OCRELIZUMAB: THE LONG ROAD TO APPROVAL

May 25 2017 Tahmeena Chowdhury, PhD

In “After 40-year odyssey, first drug for aggressive MS wins FDA Approval,” (Stat News, March 28, 2017), Ron Winslow describes the fascinating journey of Roche’s new multiple sclerosis (MS) drug to obtain US Food and Drug Administration (FDA) approval.  This drug, ocrelizumab, offers new hope to the 10% to 15% of MS patients who have primary-progressive disease (PPMS).  The approval of ocrelizumab not only provides a promising therapeutic option to patients with MS, but also represents a textbook example of the importance of innovative thinking and perseverance in scientific research; the latter being one of the main reasons I elected to write about this article.

Multiple sclerosis, affecting over 2 million people globally, is a neurological disorder in which an inflammatory response results in destruction of the insulating myelin sheaths that coat nerve fibers and aid in transmission of signals.  Clinical symptoms of disease include muscle weakness, fatigue, and ataxia.  More women than men are affected, with age of onset between 20 and 40 years.  The relapsing-remitting form of disease (RRMS), characterized by acute episodes interspersed with remissions, constitutes approximately 85% of all MS cases.  Primary-progressive disease is more aggressive, without periods of relapses or remissions.  Although several MS drugs are currently on the market, none is approved for treatment of PPMS.

Ocrelizumab (brand name OCREVUS™) is the first drug approved in the United States for treatment of PPMS; the drug is also approved for treatment of RRMS.  In contrast to currently available MS drugs targeting immune T-cells, ocrelizumab targets immune B-cells. This distinction posed one of the early challenges faced by Dr. Stephen Hauser (currently at University of California, San Francisco), whose lab pioneered the research leading to ocrelizumab.  Dr. Hauser’s laboratory established an animal model that developed MS upon concurrent exposure to antibodies from T-cells and B-cells, as opposed to antibodies from a single cell-type.  This result supported a role of B-cells in MS, in contrast to the established hypothesis, at that time, of T-cells being the only immune cells responsible for MS.

When Dr. Hauser applied for a National Institute of Health (NIH) grant to study rituximab (Genentech/ Idec), a drug approved for non-Hodgkin lymphoma that targeted B-cells, in patients with MS, the NIH agreed to approve the application only if T-cells were the therapeutic target.  Having been a bench scientist for several years, I found this part of the story particularly notable.  Striking a balance between being conservative and innovative in research can be very important for a myriad of reasons, including prioritizing limited funding.  For debilitating diseases such as MS, however, where patients are young enough to constitute a substantial part of the workforce, it is perhaps better to veer to the innovative side of the spectrum with the possibility of high rewards on multiple fronts.

Dr. Hauser did not accept the offer from the NIH, and conducted the study with funding from Genentech.  Results of the study, which demonstrated a dramatic effect of rituximab in decreasing formation of new brain lesions within 24 weeks, not only indicated the possibility of a highly efficacious new MS drug, but also introduced B-cells as a promising new target for development of future therapies.  Based on the rituximab results, Genentech/ Roche conducted two studies on ocrelizumab, a B-cell therapy with a better safety profile than rituximab.  Results of these studies indicated considerably improved efficacy of ocrelizumab relative to the comparator MS drug, Rebif ® (interferon beta-1a; EMD Serono), both in decreased relapse rates and in decreased formation of new lesions in the brain and spinal cord.

There are, however, factors that should be considered when assessing the market potential of ocrelizumab.  Although safety profiles of ocrelizumab and current MS drugs are comparable, data suggests a small increase in the risk of cancer associated with ocrelizumab use.  Given that another MS drug, TYSABRI® (natalizumab; Biogen), has also been linked to increased risk of a rare and lethal disorder, progressive multifocal leukoencephalopathy (PML), long-term safety of ocrelizumab is likely to be of concern to key stakeholders including insurance companies, physicians, and patients.

When marketed in April 2017, ocrelizumab will add to the several MS drugs already available.  Being the only approved drug for PPMS ocrelizumab is at an advantage in that niche.  How it will fare in the MS market relative to its competitors will be interesting to see.  On a broader note, efficacy of ocrelizumab in treating MS may open the door to additional B-cell targeted therapy and fuel further research into how T-cell and B-cell functions are coordinated in MS pathology.

Share This Article