Neuroprotectant Therapy Faces Uphill Battle After Failure

The necropolis of neuroprotectant drug candidates has a new resident, which is terrible news for stroke patients as well as those looking for the next pharmaceutical blockbuster.

The recent failure of the only late-stage neuroprotectant candidate, a type of drug that seeks to protect the brain from further damage after a stroke, has led some to declare that the drugs are a myth, but prominent neurologists disagree. A neuroprotective therapy could save lives and lessen the severity of many strokes, but also see such widespread use that its global sales would be measured in billions.

"There is a sense of desperation out there," says Caroline Stewart, an analyst with Piper Jaffray, "because neuroprotectants have been such a graveyard for drug development."

Stroke kills about 5.5 million people every year, according to the World Health Organization, and is the third most common cause of death in developed countries behind heart disease and cancer. Even where advanced technology and facilities are available, almost two-thirds of stroke victims die or become dependent.

One hope for the future, Renovis Inc.'s (RNVS) neuroprotectant candidate NXY-059, died in late October when it missed every endpoint in its second Phase III study. The first Phase III had raised the hopes of the medical community, as well as Wall Street, for the drug's ultimate success. The news destroyed the company's share price - now trading based on the value of the cash it holds - and left it with a relatively thin pipeline following a string of clinical failures.

Renovis's partner in the drug, British pharmaceutical giant AstraZeneca PLC (AZN), walked away in disgust after the debacle of SAINT II - the study's official name - leaving virtually no future for NXY-059 and sending shock waves to those in search of similar therapies.

AstraZeneca declared that the SAINT II trial was a landmark study in determining that neuroprotectants simply don't work and that the company abandoned the search for similar drugs.

"The people that we've worked with in the outside world, the opinion leaders, think that this really has shown them that the models that they use and the work that they've done to try and generate drugs like this, is not valid," said Dr. John Patterson, the executive director of development at AstraZeneca.

"We're talking more generally about neuroprotection and the ability for anything, whether it's a free radical trapping agent or another mechanism, to do something in man that's meaningful," he added.

Currently, the only companies with stroke neuroprotectant drugs in development are Germany's Paion AG (PA8.XE) with Enecadin and Israel's privately held D-Pharm with DP-b99, both of which are in Phase II trials.

The Long Search

Failure is not a new development in the world of neuroprotectants; none of the more than 1,000 different drug candidates tested since 1957 have made it to the market, according to a paper published in the March issue of Annals of Neurology.

In light of the number of failures, an academic and industry group published the Stroke Therapy Academic Industry Roundtable criteria, or STAIR, in 1999 to ensure that only viable neuroprotectant candidates proceeded to costly advanced clinical trials.

Renovis's NXY-059 is the first drug to meet all of the STAIR criteria and was viewed as having a promising future as a blockbuster among a field of no competition.

The only other stroke drug on the market is a clot-dissolving drug, or thrombolytic, known as tissue plasminogen activator, or tPA, which can only be used within the first three hours of a stroke. Prior to using tPA, doctors must conclude that the stroke is caused by a clot - the cause of about 80% of strokes - and not a hemorrhage because the drug can increase bleeding.

When, a stroke occurs, blood flow to a region of the brain is cut off, launching a cascade of events that kills brain cells and releases toxic free radicals that cause additional cells to perish over the ensuing hours and days.

The challenge is to restore blood flow to the struggling cells, usually by administering tPA to help remove the blockage. Theoretically, a neuroprotectant will halt the cascade, and provide the greatest benefit when used in concert with tPA.

Some neurologists feel that future success will be found through a combination therapy, possibly tPA with one or many neuroprotectant agents as well as hypothermia, which cools the brain to inhibit continued damage.

"I think a single molecule directed at a single mechanism will not work," said Dr. Patrick Lyden, director of the UCSD/VA Stroke Center in San Diego and North American coordinator for SAINT II. "If you look back at the last 20 years, we have one failure after another. They were all single-bullet approaches."

Dr. David Howells, the senior author of the Annals of Neurology paper and head of the Neuroregeneration Laboratory at the University of Melbourne in Australia, feels that neuroprotectants have performed poorly in trials because the methodology that met success in animal models wasn't adequately replicated in human trials.

"Neuroprotection isn't dead, because the neuroprotective hypothesis - that blocking cell death pathways in the very acute stages of stroke can save brain [cells] - has never been adequately tested in clinical trials," said Dr. Howells. He notes that reproducing the laboratory model would prove very difficult amid commercial pressures for quick results that are applicable to large numbers of patients.

Both Dr. Lyden and Dr. Howells stress that decreasing the amount of time it takes to get patients to treatment is the most important factor to improving both stroke therapy and clinical trials of neuroprotectants. They even note that previously unsuccessful trials, including SAINT II, might show different outcomes if such a change is made.

"We can boost the treatment rate from 4% to 20% right now with no new treatments" Said Dr. Lyden. He notes that in most areas, emergency responders are required to bring patients to the closest hospital, regardless of that hospital's facilities, instead of a stroke center where they can possibly receive tPA within three hours.

A Theoretical Blockbuster

If a neuroprotectant eventually reaches the market, analysts agree that it will be worth billions in yearly sales. Neuroprotectant candidates tend to be very safe, allowing for widespread administration and translating into high sales volume.

"Estimates varied from $1 billion-$3 billion worldwide for NXY-059," says Caroline Stewart, an analyst with Piper Jaffray who notes that the range was indicative of people's opinion of its approval prospects.

Now that NXY-059 has continued the tradition of failure, that huge market may not be tapped for a while as analysts expect a long lull in development.

"In general, early development companies should think twice after SAINT II and the strong statement from AstraZeneca," said Elemer Piros, a biotechnology analyst with Rodman & Renshaw, who notes that smaller companies are dependent on the major pharmaceutical companies to fund the large trials necessary to test neuroprotectants.

Piros says that throughout the history of failed neuroprotectants, almost every big company in the industry has tinkered with the idea due to the lure of the potentially huge payoff.

Despite this temptation, it is likely that the failure of NXY-059 will at least temporarily scare companies from investing to develop similar drugs.

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