The U.S. Food and Drug Administration (FDA) has just approved alemtuzumab (Lemtrada), a powerful new drug to treat multiple sclerosis (MS). The approval marks the culmination of more than 35 years of research. If not for the perseverance of a handful of scientists, this treatment would never have joined the ranks of other disease-modifying therapies for MS.
Perhaps the most influential person in the development of Lemtrada was professor Herman Waldmann, who, in the early 1970s, joined the department of pathology at Cambridge University.
“I entered research in 1971 because I felt that there were too few good treatments for autoimmune diseases and for prevention of transplant rejection,” Waldmann told Healthline. “My first four years were spent learning about how the immune system operated and how it avoided (most of the time) reacting to ‘self.’”
If Waldmann’s team could understand this “recognition of self,” perhaps one day they’d be able to reprogram the immune system to stop it from attacking a patient’s own tissues by mistake. That could be the key to halting autoimmune diseases.
“The discovery of monoclonal antibody technology by Cesar Milstein in 1975 provided the tools to see if this was possible,” Waldmann said. Antibodies attack foreign substances that could harm us; monoclonal antibodies can be trained to go after only very specific targets, such as our own white blood cells.
In early studies, Waldmann’s team used monoclonal antibodies to reprogram a rat’s immune system to accept transplanted tissue. They were also able to “permanently interrupt a developing autoimmune disease,” he said.
The researchers created their own unique set of monoclonal antibodies, derived from rat cells, which they called “Cambridge Pathology 1,” or CAMPATH-1. They would go on to make many versions of CAMPATH-1 as they refined their research.
Early Experiments Make Bone Marrow Transplants a Success
In 1982, Waldmann and his team used a version called CAMPATH-1M to treat a woman with aplastic anemia, in which the body’s bone marrow is unable to make new red blood cells. She was given a bone marrow transplant and then treated with the monoclonal antibody. At that time, bone marrow transplantation was not straightforward, since it carried a high risk of graft vs. host disease, in which transplanted cells attack the patient’s body.
The experiment was a huge success for the woman. Her bone marrow even recovered and was able to replenish itself after the treatment.
Then, in a small study conducted with researchers in Israel, they gave 11 leukemia patients bone marrow pre-treated with CAMPATH-1M to prevent graft vs. host.
While the experiment was a success for the majority of patients, two of the patients rejected their transplants. This outcome was unacceptable, so Waldmann’s team headed back to the laboratory.
Eventually, they developed a monoclonal antibody that could be infused directly into humans because it was less foreign to patients. This also allowed for testing in patients with autoimmune diseases. This version of CAMPATH was known as CAMPATH-1H.
Drug Company Cash Provides a Shot in the Arm
Since human studies are highly regulated and take years to complete, the scientists had little chance of success without funding from a pharmaceutical company.
Cambridge University first licensed CAMPATH-1 to the British Technology Group, and the license changed hands several times before Glaxo-Wellcome carried out clinical trials in leukemia patients.
Even though the researchers saw great success with CAMPATH-1H in treating chronic B-cell leukemia (BCLL), it wasn’t useful for all leukemias. Glaxo-Wellcome didn’t see the drug competing in the lymphoma or rheumatoid arthritis (RA) markets either, so they abandoned the drug’s development in 1994.
Determined to find out what went wrong, Waldmann pressed on. He had left Cambridge for Oxford University and began exploring ways to fund the production of CAMPATH-1H on a large scale.
The American company Leukosite, Inc. joined with the U.K.’s Medical Research Council to answer Waldmann’s call by building the Therapeutic Antibody Center at Oxford.
In 2001, CAMPATH-1H was renamed “alemtuzumab” and won FDA approval for the treatment of BCLL.
Through several more acquisitions, mergers, and buyouts, the drug’s license continued to change hands until it finally came to rest with Genzyme Corporation, now owned by Sanofi.
“With safety data emerging from the leukemia and marrow transplant studies,” Waldmann said, “local ethical approval could be obtained for treatment … of patients with severe autoimmune diseases.”
The Drug Works in MS, but Only with Early Treatment
In 1991, Waldmann began an 18-year collaboration with a clinical researcher named Alastair Compston at Cambridge to treat MS patients with CAMPATH-1H. Their goal was to prevent inflammatory T-cells from entering the brain and spinal cord.
The first MS patient they treated had been diagnosed years earlier. She tolerated the treatment very well. The researchers followed her closely for 28 months before treating another six patients.
By 1994, the Waldmann and Compston teams were convinced that CAMPATH-1H could stop relapses and reduce further attacks in MS patients. By 1999, they had treated 29 more patients with secondary progressive MS. The drug was effective at stopping the inflammatory response, but the scientists noticed that the patients’ disability continued to get worse.
The researchers found that disability wasn’t transient, but instead was the result of repeated attacks on the nerves. The researchers knew that for MS patients to have the best possible benefit from the drug, they had to be treated earlier.
They conducted the studies on people with relapsing remitting MS and discovered that not only did the drug suppress inflammation, but the patients’ disability actually improved.
Their research, along with larger studies conducted by Genzyme, led the European Commission to approve alemtuzumab (now branded Lemtrada) for MS in 2013.
FDA approval for the U.S. market was stalled in December 2013 when the FDA ruled that Lemtrada hadn’t been proven safe and effective. The agency cited poor study design because the phase III trials of the drug lacked a placebo control group and were not “blinded,” meaning that both patients and researchers knew which drugs the volunteers were taking.
Lemtrada Makes a Remarkable Comeback
The FDA ruling was not the end of the fight to make Lemtrada available to American patients, however. Genzyme submitted a supplement to their original FDA application with fresh analysis. The National MS Society (the Society) also played a role in getting the agency to reconsider.
“We testified at the advisory committee meeting convened by the FDA to review Lemtrada, and had subsequent communications with the agency regarding the drug at which we shared our thoughts and disappointment on their decision,” said Timothy Coetzee, the Society’s chief advocacy, services, and research officer, in an interview with Healthline. “We also provided FDA contact information to those of our MS constituents who wanted to reach out to them and express their opinions directly.”
After reviewing all the evidence and reconsidering the application, the FDA approved Lemtrada on Nov. 14, more than three decades after Waldmann’s first experiments.
According to renowned MS expert Dr. Jeffrey Cohen, director of the Cleveland Clinic’s Mellen Center for Multiple Sclerosis, compared to the other available drugs, Lemtrada is “among the most potent.”
For a man who has spent a lifetime dedicated to research on treating autoimmune disease, how did Waldmann take the news of the drug’s approval?
“My colleagues and I have always had great faith in the value of the drug,” Waldmann said, “and the prospect that, once licensed, ways would be found to minimize many of the unwanted side-effects. In short, we were relieved and happy for those patients who will benefit.”
Lemtrada must be given by intravenous infusion. The drug is given for five straight days initially and for three straight days one year later. The FDA opted to include a boxed warning about the potential for serious or life-threatening side effects, including thyroid conditions, infusion reactions, and a rare bleeding disorder. Less serious side effects include everything from rash, headache, and vomiting, to herpes viral infection, fungal infection, and joint pain.
Lemtrada will only be available from certified prescribers, and patients who take it will be enrolled in a long-term study to test the drug’s safety.
Waldmann, ever the optimist, is hard at work finding ways to minimize these side effects. “Despite retiring from a wonderful 20 years as head of the Sir William Dunn School of Pathology in Oxford,” he said, “I am running a small research group where we want to understand how to control which lymphocytes return after CAMPATH-1H treatment. Our goal is to make the … process as patient friendly as possible, so as to prevent the known side effects. I am optimistic that we can offer new information on how CAMPATH-1H can be used to achieve optimal outcomes, with minimal harm.”