Lilly Alzheimer’s drug, like so many others, fails; will true breakthrough happen this century?

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Eli Lilly & Co. (Indianapolis RIN) said its experimental Alzheimer’s treatment failed to slow loss of cognitive ability in patients with mild symptoms, a major setback for the company and millions of people at risk of developing the memory-robbing disease.

@LillyPad's experimental #Alzheimer’s treatment fails to slow loss of cognitive ability Click To Tweet

Lilly shares plummeted 11% after the drugmaker unveiled the long-awaited results of its large Expedition 3 study. Shares of Biogen Inc. (Cambridge MA), which is developing a similar drug, slid 3%, according to Fortune.

Many Scientists, investors and families had been counting on solanezumab to become the first approved medicine to slow progression of the disease, which the Alzheimer’s Association estimates will strike as many as 28 million Americans by midcentury.

Lilly said it would take a $150 million charge in the fourth quarter for the failed trial and provide an updated 2016 financial outlook, as well as 2017 forecasts, on Dec. 15.

“Lilly has strong growth prospects without solanezumab,” said David Ricks, the company’s incoming CEO.

He said Lilly still believed recently introduced treatments for diabetes and other conditions would ensure average annual revenue growth of at least 5% between 2015 and 2020.

Based on the failure of the Phase 3 solanezumab study, Lilly said it would not seek U.S. approval of the drug for mild dementia. It is also being tested in patients who have not yet developed Alzheimer’s symptoms but who have brain plaques.

Some analysts had said solanezumab, if approved, could eventually claim up to $10 billion in annual sales and boost Lilly’s earnings for years to come.

The infused drug works by binding in the bloodstream to a protein called beta amyloid, which is believed to cause toxic brain plaques that are considered a hallmark of Alzheimer’s.

Biogen is racing to complete its own Phase 3 trials of aducanumab, which is designed to clear beta amyloid that has already formed plaques. However, the solanezumab data raise questions about whether beta amyloid is a valid target for Alzheimer’s drugs.

“For Biogen and other companies in the Alzheimer’s field, this is a serious blow,” Leerink Partners analyst Seamus Fernandez said in a research note carrying the headline “Burnt Turkey for Biotech investors.”

Although Biogen’s drug targets the same protein as solanezumab, Fernandez said it is a considerably different antibody, is being tested on patients with milder symptoms, and is given at a different dose. Therefore, he said, aducanumab will not necessarily suffer the Lilly drug’s fate.

Lilly said patients treated with solanezumab did not experience a significantly greater slowing in cognitive decline than those given placebos.

In two original 18-month studies completed in 2012, solanezumab failed to slow cognitive decline or loss of abilities of daily living for the 1,000 patients with mild to moderate disease in each trial.

But the combined data for just the mildly affected patients suggested solanezumab caused significant slowdowns of 34% in mental decline and 18% in loss of functional abilities, compared with those taking a placebo, researchers said.

As with cancer, many experts believe combinations of medicines, each having different mechanisms, will be needed to greatly slow Alzheimer’s progress or stop it in its tracks.

One of the biggest hopes is a class of experimental drugs called BACE inhibitors, which work by blocking the beta secretase enzyme involved in producing beta amyloid. Lilly and others, including Biogen and Merck & Co. (Kenilworth NJ), are conducting late-stage trials of such drugs.

Steve’s Take:

Drug and biotech stocks might rise because of shifting political winds or the prospect of big acquisitions. But this week was a reminder that the biggest challenge facing companies that seek to invent new medicines and prove they work remains pure biology, itself.

Eli Lilly skidded to a two-year low Wednesday, after the company’s treatment for people with mild dementia due to Alzheimer’s disease failed to meet the primary endpoint in a late-stage clinical trial.

The failure, which several Wall Street analysts said was highly disappointing, could have negative implications for Lilly’s Alzheimer’s portfolio and competitors including Biogen and US-based Merck, according to MarketWatch.

More specifics about the solanezumab drug, expected the night of Dec. 9 during a meeting of the Clinical Trials on Alzheimer’s Disease (CTAD), could have repercussions for what’s called the “beta amyloid hypothesis” in Alzheimer’s disease treatments, which target protein fragments that some believe are responsible for the disease.

Though investors took the solanezumab results as a negative for Eli Lilly and competitors in the Alzheimer’s space, Wall Street analysts were more positive in the long-term.

Within Lilly’s results, some details even have positive hints for the beta amyloid hypothesis, said Evercore ISI’s John Scotti. A p-value for the primary endpoint of cognition was not statistically significant but “does suggest a trend in favor of [solanezumab],” he said.

Biogen’s treatment differs from Lilly’s, said RBC Capital Markets analyst Michael J. Yee, since “it has shown clear [statistically significant] reduction of beta amyloid via imaging, while others have not.” Earlier small studies have shown clear statistically significant cognitive benefits and it is a different antibody than Lilly’s treatment.

“These are different antibodies with different amyloid targets,” he said, predicting Biogen–which saw shares drop 3.8%–will present positive data at the December CTAD meeting.

Eli Lilly’s negative results could even be a boon for Biogen, said Bernstein analyst Ronny Gal, since the results’ “trend toward positivity”– cognitive decline didn’t decline at a statistically significant rate compared to placebo– “seems to be the best result for Biogen as it suggests that the amyloid beta hypothesis seems correct and yet this eliminates an early competitor.”

I agree with those who say that with an incoming Republican administration, we’re likely to hear a lot about getting innovative drugs to patients faster, says Forbes. But the reason drug development is slow is the same as the reason many people want to speed it up: patients’ lives are at stake.

But then again, there’s the pure biology barrier–no matter how many billions of dollars have been and will be spent banging on that impenetrable door, at least so far.

It wasn’t Albert Einstein who said the definition of doing the same thing over and over again is “insanity.” Some say the expression originated with Ben Franklin or Mark Twain, or sprang from the Narcotics Anonymous “Basic Text.” In any event, whoever coined the phrase probably was thinking about the pharmaceutical industry, and in particular, the quest for an effective treatment for Alzheimer’s.

Eli Lilly’s solanezumab has failed again and again, Forbes points out. Researchers looked at the last failed trial and decided to try again in patients with less severe Alzheimer’s who clearly had plaques in their brains visible on PET scans.

The idea was that “sola,” which works by targeting a protein fragment called amyloid that is involved in making the plaques, would work better if given earlier and only in the right patients.

That tactic didn’t work. And one lesson to drug companies is to believe the results of their clinical trials and to be careful about going back repeatedly thinking things will result differently. This is extremely problematic: it’s so tempting to believe that there is hope for a new medicine, and sometimes it turns out to be true.

The idea that the amyloid fragment that sola targeted is key to Alzheimer’s is called “the amyloid hypothesis.” In the wake of sola’s failure, some people will say the amyloid hypothesis has been proven wrong.

That matters because other companies, including Biogen and Merck, are developing other drugs that target amyloid in different ways. However, it could be that the drugs need to be used even earlier in Alzheimer’s. It could be there’s some other reason that previous amyloid drugs didn’t work. Genetics suggested amyloid does matter. But that doesn’t mean the drugs that target it will work.

The last new drug to be approved for Alzheimer’s reached the market in 2003. Since then, despite billions of dollars spent, we’ve seen only failures.

In addition to the companies mentioned earlier in this piece, Axovant Sciences Ltd. (Hamilton Bermuda), a small biotechnology company, is developing an Alzheimer’s drug, intepirdine, that doesn’t target amyloid. Instead, it builds on the existing science of drugs to treat Alzheimer’s symptoms.

The problem is that other drugs that work the same way have failed in clinical trials, and a previous study by GlaxoSmithKline PLC (London) failed. But the Glaxo study failed on a technicality–if it had used more standard measures of cognitive decline it would have been a success. Axovant also argues its drug is more potent than the ones that failed. Results are expected by the end of 2017.

Another late-stage study tests a drug aimed at tau, the other protein thought to play a key role in Alzheimer’s besides amyloid. Results are expected at a medical conference next month.

A large study is testing the blood pressure drug nilvadipine. Yet another is trying a nose spray version of insulin, which some earlier work suggested shows promise, according to The New York Times.

Several studies test various diet and nutrition studies, including one late-stage experiment with vitamin E and selenium supplements.

Finally, doctors are testing a device, sort of a pacemaker for the brain. It delivers transcranial magnetic stimulation to stimulate specific regions that appear affected by dementia.

Steve's Take: Which generation will enjoy the benefits of a cure for #Alzheimer's? Click To Tweet

Any of these approaches just might succeed. But today, if the past is any reliable indicator, the question remains–for which future generation?

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