The Alzheimer's pipeline: What's next?

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Alzheimer's is a devastating disease: Victims lose their memories, personalities, sense of time, and grip on reality as friends and families watch their loved ones slowly lose their identities, and eventually their lives.

The disease afflicts an estimated 5.4 million people in the U.S., where the memory-robbing illness is the 6th-leading killer of Americans, according to Alzheimer's Association. The association estimates that more than $200 billion will be spent between drugmakers and patients for research, medication and caregivers this year.

The efforts and research dollars of the medical industry have given us more failure than success and left more questions than answers. Research suggests that three cups of caffeinated coffee a day, reading, and crossword puzzles may prevent or slow Alzheimer's disease, but scientists have yet to agree on a cause, let alone a cure.

So far we understand neurons in the brain become clogged with plaque, consisting mostly of beta amyloid, which prevents communication between neurons and causes shrinking in the hippocampus, which plays a key role in storing memory. When the hippocampus is damaged, nothing is stored.

Up until now, drugmakers put a majority of their stock in one theory: the beta amyloid hypothesis. The recent Phase III failures of bapineuzumab and solanezumab - despite Lilly's assertion of a positive trendline in secondary analysis - aren't helping the hypothesis. 

What's next?

Research is at a critical point, particularly as investigators question whether knocking down levels of amyloid in patients with an established case of the disease can do any good. Researchers are turning away from diagnosed groups and starting to move upstream, anxious to see if new therapies can prevent the disease from occurring or if very early-stage Alzheimer's patients might respond. There's also a new focus on alternative pathways, with emphasis on prevention techniques, cognitive improvement and hormone therapies.

Researchers continue to hunt for the next clue, with a focus on biomarkers for early detection and prevention. Meanwhile, here is a roundup of what's happened with Alzheimer's medication; detection and trials, techniques and failures.

Early detection

Because of the sheer lack of medication for late-stage Alzheimer's, scientists have been focusing on early detection to more effectively use the drugs on the market.

An increase in beta amyloid in the brain is a hallmark of Alzheimer's, but a decrease of beta amyloid in the spinal fluid also occurs. Detectable up to 25 years before the first symptoms of the disease come to light, this is the earliest change and best indicator when used in conjunction with other diagnostic agents. Tau, a major protein in neuronal structure, breaks down in the brain as cognitive function decreases. Up to 15 years before Alzheimer's sets in, levels of the protein rise in the spinal fluid. The last structural change in the brain is irregularity of glucose patterns, which show themselves up to 10 years before the first symptoms of Alzheimer's.

Walking patterns are the first sign of a patient experiencing a loss of normal task function. When a person's stride becomes irregular, his or her cognitive function is suffering. Sleeping patterns may also be an indication.

In Trials

ACC-001

Launching a second try at an Alzheimer's vaccine, Elan ($ELN) and Pfizer ($PFE)--which stepped in with its acquisition of Wyeth--have an antibody in active and recruiting clinical trials. ACC-001, a further formulation of the failed AN-1792, targets the first 7 amino acids of the beta amyloid sequence as a mutant diphtheria toxin carrier, as opposed to its predecessor the 42 beta amyloid peptide inhibitor. The vaccine weakens the protein chain and quickly produces anti-beta amyloid antibodies. Due to the negative results posted for AN-1792, the vaccine is not nearly as strong and the dosage is not nearly as high as its predecessor, according to a study documented by the National Center for Biotechnology Information (NCBI).

In a Phase IIa trial, the vaccine inhibited plaque accumulation in the brain and was able to produce enough antibodies to be effective against beta amyloid without any additional, and potentially harmful, T-cell responses. The vaccine was generally successful in inhibiting plaque accumulation, however patients using it failed to show any cognitive improvement.

Hormone therapy

A Phase II/III trial was conducted to test whether independent living with late-stage Alzheimer's was possible in postmenopausal women. Estrogen has positive effects on brain homeostasis, preserving neurotransmitter pathways, and maintaining neural plasticity--keeping learning, balance and memory intact. Deficiency in the hormone accelerates aging and increases the risks of neurodegeneration.

Evista, a selective estrogen receptor modulator originally developed for osteoporosis under the brand name Raloxifene, has been linked to protecting neurons from oxidative stress damage--which in turn would help improve short-term memory. Functional as an estrogen replacement therapy, Evista binds to natural estrogen receptors, activating and deactivating estrogenic pathways in order to maximize the flow of the hormone throughout the body.

This trial consisted of women ages 55 to 90 of general health and mild-to-moderate dementia who live with caregivers. The three-month study suggested that the estrogen therapy consistently improves verbal memory as well as decreases risk of dementia. The therapy, however, demonstrated no significant conclusive improvement in cognition.

Immunoglobulin

Baxter International ($BAX) and Barcelona, Spain-based Grifols developed Gammagard liquid, an intravenous immunoglobulin (IVIG) lasting two weeks to three months, to treat immune deficiency disorders. IVIG contains various antibodies, including polyvalent, immunoglobulin antibody G (IgG) and extracted plasma. Originally developed for immunodeficient patients without antibody capabilities, the drug could contribute to beta amyloid clearance from the brain by suppressing harmful inflammation and mitigating the toxicity of the plaque.

In a Phase II clinical trial of 16 patients, Gammagard effectively shut down the progression of Alzheimer's with the optimal dosage. Patients who received a placebo or did not receive the optimal dosage continued to decline.

So far, this seems to be the most promising medication in the Alzheimer's pipeline, consistently stalling the progression of the disease for four years in a small clinical trial. Baxter's goal for the medication is to maintain high levels of functionality during the early stages of the disease. Though few patients are better than no patients, Phase III data are due in the first half next year and that, as tradition demonstrates, is where prospective Alzheimer's medications go to die.

Improving cognition

The late-stage Alzheimer's hopefuls haven't given up yet. Watching failure after failure has not discouraged Lundbeck and EnVivo Pharmaceuticals from wanting in on the multibillion-dollar cognitive impairment party. But drug candidates Lu AE58054 and EVP-6124 have obstacles to face first.

Lundbeck's selective 5-HT6-receptor antagonist has potential to improve cognitive function as well as treat Alzheimer's. The company describes its product as "augmentation therapy."

The company announced in May the primary endpoint of a 278-patient placebo-controlled Phase II study. Patients who received the optimal dose of the drug showed statistically significant improvement in cognition and tolerance of the medication. The Danish drugmaker plans to move into Phase III trials upon gaining additional funding.

EnVivo has a slightly different strategy, an alpha-7 antagonist designed to target a nicotine receptor as a way of improving the thought process and ameliorating symptoms of the disease. In a 6-month, placebo-controlled Phase IIb clinical trial of 409 patients, the company also announced statistically significant cognitive improvement, as well as plans to move into Phase III trials in 2013.

Both drugs have passed the futility test, with flying colors. And both drugmakers are looking for partnerships going forward. These are projects too big for the companies to man alone.

Beta amyloid antibodies

Until recently, Big Pharma theorized that the best way to combat Alzheimer's was to combat the neurological hallmark of it-- beta amyloid plaques. Bapineuzumab was Elan, Pfizer, and Johnson & Johnson's ($JNJ) test of that theory. Long before Big Pharma realized bapi was a failure, Eli Lilly's ($LLY) solanezumab and Genentech's crenezumab were pushed into clinical trials.

Well, it sounded good at the time. And, in 2010, solanezumab was one of two drugs able to hurdle the risk of the field altogether and make the cut. Despite the fact that the Phase II trial was oddly halted at 12 weeks, ostensibly to move the drug into Phase III as fast as possible, looking beyond the fact that there was no cognitive improvement reported in the truncated trial. Solanezumab data showed that it did not cause harm and, in Alzheimer's, a good safety profile helps to get a drug over the Phase II hurdle.

Or it was at the time. Analysts have been lambasting Lilly now for the mid-stage rush. And another big failure will undermine the company's credibility in R&D. Due to the lackluster data released Friday, Lilly is running the drug for a second round. Solanezumab failed both primary endpoints of its Phase III study, but showed marginal slowing of cognitive decline in a follow-up analysis. CEO John Lechleiter seems determined to push this drug ahead, and encouraged by even the mildest of data.

Not to be forgotten for its efforts, Roche's ($RHHBY) Genentech is now taking crenezumab in a different direction. Only mildly positive early clinical data for the antibody, along with news of failures from drugs with more positive early data, persuaded the Swiss pharma giant to switch focus from treatment to prevention. The company, in partnership with the Alzheimer's Association, is currently preparing for its first study of cognitively healthy individuals. The Big Pharma spotlight moves away from high-risk potential blockbusters to finding preventative measures for at-risk populations.

Failures

AN-1792--The first Alzheimer's vaccine to reach trials was designed to help patients develop antibodies against beta amyloid, the chief component in plaque, and mobilize participants' immune systems as opposed to using continuous medication. Though the "Alzheimer's vaccine" had an effective and profound effect on the brain, researchers learned in autopsy results that it was the cause of brain inflammation resembling meningoencephalitis.

Bapineuzumab--Elan, Pfizer and J&J's laboratory-produced beta amyloid antibody aimed at decreasing plaque levels in the brain. Recently, it failed to outperform a placebo in two of four Phase III trials, prompting J&J and Pfizer to scuttle the late-stage program early this month.

Dimebon--Though early data suggested that Dimebon improved communication between neurons, Phase II and III studies were unable to confirm any progress. Even though Medivation and Pfizer's drug showed no improvement in Alzheimer's, it has recently returned to animal studies in a rush of optimism. Whether scientists plan to renew clinical development efforts or not, the 2010 study was an abject failure.

Rosiglitazone--It was originally developed as a diabetes medication that increases a cell's sensitivity to insulin. Researchers predicted a potential treatment for Alzheimer's due to links between the disease and Type II diabetes and pushed the drug into clinical trials, but it failed to provide any cognitive improvement.

Semagacestat--Lilly's gamma-secretase inhibitor hurt patients more than helped them by producing more beta amyloid and speeding up Alzheimer's disease.

Tarenflurbil--The drug was developed to change the behavior of gamma-secretase, but it failed to improve patients' memory and/or ability to perform daily activities in trials.

Tramiprosate--This modified form of an amino acid may prevent beta-amyloid aggregation but provided inconclusive data. It is currently being sold on the market as a medical food.

Scientists are still on the hunt, using every trick in the preclinical development book from homegrown neurons to radiation to find potential answers to Alzheimer's. As some pharma companies continue to dig for late-stage gold, the focus is shifting away from treatment back to prevention. Late-stage is becoming too late.


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