Mitsubishi Tanabe Tweaks Study Design For ALS Success

By Ed Miseta, Chief Editor, Clinical Leader

A new treatment for adult patients with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is now available to patients in the U.S. RADICAVA™, produced by Mitsubishi Tanabe Pharma America, Inc. (MTPA), is the first ALS treatment to be approved by the FDA in more than 20 years. While it will not reverse the effects of ALS, a recent clinical trial for RADICAVA found it slowed the decline in physical function of patients by 33 percent.

ALS is a neurodegenerative disorder, as are Alzheimer’s and Parkinson’s disease. Among the three conditions, ALS is unique in that it is incredibly deadly. The progressive loss of skeletal muscle leads to an inability of patients to perform everyday activities such as walking, talking, chewing, dressing, and swallowing. Even involuntary activities such as breathing are impacted.

“A patient’s condition typically worsens until they are paralyzed and dependent on a ventilator and a feeding tube,” says Jean Hubble, VP of medical affairs for MTPA and a specialist in the field of neurology. “A majority of patients will die within two to five years of diagnosis. In most cases the cause of death will be complications due to respiratory failure.”

Trials Are Hard To Design

There are a few things we do know about ALS. The disease tends to strike in late middle-age, peaking among patients in their early sixties, and is virtually unheard of in children. Unfortunately, researchers do not know what causes the disease. In a small number of cases, it is hereditary, and some evidence suggests it may also be due to environmental factors. Certain gene characteristics, while not directly causing the disease, could make patients more susceptible to it. Regardless of the cause, what researchers do know is that the dysfunction and degradation of motor neurons in the brain and spinal cord is what leads to physical manifestations in the patient.

“It is the first drug approved in more than 20 years, and during that time more than 50 drugs have been tried and failed,” states Hubble. “There are many reasons for that lack of success, but one is that if you don’t know the cause of a progressive condition such as ALS, it’s very difficult to find a breakthrough therapy that can halt the disease. At the same time, clinical research for ALS is complicated by the fact that it is difficult to develop trial methodologies that allow us to precisely measure the progression of the illness in patients over a few months’ time. With a treatment like RADICAVA, the patient in a clinical study is not going to see or feel a change. Instead, we attempt to determine if there is a reduction in the rate of deterioration. That can be difficult to determine and can make this type of clinical trial very hard to design.”

Learning From Past Mistakes

The entire clinical development program for RADICAVA was conducted in Japan by Mitsubishi Tanabe Pharma Corporation, the parent company of MTPA. The FDA later accepted the filing of the New Drug Application on the basis of the trial data and did not require additional U.S. trials to be conducted prior to approval.

“The program was very interesting,” says Hubble. “One of the first controlled studies for RADICAVA in Japan did not seem to show a benefit when the drug was studied in a diverse patient population that included patients at various stages of the disease. Many were progressing quite slowly, while others were progressing at a much faster rate. Over the 24-week trial, researchers were unable to detect a firm signal in the data.”

Despite the disappointing results, researchers continued to analyze the data. They theorized that detecting a treatment effect in a relatively short time period might be possible in patients who have a more rapidly progressing form of the disease but who are still functioning fairly well on the ALS assessment scale at study entry. Those patients would allow researchers to see a separation in the slope of the lines showing the decline of ALS patients on medication versus those who are on placebo during the 24 week trial.

Evaluations Based On A Functional Scale

The assessment scale Hubble refers to is called the ALS Functional Rating Scale Revised (ALSFRS-R). It is a questionnaire consisting of 12 items that assesses the ability of a patient to talk, chew, and swallow, as well as use their hands for everyday activities. It also evaluates gross motor skills, such as the ability to walk, climb stairs, and turn over in bed. There are three additional items dealing with the patient’s ability to breathe.

Hubble notes the investigator or study coordinator asks the patient about their everyday functions and records the answers. Using walking as an example, the investigator would record a four if the patient experienced no problems, a three if the patient had slight difficulty, a two if a cane or walker was required, or a one if the patient needed to use a wheelchair.

“The tool has many subjective features,” says Hubble. “It has some inherent weaknesses, but it is recognized by both clinical researchers and health regulatory agencies such as the FDA. While there are new technologies being developed to help assess ALS patients, including sensors and cell phone technologies, they are simply not yet ready to be used in clinical trials. For now, this is the gold standard for evaluating ALS patients.”     

For a trial, it is important for the patients at study entry to have high scores on the ALSFRS-R scale so that measurable progression can be detected. Otherwise, it is very difficult to see a difference in those patients on placebo versus those receiving the active treatment.  

“To show a difference in two lines that are both declining over a relatively short period of time, the comparison group has to have a measurable decline,” states Hubble. “Many study patients had no or little measurable decline, and that was a flaw that existed in our original study. Our improved study design is what led to the approval of RADICAVA.”

Speeding Up Trials For Patients

As noted earlier, the timeline for this trial was a mere 24 weeks. Although the data may have demonstrated a clearer impact from the drug over a longer period of time, that short horizon was specifically chosen with the patients in mind. ALS is a deadly disease, and it has a severe physical impact on those afflicted. The goal was to expose as few patients as possible to the experimental drug and the placebo, and to do it for the shortest amount of time needed to demonstrate an effect. Additionally, RADICAVA is given to patients intravenously (IV). MTPA did not want to put a large number of patients through the process for an extended period of time since half of the patients would be receiving repeated placebo IV treatments.

“We had to be very aware of the ethics involved and what we would be exposing patients to,” states Hubble. “That was the main reason for limiting the trial to just 24 weeks. We opted to include 137 patients in the study, 68 in one group and 69 in the other.”

This news is certainly good for both patients and caregivers. The 33 percent decrease in functional loss is welcome news for patients who previously had no hope of relief from their physical degradation. In fact, the emotion in Hubble’s voice is hard to mask when discussing the results.

“When you see these patients, you understand what it means to them both in terms of hope as well as aspirations to maintain their ability to function for as long as they can,” adds Hubble. “For some of these patients, every moment counts. And we hope every new discovery will also bring us closer to a cure.”