By Mandy Jackson
December 19, 2013
Howard Fillit, executive director and chief scientific officer at the Alzheimer's Drug Discovery Foundation (ADDF) in New York, is optimistic about the Alzheimer's field despite multiple high-profile setbacks for late-stage therapeutics seeking to slow or stop progression of the disease.
"It's been a very intensive time for us in the field. There has been a lot of good news and research advances even though we haven't found a cure yet," Dr Fillit said in a recent interview with Scrip about current and future Alzheimer's drug development.
His assessment may be surprising to some given the recent failure of drugs targeting the amyloid beta protein and amyloid plaque buildups in the brain, which researchers have investigated since the early 1980s as causative factors in Alzheimer's disease.
Pfizer, Janssen and Elan ended all development for bapineuzumab in August after the amyloid-clearing monoclonal antibody failed in two Phase III clinical trials to provide significant cognitive and functional improvements for patients with mild-to-moderate Alzheimer's (scripintelligence.com, 7 August 2012).
Eli Lilly also reported in August that its amyloid-neutralizing monoclonal antibody solanezumab did not meet cognitive and functional endpoints in two Phase III clinical trials in mild-to-moderate Alzheimer's, but the company said the therapeutic candidate showed signals of positive effects on cognition in patients with mild forms of the disease in one of the trials ( scripintelligence.com, 26 August 2012).
That's why Lilly decided in mid-December to move forward with a new Phase III clinical trial for solanezumab in the treatment of mild Alzheimer's disease (scripintelligence.com, 13 December 2012).
"From a scientific point of view, this is an advance. The pharmaceutical industry spent literally billions of dollars to test this hypothesis in people," Dr Fillit said. "We're all disappointed that these large clinical trials failed, but they are advances in the field, because they point us in a direction - maybe away from amyloid therapies."
The field always has needed more investment in drugs that target amyloid in new ways or do not target amyloid at all, and he said the pharma industry may be encouraged by letdowns in the amyloid arena to invest in other therapeutic approaches.
Unfortunately, a potential new therapy for Alzheimer's disease ran into a roadblock when Canadian drug developer Allon Therapeutics in Vancouver, British Columbia announced on 18 December that its lead neuroprotective drug candidate davenutide failed to demonstrate any effect on primary and secondary endpoints in a Phase II/III clinical trial that enrolled patients with progressive supranuclear palsy (PSP), a type of dementia.
PSP is caused by abnormal tau, a protein that's also associated with Alzheimer's disease. Tau tangles disrupt normal nerve cell processes and lead to cell death in the brain.
Prior to the Allon announcement, Dr Fillit said the company's davenutide data could "have wide implications for our field."
Now, scientists and companies interested in therapeutics targeting tau will turn their attention to TauRx Pharmaceuticals of Singapore, which announced at the end of October that it started two Phase III clinical trials with 1,333 patients for a second-generation tau-based approach known as LMTX, that the company believes will be a disease-modifying and preventative treatment for mild-to-moderate Alzheimer's ( scripintelligence.com, 1 November 2012).
TauRx's first-generation Tau Aggregation Inhibitor (TAI) called rember showed a 90% reduction in the rate of disease progression during a two-year, 300-patient Phase II trial.
Both amyloid-targeting and tau-based approaches attempt to stop the degeneration of neurons and the axons between neurons before the degeneration causes significant neuronal cell death.
"Gamma secretase inhibitors have also failed, possibly not because the theory is wrong, but because it is so hard to target, because of the side-effects," Dr Fillit said. "Now Merck has entered into a Phase II trial for a beta secretase inhibitor. That drug will tell us whether limiting the amount of beta amyloid that's made can remove plaque and improve cognitive function."
Merck said on 3 December that it would initiate a 78-week Phase II/III study to evaluate the safety and the cognitive and functional efficacy of MK-8931 - a novel, oral beta-amyloid precursor protein site-cleaving enzyme (BACE) inhibitor - versus placebo in up to 1,700 patients with mild-to-moderate Alzheimer's disease ( scripintelligence.com, 5 December 2012).
"There are other approaches to the amyloid target, but hopefully the failures will encourage investments in others," Dr Fillit said.
Outside of the amyloid and tau arenas, researchers are evaluating therapeutic options that tackle the theory that the brain represents 3% of body weight and uses 20% of the body's energy, which explains why diabetics lose consciousness when they become hypoglycemic.
"Diabetes is a risk factor for Alzheimer's, so another increasingly important approach to developing new treatments has been to try to reduce dependence on glucose and improve the efficiency of mitochondrial energy production," which requires glucose and oxygen, Dr Fillit said.
The US government's fiscal year 2012 budget allocated $50 million for Alzheimer's drug research to the National Alzheimer's Project (NAP), which was established in 2011 to develop a coordinated plan of attack against the disease by 2025 ( scripintelligence.com, 8 February 2012). Of the 2012 funding appropriation to the NAP, $8 million was allocated to an intranasal insulin therapy for Alzheimer's patients.
"It's thought that this could be a disease-modifying treatment. It not only includes the inner workings of the brain, but the dying neurons that are getting sick due to lack of energy," Dr Fillit said.
Researchers also are conducting clinical trials to repurpose drugs for Alzheimer's that originally were intended for other diseases, including diabetes and hypertension. "That's exciting, because the drugs are on the market and if the trials are positive doctors can use them in patients," Dr Fillit said.
As Lilly is doing with its third Phase III solanezumab study with patients who have mild - rather than mild-to-moderate - Alzheimer's, the field is beginning to move away from therapies that can stop the progression of the disease to drugs that may be able to prevent Alzheimer's.
That's why ADDF has been a champion for the radioactive diagnostic agent Amyvid (florbetapir F18 injection) developed by the wholly-owned Lilly subsidiary Avid Radiopharmaceuticals, which won US FDA approval in April ( scripintelligence.com, 10 April 2012).
Amyvid, which received early funding from ADDF, is indicated for brain imaging of beta-amyloid plaques in patients with cognitive impairment who are being evaluated for Alzheimer's disease and other causes of cognitive decline.
"We've learned in the last year or two that we begin to see the amyloid accumulating 10, 15 or 20 years before people become symptomatic - the same as we know teenagers start building plaque in their arteries and they don't have heart attacks until their 70s, but we can test to see if they have plaque in their arteries. Now we can do that in Alzheimer's disease," Dr Fillit said.
"It's theoretically valuable and certainly clinically important that it can prevent disease and we can have early detection."
In addition to his teaching and research roles at the Mount Sinai School of Medicine in New York and his executive role at ADDF, Dr Fillit maintains a limited private practice in consultative geriatric medicine with a focus on Alzheimer's disease. He also has served as a consultant to pharmaceutical and biotechnology companies, health care organizations and philanthropic organizations.
"I can use that Amyvid test in my office when patients are complaining of memory loss, but they're not demented," Dr Fillit said.
Without effective preventative drug therapies on the market, at least patients can make plans for advanced care before they experience dementia in later stages of Alzheimer's - a disease that will affect one out of every three people by the age of 80.
"Part of the story here, as in other disease states, is that filling the funding gap is not just an industry-driven process. We need industry, academia and groups like ADDF to help bring drugs to market and [non-profit groups] are playing an increasingly important role in drug development," Dr Fillit said.
"We've made amazing progress, because when I started in the field 35 years ago, people would say, 'Old-timer's disease - what is that?' We've come a long way since then."