It’s no secret that the pipeline for Alzheimer’s treatments has mostly become a sinkhole for dozens of failed drugs and billions in lost R&D dollars. But with the stakes so high — no disease-modifying drug for Alzheimer’s has ever been approved — researchers are still on the hunt for a new treatment that could help the estimated 50 million Alzheimer’s patients around the world.
In March, our cover story dove into the controversy and hope surrounding Biogen’s aducanumab — a monoclonal antibody that is currently under review by the U.S. Food and Drug Administration. If ultimately approved, several analysts have predicted that the drug, which only showed modest efficacy in one phase 3 trial, could become the best-selling drug of all time.
But aducanumab, which targets beta-amyloid, a type of protein that builds up in sticky plaques in patients with Alzheimer’s, would also be a first-generation treatment for an indication begging for new options. So what other next-gen therapies could be coming down the pipes?
Here’s a look at two startups that are hoping to blaze their own trails towards a new and effective treatment for Alzheimer’s.
Oligomerix — Tau-targeting small molecules
Historically, much of the drug research for Alzheimer’s has focused on reducing beta-amyloid clumps in the brain — but times are changing. Given the large number of amyloid-targeting drugs that have failed in clinical trials, the industry has learned that even when amyloid is cleared, patients can still show clinical dementia symptoms. Researchers have thus shifted their focus to tau, a protein involved in transporting nutrients within nerve cells that can collect in tangles underneath amyloid plaques.
“Amyloid is falling, but tau is rising,” explains Pamela Spicer, a senior analyst with Informa Pharma Intelligence, who says that the number of amyloid-targeting drugs in pre-clinical and clinical development peaked in 2016 at 60 and since then has dropped to 45. Meanwhile, the number of tau aggregation inhibitors in development has risen during the same time frame from 30 to 40.
Founded in 2006, Oligomerix was ahead of the curve with the introduction of its platform designed to discover tau-inhibiting small molecules. Since then, the company has developed a lead compound from the discovery phase through to early efficacy studies. The company now plans to file for an Investigational New Drug (IND) application through the FDA by 1Q 2022, and initiate a phase 1a clinical study by 2Q 2022.
Along with amyloid, the build-up of tau can trigger a cascade of brain cell degeneration and death, ultimately leading to the hallmark symptoms of dementia. It’s that process that James Moe, president and CEO of Oligomerix, says their lead compound is designed to stop.
“We are targeting early in the aggregation cascade,” Moe says. “It’s that initial tau interaction that we’re trying to block.”
According to Moe, one of the critical decisions that Oligomerix made in its early days was moving away from the typical screening assays being used in drug discovery for tau-targeting therapies.
“It took us a long time to develop a highly sensitive screening assay compatible with screening a large library of drugs,” he explains. “We developed a differentiated high-throughput proximity-based assay for the detection of tau self-association within a short incubation time that led us to discover our small molecules.
“That decision positioned us away from where everyone else was focused, and was key to our success,” Moe continues. “We found a pathway that translates into in vivo efficacy.”
Ultimately, the company hopes its lead molecule will be effective at any stage of the disease progression. Moe also points out that one of the benefits of a small molecule is that it could be more patient friendly than other therapies — and combo well with different types of treatments in development.
“A small molecule would be a great complement to a successful immunotherapy approach,” he says. “One is operating to abruptly interrupt the disease and the other is getting into the neurons and preventing tau aggregation. The two would be very powerful.”
The company is also exploring the utility of their technology for rare neurodegenerative diseases.
“Tau is also a major pathological signature in other lesser-known neurodegenerative diseases such as progressive supranuclear palsy and frontotemporal dementia,” Moe added. “Oligomerix is also focusing our efforts on developing our small molecule tau self-association program for the treatment of a rare disease tauopathy.”
After getting its start with the help of a grant from the National Institutes of Health (NIH) and funding from the Alzheimer’s Drug Development Foundation, Moe says that the initial aim was to develop molecules that could be handed off to a large pharma company “like a relay race.” But drug development failures have dogged the Alzheimer’s pipeline and made investors skittish — which is why Moe is hopeful that a potential approval for Biogen’s aducanumab could strengthen investments in the field.
“I hope [aducanumab] is shown to be effective for the sake of all who suffer from this devastating disease,” he says. “That would also boost the whole field, including alternative therapies. And I think it would signal to all companies in the space that the FDA is highly interested in different approaches to solving this disease.”
Synaptogenix — A regenerative approach
Years ago, if you would have asked Daniel Alkon, chief scientific officer and president of Synaptogenix, if it was possible to restore synaptic wiring in the brain, he would have scoffed at the idea.
“Fifteen years ago, when I worked at the NIH…I would have said it’s impossible,” he explains.
But now, that’s exactly what Synaptogenix is aiming to do.
A clinical stage biotech company — that changed its name last year from Neurotrope Bioscience — Synaptogenix is advancing a lead drug candidate called bryostatin-1, a restorative therapy for neurodegenerative diseases, including Alzheimer’s. It’s a unique approach in an industry pipeline packed with many drugs that only target beta amyloid or tau build-up in the brain. But in the long run, Alkon says that using a regenerative medicine is what could be the most successful in actually reversing the progression of diseases like Alzheimer’s. (Although, Alkon notes that bryostatin-1 has the added bonus of targeting amyloid and tau in addition to its primary regenerative efficacy).
“When Alzheimer’s gets underway, it starts to destroy the brain’s wiring, which consists of trillions of connections between billions of neurons and the axons that link them at the synaptic connections. Its complexity far surpasses anything we’ve ever manufactured in computers,” Alkon says. “So the problem has been, and still remains, how do you restore the wiring?”
A protein kinase C (PKC) agonist, bryostatin-1’s potential ability to prevent tumor growth once kept it firmly in the area of oncology research. But after it became apparent that bryostatin-1 could also have cognitive restorative and antidepressant properties, Alkon and others began pushing into the direction of central nervous system diseases about 15 years ago.
Right now, the company’s studies are targeting patients with moderate to severe Alzheimer’s — when symptoms are more apparent — to help determine efficacy sooner. Although the only way to currently prove that byrostatin-1 physically restored synaptic connections is during an autopsy, Synaptogenix has observed positive clinical outcomes in early trials using the Severe Impairment Battery (SIB) scale, a commonly used scale to measure dementia symptoms in advanced Alzheimer’s patients.
Alkon says he has also seen the effects for himself.
“One of the patients in our studies — he was 75 — was spending his life in a chair hallucinating,” Alkon recalls. “After a couple of weeks [on the treatment], he was playing pool, swimming, eating and conversing with this wife. It was remarkable.”
Results from an initial small-scale trial showed that bryostatin-1 performed significantly better than a placebo on the SIB scale. A follow-up small-scale trial showed that treated patients improved their SIB scores by 4.8 points over their baseline — confirming what had been previously observed. Now, Synaptogenix has launched a full, six-month phase 2 trial of the drug.
Although Synaptogenix is currently targeting patients in the later stages of Alzheimer’s, Alkon believes bryostatin-1 could also be a viable treatment for patients earlier in the disease progression. The company is also developing the drug to target other neurodegenerative diseases such as multiple sclerosis and Fragile X syndrome, which causes intellectual disability.
“We have a lot of shots on goal to offer,” Alkon says.
Alkon says that the company expects to publish results of its current Alzheimer’s study, which is being backed by the NIH, by the third quarter of 2022.