A Potential New MS Treatment's Long and Winding Road

By Eric Sauter and Mika Ono

In a remarkable turn of events, a 20-year-old treatment pioneered by Scripps Research scientists for an exceedingly rare form of leukemia appears to be on the verge of becoming the first effective oral therapy for multiple sclerosis (MS), a disease that affects an estimated 2.5 million people worldwide.

The drug, cladribine, which is currently marketed under the name LEUSTATIN® by Ortho Biotech, Inc. (an affiliate of Johnson & Johnson) for the treatment of hairy cell leukemia, was initially identified and developed by Dennis Carson, a Scripps Research scientist working in collaboration with Ernest Beutler, the late Scripps Research professor and chair of the Department of Molecular and Experimental Medicine.

In January of this year, primary data from a two-year Phase III trial of cladribine tablets for MS sponsored by Merck Serono, a division of Merck KGaA, Darmstadt, Germany, was announced and showed that the drug significantly reduced the relapse rate of MS patients with the relapsing-remitting form of the disease.

The potential importance of the drug cannot be overstated, according to Associate Professor Jack Sipe, the Scripps Research scientist and M.D. who first suggested that the drug might have potential as a treatment for MS.

"Currently, there are six FDA-approved medications for the treatment of MS, all require injection, and all are expensive and difficult for patients to tolerate," he said. "Many of my MS patients have been on them for five to ten years and they're very tired of injections. I can't tell you how many times I've been asked when we were going to get an oral medication. This new treatment, if it's approved, has the potential to make a significant difference in the quality of life for people who suffer from MS."

Twists and Turns

Cladribine's story takes enough twists to border on the mythological, according to Sipe, who joined both Scripps Research and Scripps Clinic in 1978 and who is also physician and senior consultant in neurology specializing in MS.

"Although 20 years is not an unheard of time for the development of a new treatment, cladribine's journey has sometimes seemed as difficult and convoluted as Odysseus's return home from Troy, in meeting all the challenges along the way," Sipe said.

The story begins at Scripps Research in the 1970s, when Carson was studying a genetic disorder involving deficiency of adenosine deaminase (ADA). Those born with the disorder lack the enzyme ADA, which destroys T and B lymphocytes. When Carson later switched his studies to hairy-cell leukemia, in which patients have too many white cells, he applied what he knew about ADA deficiency to find a compound that would selectively destroy those proliferating malignant white cells. Of the 25 chemicals tested, cladribine (2-chlorodeoxyadenosine or 2CdA) was the one that stood out.

Beutler and Carson went on to develop and test cladribine, using a single treatment of the new compound to target abnormal white blood cells in patients suffering from hairy cell leukemia.

The treatment proved to be stunningly effective and was licensed as an orphan drug in 1994.

A Second Life

Since then, cladribine has developed a new, and potentially even more important, second life, thanks to Sipe.

"I heard Dr. Beutler speak about the drug and its use in leukemia in 1989," said Sipe, "and I thought that its targeted effectiveness against T and B lymphocytes—they are the bad guys in MS—would work well against the disease process in MS."

Multiple sclerosis (or MS) is a chronic, often disabling disease that attacks the central nervous system, including the brain and spinal cord. For reasons that are not fully understood, in the disease the body's immune system destroys myelin, a substance that covers nerve fibers. When that happens, nerve impulses are disrupted, causing a number of symptoms that can range from numbness to paralysis.

After some discussion, Sipe and Beutler ended up collaborating on several clinical studies of the drug for MS starting in 1990.

"Those studies showed that cladribine slowed or reduced MS activity and that it was well tolerated—generally, the patients taking cladribine stabilized or improved slightly while those on placebo continued to deteriorate," he said. "We published those first results in The Lancet in 1994."

For clinical development, both effectiveness and patient tolerance of the drug are important. Unlike many other cancer treatments (which target all rapidly proliferating cells and thus result in many side effects), cladribine selectively targets only lymphocytes and thus turns out to be virtually side effect-free.

Two more studies followed with equally impressive results, with the final study published in 1999. Nevertheless, at that point the cladribine story paused, Sipe said. Even though the drug had shown significant results in treating MS patients, it remained stuck in pharmaceutical development limbo for several years.

Out of Limbo and into the Spotlight

Then Serono and IVAX, both independent companies, contacted Sipe about the possibility of developing a tablet form of the drug.

"They thought our original data made the compound look promising and they were willing to devote the considerable resources necessary to do a large pivotal trial to prove its effectiveness in MS," Sipe said. (Serono was acquired by Merck KGaA in September 2006 to form Merck Serono, Inc.)

Merck Serono's CLARITY study, involving 1326 MS patients, began in 2004 and was completed in December of last year. The study found that for patients receiving a low dose treatment, cladribine reduced the relapse rate by 58 percent; in the high dose group, the relapse reduction was 55 percent compared to inactive placebo tablets.  Secondary endpoints were also met including significant reduction in MS lesions by magnetic resonance imaging (MRI), number of relapse-free patients and less disability progression.

Based on these results, Merck Serono has indicated it plans to submit cladribine tablets for approval to the U.S. Food and Drug Administration and the European Medicines Agency sometime later this year.

The full results of the study were released in January of this year and presented at the 61st Annual Meeting of the American Academy of Neurology in Seattle in April 2009.

"The room was packed with about 2000 people and both Dr. Beutler and I were acknowledged from the podium as the people who initiated the study of cladribine in MS," Sipe said.

But what is critical, Sipe said, is what this could mean for patients. If attacked early and aggressively, MS is a treatable disease and cladribine has the potential to make that treatment more effective and more patient-friendly.

"I wanted to devote my career to neuroscience because of the promise of discovering treatments for untreatable diseases," Sipe said. "And many of those promises have come true. We haven't cured Alzheimer's and Parkinson's disease yet, but when I started there was no treatment for MS at all—the patients simply went downhill and died. From that point, we've made tremendous progress. We have six FDA-approved treatments, 30 or more compounds in the pipeline, and now we have oral cladribine. If you had told me in the beginning that all of this would happen in 20 years I would have been utterly amazed. It just takes patience and perseverance—that's what Dr. Beutler would often say."

Send comments to: mikaono[at]scripps.edu

"This new treatment, if it's approved, has the potential to make a significant difference in the quality of life for people who suffer from MS," says Associate Professor Jack Sipe. Photo by Kevin Fung.