Biogen and Eisai’s lecanemab win this week provides an opportunity to stop and consider whether science is closer to a cure or symptom management for Alzheimer’s disease.
Courtesy of AmyriAD
Biogen and Eisai released topline data Wednesday from the global Phase III study of lecanemab, an anti-amyloid beta antibody that reportedly resulted in a “highly statistically significant” reduction in Alzheimer’s disease progression. This provides an opportunity to stop and consider whether science is closer to a cure or symptom management in this space.
In a Sept. 27 statement, the Alzheimer’s Association called the news “the most encouraging results in clinical trials treating the underlying causes of Alzheimer’s to date.”
The news came on the heels of more than a year of controversy in the space. In June, Biogen canceled a separate observational study of the beta-amyloid-clearing drug Aduhelm (aducanumab-avwa) after just 29 patients signed up. Aduhelm is the first FDA-approved treatment to address the biology underlying AD.
The Symptomatic Approach
Other companies, such as Annovis Bio, are focused on treatments that manage AD symptoms. Maria Maccecchini, Ph.D., founder and CEO, told BioSpace the company’s lead compound buntanetap “inhibits the production of multiple neurotoxic aggregating proteins and establishes homeostasis of the brain.”
Phase IIa trials of buntanetap “resulted in a statistically significant improvement in motor function in Parkinson’s disease patients and cognition in AD patients,” Annovis noted in a July announcement.
The buntanetap-treated patients were followed for a month during the study.
“We saw a 33% improvement in cognition, shown by ADAS-Cog11, and a 26% improvement in speed of thinking, shown by the WAIS coding test,” Maccecchini said.
Though longer treatment data is not yet available, the “mechanism of action suggests that buntanetap should act fast by improving axonal transport and synaptic function, and have long-lasting effects by preventing neuronal death, thus preserving function in the long run,” Maccecchini added. The company plans to test buntanetap in “longer and larger studies” next.
When enrolling clinical trials, Maccecchini said the company considers age and frailty of AD patients and works to make the experience smooth for both participants and caregivers.
“We don’t use invasive CSF sample collection. Instead, we use minimally invasive methods like plasma or skin biopsies,” she shared. “We also reduce the unnecessary tests, so patients and caretakers don’t have to spend their entire day in the clinic.”
Additionally, “buntanetap is an oral formulation that is administered once a day in the comfort of a patient’s home. By designing a very simple study, we increase patient wellbeing and reduce the burden on family and caretakers,” Maccecchini said.
She noted the Alzheimer’s field is lacking in both symptomatic management and disease-modifying solutions.
“So far, there is no disease-modifying solution and the symptomatic treatments are only partially helpful. The need for innovation in this field is extraordinary,” she said. “This is precisely why it is important to encourage diverse and novel approaches.”
Down the line, Maccecchini hopes “buntanetap will not only improve patients’ memory, cognition and function for the short term but also preserve the improvement and provide patients continued independence.
“We can’t prevent Alzheimer’s disease, but we believe we can prevent it from stealing your life,” she said.
AmyriAD Therapeutics is also working to manage the symptoms of AD.
“Neither donepezil (a standard-of-care treatment for AD) nor any other treatment cures Alzheimer’s disease,” said Sharon Rogers, Ph.D., chief executive officer, in an interview with BioSpace. However, “Donepezil does improve memory, awareness, comprehension and speaking skills. In doing so, it also improves the ability of a patient to function with less reliance on caregivers and skilled medical professionals and has been shown to delay nursing home placement, even in patients with severe disease.”
AmyriAD is also developing AD101, a tablet meant to work in parallel with donepezil. Rogers said that if approved, AD101 will increase “the amount of circulating acetylcholine (a neurotransmitter),” while donepezil protects it. “In other words, it is sort of like if you’re giving a talk to a large group of people and you have no microphone and then someone gives you one. Your message goes out easier, clearer and is more readily understood.”
When enrolling patients with AD and other neurodegenerative diseases in trials, AmyriAD remains mindful of informed consent.
“If patients cannot understand what they are being enrolled in, it is not ethical to place them in a clinical trial,” Rogers said.
She named two important considerations for involving AD patients in clinical trials. The first is ensuring a correct diagnosis.
“We want to be certain the patient has Alzheimer’s disease,” and not a condition that could be mistaken for AD, such as stroke or a treatable non-Alzheimer’s cognitive impairment caused by thyroid disease or vitamin deficiencies, for example, she said.
The second consideration is that the patient has support to take treatments and make it to clinic visits.
Rogers noted that though some trials aimed at disease modification showed “modest slowing of disease progression, nothing has arrested the development of AD.
The Clinical Significance of Symptom Management
“Cognitive deficits are not halted, and many patients do not begin to seek treatment until disease symptoms are significant. Alzheimer’s disease is complex,” she said. “Symptom management will be clinically useful for AD well into the foreseeable future.”
There have been multiple scientific iterations of AD research, Rogers added.
“We have devoted a majority of the last 20 years to testing hypotheses on disease modification rather than management of symptoms,” she said. “Initially, we hoped for a cure. Time and experience have demonstrated this likely will not be the case.”
Given this theory, Rogers offered two instructions for the future.
“The first is that we must do a better job of addressing symptom management, meaning introducing new treatments to improve patient cognition and function,” she said. “The victories achieved with symptom improvement are not small; they are clinically significant and should be appreciated as such.”
Secondly, researchers must “continue untangling the complexity of AD,” she said. “Disease modification will likely be achieved by addressing several factors. AD has no single cause, and at this point, no one can predict which paths will lead us to additional successes. We are making progress. We need to continue working, not with an either/or mindset, but with full respect for the complexity of AD.”
Rogers outlined the difference between disease modification and symptom management trials, noting the latter are “far shorter in duration and put less burden on patients and caregivers.
“Generally speaking, symptom management trials do not require repeated imaging studies, spinal taps or invasive genetic testing. Most symptom management trials employ simple tablets taken by mouth and not complex infusion protocols or subcutaneous injections,” she added.
According to Clinical Trials Arena, the lecanemab Phase III trial readout took place at 78 weeks.
An overview of the AD drug development pipeline, as of Jan. 2022 found 83.2 percent of agents in trials were disease-modifying, 9.8 percent were cognitive enhancing treatments and 6.9 percent were neuropsychiatric symptom treatments.
Ethical Considerations in Alzheimer’s Trials
Dr. James Giordano, Ph.D., Pellegrino Center professor of neurology and biochemistry at Georgetown University Medical Center in Washington D.C. discussed the ethical implications of involving AD patients in clinical trials.
“It’s absolutely essential that the patient’s neurocognitive capacity, which then speaks to their legal competency, be evaluated relative to their ability to provide active, informed consent,” Giordano told BioSpace.
Giordano added that the patients must be able to understand the full breadth of their participation in the trial, including any consequences that may arise. With a dementing disorder such as AD, however, complications are introduced.
“The actual signs and symptoms that may be the focus of a subject’s participation might be the loss of cognitive function. Although primarily that involves short-term memory, it also involves cognitive constructs such as being able to understand information and the consequences of participatory behavior,” he said.
Additionally, in cases where patients are showing impairment of cognitive function, patients must be assessed for vulnerability and also have an ethical legal proxy to second their ability to consent, Giordano added.
The Secretary’s Advisory Committee on Human Research Protections provides guidance on the ethical obligations of working with vulnerable populations. In the same vein, Giordano said these vulnerable populations need to be involved in certain trials when the outcomes directly affect their lives.
“An overall consideration for inclusion, as represents diversity and subject vulnerability, certainly represents frank considerations of any trial,” he noted. This specifically pertains to “those in which the patient’s vulnerability of neurocognitive capacity may be both axiomatic to the nature of the trial and an important consideration, and therefore a concern.”
For many neurodegenerative disorders including AD, Giordano notes that a wider range of treatments are becoming available.
“Understanding what contributes to the onset of the actual disease process that initiates or accelerates neurodegeneration represents a preventive or mitigating approach,” he said.
At the same time, Giordano noted the “increased interest in developing a broader armamentarium to be able to decrease both the actual neurodegenerative spread and the expressed clinical signs and subjective symptoms that are occurring as a consequence of neurodegeneration.”
Another consideration is whether the treatment being evaluated is truly curative, or just delaying disease onset. Giordano said it is important to meet the obligations of potentially longitudinal prospective trials with participating patients, especially if they believe it to be curative.
“Saying ‘cure’ suggests we’ve completely eradicated the underlying process that leads to the disease in such a way that it will not recur,” he stated. “If it’s recurrent, it will require multiple attempts at interventions that are curative to eradicate the causative factor and present to the onset of the disease process.”
Giordano related that patients may be reluctant to participate in trials for symptomatic treatments until their disease has progressed to a problematic point. Either way, patients must give informed consent.
“There are distinct ethical issues that need to be considered and informationally provided to prospective patients so they are allowed to make the necessary informed decision as to whether or not they wish to participate in a study that examines curative effects versus just mitigating effects,” he said.
