managing partner of SV Health Investors, a venture-capital firm based in London that in 2015 started the first fund dedicated to discovering new treatments for dementia in 2015. At the time the drug pipeline for Alzheimer's was mainly focused on tackling amyloid. She says the growing diversity of potential targets today gives her increased optimism. Fully one-third of the new drugs are repurposed, which means they are already approved for use in other conditions and are being redeployed to Alzheimer's. The appeal of this approach is that the drugs already have known safety and toxicity profiles, and can be approved quickly and developed cheaply. One of the more well-known is semaglutide, a diabetes and weight-loss drug whose anti-inflammatory and metabolic benefits have led to its being tested as a treatment for mild cognitive impairment. The drug piromelatine, meanwhile, works on melatonin and serotonin receptors in the brain, which help regulate sleep. As healthy sleep is thought to increase the rate at which amyloid and other waste proteins are cleared, improving it may slow the progression of Alzheimer's. Then there is AR1001 (also known as mirodenafil), which was originally developed for erectile dysfunction and is being tested for its neuroprotective properties. The drug increases levels of a molecule in the brain called cGMP which, in turn, activates pathways that support the survival of nerve cells and improve connections between brain cells. Drugs in this category are known to improve blood flow, so the drug might also have an impact on the brain's vascular health. Another repurposed drug is nabilone, which interacts with the cannabinoid receptors in the body. (The most well known molecule of this kind is tetrahydrocannabinol, the active compound in cannabis). It was originally developed to treat nausea and vomiting in those undergoing cancer chemotherapy. It is now being tested as a potential treatment for agitation and behavioural problems in those with Alzheimer's. Guanfacine, a drug that improves attention and executive function in those with ADHD, is also being tested to see if it can offer similar benefits. Repurposed drugs do not necessarily have a higher chance of success in late-stage trials than those with a novel mechanism. Dame Kate argues that innovative approaches that use new molecular targets, rather than repurposing, will have the greatest impact on the disease. One area of innovation centres around drugs that can tackle inflammation in the brain. Particular attention is being paid to brain cells called microglia, which play a central role in the brain's immune response and, most probably, its fight against Alzheimer's. Microglia have been described as acting as the brain's fire service, police and binmen, because they respond to emergencies, maintain order and clear up debris. A number of drugs are trying to target the protein TREM2 on the surface of microglia in the hope of boosting their activity. Combinations of drugs are also being tested. For example, it is hoped that a pairing of dasatinib, a cancer drug, and quercetin, a molecule derived from plants, will clear ageing and dysfunctional cells. Drug combinations that target different pathways and components of an illness have made big inroads into other complex and intractable diseases such as cancer and HIV. Some of the errors of the past have been corrected. Dr Rowe says that early attempts to design amyloid-clearing drugs did not remove enough amyloid, or did so too slowly. The patient selection in trials was also poor, with many patients included who—it later turned out—did not have Alzheimer's at all. Today's trials still have blind spots, warns Antonella Santuccione-Chadha, the founder of the Women's Brain Foundation, a non-profit that studies how sex affects brain and mental health. Many still fail to differentiate patients by sex, she says. Yet women are twice as likely to develop Alzheimer's, a difference that cannot be explained solely by their longer lifespans, and the disease seems to progress differently in their brains. At any given stage of the disease, tau proteins spread farther in women than in men, says Dr Chadha. It would help the trials—and patients—if more people were tested for Alzheimer's earlier on, so that they could be enrolled to try the new drugs. A single register of those with the disease would also be useful, making it easier for patients to find trials, and for drug companies to find patients. Much, therefore, remains to be done. But for those suffering from a horrible and as yet insurmountable disease that steals so many minds, there is also some much needed hope.

The Alzheimer's drug pipeline is healthier than you might think
The Alzheimer's drug pipeline is healthier than you might think

Hindustan Times

time04-06-2025

  • Business
  • Hindustan Times

The Alzheimer's drug pipeline is healthier than you might think

OF ALL THE medical challenges that scientists have faced, Alzheimer's disease, the most common form of dementia, has been one of the trickiest. Between 1995 and 2021 private money spent on Alzheimer's research totalled $42.5bn, but more than 140 trials failed to deliver a single drug capable of slowing the disease. Yet the tide may be turning. There are two working drugs, offering modest benefits, on the market. A new review paper suggests more could soon follow. There are 182 clinical trials for Alzheimer's treatments under way in 2025—an 11% increase on the previous year—testing 138 different drugs, of which 12 are set to complete their final 'phase 3' trials this year. Moreover this pipeline includes medicines aimed at a diverse range of targets in the brain, reflecting an increasingly sophisticated understanding of the molecular processes behind Alzheimer's and dementia more broadly. For decades, the theory that has dominated Alzheimer's research, and drug pipelines, is known as the amyloid hypothesis. It argues that the primary cause of the disease is the accumulation of plaques of beta-amyloid proteins in the brain. These would lead to a cascade of negative effects including neuronal dysfunction, brain-cell death and neuroinflammation. The amyloid hypothesis was supported by genetic evidence, which showed mutations in key genes within families to be linked to early onset of the disease. The success of the two drugs already treating Alzheimer's—lecanemab and donanemab, which arrived on the market in 2023 and 2024, respectively—proves that a connection exists. Both help to clear amyloid from the brain, and offer modest help to a subset of patients for whom the drug is thought to be safe and useful. They slow the progression of the disease by about one-third, according to clinical trials, meaning patients can retain their quality of life for longer. The excitement generated by these drugs was tinged, however, with a feeling that they were not much to show for decades of effort. The singular focus on amyloid was probably misplaced. James Rowe, a professor of cognitive neurology at the University of Cambridge, says that although amyloid accumulation is a critical 'early trigger' for the disease, by the time patients arrive at his clinic there are other neural processes accelerating the illness. These include the accumulation of a misshapen version of a protein called tau; increased metabolic stress on brain cells; neuroinflammation; and degeneration of the brain's blood supply. A more nuanced understanding of Alzheimer's is at last being reflected in drug development. That is the conclusion of Jeffrey Cummings at the University of Nevada, Las Vegas, and colleagues in a review published on June 3rd in the journal Translational Research & Clinical Interventions. Academic experts, and investors, agree. Dame Kate Bingham is the managing partner of SV Health Investors, a venture-capital firm based in London that in 2015 started the first fund dedicated to discovering new treatments for dementia in 2015. At the time the drug pipeline for Alzheimer's was mainly focused on tackling amyloid. She says the growing diversity of potential targets today gives her increased optimism. Fully one-third of the new drugs are repurposed, which means they are already approved for use in other conditions and are being redeployed to Alzheimer's. The appeal of this approach is that the drugs already have known safety and toxicity profiles, and can be approved quickly and developed cheaply. One of the more well-known is semaglutide, a diabetes and weight-loss drug whose anti-inflammatory and metabolic benefits have led to its being tested as a treatment for mild cognitive impairment. The drug piromelatine, meanwhile, works on melatonin and serotonin receptors in the brain, which help regulate sleep. As healthy sleep is thought to increase the rate at which amyloid and other waste proteins are cleared, improving it may slow the progression of Alzheimer's. Then there is AR1001 (also known as mirodenafil), which was originally developed for erectile dysfunction and is being tested for its neuroprotective properties. The drug increases levels of a molecule in the brain called cGMP which, in turn, activates pathways that support the survival of nerve cells and improve connections between brain cells. Drugs in this category are known to improve blood flow, so the drug might also have an impact on the brain's vascular health. Another repurposed drug is nabilone, which interacts with the cannabinoid receptors in the body. (The most well known molecule of this kind is tetrahydrocannabinol, the active compound in cannabis). It was originally developed to treat nausea and vomiting in those undergoing cancer chemotherapy. It is now being tested as a potential treatment for agitation and behavioural problems in those with Alzheimer's. Guanfacine, a drug that improves attention and executive function in those with ADHD, is also being tested to see if it can offer similar benefits. Repurposed drugs do not necessarily have a higher chance of success in late-stage trials than those with a novel mechanism. Dame Kate argues that innovative approaches that use new molecular targets, rather than repurposing, will have the greatest impact on the disease. One area of innovation centres around drugs that can tackle inflammation in the brain. Particular attention is being paid to brain cells called microglia, which play a central role in the brain's immune response and, most probably, its fight against Alzheimer's. Microglia have been described as acting as the brain's fire service, police and binmen, because they respond to emergencies, maintain order and clear up debris. A number of drugs are trying to target the protein TREM2 on the surface of microglia in the hope of boosting their activity. Combinations of drugs are also being tested. For example, it is hoped that a pairing of dasatinib, a cancer drug, and quercetin, a molecule derived from plants, will clear ageing and dysfunctional cells. Drug combinations that target different pathways and components of an illness have made big inroads into other complex and intractable diseases such as cancer and HIV. Some of the errors of the past have been corrected. Dr Rowe says that early attempts to design amyloid-clearing drugs did not remove enough amyloid, or did so too slowly. The patient selection in trials was also poor, with many patients included who—it later turned out—did not have Alzheimer's at all. Today's trials still have blind spots, warns Antonella Santuccione-Chadha, the founder of the Women's Brain Foundation, a non-profit that studies how sex affects brain and mental health. Many still fail to differentiate patients by sex, she says. Yet women are twice as likely to develop Alzheimer's, a difference that cannot be explained solely by their longer lifespans, and the disease seems to progress differently in their brains. At any given stage of the disease, tau proteins spread farther in women than in men, says Dr Chadha. It would help the trials—and patients—if more people were tested for Alzheimer's earlier on, so that they could be enrolled to try the new drugs. A single register of those with the disease would also be useful, making it easier for patients to find trials, and for drug companies to find patients. Much, therefore, remains to be done. But for those suffering from a horrible and as yet insurmountable disease that steals so many minds, there is also some much needed hope. Curious about the world? To enjoy our mind-expanding science coverage, sign up to Simply Science, our weekly subscriber-only newsletter. 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