Experimental MS Drug Ocrelizumab Deemed A Success In Progressive MS Trial, But Questions Remain

Last week, the drug company Genentech (a subsidiary of Swiss drugmaker Roche Pharmaceuticals) announced that its Phase III trials for treating Primary Progressive Multiple Sclerosis with the experimental MS drug Ocrelizumab had met with success. According to a press release titled “Roche’s Ocrelizumab First Investigational Medicine to Show Efficacy in People with Primary Progressive Multiple Sclerosis in Large Phase III Study”, the drug met the trial’s primary endpoint, “showing treatment with Ocrelizumab significantly reduced the progression of clinical disability sustained for at least 12 weeks compared with placebo, as measured by the Expanded Disability Status Scale” (click here). Earlier this summer two previous trials had shown Ocrelizumab to be more effective than the beta interferon drug Rebif for treating RRMS, resulting in reduced relapse rates, number of MS lesions, and a reduction in progression of disability (click here). Ocrelizumab is an intravenous drug that is administered twice over a two-week period, and then not again for six months.

While this would all appear to be great news, especially for people with PPMS who currently have no approved treatment options, just how great this news actually is remains to be seen as the press release provided absolutely no details on the study results, which will only be revealed on October 9 and 10^th at the annual European MS conference ECTRIMS, being held in Barcelona, Spain. Understandably, news of Ocrelizumab’s success in treating PPMS has created quite a buzz in the MS community as well as in the financial pages of publications around the world, as the drug stands a good chance of becoming the latest multibillion-dollar blockbuster MS treatment (click here).

There is reason to believe, however, that Ocrelizumab may only be effective in treating a subset of patients suffering from Primary Progressive MS, specifically those who are less disabled (still walking), younger, and who display enhancing lesions on their MRIs. And though the press release states that the side effects experienced by study subjects taking Ocrelizumab were not much different than those who were given a placebo, back in 2010 trials testing Ocrelizumab for the treatment of Lupus and Rheumatoid Arthritis had to be abandoned because of an unacceptable number of serious and sometimes fatal opportunistic infections seen in trial subjects (click here).

How can I make any assumptions on Ocrelizumab’s efficacy at all based on the scant details divulged in Roche’s press release, you may ask? Well, it turns out that Ocrelizumab’s mechanism of action is nearly identical to that of a much older drug also manufactured by Roche, called Rituxan (Rituximab), which has been used for decades to treat cancers of the blood and for the last seven or eight years, on an off label basis, to successfully treat Relapsing Remitting Multiple Sclerosis.

In fact, back in 2008 Rituxan completed early stage trials (phase I and phase II) investigating its use in treating both RRMS and PPMS. In these earlier trials, Rituxan was deemed successful in treating RRMS (click here), but the drug failed in its much-anticipated trial for PPMS (click here). Subsequent to the PPMS trial’s completion, however, researchers combing through the data discovered that Rituxan did appear to have a beneficial effect on a subset PPMS patients, specifically those who were less disabled, were 50 years old or younger, and who had enhancing lesions, (click here). Ocrelizumab’s mechanism of action is so nearly identical to Rituxan’s that within the industry the drug has been nicknamed “brother of Rituxan”.

Why then was Rituxan not further investigated for the treatment of RRMS and PPMS, Roche and Genentech instead shifting their all of their attentions to costly process of developing a brand new drug that works in a very similar fashion, Ocrelizumab? Well, this is where things get interesting and more than a little bit curious. If I were a cynical man I might conclude that purely financial considerations were involved, but far be it for me to be so cynical. Instead, I’ll present you with the evidence as I know it, from which you may draw whatever conclusions you wish.

As I mentioned earlier, Rituxan is an older drug, and it is scheduled to lose its patent protection this year. Once the Rituxan comes off patent, Roche will lose its exclusive rights to the drug and thus the ability to generate tremendous profits from marketing it (click here). This fact made the return on investment of proceeding with very costly late stage MS trials in 2008 decidedly negative even if they proved wildly successful, because after 2015 another company could step in and market a generic version of Rituxan, thereby killing the drug’s profit making potential for Roche.

Both Rituxan and Ocrelizumab are in a class of drug called monoclonal antibodies, which are manufactured antibody cells that work by targeting specific cells in the human body. Rituxan and Ocrelizumab work by attacking B cells, one of the two primary types of cells that comprise the human immune system (these two types of cells are called T cells and B cells). They both seek out the same protein expressed on the cell walls of B cells, CD 20, and both drugs ultimately destroy almost all of the B cells in the human body using nearly identical mechanisms.

This anti-B cell approach is not taken by any other current MS drug, as until very recently it was believed that the MS disease process was driven primarily by T cells, which are the focus of drugs such as Tysabri and Gilenya (the latter of which recently failed in a recent PPMS trial). The fact that Rituxan and Ocrelizumab – which exclusively target B cells – are proving to be so effective in battling MS is forcing researchers to completely rethink much of what has been assumed in the understanding of the disease. Roche’s recent Ocrelizumab press release also contains hints that the drug’s action on B cells may have some neuroprotective properties, which if true would be truly remarkable. Of course, since Rituxan has already been used successfully to treat RRMS for quite a few years, the knowledge that a B cell immunosuppressant was capable of dramatically impacting the Multiple Sclerosis disease state was readily available, but also easy to ignore given the somewhat rogue nature of treating MS with Rituxan.

The difference between Ocrelizumab and Rituxan is the fashion in which they are manufactured. All monoclonal antibodies are “biologic” drugs, meaning they are derived from living animal cells, usually from a combination of mouse and human tissues. Most older monoclonal antibody drugs, such as Rituxan, are what is known as “chimeric monoclonal antibodies” (click here), meaning they contain both mouse and human DNA. Newer drugs such as Ocrelizumab are “humanized monoclonal antibodies” (click here), and have their DNA structure manipulated to more fully resemble completely human cells.

Although one might assume that humanized monoclonal antibodies would always be preferable to those that contain non-human DNA, Rituxan has been used for decades and has shown itself to be a very safe and effective drug. Although some cases of opportunistic infections, including PML, have been associated with Rituxan, they’ve appeared far less frequently than those seen with Tysabri (click here). Rituxan has proven itself successful in treating RRMS both in trials and in real life practice (the drug is FDA approved for the treatment of Rheumatoid Arthritis, and is used off label to treat a variety of other autoimmune diseases).

The Rituxan PPMS trials, though at first deemed a failure, did reveal a subset of PPMS patients on whom there was evidence of efficacy, and it appears that the Ocrelizumab PPMS trial was designed to capture as many of this type of patient as possible (click here). Had Roche pushed ahead with its Rituxan MS trials even in the face of a looming patent expiration we might have had another very effective treatment for RRMS, and perhaps even PPMS, for at least the last five years. Alas, ‘twas not to be, quite likely because Rituxan was scheduled to soon lose its patent protection.

I truly hope that when the full details of the Ocrelizumab trials are revealed at the upcoming European MS conference they exceed all expectations and make Rituxan look like a rusty old Model T compared to Ocrelizumab’s shiny brand new Maserati. If the new drug is in fact capable of stabilizing the disease progression of the majority of PPMS patients we will have a true game changer on our hands. Even if, as I suspect, the drug is shown to be effective on just a subset of PPMS patients – those who are younger, less disabled, and have enhancing lesions – it will represent a tremendous leap forward in the treatment of what has up until now been an untreatable disease. The fact that the drug exclusively targets B cells and benefits both the relapsing remitting and progressive forms of Multiple Sclerosis should send researchers scrambling to develop an entirely new model of the MS disease process, and, who knows, may lead to an eventual understanding of the ever elusive underlying cause of Multiple Sclerosis.

Here’s to hoping that the new drug proves to be as safe and reliable as the old one, Rituxan, and Ocrelizumab will become not only a powerful new weapon in the fight against MS, but also a catalyst for an entirely new way of thinking about the disease. For people with PPMS, this successful drug trial, even if limited, finally opens a door to treatment options and allows rays of hope to filter in through the clouds. We’ll begin to get our answers in just about a week, and I for one can’t wait for the data to be released.

Geez, that last line may be just about the wonkiest sentence I’ve ever written. I guess I just have to own up to the fact that I’m now a full-fledged MS research nerd…