Aducanumab About-Face: Experts Weigh In

Pauline Anderson

November 07, 2019

Reaction is mixed among Alzheimer disease (AD) experts following the recent announcement by the drug company Biogen that it will pursue regulatory approval of its investigational drug aducanumab after all. For the most part, researchers are excited about the move, but there is some scepticism.

Earlier this year, as reported by Medscape Medical News, Biogen scrapped two phase 3 clinical trials of aducanumab, a recombinant human monoclonal antibody targeting β-amyloid (Aβ), after an interim analysis showed that it was not likely that the drug would yield meaningful benefit.

However, further analysis, which included more data, showed that the EMERGE trial met its primary endpoint of a significant reduction in clinical cognitive decline in patients treated with the higher of two tested doses of the drug.

Biogen noted that new data from the second trial, known as the ENGAGE study, support these findings, although that study did not meet its primary endpoint.

The drug company plans to submit a biologics license application to the US Food and Drug Administration (FDA) in early 2020. In the interim, it will offer access to aducanumab to eligible participants enrolled in these trials.

Dr Ronald Petersen

Biogen's announcement has created a "buzz" in the scientific community, Ronald Petersen, MD, PhD, who directs the Mayo Clinic Alzheimer's Disease Research Center in Rochester, Minnesota, told Medscape Medical News.

The data he's seen so far "were reasonably impressive," although he and his colleagues haven't yet seen the entire picture, said Petersen. "Once we see the more complete data set, I think people will be able to evaluate it more completely, but at first blush, it seems encouraging for the field."

Once we see the more complete data set, I think people will be able to evaluate it more completely, but at first blush, it seems encouraging for the field. Dr Ronald Petersen

Biogen is expected to present these new data at the Clinical Trials on Alzheimer's Disease meeting in San Diego, California, in early December.

Petersen emphasized how unusual it is for the FDA to evaluate a drug after two studies met criteria for futility and were stopped. He also cautioned, "This is just approval to file; it's not approval of the drug, and it doesn't necessarily imply the FDA will approve the drug."

However, after years of negative trial results that had AD researchers wondering whether the amyloid hypothesis is viable, the news that an antiamyloid agent may possibly be approved is reason for optimism, AD researcher Justin M. Long, MD, PhD, Washington University School of Medicine, St. Louis, Missouri, told Medscape Medical News.

According to the amyloid hypothesis, AD pathogenesis is triggered by the accumulation of Aβ in the brain.

Like other AD experts, Long is waiting to see the full data set. He noted that if what he's heard to date "is to be believed," it will give the field a badly needed "shot in the arm."

"From what I've gathered, the drug seems effective at engaging the target and clearing amyloid, and there could be a marked benefit on cognition," said Long.

Leave No Stone Unturned

This new development represents a first and "is encouraging" for the AD community, Rebecca Edelmayer, PhD, director of scientific engagement, Alzheimer's Association, told Medscape Medical News.

"We are hopeful that this is just an example of how investments of time, energy, and dollars move clinical trials through the pipeline for Alzheimer's disease and all dementias. It's going to play out very successfully for us in the future if we continue to fight the fight."

Maria Carrillo, PhD, chief science officer, Alzheimer's Association, echoed those sentiments.

Dr Maria Carrillo

"No stone can be left unturned," Carrillo said in a statement. "All currently pursued treatments that are considered safe should be continued to determine their efficacy."

However, other experts were more pessimistic. Clinical neurologist David S. Knopman, MD, Mayo Clinic, Rochester, who is an expert in late-life cognitive disorders, told Medscape Medical News that he's "disappointed" that both trials showed no initial positive results with respect to prespecified endpoints and that the company "can't declare victory."

Dr David Knopman

Knopman believes it may be difficult to receive FDA approval for aducanumab because results were positive for only one of the two trials.

"An advisory committee made up of people who adhere to usual practices and beliefs and philosophies of statistics would have a hard time approving this," he said. "Unfortunately for the public and Biogen, another study will be necessary," he said.

An advisory committee made up of people who adhere to usual practices and beliefs and philosophies of statistics would have a hard time approving this. Unfortunately for the public and Biogen, another study will be necessary. Dr David S. Knopman

Biogen released the additional study results in a press release. EMERGE patients who took the high dose of aducanumab showed a significant reduction in clinical decline, as measured by scores on the Clinical Dementia Rating Scale Sum of Boxes at 78 weeks (23% vs placebo; P = .01), which was the primary endpoint.

These patients also showed a consistent reduction in clinical decline on secondary endpoints, including the Mini–Mental State Examination (15% vs placebo; P = .06), the AD Assessment Scale–Cognitive Subscale 13 (27% vs placebo; P = .01), and the AD Cooperative Study–Activities of Daily Living Inventory Mild Cognitive Impairment Version (40% vs placebo; P = .001).

Amyloid plaque burden was reduced with both doses in comparison with placebo at 26 and 78 weeks (P < .001), and additional biomarker data of tau levels in the cerebrospinal fluid supported these findings.

New data from ENGAGE also suggest that there was less cognitive decline in study participants who had sufficient exposure to the higher dose.

"Endless Parade of Failures"

In both the EMERGE and ENGAGE studies, the most common adverse events were headache and amyloid-related imaging abnormalities–edema (ARIA-E). ARIA-E episodes generally resolved within 4 to 16 weeks.

There are now four FDA-approved medications for the management of cognitive impairment and dysfunction in global activities in patients with symptomatic AD. These include three cholinesterase inhibitors ― donepezil, rivastigmine, and galantamine ― as well as memantine, an uncompetitive N-methyl-D-aspartate receptor modulator.

However, to date, no disease-modifying therapies have been approved.

Aducanumab is among the more than 20 compounds for which large phase 3, double-blind, randomized control trials have been completed in cohorts of patients at various stages of AD. Until now, none have demonstrated any efficacy in slowing cognitive decline or improving global functioning.

In a recent review article in Cell, Long, in collaboration with colleague David M. Holtzman, MD, note that "the history of pharmaceutical development for AD has been plagued by a seemingly endless parade of mid-to-late-stage clinical trial failures."

In addition to aducanumab, five other monoclonal antibodies directed against Aβ have been investigated. In their article, Long and Holtzman provide an update of where these studies stand:

Bapinezumab: This antibody was tested in two parallel phase 3 trials in patients with mild to moderate AD. It had no effect on cognition or activities of daily living (ADL) at the doses tested. In high concentrations, it was associated with ARIA-E and microhemorrhages.

Solanezumab: Two phase 3 trials in patients with mild to moderate AD failed to demonstrate a marked benefit on cognition or ADL and did not reduce cerebral amyloid deposition. A third phase 3 trial in patients with mild AD also failed to demonstrate a significant benefit on the primary endpoint.

Crenezumab: Two phase 3 trials of this antibody were terminated early in January of this year for futility after an interim analysis failed to demonstrate any benefit.

Gantenerumab: This investigational drug entered a phase 3 clinical trial for mild AD that stopped enrolling patients early because of futility. The study was continued as an open-label extension at the high dose for 2 years.

Follow-up analyses demonstrated a dramatic decline in Aβ deposition in participants in the open extension. For some patients, imaging indicated an absence of amyloid.

On the basis of this, a new high-dose phase 3 trial has been launched involving patients with very mild to mild AD. So this agent "is not dead in the water like some of the others," Long told Medscape Medical News.

Donanemab: This agent is currently under investigation in a phase 2 trial.

Amyloid Hypothesis Not Dead Yet

Long and Holtzman point out that most of the failed trials included patients with mild to moderate symptomatic AD, which represents an advanced stage of disease progression.

"At this stage of disease pathogenesis, significant and irreversible synaptic and neuronal loss has occurred, and the pathological cascade would likely be very difficult to reverse," they note.

Disease-modifying interventions initiated earlier in the preclinical phase of disease might have a better chance of changing the disease trajectory before the onset of frank neurodegeneration, they add.

To that end, prevention studies are now underway that involve administering antibodies at an earlier disease stage. For instance, the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) is testing solanezumab and gantenerumab in patients with autosomal-dominant AD mutations who are destined to develop the disease.

Another study ― the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) ― is investigating higher doses of solinezemab. This trial includes cognitively normal older adults at risk for progression to AD dementia, as determined on the basis of evidence of amyloid accumulation in the brain.

"It's likely that targeting the amyloid cascade at the earliest stage of the disease would be the best treatment strategy, and so it gives me optimism that we may be able to have data soon that a preventive treatment strategy will be effective," said Long.

It's likely that targeting the amyloid cascade at the earliest stage of the disease would be the best treatment strategy, and so it gives me optimism that we may be able to have data soon that a preventive treatment strategy will be effective. Dr Justin M. Long

He believes that many clinical trials have not been designed well enough to robustly test the amyloid hypothesis, so negative trial results can't necessarily be interpreted as a rejection of this theory.

"It's important to ensure that the drugs are being used at an appropriate dose to actually clear the amyloid beta peptide and are given for a significant duration of time and at the right time," said Long.

In addition to immunization strategies, researchers have been exploring secretase inhibitors to target Aβ, but so far, the β-secretase enzyme (BACE1) inhibitors have failed.

Two γ-secretase inhibitors have been tested clinically as disease-modifying therapies for AD, but each has failed, owing to lack of efficacy or worsening of cognition as well as dose-limiting adverse side effects, Long and Holtzman note in their article.

An alternative ― γ-secretase modulators (GSMs) ― alter processing of Aβ precursor protein without influencing processing of other substrates. Promising GSMs are under development and may enter human trials in the near future, they add.

Because amyloid-related therapies have generally not lived up to expectations, it's "more important than ever" to also pursue nonamyloid-based therapies, the authors write.

Targeting Tau

Researchers are also investigating tau as a target. Along with extracellular Aβ plaque deposition, intracellular neurofibrillary tangles of hyperphosphorylated tau is a main neuropathologic feature of AD.

As with Aβ, there's been a significant amount of investment in developing immunotherapies to clear tau from the brain. Numerous tau-directed monoclonal antibodies are currently under investigation in clinical trials.

Gene therapies directed at the ApoE allele are also in early stages of development. As with tau, they hold great promise, Long and Holtzman note. Although there have been no human AD clinical trials that target ApoE, a number of preclinical studies in animal models have investigated ApoE-directed therapies that may eventually translate clinically.

Anti-inflammatory approaches are also being explored. Multiple epidemiologic studies have shown that the long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a lower incidence of AD.

However, follow-up trials testing the effect of low-dose prednisone, low-dose aspirin, NSAIDs, and selective COX-2 inhibitors failed to show any reduction in the rate of cognitive decline in patients with mild to moderate AD. Prevention studies of naproxen and celecoxib in patients at risk for preclinical AD also failed to demonstrate any protective effect.

"Therefore, a generic anti-inflammatory treatment approach for AD does not appear viable for secondary prevention or treatment of symptomatic patients," the researchers note.

Yet another avenue of investigation involves use of young blood. Animal experiments suggest that the introduction of blood from young mice into old mice leads to increased neurogenesis and improved age-related cognitive impairment. This effect is also produced with the injection of human umbilical cord blood, an approach that is now being tested in clinical trials.

Combination therapy should be more widely tested in AD clinical trials, said Long.

Carrillo, at the Alzheimer's Association, agrees. "We must advance all potential treatment avenues and also explore methods for combining these approaches," she said.

In a recent editorial in Journal of Prevention of Alzheimer's Diseases, Carrillo and colleagues note that with new developments and financial interest, research in the AD field has reached "a turning point."

"With accelerated momentum and more funding, the field is poised to hasten the discovery of interventions to stop, slow, or prevent disease progression and improve care and quality of life for those affected," they write.

With accelerated momentum and more funding, the field is poised to hasten the discovery of interventions to stop, slow, or prevent disease progression and improve care and quality of life for those affected. Dr Maria Carrillo and colleagues

In addition to furthering the understanding of the biological underpinnings of AD and related dementias, a "guiding principle" will be to advance strategies similar to those used for cancer and heart disease, Carrillo and colleagues note. "These strategies focus on early detection and prevention, as well as a combination of lifestyle and pharmacologic interventions."

Focus on Prevention

In keeping with efforts to address AD at all stages, there is now a more intense focus on prevention, which has led to number of key secondary prevention trials.

The large-scale, 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) study showed that a combination approach that included physical exercise, nutritional modification, cognitive stimulation, and self-monitoring of heart-health risk factors had a protective effect on cognitive function.

To determine whether such factors might also prevent dementia, researchers have launched the US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk. Led and funded by the Alzheimer's Association, this 2-year clinical trial will include about 2000 patients aged 60 to 79 years who are at increased risk for cognitive decline.

The Alzheimer's Association is currently investing over $165 million in more than 450 projects in 25 countries.

That investment should grow now that Bill Gates has awarded $10 million to the Alzheimer's Association's Part the Cloud program. This program, which Edelmayer called "our translational clinical trial pipeline," funds projects that target numerous aspects of the disease, such as neuroinflammation and vascular contributions. The Alzheimer's Association will contribute $20 million, which, together with a previous $30 million investment, brings the total $60 million.

Petersen has consulted for Biogen, Roche, Merck, Genentech, and Eisai; he has also made presentations for GE Healthcare. Knopman was a site investigator for one of the aducanumab studies but was not personally paid; he is a member of the Data Safety Monitoring Board for a Biogen anti-tau drug, for which he is not personally paid; and he's a site investigator for the A4 prevention study. Long has served as subinvestigator on the Lilly TRAILBLAZER trial but receives no financial compensation.

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