Pooled outcomes as mean difference or odds ratio values with 95% confidence interval were reported. The network estimates with confidence and predictive intervals for all pairwise relative effects was evaluated. Optimal intervention was ranked by benefit-risk ratio based on the surface under the cumulative ranking curve. Eleven eligible RCTs from 9 literatures, including 5141 patients and 5 interventions were included. The quality of evidence was rated low in comparisons. For efficacy, in terms of Mini-Mental State Examination, aducanumab and solanezumab are significantly effective than placebo. For safety, in terms of Amyloid-Related Imaging Abnormalities (ARIA), bapineuzumab and aducanumab are significantly worse than placebo. There were no significant differences in outcomes of Alzheimer's disease Assessment Scale-Cognitive subscale, Disability Assessment for Dementia, Adverse Events, and mortality. Given the clinical therapeutic effects of anti-Aβ immunotherapies for AD, aducanumab and solanezumab improve the cognitive function, while aducanumab and bapineuzumab may increase the risks of ARIA.
Reference: JJ Mo et al. Annals of Clinical and Translational Neurology. 10.1002/acn3.469
Novartis AG thinks its best bet for testing two new Alzheimer's drugs is on people who don't actually have Alzheimer's.
The Swiss drug giant is looking for people whose genes put them at high risk of developing Alzheimer's, but who haven't yet fallen victim to the mind-robbing disease. It hopes such early treatment proves more successful than past efforts to tackle the disease once it has taken hold.
The history of Alzheimer's research is marked by disappointment. In November, a high-profile Eli Lilly & Co. drug called solanezumab was the latest to fail a late-stage clinical trial. That drug aimed to clear clumps of a protein called beta amyloid in the brain, which are closely linked with Alzheimer's. So far, no company has produced a drug that can delay the progression of Alzheimer's.
One of the new Novartis drugs, known as CAD106, is designed to boost the immune system's ability to clear beta amyloid from the blood. The other, which Novartis is developing with Amgen Inc. and is called CNP520, aims to stop its formation in the first place.
"If an anti-amyloid strategy is going to work, the best way to do so is with prevention," said Steven Arnold, a neurologist at Massachusetts General Hospital in Boston.
Recruiting patients to receive treatment for a disease they don't have -- and may never develop -- is riven with logistical and ethical challenges.
The company is looking for people with two copies of a gene called APOE4 to participate in its study. Having two copies of the gene doesn't inevitably lead to Alzheimer's, but the roughly 2% of people who fit this profile are around three times as likely to develop dementia as the general population, according to a recent analysis in the scientific journal PLOS Medicine.
The Banner Alzheimer's Institute, a Phoenix nonprofit, is helping Novartis find eligible participants with a campaign launched at the end of 2015 to test people for the APOE4 gene. The institute places television and newspaper ads, does mass mailings and runs events in clinics to publicize the program, called Genematch.
So far, around 35,000 people have signed up, agreeing to send swabs of their cheek cells for testing. "We seem to have tapped into a very motivated group of people," said Pierre Tariot, director of Banner. "Not surprisingly, a lot of them have a family history of Alzheimer's."
Margaret, a 71-year-old from Virginia, discovered two weeks ago that she has two copies of the APOE4 gene. She signed up for the Genematch program earlier this year after hearing about it through the hospital that is caring for her older sister, who has Alzheimer's.
"It is shocking," said Margaret, who declined to give her last name because she hasn't yet told her family. But "if this works and can prevent or slow it down, then obviously I'd like to participate. That part of it is a no-brainer."
Only a fraction those who sign up will be eligible for the trial. As well as having two copies of the APOE4 gene, participants in the Novartis study must be healthy, between the ages of 60 and 75, and have no outward signs of Alzheimer's, such as cognitive decline. Fewer than 10% of the roughly 1,300 participants needed for the trial have been recruited so far, Dr. Tariot said.
The Genematch staff doesn't know any individual participant's genetic results. Instead, a computer program provides a list of names -- only some of whom are genetic matches -- for them to call. On that call, Genematch will tell the person they might be eligible for a trial and tell them about nearby participating hospitals.
Participants are informed of their genetic profile -- usually by a genetic counselor -- only after a lengthy assessment by staff at the clinical-trial site to determine that they are eligible for, and willing to enroll in, the study.
"The critical thing is that this is done in a highly ethical way," said Vas Narasimhan, global head of drug development at Novartis. "If a patient is not selected for the study, we are not intervening to help them so there is no reason to provide them with this information."
Later this year, Novartis plans to start a further trial that will be open to people who have just one copy of the APOE4 gene, Dr. Narasimhan said. Around a quarter of the population is thought to fit this profile, and they are about 1 1/2 times as likely to develop mild cognitive impairment or dementia as the general population.
After the string of high-profile failures in amyloid-busting drugs, experts are divided over whether they are the right approach to tackling Alzheimer's. "The field is very pessimistic right now," said Murali Doraiswamy, director of the neurocognitive disorders program at Duke University Health System in Durham, N.C.
But the Novartis study was among a small group of trials that could still vindicate this approach, Dr. Doraiswamy said. "We've learned a lot from previous [failed] trials," he said, adding that the "elegant" design of the Novartis study -- in focusing on a narrow band of people known to have heightened risk of Alzheimer's -- makes it a "near-perfect model to test the amyloid thesis."
Objective: We tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia.
Methods: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants.
Results: No beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Aβ42 (but not Aβ40) levels were observed in IVIg-treated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo.
Conclusions: Participants with mild to moderate AD showed good tolerability of treatment with low-dose human IVIg for 18 months but did not show beneficial effects on cognition or function relative to participants who received placebo.
Merck & Co Inc said on Tuesday it will halt a late-stage trial of an Alzheimer's drug after it was determined that it had no chance of working, marking the latest in a long line of crushing disappointments in efforts to find an effective treatment for the mind-wasting disease.
The company was testing its drug, verubecestat, in patients with mild to moderate Alzheimer's disease. But an independent data monitoring committee determined that there was "virtually no chance of finding a positive clinical effect" and recommended the trial be stopped for futility.
The news sent Merck shares down nearly 2 percent in after hours trading.
Verubecestat belongs to a class of experimental Alzheimer's drugs called BACE1 inhibitors that target an enzyme involved in the formation of the toxic amyloid protein that turns into plaques in the brains of Alzheimer’s patients.
Several companies are pinning hopes on Alzheimer's treatments using the BASE inhibitor mechanism, including Eli Lilly and Co, Biogen and Novartis in collaboration with Amgen Inc.
Lilly previously endured multiple failures with its solanezumab, which also targets beta amyloid, but in a different way. In the most recent setback, Lilly said that drug failed to slow declines in mental capacity of patients with even mild symptoms.
Researchers are increasingly focusing on attacking the disease earlier as it appears likely that once symptoms have taken hold current approaches fail to work.
Merck said another study of its drug in patients with prodromal, or very early, Alzheimer's disease would continue with results expected by February 2019.
Patients with prodromal Alzheimer's disease have objective memory problems but relatively normal functioning in activities of daily living.
Blinded clinical trials use independent monitors to watch for any unexpected safety problems that may crop up. They can also recommend stopping a study early if it becomes clear that a drug is going to fail or if the data looks so compelling that it believes the treatment should be offered to those getting a placebo or other standard treatments.
Merck shares fell to $64.48 in extended trading from a close at $65.66.
We already know Eli Lilly’s big bet on Alzheimer’s disease didn’t work. But a deep dive into just how it failed has provided a bit of encouragement to Biogen and the many companies still hoping to succeed where their rival fell short.
Lilly’s treatment, solanezumab, had no significant effect on the buildup of toxic brain plaques believed by many to be responsible for Alzheimer’s neuron-destroying effects. The company had already disclosed that the treatment failed to improve patients’ cognition and function, but the new data, released Thursday night, shed some important light on the underlying biology.
Here’s why it matters: Lilly’s therapy is among many designed to treat Alzheimer’s by clearing away brain deposits of a protein called beta-amyloid. Doing so, the thinking goes, can at least delay the progression of the memory-robbing disease. Because Lilly’s failed treatment didn’t have a marked effect on those deposits, the so-called amyloid hypothesis lives to fight another day.
This is particularly important for Biogen, which is now in the midst of two huge studies testing an amyloid treatment of its own. In a small, early trial, Biogen’s therapy showed signs that it could improve cognition by blasting away amyloid proteins, and many in the Alzheimer’s field consider it the most promising drug in its class.
Furthermore, the two treatments are quite different. Biogen’s drug, aducanumab, targets plaques once they have already settled in patients’ brains, while Lilly’s was meant to attack the free-flowing proteins that eventually aggregate and form those sticky clumps. And Biogen is testing its therapy in patients in the very early stages of Alzheimer’s, while Lilly pursued those who already had mild dementia.
In data presented at the annual Clinical Trials Conference on Alzheimer’s Disease in San Diego, Lilly’s treatment had only glancing effects on amyloid levels in the brain, beating placebo by too narrow a margin to rule out random chance. But solanezumab did markedly reduce amyloids floating around in the cerebral spinal fluid, suggesting that the problem may have been that it didn’t go after the proteins already clumping in the brain.
“I think this is not a refutation of the amyloid hypothesis,” said Dr. Paul Aisen, a professor of neurology at the University of Southern California. “In fact, I think this is our strongest confirmation to date.”
Solanezumab’s lack of potency is also positive for Merck, which is in the final stage of trials with a pill that takes an upstream approach to the amyloid question. Called a BACE inhibitor, Merck’s drug targets an enzyme responsible for the production of amyloid, seeking to stem the flow of toxic materials at the source.
And, somewhat paradoxically, the news is good for Lilly, too. Solanezumab wasn’t the company’s only Alzheimer’s project. It has a BACE drug of its own, developed in partnership with AstraZeneca, and two more amyloid-targeting treatments in early trials.
Each contender is racing to commercialize the first-ever therapy that can modify the course of Alzheimer’s rather than just treat its symptoms.
The field has a daunting rate of failure, with more than 99 percent of therapies coming up short in the past decade. But the rapid growth of Alzheimer’s, which now affects an estimated 5 million Americans, has presented a multibillion-dollar market opportunity for whoever can finally beat the odds.
Trouble is, there’s no consensus that targeting amyloid will ever show an effect on the progression of Alzheimer’s disease. Many scientists are bitterly divided on the issue, and the drug industry is yet to come up with a molecule that can prove it once and for all.
The next big test of the amyloid hypothesis is still years away, as Biogen isn’t expected to have final data on its treatment until 2019 at the earliest.
The company got some incremental good news of its own at the CTAD conference, as an extension of its earlier trial on aducanumab found that patients who got gradually increasing doses of the treatment experienced similar benefits with fewer side effects compared with those who got one lump injection, according to data presented at the same conference. The results bode well for Biogen’s ongoing Phase 3 studies, analysts said, but with the caveat that it’s still too early to make any conclusions.
An experimental Alzheimer’s drug that had previously appeared to show promise in slowing the deterioration of thinking and memory has failed in a large Eli Lilly clinical trial, dealing a significant disappointment to patients hoping for a treatment that would alleviate their symptoms.
The failure of the drug, solanezumab, underscores the difficulty of treating people who show even mild dementia, and supports the idea that by that time, the damage in their brains may already be too extensive. And because the drug attacked the amyloid plaques that are the hallmark of Alzheimer’s, the trial results renew questions about a leading theory of the disease, which contends that it is largely caused by amyloid buildup.
No drug so far has been able to demonstrate that removing or preventing the accumulation of amyloid translates into a result that matters for patients: stalling or blocking some of the symptoms of dementia. “It’s not going to be disease-modifying therapy for mild patients, so that’s heartbreaking,” said Dave Ricks, the incoming president and chief executive of Eli Lilly.
There are clinical trials underway with several similar drugs made by other companies, and two large trials with solanezumab are in the works. Experts said on Wednesday that they still held out hope for those studies, noting that many involve people who are at high risk for Alzheimer’s but do not display symptoms.
Some Alzheimer’s experts not involved in trials testing anti-amyloid drugs said they were not surprised by Lilly’s results, saying they reflect an emerging scientific understanding of Alzheimer’s as a disease with a multipronged cascade of causes, including amyloid buildup.
“We’re much more really appreciative of how complex this disease is,” said Dr. Lon Schneider, director of the California Alzheimer’s Disease Centerat the University of Southern California. “There’s so much going on, and as the brain is failing or dying, it is dying on all levels.”
It has also become clear that Alzheimer’s pathology begins damaging the brain years before symptoms emerge, leading many experts to think a drug given to people with even mild dementia may have little chance of success.
“Once you see amyloid on a scan, it’s probably been there for decades,” said Dr. Samuel Gandy, an Alzheimer’s researcher at Mount Sinai Hospital.
The Eli Lilly and Company corporate headquarters in Indianapolis. A potential Alzheimer’s treatment, solanezumab, failed in another large clinical study, the company announced.
“I’m worried and have been worried that that’s just too late,” he said. “I think it has a better chance of working much earlier.”
But, he said, testing a drug before people have begun showing symptoms is challenging and costly. Such trials need to involve even larger numbers of patients to produce a useful result, and because the patients are healthy, without symptoms, the drugs cannot have side effects that might make them feel sick.
Solanezumab had previously failed in two large clinical trials involving patients with mild or moderate Alzheimer’s disease. But when Lilly reported the results of those trials in 2012, the company said the drug did have an effect in a subset of patients with mild symptoms. So it started another trial with 2,100 patients with mild dementia caused by Alzheimer’s.
In a news release on Wednesday, the company said that although some of the effects looked promising, “patients treated with solanezumab did not experience a statistically significant slowing in cognitive decline compared to patients treated with placebo.”
The company said it would evaluate future plans for solanezumab, but no longer planned to seek regulatory approval for use of the drug in treating symptomatic patients. Eli Lilly stock initially dropped after the news.
“This is very disappointing,” said Dr. Reisa Sperling, a neurologist who is recruiting patients for a trial testing whether solanezumab can help people with amyloid buildup who are about 10 years away from having symptoms. “But I have to be honest that I’ve always thought we needed to treat much earlier, because by the time people have mild dementia, they already have a lot of irreversible damage,” she said.
The trial she is leading, called Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4), which has funding from Lilly and the federal government, had hoped to reach its goal of about 1,150 patients by the middle of next year, said Dr. Sperling, who directs the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital and Massachusetts General Hospital.
“I have several patients within my practice who were hoping to take this drug,” she said. But she said it was at least encouraging that patients taking solanezumab in Lilly’s trial did show improvement, just not enough to be statistically significant, and she plans to evaluate the data to see if changes should be made to the design of the A4 trial.
“What does that mean for an earlier population?” Dr. Sperling said. “Do we need more people? Do we need a longer time? I just want to get a clear result.”
The other major solanezumab trial, the Dominantly Inherited Alzheimer Network Trials Unit, is also testing a Roche drug, gantenerumab, and is funded by industry, the federal government and the Alzheimer’s Association. It involves people who have not yet shown symptoms, but have a very high risk of an early-onset version of the disease because they have a genetic mutation that causes a small subset of cases.
Other trials are using anti-amyloid drugs that work in different ways, experts said. Solanezumab is a monoclonal antibody that removes amyloid by attaching itself to free-floating amyloid protein before the protein forms into plaques, while several other antibody drugs also attack amyloid fibrils that are part of the plaques.
Another class of anti-amyloid drugs are called BACE inhibitors, which block an enzyme that makes a protein needed for amyloid production.
“You can’t really say that the solanezumab results predict that a drug with a different mechanism will fail,” Dr. Schneider said.
Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute, is leading a prevention trial involving members of a large extended family in Colombia who do not have symptoms but have a genetic mutation that causes early Alzheimer’s. They are taking Genentech’s crenezumab.
Dr. Reiman said Wednesday’s results raised questions about whether Lilly’s dose was high enough, whether the researchers were “attacking the right form of amyloid,” and whether they were they treating patients too late in the disease process. The results may also support theories that the ultimate answer will be combinations of drugs addressing different aspects of Alzheimer’s.
He and other experts continue to believe that “the accumulation of amyloid serves as the kindling for other events” that ignite the fire of Alzheimer’s disease, he said, and “it would be a grave mistake to throw out the baby with the bathwater and not give the amyloid hypothesis its best real test.”
Still, “a win for Lilly would have been a win for the entire field,” Dr. Reiman said, and “would have opened up new opportunities for patients.”
Background: Recent studies have implicated specific assembly subtypes of β-amyloid (Aβ) peptide, specifically soluble oligomers (soAβ) as disease-relevant structures that may underlie memory loss in Alzheimer disease. Removing existing soluble and insoluble Aβ assemblies is thought to be essential for any attempt at stabilizing brain function and slowing cognitive decline in Alzheimer disease. IV immunoglobulin (IVIg) therapies have been shown to contain naturally occurring polyclonal antibodies that recognize conformational neoepitopes of soluble or insoluble Aβ assemblies including soAβ. These naturally occurring polyclonal antibodies have been suggested to underlie the apparent clinical benefits of IVIg. However, direct evidence linking anti-Aβ antibodies to the clinical bioactivity of IVIg has been lacking.
Methods: Five-month-old female Dutch APP E693Q mice were treated for 3 months with neat IVIg or with IVIg that had been affinity-depleted over immobilized Aβ conformers in 1 of 2 assembly states. Memory was assessed in a battery of tests followed by quantification of brain soAβ levels using standard anti-soAβ antibodies.
Results: We provide evidence that NU4-type soAβ (NU4-soAβ) assemblies accumulate in the brains of Dutch APP E693Q mice and are associated with defects in memory, even in the absence of insoluble Aβ plaques. Memory benefits were associated with depletion from APP E693Q mouse brain of NU4-soAβ and A11-soAβ but not OC-type fibrillar Aβ oligomers.
Conclusions: We propose that targeting of specific soAβ assembly subtypes may be an important consideration in the therapeutic and/or prophylactic benefit of anti-Aβ antibody drugs.
