Drugs for Alzheimer’s disease (AD) are undergoing a revolution, as the search for disease-modifying medications continues. Clarivate data shows 750 AD candidates in various stages of development. These drugs include monoclonal antibodies such as BIIB-076, a Phase I drug developed by Neurimmune Holding, as well as repurposed therapies, such as montelukast, an asthma treatment that is currently in Phase II trials for AD. Other notable drugs in clinical testing include the placenta-derived stem cell treatment CBAC-02, made by CHA Biotech, currently in Phase II trials, and NTRX-07, an investigational cannabinoid receptor agonist developed by NeuroTherpia.
Ward says that AD is an interesting space to watch, given that there is now an established route for drug approval. He explains that because the first products for AD have already been approved, the space has attracted much more interest in recent years from pharma companies.
“There was a paper published in the past few weeks that suggested the concept of cell death in Alzheimer’s patients,” notes Ward. “It’s one of those diseases we knew was a problem, but nobody had created any acceptable solutions. We’re going to see a lot more effort put into neurodegenerative diseases, so the prospects over the next decade certainly look promising.”
Ward adds that there are several products in clinical development right now, some of which appear to be disease-modifying efforts, which represents an important breakthrough. Prior AD drugs such as Aricept, he says, merely slowed disease progression; an approved, effective disease-modifying AD treatment is something of a holy grail for the life sciences industry.
One of the newest AD candidates undergoing clinical testing is zagociguat (CY6463), a CNS-penetrating soluble guanylate cyclase (sGC) stimulator. Developed by Ironwood Pharmaceuticals subsidiary Cyclerion Therapeutics, zagociguat recently underwent its first human trial, which examined the safety, pharmacokinetics, and pharmacodynamics of varying dosages of zagociguat in a group of healthy adults. The trial found that zagociguat was well-tolerated in the study group and penetrated the central nervous system, resulting in sGC stimulation. The study validated the drug’s mechanism of action, paving the way for future studies.15
Other hopeful therapies are closer to potential market entry. One Phase III clinical trial completed this year examined the effects of Lilly’s biologic drug donanemab, a monoclonal antibody that targets amyloid beta protein, in 1,736 subjects with early symptomatic AD, including mild cognitive impairment and mild dementia. Subjects were randomly assigned to receive either donanemab (n = 860) or a placebo (n = 876) intravenously once every four weeks for 76 weeks. The subjects were scored on the integrated Alzheimer Disease Rating Scale (iARDS) at baseline and on study completion; secondary outcomes included Clinical Dementia Rating Scale (CDRS) scores. After 76 weeks, the subjects in the treatment group exhibited significantly better CDRS and iARDS scores than the placebo group. The study authors concluded that donanemab slowed the clinical progression of AD.16 Lilly completed its FDA submission for approval of donanemab in July, and an agency decision is expected by the end of the year.17
Monoclonal antibodies have attracted significant attention in AD treatment, particularly since the COVID-19 pandemic. In July, FDA granted accelerated approval to the Eisai/Biogen drug Leqembi (lecanemab), an antibody intravenous infusion therapy that targets removal of amyloid beta from the brain.18 Leqembi underwent a 2023 Phase III trial on 1,795 subjects with AD; subjects were randomingly assigned to receive either 10 mg/kg of intravenous lecanemab once per day, (n = 898) or a placebo (n = 897), for two weeks. Subjects were assessed via the Clinical Dementia Rating-Sum of Boxes scale, through PET scans for amyloid plaque, on the Alzheimer’s Disease Assessment Scale, the Alzheimer’s Disease Composite Score, and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment. All of the subjects were followed for 18 months. After this period, the patients receiving lecanemab exhibited significantly reduced amyloid plaque markers as well as moderately less decline on measures of cognitive function compared to placebo.19
Other notable drug candidates in development for AD include mecripyrine hydrochloride, an acetylcholinesterase and tau protein inhibitor in Phase I trials, [18F]-AM-PBB3, an investigational tau tracer in Phase II studies, and donepezil, a cholinesterase inhibitor currently in Phase I.
COPD ON VERGE OF BREAKTHROUGH?
It’s been several years since a new drug for COPD came to market. To date, the major therapies for the debilitating condition, often linked to smoking, have consisted primarily of corticosteroids, bronchodilators, methylxanthines, and biologics; these drugs typically aim to reduce symptoms.
Today, however, therapies are in the pipeline that target specific COPD biomarkers. One such candidate, dupilumab, holds promise as a disease-modifying drug for the condition. The monoclonal antibody, already a blockbuster seller, branded as Dupixent, for several indications, including atopic dermatitis and asthma, recently underwent a Phase III trial in patients with COPD with 300 blood eosinophils per microliter and an elevated exacerbation risk. In this study, subjects were randomly assigned to receive either 300 mg of dupilumab via subcutaneous injection (n = 468), or a placebo (n = 471), once every two weeks. The subjects were assessed for number of COPD exacerbations after one year, as well as for forced expiratory volume (FEV) and St. George’s Respiratory Questionnaire (SGRQ) scores at baseline and after one year. Finally, subjects had blood taken at baseline and after one year, and were assessed for blood eosinophil count. After one year, those who received dupilumab had superior lung function, a better quality of life, and fewer exacerbations than the placebo group.20
Meanwhile, several other biologics originally designed as asthma treatments are in the midst of human trials for COPD,21 including mepolizumab, benralizumab, and itepekimab. These treatments are in various stages of clinical development for COPD based on their strong effects on asthma exacerbation frequency.22
But monoclonal antibodies aren’t the only major investigational efforts underway hopeful of reshaping COPD therapy. Ensifentrine, a PDE3/PDE4 dual inhibitor, has completed two Phase III trials and has been submitted for US approval with a PDUFA date of June 26, 2024. During Phase II studies in subjects with COPD, ensifentrine was found to have bronchodilatory properties, to improve symptoms in COPD patients, and to improve quality of life. These findings held, regardless of whether ensifentrine was administered alone or in combination with other drugs.23
Combination treatments are also a growing trend in COPD research. One Phase III trial examined the effects of a triple-combination of inhaled budesonide, glycopyrrolate, and formoterol relative to dual therapies. The study found that triple-therapy resulted in a lower rate of moderate-to-severe COPD exacerbations after one year compared to dual therapy.24
Big Pharma organizations such as AstraZeneca are continuing to innovate in COPD research, having identified various proteins, such as IL-33, myeloperoxidase, and forkhead box O4, as major disease pathways.25
This primary research is illuminating potential new mechanisms of action that could warrant pharmaceutical development.
PSYCHEDELICS ATTRACT ATTENTION AND CAPITAL
Psychedelic medicine has sparked notable advances in mental health treatment, and is considered the first major innovation in the field since the rise of selective serotonin reuptake inhibitors (SSRIs) in the 1980s. While much of the research around psychedelics has been in existence since the 1970s, the Nixon Administration’s War on Drugs put a significant chill on psychedelic research for several decades. Now, though, psychedelics are once again coming to the forefront of medical research, given their promising therapeutic results.
“Psychedelics are quite hot in terms of their potential for mental health,” Ward tells Pharm Exec. “I think that’s going to be a challenge for regulators. We’re seeing a lot of venture capital going into the psychedelics space, which is a proxy for what will be hot in five or 10 years’ time.”
Clarivate data shows more than 270 psychedelic drugs currently in various stages of development. These treatments are primarily focused on mental health and addiction conditions, including depression, eating disorders, post-traumatic stress disorder, and alcoholism.
David Cavanaugh, founding partner at DeciBio Consulting in Los Angeles, says several of these drugs are now coming to market. FDA approved ketamine several years ago, he notes, and methylenedioxymethamphetamine (MDMA)-assisted therapy is slated to enter the market within the next 18 months.
“There are a lot of interesting uses for these drugs,” says Cavanaugh. “There are several challenges, though, because they’re not the typical pharmaceuticals. This model is very different because of the fact that it’s drug-assisted therapy.”
Cavanaugh explains that psychedelics enable patients to interact with their trauma in ways they couldn’t before, enabling a superior benefit of psychiatric therapy when medication and therapy are combined.
This combination approach is a new and different model for pharma companies; Cavanaugh notes that the Multidisciplinary Association for Psychedelic Studies (MAPS) protocol for MDMA requires 40 hours of therapy. He adds that therapy is required before, during, and after drug-assisted procedures; while this is very intensive and burdensome for providers, Cavanaugh says the clinical results are excellent.
“Most of the drugs in the mental health space are decades old,” he tells Pharm Exec. “If you look at drugs for PTSD, they don’t really work well. They don’t resolve the PTSD. The psychedelics are game-changing.”
Cavanaugh points to the MAPS trial as proof of psychedelics’ potential; in this study, a majority of patients on the treatment protocol no longer qualified for the definition of PTSD after treatment. However, he notes there are several barriers to entry that psychedelics face.
“The go-to-market for these drugs is quite different,” says Cavanaugh. “We have a shortage of mental health clinicians, so how do you bring these drugs to market when the therapists aren’t available? Plus, finding spaces to do the drug intervention sessions will be challenging. The sessions are eight hours long, and they’re typically done in a place with a bed so the patient can relax.”
Cavanaugh also notes that because psychedelics are controlled substances, there are significant restrictions around who can administer them. He says MDMA-assisted therapy will likely require an FDA risk evaluation and mitigation strategy (REMS) due to the addictive nature of psychedelics. Furthermore, therapists will require specialized training in administering the therapy. The most substantial barrier to access, though, will be reimbursement.
“For commercial private-pay insurance, there are even more challenges, because the drug and the therapy are insured in different groups within these payers,” says Cavanaugh. “The groups who evaluate whether a drug is part of their formulary would make decisions around the drug, but there are different groups who make decisions around therapy. And, frankly, therapy isn’t well-covered in the United States.”
As a result of these challenges, according to Cavanaugh, there will likely be substantial restrictions around who can access psychedelic therapy. For instance, insurers will likely require patients to try and fail conventional treatments first before covering a psychedelic option. There will also be a question of copays; those associated with psychedelics could be prohibitively expensive.
Still, these drugs are demonstrating strong efficacy in clinical trials. One 2023 open-label trial examined the efficacy of ketamine therapy (n = 195) relative to electroconvulsive therapy (n = 170) in treatment-resistant depression. The patients received either electroconvulsive therapy (ECT) three times per week, or a 0.5 mg/kg ketamine infusion twice per week. Subjects were assessed for scores on the Quick Inventory of Depressive Symptomology Self-Report, as well as memory tests and self-reported quality of life.
Fifty-five percent of patients in the ketamine group showed a response, compared to 41% of patients in the ECT group. The latter was also associated with memory impairment and adverse musculoskeletal effects, while ketamine therapy was linked with disassociation. The study authors concluded that ketamine therapy was noninferior to ECT for treatment-resistant depression.26
There are several other psychedelic candidates currently in various stages of clinical and preclinical development, including midomafetamine, mebufotenin, esketamine, and mescaline, to name a few.
‘FIRST’-IN-CLASS HOPEFULS
The emerging drug development pipeline is full of advanced therapies designed to target so-called “first-world problems” or afflictions. From obesity, to Alzheimer’s disease, to COPD, to osteoarthritis, to psychedelics for mental health conditions, these promising medications are pushing the boundaries of science and building on innovative paths to deliver promising results. As the research activity continues and intensifies, the opportunities to reshape these disease settings—from treatment outcomes to quality of life—should be ample.
About the Author
Mike Straus is a freelance writer based in British Columbia, Canada. His work has appeared in Nutritional Outlook, Hoist, and Massage Therapy Canada, among other publications.
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