Monday, October 19, 2015

Video: Promising FDA Approved Stem Cell Trial, Repeatedly Rejected for Funding by NMSS, Featured in TV News Segment

The only FDA approved Multiple Sclerosis stem cell trial currently underway in the US was featured last week in “The Big Idea”, a monthly segment seen on the local New York Fox Network affiliate’s evening newscast. The segment features the study’s lead researcher, Dr. Saud Sadiq (full disclosure: he’s my neuro), detailing the trial, and highlights a patient currently enrolled in the study who appears to be benefiting from the treatment.

The stem cell trial is being conducted by the Tisch Multiple Sclerosis Research Center of New York, and utilizes proprietary methodologies unlike those being used in any other stem cell study or treatment center in the world. As is detailed in the below video, raw mesenchymal stem cells are extracted from a patient’s own bone marrow and are then transformed in the laboratory into Neural Progenitor cells, stem cells specific to the central nervous system. The cells are then introduced directly into the patient’s central nervous system via intrathecal injection. Unlike HSCT, the type of stem cell therapy that seeks to stop or slow down MS disease progression by rebooting the immune system after ablating it using chemotherapy drugs, the Tisch Center’s trial is aimed directly at regenerating and restoring the damage done to brain and spinal cord tissues by the MS disease process.

Regular Wheelchair Kamikaze readers will recognize this as the very same trial that the National Multiple Sclerosis Society has repeatedly refused to fund for reasons that can only be deemed suspect, as I’ve detailed in several previous blog posts (click here and here). The Tisch Center’s trial is currently an early phase 1 study and is in urgent need of additional funding in order to expand into a larger and more comprehensive phase II trial.

As the Tisch Center is not affiliated with any academic institution or hospital and is a completely independent nonprofit organization, its research efforts are entirely reliant on private donations and institutional grants for continuation. Due to funding shortfalls, the trial is currently on precarious financial footing despite showing tremendous potential and promising early results. One would hope that the NMSS would see fit to reconsider its previous withholding of funds and do its part to help further the only FDA approved Multiple Sclerosis stem cell trial in the USA.

As is evidenced by this news segment, the Tisch Center stem cell trial has the potential to dramatically change the MS treatment landscape. I’d urge all who feel that the National Multiple Sclerosis Society should reverse course and support the Tisch Center to contact the Society and voice their opinions. The  email addresses of the Society’s executive staff can be accessed by (clicking here), and the phone number of the NMSS is 1-800-344-4867

Please keep all communications polite, as the NMSS may in this instance be misguided, but it is not an adversary. As my grandmother used to tell me, you can catch more flies with honey than you can with vinegar…

Thursday, October 15, 2015

Ocrelizumab Update – RRMS Trials Successful; PPMS Trial Shows Positive Effect, But Many Questions Left Unanswered

When I last posted to Wheelchair Kamikaze, I profiled the experimental MS drug Ocrelizumab, which was developed by Swiss drug giant Roche (and their US subsidiary Genentech). In press releases put out by the company two weeks ago (click here), Ocrelizumab was touted as the first MS drug shown capable of putting the brakes on Primary Progressive Multiple Sclerosis (PPMS) – a subtype of the disease which until now has been largely untreatable – as well as it being highly effective in treating the more common Relapsing Remitting Multiple Sclerosis (RRMS). These results were even more noteworthy because Ocrelizumab is the first MS drug to specifically target immune system B cells, while other currently available MS drugs (Tysabri, Gilenya) were developed to target T cells, which until now were believed by many to be the primary culprits driving the MS disease process.

Though the initial Ocrelizumab press releases were scant on details, the news certainly appeared promising, though reservations were expressed by many MS researchers based on Ocrelizumab’s development history and its close similarity with another Roche product, Rituxan, a much older drug that had gone through early trials in RRMS (very successful) and PPMS (largely a failure, but with some hints of success) back in 2005-2008. Rituxan’s development as an MS treatment was halted by Roche because of what many believe to be strictly financial concerns. Reading my previous essay (click here) will provide much background on Ocrelizumab’s development and the issues surrounding the drug.

Roche presented the details of the Ocrelizumab RRMS and PPMS trials this past weekend at the ECTRIMS conference in Barcelona, Spain. The RRMS trials were named OPERA I and OPERA II, and the PPMS trial was named ORATORIO. The results of the OPERA I and OPERA II RRMS studies were indeed impressive. These studies compared Ocrelizumab to Rebif, an interferon drug long used to treat RRMS, and found that treatment with Ocrelizumab resulted in a 50% reduction of annualized relapse rates, a 40% reduction in progression, and an 80% reduction in enhancing lesions as shown on MRI when compared to patients taking Rebif (click here – login required, but sign-up process is easy and well worth it). Adverse events were found to be similar in both groups, which is encouraging as Rebif is considered one of the safer MS medications currently available.

It should be noted, however, that the two-year length of these trials may be insufficient to detect longer-term problems that may develop as a result of the intense B cell suppression that is Ocrelizumab’s primary mechanism of action. Nevertheless, it does appear that Ocrelizumab will become a very valuable weapon in the growing arsenal of drugs used to combat RRMS, though, like all current MS drugs, it doesn’t do a thing towards actually curing the disease. But I’ll save that rant for another day…

(Please note, the following information and accompanying commentary were largely gleaned from materials contained in articles and interviews that can be accessed by clicking here, here, here, and here. I would urge all to read them for greater context and background)

Results of the ORATORIO PPMS study, while initially impressive, still remain riddled with questions. Despite the screaming headlines hailing Ocrelizumab as a “revolutionary new MS drug” by the – as usual – hyperbolic mainstream medical media (click here), the actual picture remains far more nuanced. The ORATORIO trial design was heavily influenced by the results of the failed Rituxan PPMS trial back in 2008. Though that trial was officially deemed unsuccessful, subsequent examination of the data revealed that a subset of PPMS patients in the study were seemingly helped by the drug. These patients were generally younger, had shorter disease duration, were less disabled, and had enhancing lesions on their MRIs. It’s thought that patients who fall within these parameters make up about 15% of the overall PPMS population.

It appears that in designing the ORATORIO study, Roche chose trial subjects who were most likely to benefit from Ocrelizumab treatment, specifically those who fit the demographic and disease parameters outlined above. As presented at ECTRIMS, the results of the ORATORIO study are indeed impressive, demonstrating a marked slowing of disease progression, a reduction in MS enhancing lesions, a reduction in brain volume loss, and a stable time to walk 25 feet when compared to trial subjects given a placebo. Of course, these results also mean that many of the ORATORIO trial subjects were patients with enhancing lesions (only a fraction of PPMSer’s have such lesions) and who were relatively less disabled (as evidenced by the fact that they could still walk). The majority of trial subjects also appear to have been relatively recently diagnosed, with a disease duration of approximately 3-5 years, and were under 50 years old.

Unfortunately, when Roche presented the ORATORIO results at ECTRIMS, they declined to detail the breakdown of results by patient subgroups, claiming that such subgroup analysis had not yet been satisfactorily completed. This beggars belief, as one would think that examining the data in such a way as to determine which patient groups benefited the most from treatment would be among the highest research priorities, especially given the mixed results of the previous Rituxan PPMS trials. Instead, Roche chose to give a broad overview of favorable trial results without answering some of the most important questions about those results, primary among them whether or not the patients who most benefited were those with enhancing lesions. Indeed, in the Q&A period following Roche’s presentation, presenters were questioned on just this issue by conference attendees, who were given no suitable answers other than promises that the data would be forthcoming. Roche's presentation led several experts to say the primary progressive data were less impressive than those seen with Ocrelizumab in relapsing remitting disease.

Although Roche portrayed the safety profile of Ocrelizumab in the ORATORIO trial to be excellent, they did note that there were 11 cancers detected during the ORATORIO trial on patients taking Ocrelizumab, versus only two in the placebo group.

The results of the Ocrelizumab RRMS and PPMS studies have not yet been published in any scientific journals, and it is expected that much additional data will need to be provided to publishers before the trial results will be deemed fit for publication. Getting the drug through the regulatory approval process required by government agencies such as the FDA will also necessitate a much greater detailing of trial results, including subgroup analysis which will shed light on just which patient groups were treatment responders. While it seems that the RRMS results will likely stand up to more intense scrutiny, the PPMS results may prove to be less dramatic than originally portrayed when subjected to the spotlight of journal publication and regulatory approval.

That said, even in a worst-case scenario in which only a small subgroup of PPMS patients, those with enhancing lesions,  prove to benefit from Ocrelizumab treatment, the fact that any headway at all has been made in treating PPMS is a significant step forward. If in fact the drug’s efficacy is limited to patients with enhancing lesions, and such lesions are most likely to be found in patients in the earliest stages of the disease, the importance of early diagnosis will be brought to the forefront. Given current diagnostic tools and techniques, many patients with PPMS aren’t correctly diagnosed until the disease has long since taken hold, beyond the period when enhancing lesions are likely to be present. Additionally, the fact that Ocrelizumab targets B cells should open up new avenues of investigation for MS researchers worldwide, as this potential mechanism of MS disease action has until now been largely discounted by most mainstream researchers. Perhaps these investigations might finally unravel some of the deepest mysteries of the disease, and (crossing the fingers I can still cross) eventually lead to a cure for all forms of the disease.

At this point, only time will provide us with the answers we seek. The next chapters of the Ocrelizumab saga will be getting these studies peer-reviewed and published in medical journals, a process which will shed much light on issues still in need of clarification. Roche is targeting the first quarter of 2016 for regulatory approval in both RRMS and PPMS. It will be very interesting to see whether or not Ocrelizumab is approved for the PPMS population as a whole, or, as many researchers suspect, for only a subgroup of progressive MS patients. Again, even if the latter case holds true, we will have at least made some headway in the fight against an insidious form of Multiple Sclerosis that until now has defied efforts to combat it.

At long last, it appears that the attentions of Multiple Sclerosis researchers are finally focusing on progressive MS, an area of investigation which until very recently had largely been neglected. The confounding problems represented by progressive MS will never be solved until well-funded trials are directed specifically at this disease subtype, a circumstance that finally seems to be coming to fruition. And that’s no small thing…

Sunday, October 4, 2015

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 10th 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…