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Insight & Intelligence : Jun 11, 2013
Seeking New Tools Against Alzheimer’s
Numerous failures, many in late stages, litter the road to a safe, effective drug.!--h2>
With just five successes, all just slowing progression of symptoms for six to 12 months, the road to an Alzheimer’s drug has been paved with failure. And the setbacks keep coming, most recently in May, when Baxter International’s Gammagard failed in Phase III to reduce cognitive decline or preserve functional ability in mild-to-moderate Alzheimer’s patients.
Baxter did point a possible bright spot: Moderate Alzheimer’s patients and ApoE4 carriers showed between 16% and 29% cognition improvement over placebo. That could lead to a new trial for a subpopulation likelier to benefit from the drug, much as Lilly plans a new Phase III study of solanezumab in patients with mild Alzheimer’s by year’s end.
Gammagard joins a growing number of failed, late-stage Alzheimer’s candidates. Last year alone, Johnson & Johnson’s Janssen Alzheimer Immunotherapy unit and Pfizer ended development of bapineuzumab after it missed co-primary clinical endpoints in Phase III studies of patients who are, and aren’t, ApoE4 carriers. Eli Lilly’s solanezumab missed Phase III cognitive and functional primary endpoints against beta-amyloid plaques.
Among some later-stage Alzheimer’s drug efforts in progress:
A One-Two Punch
Lilly recently signaled a change in its strategy against Alzheimer’s. In April, the firm acquired from Siemens Medical Solutions two investigational positron emission tomography (PET) tracers for an undisclosed price. Both aim to image the accumulation in the brain of tau protein that blocks the transport of nutrients and essential molecules.
Richard C. Mohs, Ph.D., distinguished research fellow with Lilly, told GEN the company’s new focus on imaging tau tangles—one hallmark of the memory-robbing ailment—is not a retreat from fighting the other hallmark, amyloid-beta protein deposits that form amyloid plaques outside of neurons, but a one-two punch against Alzheimer’s.
“It’s biologically complex enough that you have to go after it in multiple different ways,” Dr. Moh said in an interview at the BIO 2013 International Convention in Chicago. “For complex, common diseases like Alzheimer’s, the likelihood that you’re going to solve the problem with only one approach is extremely low. Hopefully, by targeting each of these, we would be able to make some independent contribution to the overall aim of making Alzheimer’s more of a manageable disease for people who get it.”
Two years ago, NIH’s National Institute on Aging and the Alzheimer's Association issued revised diagnostic guidelines that divided the disease into preclinical, mild cognitive impairment, and dementia phases—an acknowledgement that Alzheimer’s cannot be fought as a single-start disease.
“It’s a gradual process,” Dr. Mohs said. “In order to treat it, most people now think we’re better off moving toward the earlier stages of the disease, where the traditional diagnostic criteria are somewhat more difficult to operationalize, because they are dependent on the appearance of frank symptoms. Those are sort-of hard to discern early on.”
A smaller drug developer long interested in tau, Oligomerix, last month won $2.8 million in Series B financing. The proceeds will in part advance into preclinical drug discovery programs targeting tau protein oligomers, the company’s focus since its founding in 2006.
“So many people were focused on amyloid that we didn’t see an opportunity to move into that direction, so we sort of serendipitously became tau-ists,” James Moe, Ph.D., the company’s president and CEO, told GEN.
Years before Oligomerix was launched, its founders worked with Columbia University researcher Ottavio Arancio, M.D., Ph.D., to learn more about the correlation between Alzheimer’s progression and disulfide-mediated tau oligomers in cerebrospinal fluid. “We showed with statistical significance that if you infuse these oligomers into the hippocampi of living mice, wild-type mice, you get a significant reduction in fair conditioning response, a measure of memory formation,” Dr. Moe added.
Also last month, NeuroPhage Pharmaceuticals scored $6.4 million in private equity financing for ongoing pre-IND studies of lead compound NPT002, set to advance to clinical trials next year. NPT002 mediated clearance of misfolded protein deposits—including amyloid-beta, tau, and alpha-synuclein—in multiple animal models, resulting in cognitive and behavioral improvements.
Amyloid: Path of Resistance
A number of reasons explain why the amyloid pathway has proven resistant to a successful drug, according to Howard Fillit, M.D., executive director and CSO of the Alzheimer’s Drug Discovery Foundation (ADDF). He said the thinking that amyloid plays a critical role in the disease process is still a hypothesis based primarily on preclinical data.
“It may just be that amyloid production in the brain is a response to injury, a mechanism of cells to repair, and it’s basically similar to the formation of a scar, but not necessarily a primary driver. Indeed, there are many other proteins in the plaques besides amyloid," Dr. Fillit said.
He cited evidence in recent years of amyloid plaques being present in people who die of head trauma. These plaques, he said, can occur acutely after injury, so they cannot be said to cause injury. Other reasons, he added, may include clinical trial models and robustness of drugs.
ADDF has invested nearly $60 million to fund 400 Alzheimer’s drug discovery programs and clinical trials at academic centers and biotech companies in 18 countries, including some 60 mission-related investments to biotech companies.
“We’ve seen upwards of 3,000 new ideas for new drugs for Alzheimer’s disease since 1998, so just the depth and the breadth of innovation that is going on in the field right now is incredible,” Dr. Fillit said.
Alzheimer’s, Dr. Fillit said, requires a focus on several risk factors, key among them aging. “As we age, we have multiple medical co-morbidities, like hypertension and diabetes, that in themselves are risk factors for Alzheimer’s disease, and have their own mechanisms that include insulin resistance in the brain, insulin resistance of the mitochondria in the brain, advanced glycation endproducts in the brain, the effects of hypertension on blood vessels in the brain, and hypoxia."
That thinking is shared by Salk Institute for Biological Studies researchers developing J147, a preclinical synthetic drug that reversed memory loss, reduced amyloid levels and slowed disease progression in mice, according to a study published May 14 in Alzheimer’s Research and Therapy. The researchers showed that J147 protected neurons by increasing supply of brain-derived neurotrophic factor, rather than attacking amyloid or tau.
“I think it’s very realistic that in the next five years, and certainly outside in the next 10 years, we’ll have some disease-modifying drugs approved for Alzheimer’s,” Dr. Fillit said. “I doubt that they’ll be cures. I think they will be drugs that will have an impact on the illness in demonstrating a slowing of the progression. Then, the next step will be employing those agents earlier and earlier in disease prevention.”
Last year, the U.S. Department of Health and Human Services committed the nation to “prevent and effectively treat Alzheimer’s disease by 2025” in its “National Plan” for the disorder. If Washington truly wants to fulfill that goal, the Obama administration will need to increase NIH basic-research spending well beyond the $503 million of FY ’12, projected to drop to $484 million this fiscal year.
Obama’s proposals for an extra $50 million for Alzheimer’s research in FY 2013 and $80 million in FY ’14 are steps in the right direction, though not much more—not when NIH spends $3 billion a year on AIDS and $5.6 billion on cancer. Given today’s tight budgets, however, any more money the agency spends on Alzheimer’s will likely come at the expense of some other equally worthy disease or program.
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