FDA Advisory Committee Recommends Against Modification of Clinical Progression Status for Azilect (Rasagiline)
Today, the Peripheral and Central Nervous System Drugs Advisory Committee of the Food and Drug Administration (FDA) recommended that Teva Neuroscience's drug rasagiline, brand name Azilect, should not be granted status "to slow the clinical progression of Parkinson's disease (PD)." Rasagiline is already FDA-approved as a therapy for PD, often taken alone or in conjunction with levodopa to treat the symptoms of the disease. Today's decision is only a committee recommendation and is not binding; the FDA will officially rule on the Teva request in the coming months.
The Michael J. Fox Foundation (MJFF) spoke with Ken Marek, MD, president, co-founder, and senior scientist at the Institute for Neurodegenerative Disorders in New Haven, Connecticut, and principal investigator of the Parkinson's Progression Markers Initiative (PPMI), to gauge what today's recommendation could mean for Parkinson's patients considering the drug. Dr. Marek also explains the imperative of PD researchers to find disease-modifying therapies, the major unmet need of Parkinson's patients today, and how PPMI could be instrumental in one day measuring the efficacy of such drugs.
MJFF: What is rasagiline, and how has it been used to treat PD up until now?
KM: Rasagiline, brand name Azilect, is a type of drug called a monoamine oxidase inhibitor (MAO-inhibitor) that works in people with Parkinson's by inhibiting an enzyme that breaks down dopamine. To date, it has been used to treat PD symptoms in both early- and late-stage Parkinson's patients, both alone and in combination with levodopa.
MJFF: Teva is seeking "to slow the clinical progression of Parkinson's disease" status for the drug. What does this mean?
KM: It's important to distinguish between a symptomatic drug, one that is disease-modifying, and one that slows the clinical progression of the disease, which is what Teva was seeking here.
--The drugs we have today are called symptomatic because they treat some of the symptoms of the disease albeit for a limited time, while the underlying disease continues to worsen.
--A disease-modifying drug would change the progression of the underlying cause or pathology of the disease. There is no such drug currently available for Parkinson's. A disease-modifying drug is the most significant unmet need for people living with Parkinson's today.
--Teva is seeking to define rasagiline as a drug that slows clinical progression. They are making the case that individuals who took their drug had a slower change in their symptoms as measured by a clinical scale rating compared to people who were not treated with the drug. But it can be very difficult to objectively define and measure clinical progression. The gold standard clinical evaluation for PD is called the Unified Parkinson's Disease Rating Scale (UPDRS). Clinicians use UPDRS to evaluate patients over time through clinical observation and interviews. The idea of showing a reduction in the rate of change in UPDRS is a reasonable approach for identifying the progression of motor symptoms in people with PD. However, UPDRS is not an exact science. The way a patient feels on a given day could be affected by the medication they are taking, or by something as simple as how they've been sleeping, their mood on a given day or whether they've eaten. Moreover, when a drug itself improves the symptoms of the disease, it is very difficult to distinguish any effect on clinical progression from is symptomatic benefit.
-- This distinction between disease-modifying and slowing clinical progression is potentially problematic and confusing.
Dr. Russell Katz, director of the FDA's Division of Neurology Products, told Scrip that, from the point of view of the FDA, "there's little to no difference between a claim for clinical progression and a claim for disease modification." Once the word "progression" is included in the labeling of the drug, he explained, it is strongly implied that the drug does in fact affect the progression of the underlying disease itself.
This conflation of terms is of concern because such a label recognizing modification of clinical progression could suggest that, in fact, it is slowing the disease process itself, even if the data doesn't support this finding. This, of course, could have implications on patient /physician decisions surrounding use of the drug. Katz' explanation suggests that, for this reason, the FDA would exercise caution in granting this type of status.
MJFF: Are there other drugs in development that could modify disease progression?
KM: Rasagiline is one of many therapies that are being actively evaluated and investigated for its potential to modify the progression of the disease. There are many strategies under study, including projects being funded by MJFF. They include a clinical trial with biotech Ceregene to investigate the neurorestorative properties of the trophic factor neurturin. Recently, the Foundation just announced that it is partnering with Austria-based company AFFiRiS on the first-ever clinical trial of a PD vaccine candidate targeting alpha-synuclein, a gene that plays a major role in Parkinson's disease. Other treatments that are being evaluated for disease modifying potential in PD include isradipine, a drug for high blood pressure now in clinical studies of PD, and inosine, a naturally occurring chemical that gives rise to urate in the body, which could be neuroprotective in cases of PD.
MJFF: Are these close to market?
KM: There is a strong sense of urgency in the PD research community around the development of disease-modifying treatments. But one of the major roadblocks is that we don't have a good way to monitor the effect of treatments over time and understand whether they are working. The need for objective tools or biomarkers to measure PD progression has led to a major study called the Parkinson's Progression Marker Initiative (PPMI). As PD doctors, we need tools for PD like the cholesterol or blood pressure tests that have helped to understand whether a medication is working in people with heart disease.
Biomarkers can address the underlying disease mechanisms and then help to confirm that a drug is in fact working as hoped. While any treatment must have a clear clinical benefit to be effective, biomarkers of PD could eliminate some of the subjectivity of clinical rating scales, and in turn, provide the additional clarity needed to demonstrate that a drug is disease modifying.
MJFF is sponsoring PPMI in the United States and Europe to find biomarkers for PD. If PPMI is successful in identifying these biomarkers, it could help lay the groundwork to effectively assess drugs under development as potentially disease modifying.
MJFF: If the FDA ultimately agrees with today's recommendation that Azilect does not modify the clinical progression of the disease, what would you say to patients, moving forward?
KM: The FDA will have made the decision that there isn't enough evidence in this study to indicate that rasagiline modifies clinical progression. Still, I think the drug has benefit as a symptomatic therapy.
Moreover, this decision is further evidence for how challenging it is to be able to show that a drug has effect on clinical progression and ultimately, that it is disease-modifying. It also shows how critical it is to focus research, like PPMI is doing, into tools like biomarkers that could help us clearly determine if certain drug candidates might in fact slow the progression of PD.
NOTE: The medical information contained in this article is for general information purposes only. The Michael J. Fox Foundation has a policy of refraining from advocating, endorsing or promoting any drug therapy, course of treatment, or specific company or institution. It is crucial that care and treatment decisions related to Parkinson's disease and any other medical condition be made in consultation with a physician or other qualified medical professional.