As the world’s top researchers working in Alzheimer’s disease (AD) descend into Toronto for the Alzheimer’s Association International Conference (AAIC) this week, all will be coming with a continued show of hope--despite the slew of late-stage failures for the disease over the past decade.
In fact, the failure rate over this period has been a staggering 99% in a disease that affects an estimated 5.4 million Americans and will eventually prove fatal--with its prevalence only expected to rise as the population ages.
Big Pharmas, including Eli Lilly ($LLY), AstraZeneca ($AZN), Biogen ($BIIB), Johnson & Johnson ($JNJ) and Pfizer ($PFE), have all thrown billions of dollars at this research area, but in return have been beset by failures and setbacks--with many now looking to restrict their spending on an area that yields so little ROI.
While there are meds on the market for the disease, such as Pfizer/Eisai’s Aricept (donepezil) and others (as well as generics), these have no long-term curative effect and are described by physicians as merely “lifting the fog” for a few weeks or months, only for the disease to come back with a vengeance.
One of the many drugs to have failed is tramiprosate, an experimental treatment originally developed by Quebec-based Bellus Health, formerly known as Neurochem. The drug, which binds to beta amyloid--a protein that is believed to suffocate the brain in Alzheimer’s--flopped in 2009 after failing to help a broad set of AD patients with cognition.
Tramiprosate, like so many others, could have been consigned to the scrap heap of once-promising AD meds that didn’t quite make the grade, never to be studied again.
But then in stepped small Framingham, MA-based biotech Alzheon, led by industry veteran Dr. Martin Tolar, who saw potential in the data, and the amyloid hypothesis.
The company, which started out in earnest back in 2013 and raised $10 million last year, tweaked the drug and aimed it at a specific patient population, and after posting some encouraging early data today, is now set to enter into the precarious Phase III stage.
This follows the same path as oncology did around a decade ago with TKI inhibitors that targeted certain mutations in smaller groups of patients.
In those without these mutations, a drug could essentially show up in large trials as useless--but in those with certain mutations, these drugs could produce stronger survival rates.
New diagnostics were created alongside these meds and the era of personalized cancer medicine was born. Alzheon now hopes it will produce the same kind of paradigm shift in AD.
Presenting at AAIC in Canada ALZ-801--the new name for the tweaked prodrug version of tramiprosate--showed in two Phase Ib studies that the drug was safe, as well as showing a favorable gastrointestinal tolerability, consistent and sustained plasma levels, and allowed selection of an ALZ-801 clinical dose that is bioequivalent to the tramiprosate dose that showed some efficacy in prior Phase III trials (when it was run by Neurochem).
The drug is specifically aimed at a subpopulation of patients with a genotype identified as APOE4/4 homozygous. These patients are genetically at risk for the disease and their brains are more likely to have excess deposits of amyloid, the toxic clusters that many believe--but have yet to absolutely confirm--spurs the memory-destroying condition.
Tolar, a former exec from Pfizer, CoMentis and Knome, told FierceBiotech that Alzheon now has the data needed to go into late-stage testing and run the gauntlet that the efficacy signals so far seen will turn out to be a winner in Phase III.
Tolar says that his company plans to start this program for the first half of next year. He’s not giving away patient numbers, but in terms of study design he said the biotech will be “following the Alzheimer’s clinical trial guidelines that are in standard practice by the FDA.”
This includes a 65-week treatment period, as well as patients having APOE4/4 homozygotes and being at a mild to moderate stage of the disease.
Tolar believes that he could be onto a real winner with ALZ-801 and goes as far as to say that it could potentially go beyond current treatments.
“We believe that ALZ-801 has disease modification potential,” he says, based on the biotech’s analysis of the previously released Phase III data for tramiprosate--before it got hold of the drug--when it drilled down into the subpopulation of patients with the APOE4 genotype.
In these patients, “these analyses showed clinically meaningful improvements in endpoints for both cognition and function,” Tolar explains.
Tramiprosate works by direct binding with abeta monomers, which leads to blocking the formation of neurotoxic soluble abeta oligomers in brain. This action, in turn, is believed to protect neuronal synapses from toxicity, preventing amyloid aggregation and facilitating removal of amyloid from the brain.
The central thesis behind the drug, like many in recent years, is that of beta amyloid. But it is not the only theory. A second, known as tau, is slowly gaining more research time.
This theory associates the onset of the disease to fibrillary tangles called tau protein. Neurofibrillary tangles group in an insoluble form in neurons, affecting normal neuronal functions.
Scientists in support of this theory, the “tauists,” are attempting to target and block tau hyperphosphorylation in Alzheimer’s patients in hopes of relieving the negative consequences of the disease.
And just last month, Slovakian biotech Axon Neuroscience treated the first patient with its closely watched Alzheimer’s vax AADvac1--which is aiming to be the first disease-modifying tau vaccine for the memory-stealing disease.
But Tolar believes the amyloid thesis is still the way forward for his biotech, despite the setbacks from Big Pharma trials over the past four years.
“Yes, we absolutely agree with experts in the field that there is growing and compelling clinical data showing that amyloid pathology is central to pathogenesis and progression of AD, making amyloid pathology a viable target,” Tolar says.
He points to recent data coming from Biogen and its AD candidate aducanumab, which Tolar says “showed a relationship between disease progression and amyloid load, as well as clinical benefit tied to reduction in brain amyloid; this serves as a crucial proof of concept validation of the amyloid hypothesis.”
It has not all been smooth sailing for Biogen however, and after posting eyebrow-raising data last year, it later fell short of clinical significance on two key measures of efficacy that would have pointed toward a clear path ahead in a pivotal study. And worryingly for its future, the safety data on the drug also worsened.
However, Tolar says that outside of this, and in contrast to the earlier trials, in the aducanumab study the high doses that cleared amyloid on imaging “seemed to show clinical benefit.”
Tolar also believes some of the failures of the past few years were due in part because the first-generation AD trials, which did not require amyloid imaging, were thus “not an adequate test of the amyloid hypothesis.”
He explained that in APOE4 noncarriers and heterozygotes, 38% and 12% respectively did not have amyloid pathology on PET imaging. Only in APOE4/4 homozygotes was the accuracy rate high, with around 5% being amyloid negative.
“In addition, the first generation of AD trials were conducted with amyloid-targeted antibodies (injectable biologic drugs), which did not push to higher doses due to some concerns about safety with some antibodies; therefore, dosing may not have been adequate to affect amyloid and improve clinical outcomes.”
On the business side, Tolar was not giving much away. They will need more money, but is an IPO in the cards? “We are exploring a range of options for our future financing and strategic plans, including IPO and strategic partnering, and will make such decision based on future opportunities and market conditions,” he explained.
“With a Phase III ready drug candidate for Alzheimer’s disease, we have had significant partnering and transaction interest across the spectrum of business stakeholders.”
He also says that funding is not drying up in this area, despite the headline failures from big players like Pfizer.
“Driven by the recent data from Biogen and Eli Lilly [which is also conducting new trials in a subpopulation of patients for its solanezumab], we definitely are seeing increased interest in funding for Alzheimer’s, and more broadly in CNS from both private and public investors,” he said.
- check out the release
Alzheimer's startup Alzheon bags $10M and beats a path to Phase III
Axon’s Alzheimer’s vaccine hits Phase II as it seeks to prove efficacy
In a setback, Biogen's mid-range dose of aducanumab flops in Alzheimer's study
AstraZeneca, Eli Lilly move closely watched BACE Alzheimer's trial