Bexarotene on the Move: Landreth, Cramer, and CWRU form ReXceptor Inc.

Tests show that bexarotene can reverse similar disease in mice. Bexarotene works like a charm in mice, but can it reverse Alzheimer’s in humans?

Gary Landreth and Paige Cramer aim to find out: The two researchers and their employer, Case Western Reserve University, have founded a company called ReXceptor Inc., which is working to figure out whether the cancer drug has potential to become an Alzheimer’s drug.

They’re in the process of raising money to finance a phase I clinical trial designed to show how the drug affects healthy people. If that small study goes well, larger studies testing the drug in Alzheimer’s patients will follow.

There’s no guarantee the drug will make it through clinical trials, Dr. Landreth said, noting that many drugs that work well in mice fail in humans.

But it does work really, really well in mice.

After four years of testing bexarotene on hundreds of mice that were genetically engineered to develop a condition similar to Alzheimer’s, Drs. Landreth and Cramer have found the drug almost immediately triggers their bodies to ramp up production of a key protein called apolipoprotein E, or ApoE.

That protein helps the brain get rid of beta-amyloid protein fragments, which build up in the brains of Alzheimer’s patients, who can’t produce enough ApoE.

“If you had more of these garbage disposal units … things should get faster and you should get smarter,” Dr. Landreth said.

And that’s what happened in the mice. The level of soluble beta-amyloid in their brains dropped 25% 24 hours after they received the drug, and the level of beta-amyloid plaques in their brains fell by 75% after three days.

Plus, the mice over time started showing improved brain function. They built nests again. They more easily found their way through mazes. They even got their sense of smell back.

After Dr. Cramer ran the first test four years ago, Dr. Landreth didn’t believe the results.

“I thought she’d screwed up,” he said.

Other scientists have been impressed by the research, published in February in the online version of the journal Science. Among them is Dr. Michael Rafii, associate medical director of the Alzheimer’s Disease Cooperative Study, a group based in La Jolla, Calif., that works to advance research related to the disease.

Dr. Rafii described the results as “startling.” Though other drugs have shown the ability to remove beta-amyloid from the brains of mice, Dr. Rafii said he knows of no drugs that have done so as rapidly as bexarotene.

The research also is important because it represents “a different pathway to target in the treatment of Alzheimer’s,” Dr. Rafii said. Whereas bexarotene uses ApoE to remove beta-amyloid, other drugs being tested use either antibodies to bind with the protein fragments or molecules that block the enzymes that produce them.

Still, the drug needs to be proven in humans, Dr. Rafii said.

Not only are humans and mice physically much different, but the mouse version of Alzheimer’s is different than the human version, he said. For one, the mice, bred to have a rare dominant gene that causes Alzheimer’s in humans, don’t suffer permanent neural damage, but humans with Alzheimer’s eventually do.

Words of warning

Dr. Bill Thies, chief medical and scientific officer for the Chicago-based Alzheimer’s Association, voiced similar cautions, noting that several researchers have created treatments that worked in mice but failed in Alzheimer’s patients.

Still, Dr. Thies lauded the study. Drs. Landreth and Cramer are off to a good start, he added, given that the drug already has been approved by the U.S. Food & Drug Administration for treating skin cancer. The rarely prescribed drug is sold under the brand name Targretin by pharmaceutical firm Eisai Co. of Japan. The company’s patent on the drug expires this year.

“It’s got a history. We know something about its safety,” he said.

The research has caught the attention of families affected by Alzheimer’s.

Dr. Landreth said he has received hundreds of emails and phone calls from people clamoring to receive the drug. He instead directs them to the Alzheimer’s Association, which pairs patients with clinical trials testing various Alzheimer’s treatments.

There’s a huge amount of desperation among the estimated 5.4 million U.S. residents that have Alzheimer’s, Dr. Landreth said. Existing drugs just treat symptoms while the condition grows worse, he said. Multiple drugs that could reverse the condition are in clinical trials, but none have received FDA approval.

Even though bexarotene is on the market, Dr. Landreth strongly recommends doctors avoid prescribing it for off-label use. For instance, he noted that no one knows what happens to a person’s brain if you remove beta-amyloid so quickly.

Needed: Lots of money
If a phase I clinical trial was to start today, it still would take five to seven years before ReXceptor could finish testing the drug in Alzheimer’s patients and win FDA approval to start selling bexarotene for use in treating Alzheimer’s, said Michael Haag, a technology transfer official at CWRU who is serving as ReXceptor’s CEO.

And there’s no telling whether the drug will make it through clinical trials or whether the company will attract the “hundreds of millions of dollars” that will be needed to complete all of them, Mr. Haag said.

“We are going to be in need of a strategic partner with that kind of money,” he said.

However, the team wants to build ReXceptor in the Cleveland area, Dr. Landreth said.

“We’re committed to staying in Northeast Ohio,” he said.


4:30 am, April 16, 2012

© 2012 Crain Communications Inc.