Ocrevus: Prominent MS Clinic Issues Cautionary Statement

 

On March 28, 2017, the new MS drug Ocrevus was approved for both relapsing MS and progressive MS, becoming the first drug to achieve FDA approval for the progressive form of the disease.

One of the nation's leading multiple sclerosis clinics, the International Multiple Sclerosis Management Practice (IMSMP), today published a statement on their website regarding Ocrevus and its possible link to cancer and opportunistic infections (click here). Here is the clinic's statement in full:

Ocrelizumab (OCREVUS™), an anti-B cell therapy has been approved by the FDA as of March 28th 2017, for the treatment of Relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS). This treatment is highly effective for RRMS, based on the data from the Phase III clinical studies. It is also the first drug approved for use in PPMS. At IMSMP/TISCH we have used Rituximab, a similar anti-B cell treatment, for the past 16 years with great success. It is because of the effectiveness of this therapy (Rituximab) we were able to persuade Medicare to cover the costs of this therapy in New York.

Rituximab, however, is NOT approved by the FDA for use in MS. At our center we use it as an off-label drug. This unfortunately can require several weeks to obtain approval from insurance carriers and often approval may be denied.

Therefore, the approval by the FDA of Ocrelizumab, which should have almost identical anti-B cell activity to Rituximab, appears to be good news for MS patients. However, there are some serious concerns with Ocrelizumab that patients need to be made aware before they consider this therapy. First, in the RRMS trial, there were 9 patients who developed various malignancies within three years of taking Ocrelizumab (4 patients within the first 2 years and 5 patients in the following year). This is alarmingly high considering that these patients were mostly in their third decade of life and had no previous history of cancer. In the trial for PPMS patients, 13 patients developed cancer within the three years of taking Ocrelizumab (11 in the first two years and 2 additional cases in the following year). This means that more than 1 in 50 patients developed cancer within three years of taking Ocrelizumab among the PPMS patients. These risks of malignancy associated with Ocrelizumab are not seen with Rituximab (more than a thousand patients just at our center since 2001 and several hundred thousand worldwide). This risk of cancer with Ocrelizumab is not explained at present and the magnitude of the problem cannot be defined, as the medication has not been given for a period longer than 3 years.

There are also additional concerns with Ocrelizumab, such as the risk of life threatening infections which caused the trials in patients with Rheumatoid arthritis and SLE to be halted in 2010.

Although, it is indeed progress that the first medication for PPMS has been approved, the patients should be fully informed of its’ potential risks. For patients who can obtain Rituximab, it would be safer to continue with this therapy, until with time, we are better able to advise patients about the risks associated with Ocrelizumab.

The IMSMP is the clinic at which I receive my MS care, and I am personally acquainted with all of the medical professionals who work there. I know firsthand that the staff is wholly dedicated to the well-being of MS patients and that they wouldn't issue such a statement without diligent consideration.

Having said that, in the interest of fairness, I reached out to Genentech, the makers of Ocrevus, for a statement on the IMSMPs comments on their drug.  I received the following response from Genentech spokesperson Kimberly Muscara:

The FDA approved Ocrevus as an important new medicine for people with relapsing forms of MS and the first and only treatment for people with primary progressive MS. Genentech encourages healthcare providers to prescribe medicines as per their label and indication, and as a company we cannot comment on off-label usage. As you know, Rituxan is not an FDA approved medicine for multiple sclerosis and has not been rigorously investigated in Phase III clinical trials.  

Additionally, Rituxan and Ocrevus are different molecules in structure and how they interact with the immune system. 

In controlled clinical trials, there was an imbalance in malignancy. An increased risk may exist. The incidence of malignancy was within background rates, and to date continued follow-up in the open-label extension study has not shown increased risk of malignancy with longer time on Ocrevus. Patient safety is very important to us at Genentech and we are committed to conducting long-term post-approval safety studies on Ocrevus.

Muscara also noted that some patients have been on Ocrevus longer than three years, as enrollment in the phase III trial started in 2011 and a number of patients have remained on the drug in extension studies. It should also be noted that Ocrevus is the first anti-B cell therapy approved for use in MS, and that the research that led to the drug has profoundly shifted the thinking of many MS researchers.

In the days since Ocrevus received FDA approval, I've seen and read countless articles and reports in the mainstream media heralding the drug as the latest medical miracle. While Ocrevus may indeed prove to be a major step forward in the treatment of MS, there are legitimate reasons to exercise discretion when considering this new drug. I'd urge all patients to have well-informed conversations with their neurologists before embarking on any new MS treatment. Each MS patient has their own set of priorities and tolerance for risk. What is completely unacceptable for one patient may be well within another's comfort zone.

I wrote a thorough review of the complicated history of Ocrevus (click here), and also conducted a lengthy interview with one of the drug's researchers, Dr. Peter Chin (click here). I hope that patients can glean valuable information from both of these articles.

Remember, the patient-doctor relationship MUST be a partnership, not a dictatorship, especially when it involves a chronic progressive illness such as multiple sclerosis. Arriving at any treatment decision is a multifactorial process, and as patients suffering from a potentially devastating disease we owe it to ourselves to fully participate in all decisions related to our ultimate well-being. Knowledge is power, my friends, use it wisely.

Ocrevus Commentary: A New MS Drug With Breakthrough Potential And A Complicated History.

(What follows is my analysis of the potential promises and pitfalls associated with the new MS drug Ocrevus (Ocrelizumab). For those who have not already done so, I urge you to read – or at least scan – the interview I conducted with Dr. Peter Chin, one of the pioneering researchers who worked on this drug. Dr. Chin is the Group Medical Director of Neuroscience at the pharmaceutical company that makes ocrelizumab, Genentech – click here for the interview)


Ocrevus, a new MS drug which was approved by the FDA on March 28, 2017, has garnered breathless headlines in both the mainstream and medical press as a breakthrough medicine which has the potential to change the MS treatment landscape. Particularly heralded is the drug’s success in clinical studies in treating Primary Progressive Multiple Sclerosis (PPMS), a pernicious subtype of MS that currently has no approved therapies.

Assessing the overall potential of Ocrevus is more difficult than with most new drugs, as the therapy has a complicated history that must be considered when synthesizing informed views about it. Ocrevus, which will be marketed under the brand name Ocrevus, is a close sibling of the much older drug Rituxan (rituximab), whose mechanism of action Ocrevus closely mirrors. Rituximab, which is manufactured by the same company that makes Ocrevus, is already being used in many parts of the world as an effective MS therapy, even though it was never officially approved for this purpose. The reasons why Ocrevus rather than rituximab was advanced in studies as an MS therapy are somewhat controversial; complicating matters further are Ocrevus’s failure in trials for use in treating other autoimmune diseases (lupus and rheumatoid arthritis). Therefore, when attempting to make a sober assessment of Ocrevus, one must look not only at the drug itself, but also at how it currently came to be on the verge of FDA approval.

First, let’s look at Ocrevus itself, in terms of how the drug works and what recent clinical trials reveal about its effectiveness in the treatment of both relapsing and primary progressive multiple sclerosis.

Ocrevus is the first B cell therapy for MS proven to be effective in late stage clinical trials. In very simplistic terms, the human immune system is comprised chiefly of 2 types of cells, T cells and B cells, which each use different mechanisms to attack and kill invading bacteria or viruses. Until very recently, the vast majority of MS researchers, who see MS as an autoimmune disease in which the immune system turns against the body’s own cells, considered the multiple sclerosis disease process to be driven almost exclusively by T cells. MS drugs such as Tysabri and Gilenya were designed to specifically target these cells. B cells were given short shrift, and were largely dismissed as having no real relevance in the MS disease process.

The success of Ocrevus – a drug which destroys B cells – in treating MS has upended these prior assumptions and has forced researchers to rethink their multiple sclerosis disease models. In clinical trials, Ocrevus, an intravenous drug administered approximately every 6 months, proved to be remarkably effective in treating relapsing multiple sclerosis, and even had a modest effect on PPMS. Let’s look at the actual trial results.

Two separate trials were conducted testing Ocrevus against the interferon drug Rebif in patients with relapsing multiple sclerosis. These two trials were called OPERA 1 and OPERA 2 (click here). Both two-year trials involved one group of patients taking Ocrevus and another taking the interferon drug Rebif, and comparisons were made as to the overall effectiveness of Ocrevus versus the interferon drug. The results were very impressive. Compared to the Rebif treated patients, the Ocrevus trial subjects experienced a reduction in relapse rates of 46% and 47% in the two trials. Additionally, there was a 40% reduction in confirmed disability progression and a 95% reduction in new enhancing lesions. These results rival or surpass any of the other MS drugs currently on the market. There were no significant differences in the number of adverse events (bad side effects) between the Ocrevus and Rebif treated patient populations in the relapsing multiple sclerosis trials.

The Ocrevus PPMS trial was named ORATORIO (click here). This trial lasted 2 ½ years, and randomly assigned 732 patients in a 2 to 1 ratio to receive either Ocrevus or a placebo. In other words, twice as many trial subjects received Ocrevus than received placebo. The highlight of this study was that the Ocrevus treated patients experienced a 25% reduction in time to progression when compared to their placebo-controlled counterparts. Specifically, 29.6% of Ocrevus treated patients and 35.7% of placebo treated patients experienced a measure of disability progression over the course of the study. This is the first time in a placebo-controlled scientific trial that any multiple sclerosis drug has displayed effectiveness in slowing down the progression of disability in Primary Progressive patients. Ocrevus also displayed efficacy over placebo in a number of other outcome measures as well, including the timed 25 foot walk.

As I discussed with Dr. Chin during our interview, it’s important to understand that Ocrevus did not reverse or even stop the progression of disability in trial subjects. It slowed progression by about 25%. What does this mean for patients in a real-world setting? Well, speaking strictly in a broadly hypothetical basis, if an individual PPMS patient left untreated might need a cane four years after diagnosis, that same patient, if responsive to Ocrevus, might not need a cane for five years. Again, this is strictly a hypothetical case; PPMS effects patients in widely varying degrees of severity. Additionally, the ORATORIO trial only lasted 2 and half years. How the drug's effectiveness manifests over longer periods of time is not yet understood.

Unlike the relapsing multiple sclerosis Ocrevus trials, the PPMS trial did reveal some potentially troubling adverse events. Opportunistic infections (mostly respiratory infections and oral herpes) were more common in Ocrevus than placebo, and the rate of cancer in Ocrevus treated patients was approximately 3 times that found in placebo treated patients, 2.3% versus 0.8%. Though Genentech says that no direct causal relationship between the cancers in Ocrevus treated patients could be established, the fact that slightly more than 1 in 50 trial subjects on the drug developed cancer is sure to raise eyebrows, but since similar cancer rates were not seen in the relapsing multiple sclerosis trials these numbers are surely open to question.

There are also some concerns regarding the design ORATORIO study. Back in the mid-2000’s, Genentech conducted a PPMS trial using rituximab, which at first was deemed a failure. Later review of the trial data revealed, though, that a subset of PPMS patients did appear to gain benefit from rituximab therapy (click here). These patients were generally younger than 50 years old, were less disabled, and had enhancing lesions on their MRIs. It’s generally thought that patients fitting this description account for between 10%-15% of the overall PPMS population. The Ocrevus PPMS trial, though, included about 26% of patients fitting this profile, or approximately double that seen among real-life PPMSer’s. This means that the ORATORIO trial was heavily weighted with patients who were likely to respond to Ocrevus, since the drug acts in much the same way as rituximab. The Ocrevus PPMS trial was not designed to discern differences in the effectiveness of the drug between patients with enhancing lesions and those without, but Genentech says there was a “directional consistency” to the trial results, suggesting that the drug was effective in all patient subgroups to one degree or another. Still, the fact that the trial was frontloaded with likely responders is another eyebrow raiser, and may be something that the FDA looks at when making its approval decisions.

Okay, now that we’ve looked at the Ocrevus MS trials themselves, let’s dive into the history of the drug. Back in the early 2000’s, some MS researchers began investigating whether therapies that destroy B cells might be effective in treating MS. As mentioned earlier, at the time this with a rather radical idea. The drug that was chosen for study was Rituxan (whose generic name is rituximab – click here), a drug developed by Genentech years earlier that had been approved in 1997 for use in fighting non-Hodgkin’s lymphoma and certain types of leukemia. Rituximab, like Ocrevus, works by zeroing in on a protein found on most types of B cells, called CD20, and then killing the cells on which this protein is located. Though both drugs target and kill B cells, they do so in slightly different ways, and these differences may result in variances in safety and efficacy. Think of the drugs as two hitmen; one likes to slit his victims throats, the other prefers to strangle them. Both get the job done, but their differing killing techniques might effect witnesses differently. In the case of Ocrevus and rituximab, these differences may effect the actions of other immune cells, thus accounting for possible differences in the safety and efficacy of the drugs.

In the mid-2000’s, MS researchers put rituximab to the test by using it in “proof of concept” trials in patients with RRMS and PPMS. When the trial results were revealed in 2008, the drug proved itself to be extremely effective in treating relapsing remitting MS, but not effective in treating PPMS (click here and here). It’s important to note that the RRMS trials were small, early stage trials, but the PPMS trial was larger and later stage. As mentioned earlier, later parsing of the PPMS data did reveal a subgroup of patients on whom the drug appeared to have some positive effect.

Given the success of the rituximab RRMS trials, the fact that a subset of the PPMS trial population appeared to benefit from the drug, and rituximab’s long history as a successful oncology drug, it’s reasonable to assume that the drug would have been greenlighted for further development as an MS treatment. Instead, all development of rituximab as an MS treatment was halted, and the focus shifted instead to Ocrevus, a new experimental Genentech product that also targeted B cells via the CD20 protein. While there is some perfectly valid scientific rationale for this choice, many facts and circumstances point to financial motivations playing an oversized role in the decision to advance Ocrevus rather than rituximab as a potential treatment for MS.

The scientific rationale for choosing to proceed with Ocrevus is that the drug is comprised primarily of human proteins (the drug is a “humanized” monoclonal antibody), while rituximab contains a mix of mouse and human proteins (making it a “chimeric” monoclonal antibody, meaning that it contains proteins from more than one species). Theoretically, a humanized molecule should be better tolerated by patients than a chimeric drug, especially when used for treating chronic diseases which require continued administrations of the drug. That said, rituximab did have a very good safety profile in its role as an oncology drug, and very few adverse effects were seen in the early rituximab MS trials.

Genentech’s financial motivations for switching from rituximab to Ocrevus were many. First and foremost was the fact that rituximab was due to come off patent in 2015, meaning that other drugmakers would be free to come in and market their own versions of the drug at that time. As Ocrevus is a brand-new product, Genentech will have exclusive rights on it for decades to come. In addition, several corporate partnerships were also at play which made Ocrevus the preferred candidate for further development. Here’s an explanation of the situation, from an article that appeared on the biotech industry news site Genetic Engineering and Biotechnology News in 2010 (click here). Keep in mind that Roche is the parent company of Genentech:

“The operating profits for Rituxan are currently split 60–40 between Roche and Biogen Idec, respectively. But profits for Ocrevus would be split 70–30 in Genentech's favor, accounting for Genentech’s enthusiasm to move ahead with the development of Ocrevus in MS, at the expense of Rituxan, which loses patent protection in 2015.”

Of course, there is no direct proof that the switch from Rituxan to Ocrevus was driven primarily by financial considerations (except, perhaps, in files tucked away in the executive offices at Genentech), but I’ve learned through my years researching and writing about these topics that one can never be too jaded in assessing the motivations of the upper echelon decision-makers of Big Pharma. These are publicly traded companies whose officers are, by law, mandated to be beholden to their shareholders, not to the patients taking their products. Welcome to the realities of the medical industrial complex, in which diseases have been transformed into multibillion-dollar a year industries.

Whatever the circumstances, plans for further studies into the use of rituximab in treating MS were abandoned, and early trials using Ocrevus to treat MS were initiated. In addition to the MS trials, Ocrevus trials were also started on patients with rheumatoid arthritis (RA) and lupus erythematosus (LE). It’s interesting to note that rituximab was approved for use in treating rheumatoid arthritis in 2007, and has been used effectively and safely in that role since then (click here).

Genentech’s grand plans for Ocrevus were almost completely disrupted in 2010, when the trials in RA and lupus were halted due to patient deaths and the occurrence of opportunistic infections (click here ). In the parlance of medical research, the risk versus benefit analysis in these trials did not warrant further study. In the parlance of everyday people, dead patients suck. It should be noted that patients in the Ocrevus rheumatoid arthritis trial were also taking other immunosuppressive drugs, but then again so are most of the patients who have been using rituximab to treat their RA since its approval in 2007.

Ocrevus studies in MS were continued because these disastrous infections and patient deaths were not seen in early Ocrevus MS trials, and also because it’s generally assumed that MS patients and their doctors have a higher tolerance for risk due to the potentially catastrophic nature of the disease (click here). This assumption is borne out by the MS community’s acceptance of drugs like Tysabri, which has a proven link to the deadly brain infection PML. Hundreds of MS patients have contracted this infection due to their taking Tysabri. Other MS drugs, such as Gilenya and Tecfidera, have also been linked to opportunistic infections such as PML. MS certainly isn’t a disease for the faint of heart.

In the years since the rituximab MS studies were shelved by Genentech, MS neurologists have been using the drug on an “off label” basis due to the obvious potential of the drug displayed in those early trials. “Off label” refers to the fact that doctors are free to prescribe any FDA approved drug for any indication whatsoever, even if the drug has not been approved for that purpose (click here). Many MS neurologists here in the USA as well as in Europe have been using rituximab to treat MS patients safely and effectively for years. The use of rituximab in MS is especially prevalent in Sweden, and a recent study out of that country that took a retrospective look at MS patients treated with rituximab found that the drug was startlingly effective and had an excellent safety profile (click here). As noted earlier, rituximab has also proven safe and effective in treating rheumatoid arthritis. Remember, the RA trials for Ocrevus had to be halted due to opportunistic infections and patient deaths.

It should be noted that over its 20-year history rituximab has been linked to some cases of PML, but to a far lesser degree than drugs like Tysabri. In rheumatoid arthritis patients, it appears the rate of PML in Rituxan treated patients is on the order of 1 in 25,000 (click here). Rituximab has also been linked to other opportunistic infections, but again, at a lower rate than is seen in most other MS drugs. Let’s face it, any drug that profoundly changes the highly evolved human immune system is bound to open patients up to infections they wouldn’t otherwise contract. Ocrevus and rituximab both destroy B cells, one of the major components of the human immune system. No one knows what the long-term effects of living without any B cells might be. We do know, though, that the long-term effects of living with MS can be harrowing. Such is the state of the current MS treatment paradigm.

In conclusion, while the excitement generated by the impending approval of Ocrevus for relapsing multiple sclerosis and primary progressive multiple sclerosis is certainly warranted, expectations, especially for those with PPMS, should be kept realistic. Ocrevus will likely slow the rate of disability progression for some progressive MS patients, and even though this isn’t the revolutionary change patients battling PPMS are so fervently hoping for, it is a start. Relapsing multiple sclerosis patients can expect Ocrevus to be among the most effective disease modifying drugs on the market.

The fact that rituximab, a very similar drug with a proven record of efficacy and safety, is an available and very viable option should play into treatment decisions, as should the failed Ocrevus trials in RA and lupus, and the increased cancer rates seen in the Ocrevus PPMS trials (again, these rates could be aberrations). These factors need not make patients shy away from Ocrevus, but there is every reason to explore them with your neurologist. Don’t be afraid to ask your doctor why they might favor one drug over another. This holds true when deciding on any MS treatment. Remember, the doctor-patient relationship should never be a dictatorship, but a partnership. Here’s to hoping that Ocrevus proves itself worthy of the buzz it’s generated in advance of its anticipated FDA approval.

And here’s to more desperate hoping that MS researchers soon come up with methods other than profoundly kneecapping the human immune system in their search for ways to treat MS.

Ocrelizumab Commentary: A New MS Drug With Breakthrough Potential And A Complicated History.

(What follows is my analysis of the potential promises and pitfalls associated with the experimental MS drug ocrelizumab. For those who have not already done so, I urge you to read – or at least scan – the interview I conducted with Dr. Peter Chin, one of the pioneering researchers who worked on this drug. Dr. Chin is the Group Medical Director of Neuroscience at the pharmaceutical company that makes ocrelizumab, Genentech – click here for the interview)

Ocrelizumab, a new MS drug scheduled for review by the FDA on March 28, 2017, has garnered breathless headlines in both the mainstream and medical press as a breakthrough medicine which has the potential to change the MS treatment landscape. Particularly heralded is the drug’s success in clinical studies in treating Primary Progressive Multiple Sclerosis (PPMS), a pernicious subtype of MS that currently has no approved therapies.

Assessing the overall potential of ocrelizumab is more difficult than with most new drugs, as the therapy has a complicated history that must be considered when synthesizing informed views about it. Ocrelizumab, which will be marketed under the brand name Ocrevus, is a close sibling of the much older drug Rituxan (rituximab), whose mechanism of action ocrelizumab closely mirrors. Rituximab, which is manufactured by the same company that makes ocrelizumab, is already being used in many parts of the world as an effective MS therapy, even though it was never officially approved for this purpose. The reasons why ocrelizumab rather than rituximab was advanced in studies as an MS therapy are somewhat controversial; complicating matters further are ocrelizumab’s failure in trials for use in treating other autoimmune diseases (lupus and rheumatoid arthritis). Therefore, when attempting to make a sober assessment of ocrelizumab, one must look not only at the drug itself, but also at how it currently came to be on the verge of FDA approval.

First, let’s look at ocrelizumab itself, in terms of how the drug works and what recent clinical trials reveal about its effectiveness in the treatment of both relapsing and primary progressive multiple sclerosis.

Ocrelizumab is the first B cell therapy for MS proven to be effective in late stage clinical trials. In very simplistic terms, the human immune system is comprised chiefly of 2 types of cells, T cells and B cells, which each use different mechanisms to attack and kill invading bacteria or viruses. Until very recently, the vast majority of MS researchers, who see MS as an autoimmune disease in which the immune system turns against the body’s own cells, considered the multiple sclerosis disease process to be driven almost exclusively by T cells. MS drugs such as Tysabri and Gilenya were designed to specifically target these cells. B cells were given short shrift, and were largely dismissed as having no real relevance in the MS disease process.

The success of ocrelizumab – a drug which destroys B cells – in treating MS has upended these prior assumptions and has forced researchers to rethink their multiple sclerosis disease models. In clinical trials, ocrelizumab, an intravenous drug administered approximately every 6 months, proved to be remarkably effective in treating relapsing multiple sclerosis, and even had a modest effect on PPMS. Let’s look at the actual trial results.

Two separate trials were conducted testing ocrelizumab against the interferon drug Rebif in patients with relapsing multiple sclerosis. These two trials were called OPERA 1 and OPERA 2 (click here). Both two-year trials involved one group of patients taking ocrelizumab and another taking the interferon drug Rebif, and comparisons were made as to the overall effectiveness of ocrelizumab versus the interferon drug. The results were very impressive. Compared to the Rebif treated patients, the ocrelizumab trial subjects experienced a reduction in relapse rates of 46% and 47% in the two trials. Additionally, there was a 40% reduction in confirmed disability progression and a 95% reduction in new enhancing lesions. These results rival or surpass any of the other MS drugs currently on the market. There were no significant differences in the number of adverse events (bad side effects) between the ocrelizumab and Rebif treated patient populations in the relapsing multiple sclerosis trials.

The ocrelizumab PPMS trial was named ORATORIO (click here). This trial lasted 2 ½ years, and randomly assigned 732 patients in a 2 to 1 ratio to receive either ocrelizumab or a placebo. In other words, twice as many trial subjects received ocrelizumab than received placebo. The highlight of this study was that the ocrelizumab treated patients experienced a 25% reduction in time to progression when compared to their placebo-controlled counterparts. Specifically, 29.6% of ocrelizumab treated patients and 35.7% of placebo treated patients experienced a measure of disability progression over the course of the study. This is the first time in a placebo-controlled scientific trial that any multiple sclerosis drug has displayed effectiveness in slowing down the progression of disability in Primary Progressive patients. Ocrelizumab also displayed efficacy over placebo in a number of other outcome measures as well, including the timed 25 foot walk.

As I discussed with Dr. Chin during our interview, it’s important to understand that ocrelizumab did not reverse or even stop the progression of disability in trial subjects. It slowed progression by about 25%. What does this mean for patients in a real-world setting? Well, speaking strictly in a broadly hypothetical basis, if an individual PPMS patient left untreated might need a cane four years after diagnosis, that same patient, if responsive to ocrelizumab, might not need a cane for five years. Again, this is strictly a hypothetical case; PPMS effects patients in widely varying degrees of severity. Additionally, the ORATORIO trial only lasted 2 and half years. How the drug's effectiveness manifests over longer periods of time is not yet understood.

Unlike the relapsing multiple sclerosis ocrelizumab trials, the PPMS trial did reveal some potentially troubling adverse events. Opportunistic infections (mostly respiratory infections and oral herpes) were more common in ocrelizumab than placebo, and the rate of cancer in ocrelizumab treated patients was approximately 3 times that found in placebo treated patients, 2.3% versus 0.8%. Though Genentech says that no direct causal relationship between the cancers in ocrelizumab treated patients could be established, the fact that slightly more than 1 in 50 trial subjects on the drug developed cancer is sure to raise eyebrows, but since similar cancer rates were not seen in the relapsing multiple sclerosis trials these numbers are surely open to question.

There are also some concerns regarding the design ORATORIO study. Back in the mid-2000’s, Genentech conducted a PPMS trial using rituximab, which at first was deemed a failure. Later review of the trial data revealed, though, that a subset of PPMS patients did appear to gain benefit from rituximab therapy (click here). These patients were generally younger than 50 years old, were less disabled, and had enhancing lesions on their MRIs. It’s generally thought that patients fitting this description account for between 10%-15% of the overall PPMS population. The ocrelizumab PPMS trial, though, included about 26% of patients fitting this profile, or approximately double that seen among real-life PPMSer’s. This means that the ORATORIO trial was heavily weighted with patients who were likely to respond to ocrelizumab, since the drug acts in much the same way as rituximab. The ocrelizumab PPMS trial was not designed to discern differences in the effectiveness of the drug between patients with enhancing lesions and those without, but Genentech says there was a “directional consistency” to the trial results, suggesting that the drug was effective in all patient subgroups to one degree or another. Still, the fact that the trial was frontloaded with likely responders is another eyebrow raiser, and may be something that the FDA looks at when making its approval decisions.

Okay, now that we’ve looked at the ocrelizumab MS trials themselves, let’s dive into the history of the drug. Back in the early 2000’s, some MS researchers began investigating whether therapies that destroy B cells might be effective in treating MS. As mentioned earlier, at the time this with a rather radical idea. The drug that was chosen for study was Rituxan (whose generic name is rituximab – click here), a drug developed by Genentech years earlier that had been approved in 1997 for use in fighting non-Hodgkin’s lymphoma and certain types of leukemia. Rituximab, like ocrelizumab, works by zeroing in on a protein found on most types of B cells, called CD20, and then killing the cells on which this protein is located. Though both drugs target and kill B cells, they do so in slightly different ways, and these differences may result in variances in safety and efficacy. Think of the drugs as two hitmen; one likes to slit his victims throats, the other prefers to strangle them. Both get the job done, but their differing killing techniques might effect witnesses differently. In the case of ocrelizumab and rituximab, these differences may effect the actions of other immune cells, thus accounting for possible differences in the safety and efficacy of the drugs.

In the mid-2000’s, MS researchers put rituximab to the test by using it in “proof of concept” trials in patients with RRMS and PPMS. When the trial results were revealed in 2008, the drug proved itself to be extremely effective in treating relapsing remitting MS, but not effective in treating PPMS (click here and here). It’s important to note that the RRMS trials were small, early stage trials, but the PPMS trial was larger and later stage. As mentioned earlier, later parsing of the PPMS data did reveal a subgroup of patients on whom the drug appeared to have some positive effect.

Given the success of the rituximab RRMS trials, the fact that a subset of the PPMS trial population appeared to benefit from the drug, and rituximab’s long history as a successful oncology drug, it’s reasonable to assume that the drug would have been greenlighted for further development as an MS treatment. Instead, all development of rituximab as an MS treatment was halted, and the focus shifted instead to ocrelizumab, a new experimental Genentech product that also targeted B cells via the CD20 protein. While there is some perfectly valid scientific rationale for this choice, many facts and circumstances point to financial motivations playing an oversized role in the decision to advance ocrelizumab rather than rituximab as a potential treatment for MS.

The scientific rationale for choosing to proceed with ocrelizumab is that the drug is comprised primarily of human proteins (the drug is a “humanized” monoclonal antibody), while rituximab contains a mix of mouse and human proteins (making it a “chimeric” monoclonal antibody, meaning that it contains proteins from more than one species). Theoretically, a humanized molecule should be better tolerated by patients than a chimeric drug, especially when used for treating chronic diseases which require continued administrations of the drug. That said, rituximab did have a very good safety profile in its role as an oncology drug, and very few adverse effects were seen in the early rituximab MS trials.

Genentech’s financial motivations for switching from rituximab to ocrelizumab were many. First and foremost was the fact that rituximab was due to come off patent in 2015, meaning that other drugmakers would be free to come in and market their own versions of the drug at that time. As ocrelizumab is a brand-new product, Genentech will have exclusive rights on it for decades to come. In addition, several corporate partnerships were also at play which made ocrelizumab the preferred candidate for further development. Here’s an explanation of the situation, from an article that appeared on the biotech industry news site Genetic Engineering and Biotechnology News in 2010 (click here). Keep in mind that Roche is the parent company of Genentech:

“The operating profits for Rituxan are currently split 60–40 between Roche and Biogen Idec, respectively. But profits for Ocrelizumab would be split 70–30 in Genentech's favor, accounting for Genentech’s enthusiasm to move ahead with the development of Ocrelizumab in MS, at the expense of Rituxan, which loses patent protection in 2015.”

Of course, there is no direct proof that the switch from Rituxan to ocrelizumab was driven primarily by financial considerations (except, perhaps, in files tucked away in the executive offices at Genentech), but I’ve learned through my years researching and writing about these topics that one can never be too jaded in assessing the motivations of the upper echelon decision-makers of Big Pharma. These are publicly traded companies whose officers are, by law, mandated to be beholden to their shareholders, not to the patients taking their products. Welcome to the realities of the medical industrial complex, in which diseases have been transformed into multibillion-dollar a year industries.

Whatever the circumstances, plans for further studies into the use of rituximab in treating MS were abandoned, and early trials using ocrelizumab to treat MS were initiated. In addition to the MS trials, ocrelizumab trials were also started on patients with rheumatoid arthritis (RA) and lupus erythematosus (LE). It’s interesting to note that rituximab was approved for use in treating rheumatoid arthritis in 2007, and has been used effectively and safely in that role since then (click here).

Genentech’s grand plans for ocrelizumab were almost completely disrupted in 2010, when the trials in RA and lupus were halted due to patient deaths and the occurrence of opportunistic infections (click here ). In the parlance of medical research, the risk versus benefit analysis in these trials did not warrant further study. In the parlance of everyday people, dead patients suck. It should be noted that patients in the ocrelizumab rheumatoid arthritis trial were also taking other immunosuppressive drugs, but then again so are most of the patients who have been using rituximab to treat their RA since its approval in 2007.

Ocrelizumab studies in MS were continued because these disastrous infections and patient deaths were not seen in early ocrelizumab MS trials, and also because it’s generally assumed that MS patients and their doctors have a higher tolerance for risk due to the potentially catastrophic nature of the disease (click here). This assumption is borne out by the MS community’s acceptance of drugs like Tysabri, which has a proven link to the deadly brain infection PML. Hundreds of MS patients have contracted this infection due to their taking Tysabri. Other MS drugs, such as Gilenya and Tecfidera, have also been linked to opportunistic infections such as PML. MS certainly isn’t a disease for the faint of heart.

In the years since the rituximab MS studies were shelved by Genentech, MS neurologists have been using the drug on an “off label” basis due to the obvious potential of the drug displayed in those early trials. “Off label” refers to the fact that doctors are free to prescribe any FDA approved drug for any indication whatsoever, even if the drug has not been approved for that purpose (click here). Many MS neurologists here in the USA as well as in Europe have been using rituximab to treat MS patients safely and effectively for years. The use of rituximab in MS is especially prevalent in Sweden, and a recent study out of that country that took a retrospective look at MS patients treated with rituximab found that the drug was startlingly effective and had an excellent safety profile (click here). As noted earlier, rituximab has also proven safe and effective in treating rheumatoid arthritis. Remember, the RA trials for ocrelizumab had to be halted due to opportunistic infections and patient deaths.

It should be noted that over its 20-year history rituximab has been linked to some cases of PML, but to a far lesser degree than drugs like Tysabri. In rheumatoid arthritis patients, it appears the rate of PML in Rituxan treated patients is on the order of 1 in 25,000 (click here). Rituximab has also been linked to other opportunistic infections, but again, at a lower rate than is seen in most other MS drugs. Let’s face it, any drug that profoundly changes the highly evolved human immune system is bound to open patients up to infections they wouldn’t otherwise contract. Ocrelizumab and rituximab both destroy B cells, one of the major components of the human immune system. No one knows what the long-term effects of living without any B cells might be. We do know, though, that the long-term effects of living with MS can be harrowing. Such is the state of the current MS treatment paradigm.

In conclusion, while the excitement generated by the impending approval of ocrelizumab for relapsing multiple sclerosis and primary progressive multiple sclerosis is certainly warranted, expectations, especially for those with PPMS, should be kept realistic. Ocrelizumab will likely slow the rate of disability progression for some progressive MS patients, and even though this isn’t the revolutionary change patients battling PPMS are so fervently hoping for, it is a start. Relapsing multiple sclerosis patients can expect ocrelizumab to be among the most effective disease modifying drugs on the market.

The fact that rituximab, a very similar drug with a proven record of efficacy and safety, is an available and very viable option should play into treatment decisions, as should the failed ocrelizumab trials in RA and lupus, and the increased cancer rates seen in the ocrelizumab PPMS trials (again, these rates could be aberrations). These factors need not make patients shy away from ocrelizumab, but there is every reason to explore them with your neurologist. Don’t be afraid to ask your doctor why they might favor one drug over another. This holds true when deciding on any MS treatment. Remember, the doctor-patient relationship should never be a dictatorship, but a partnership. Here’s to hoping that ocrelizumab proves itself worthy of the buzz it’s generated in advance of its anticipated FDA approval.

And here’s to more desperate hoping that MS researchers soon come up with methods other than profoundly kneecapping the human immune system in their search for ways to treat MS.

Outrageous! Doctors Earn Luxury Goods by Answering Pharma Funded Surveys

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Recent Research on HSCT, the Stem Cell Therapy That May Soon Change the MS Treatment Landscape.

(Please note: the following article is quite long. Though it covers a very important topic and I’ve tried to make it as accessible as possible, I’d suggest getting comfy and grabbing a nice beverage before diving in…)

Over the last six months or so, there has been a wave of new and encouraging research published regarding HSCT (Hematopoietic Stem Cell Therapy) for the treatment of multiple sclerosis. HSCT is the type of stem cell therapy in which a patient’s existing immune system is completely eradicated through the use of powerful chemotherapy drugs and is then rebooted via an infusion of their own stem cells. Some of the results reported have been nothing short of astounding, and even previously skeptical neurologists are now being forced to consider HSCT as a potential game changer that may significantly impact the MS treatment landscape sometime in the not-too-distant future.

So that this article doesn’t take on the length of a Russian novel, rather than getting into the detailed specifics of what HSCT is and isn't I’d like to concentrate on the recent HSCT published research and its implications. For a comprehensive overview of HSCT, please read my previous post on the subject by (clicking here). For a rundown on the different types of stem cell therapies currently being trialed in MS, please (click here).

Just a few things before delving into the research. It’s vitally important that patients not confuse HSCT with regenerative stem cell therapy, which attempts to directly repair the central nervous system damage done by MS. HSCT is a completely different approach with a completely different goal. Regenerative stem cell therapy, such as that being trialed at the Tisch Center in New York (click here) generally does not involve any direct manipulation of patients’ immune systems. HSCT, on the other hand, is entirely directed at providing patients with a new immune system after completely wiping out their presumably defective existing set of immune cells. The two treatment approaches couldn’t be any more different; their only similarity is that they both use stem cells in an attempt to combat multiple sclerosis, albeit in very different ways.

There are currently two forms of HSCT being trialed on MS patients, termed the myeloblative and non-myeloblative treatment protocols. The myeloblative protocol uses a combination of very strong chemotherapy drugs to completely ablate (a fancy word for “destroy”) patients’ immune systems as well as their bone marrow (immune system cells are manufactured in the bone marrow). Non-myeloblative HSCT uses a gentler chemotherapy regimen that takes down the immune system but leaves bone marrow intact. There is some debate among researchers as to which treatment protocol is best suited for combating MS, an issue that is still being sorted out.

There’s also the question of which patients are most likely to respond to HSCT. Because HSCT is directed entirely at replacing a patient’s presumably defective immune system with a new one that doesn’t attack the body’s own nervous system cells, the prevailing thinking is that only patients displaying the hallmarks of immune system driven multiple sclerosis would likely respond well to the treatment. With this in mind, most HSCT research and treatment centers restrict the treatment to patients with active inflammatory MS, meaning that eligible patients must have recently experienced multiple MS relapses and/or displayed enhancing lesions on their MRI images (enhancing lesions are indicators of immune activity within the central nervous system). Since this excludes many secondary progressive (SPMS) and most primary progressive (PPMS) patients, who experience increasing disability in the complete absence of relapses or enhancing lesions, these requirements are understandably the source of much consternation among this patient population (myself included), who are currently presented with no effective treatment options. More on this later.

With these issues in mind, let’s take a look at some of the recently published HSCT research and explore the issues they raise…

A study out of Chicago that used the gentler, non-myeloblative form of HSCT on 151 MS patients (123 RRMS, 28 SPMS) resulted in some startling results on the RRMS patients taking part in the trial (click here). Not only did the vast majority of these patients see their disease stop in its tracks, but a large proportion also saw their levels of disability improve. Four years after treatment, 80% of trial subjects remained relapse free, and 87% showed no signs of disease progression. Furthermore, and perhaps even more astounding, there was a decrease in the disability scores in 50% of patients two years after treatment, and in 64% of patients four years after undergoing the treatment protocol without any further follow-up treatment (click here). Given that a reduction in disability scores is almost unheard of when treating MS patients, these are eye-popping results, to say the least, tempered only by the fact that the SPMS patients included in the trial were reported to have shown no benefit.

This trial was headed up by Dr. Richard Burt of Northwestern University, a leading HSCT researcher. I tried to reach out to Dr. Burt via email with several questions before writing this piece, but unfortunately received no reply. A very informative interview with Dr. Burt is available by (clicking here). If anybody out there knows Dr. Burt, please tell him I’m still patiently waiting for his email reply, fully understanding that he’s a very busy man. In the meantime, if Dr. Burt should find himself in New York City and happens to get run over by a speeding wheelchair, I’ll swear on a stack of research papers that I had nothing to do with it.

A smaller, 25 patient study, called HALT-MS, which used a harsher myeloblative chemotherapy regimen on patients with highly active relapsing disease who had failed to see benefit from at least two previous MS drugs reported impressive interim results (click here). Though study subjects are scheduled to be tracked for five years, the results reported were a snapshot of these patients at the three year mark after treatment. After three years, 78.4% of trial subjects were reported to be free of any disability progression, relapses, or new lesions. Digging deeper into the results revealed that 90.9% of subjects were progression free and 86.3% were relapse free after 36 months. Very impressive.

I managed to get hold of the full published paper of this study, which indicated that although the numbers had not yet been fully crunched, it did appear that the effect of the treatment lessened with time, as fewer patients were reported to be free of signs of the disease at the four and five year marks (68.6% and 58.8% respectively). Again, though, these four and five year numbers were very preliminary, as not all patients had reached this duration after treatment.

A friend of mine, Dave Bexfield, who runs the terrific MS website/forum Active MSers (click here) was one of the participants in the HALT-MS trial. Five years ago Dave was getting absolutely slammed by his disease despite having been on a series of MS drugs. He qualified for the HALT-MS trial and received myeloblative HSCT. His tremendously aggressive RRMS was put entirely into remission for several years, but unfortunately, after five years, Dave recently reported that his disease has shown signs of reawakening (click here) and he is now planning on going on one of the newer, more powerful MS drugs. Dave told me that even though his disease has returned, he has no regrets about undergoing HSCT back in 2010. Without the treatment he is sure the disease would have by now left him completely disabled, and HSCT bought him time at a point when it looked like multiple sclerosis would get the better of him. There are highly effective treatment options available today that weren’t available five years ago, and despite the reemergence of some of his MS symptoms, Dave is very grateful to have taken part in the study.

An Italian team did a head-to-head test of the effectiveness of HSCT versus mitoxantrone (also known as Novantrone) on SPMS patients who had enhancing lesions on their MRIs (click here), the presence of which indicated that they still had an active inflammatory component to their disease.

Currently, mitoxantrone is the only approved drug for use on patients suffering from SPMS. It’s a fairly wicked drug, so toxic to the heart that patients can only stay on it for a limited amount of time. Additionally, mitoxantrone has been linked to a dangerous increase in specific forms of leukemia and lymphoma. As a result of this daunting side effect profile, the use of mitoxantrone has largely fallen out of favor with most MS neurologists.

This phase 2 study used an intensive myeloblative form of HSCT on a small group of study subjects (21, 17 of whom completed the study), and the primary endpoint of the study was a reduction in the number of enhancing lesions detected by MRI. Four years after treatment, HSCT resulted in a 79% reduction in new lesions as compared to those treated with mitoxantrone Unfortunately, no difference in disease progression was reported, but the study was not ideally set up to detect changes in disease progression, a metric which has proven to be very difficult to track even in studies specifically designed to detect disability progression. An editorial accompanying the study, which adds commentary to the statistics provided in the study abstract, should be of interest to all readers (click here).

A very small study out of Hamburg, Germany attempted to directly address the difference in effectiveness of HSCT between RRMS patients with enhancing lesions and progressive MS patients not displaying lesion enhancement (click here). This very small 10 patient trial (four progressive MSers, six with RRMS) compared the results between the two groups two and half years after treatment. The researchers found that although five of the six RRMS patients did show benefit from treatment, none of the progressive patients followed suit. It should be noted that the RRMS patients were considerably less disabled at the start of the study than the progressive test subjects (EDSS 4.25 versus EDSS 6.25).

Previous studies have found that approximately 40% of patients with early PPMS display enhancing lesions on their MRIs (click here) and the presence of such lesions early in the disease may be an indicator of a more aggressive disease course. Patients undergoing the transition from RRMS to SPMS frequently continue to have enhancing lesions for some time after their disease has gone mostly progressive. Remember, enhancing lesions are a sign of active inflammation in the central nervous system, an indicator that the immune system is playing a primary role in driving the disease forward. Since HSCT directly attacks the peripheral immune system, it stands to reason that the treatment would be most effective on patients with active immune system involvement. In the later stages of SPMS, and in the majority of cases of PPMS, it appears that some other as yet undiscovered neurodegenerative process is at work, a process which seems impervious to treatments targeting the peripheral immune system. Studies testing some of the latest potent immunosuppressive drugs – which are highly effective in treating RRMS – on progressive patients have repeatedly failed, the latest such study involving the drug Gilenya (click here). For those of us with progressive MS such failures are very discouraging, and it is with great hope that I’ve looked for hard data supporting the notion that HSCT may benefit even hard-core progressive MSers, which leads us to the final study to be discussed…

Lastly, a study out of Moscow, Russia (click here) provided data suggesting that HSCT might be beneficial to progressive patients who don’t have enhancing lesions (as stated earlier, this includes many SPMS patients and the majority of PPMS patients). Unlike most HSCT treatment centers, the center in Moscow accepts patients with all types of MS (RRMS, SPMS, PRMS, and PPMS), regardless of whether or not they have enhancing lesions on their MRIs or have recently experienced relapses.. A total of 99 patients were included in the study, 43 with RRMS and 56 with various forms of progressive MS.

The summary of this study revealed that 49 months after undergoing treatment, 83.3% of RRMS patients and 75.5% of progressive patients exhibited no signs of relapses or disease progression. After eight years, 45% of treated patients exhibited an improvement in mobility scores, while 45% remained stable. These are compelling numbers, to say the least, particularly for someone like me who has never had enhancing lesions but has nevertheless experienced a constant progression of disability. So compelling, in fact, that I asked a physician friend of mine to provide me the full paper (I could have bought it myself for $40 but most doctors can get research papers for free, and, hey, that’s what friends are for) so that I could dig deeper into this apparently promising research.

Upon reading the full paper (sorry, I can’t link to it because of copyright laws) my enthusiasm was tempered a bit. Although the paper states that only 40% of study subjects had exhibited enhancing lesions before undergoing HSCT, it turns out that this statistic was based on a single MRI done soon before the patients underwent therapy. A single MRI can easily miss enhancing lesions, especially if patients had been on disease modifying drugs, which is why most HSCT centers require patients to have exhibited enhancing lesions and/or relapses (which are almost universally accompanied by enhancing lesions) at some point during the full year prior to treatment.

Additionally, the scope of the disease histories of the patients treated in Moscow varied widely and in many cases was severely deficient. The full paper clearly states this, saying that “patients enrolled in the study previously have been treated in different centers, and the information about disease activity prior in the disease course and its treatment was inhomogeneous and in some cases quite scarce.” I found this sentence to be disquieting, as without comprehensive disease and treatment histories it’s almost impossible to accurately assess the disease state of any individual patient suffering from an illness as complicated as multiple sclerosis. In fact, the abstract of the study, which is available to the general public, even warns that because of this dearth of patient info “comparison with the results in the literature should be done with caution.” This line throws up a big red flag, as the ability to compare and replicate results from study to study is among the foundational basics of the scientific method.

Furthermore, despite publishing statistics that appear to indicate the treatment as practiced in Moscow was effective across a wide spectrum of MS patients, the authors state that “the best candidates for transplantation seem to be relatively young patients with active inflammatory lesions of relatively short duration and rapidly progressive disease, but still low disability scores, unresponsive to conventional therapy.” This was among a number of apparently contradictory elements contained in this research that left me with more questions than answers. While these results certainly can’t be discounted entirely, without a comprehensive, detailed data set it’s impossible to properly discern their value and validity when compared to other studies, a point the authors themselves reiterate on several occasions.

Based on this accumulated HSCT research, certain trends seem clear. HSCT treatment definitely seems remarkably effective on patients with active inflammatory relapsing remitting multiple sclerosis, in the majority of cases resulting in complete remission of the disease for five or more years, sometimes accompanied by a reduction in disability as well. This is far more effective than any of the currently approved disease modifying drugs with the possible exception of Lemtrada, whose mechanism of action in many ways mirrors that of HSCT (for more information on Lemtrada, which was recently approved by the FDA and is covered by most insurance companies, please click here and here).

The safety profile of HSCT as now practiced seems quite robust. None of the above studies reported any HSCT related mortalities, although some serious adverse events above and beyond those that would be considered normal for patients undergoing chemotherapy were described (most in the form of opportunistic infections). Clearly, the decision to undergo HSCT should not be taken lightly, as at its heart the treatment involves using strong chemotherapy drugs to completely eradicate a patient’s existing immune system. Multiple sclerosis is serious business, though, and many patients would gladly accept this risk/reward scenario for a chance at complete remission lasting years or even decades.

Despite the fact that there are credible anecdotal reports on various HSCT websites from progressive MS patients who state that they’ve been helped by the treatment, and even though I’ve desperately wanted – for my own selfish reasons – to find research to back up such statements, I’ve yet to come across any hard data to back up these claims. Research has shown that the treatment can be effective on progressive patients showing signs of active inflammatory disease (enhancing lesions), but there is little hard objective evidence to support the notion that HSCT benefits patients experiencing progression in the absence of active inflammation.

Because the rate of disability progression varies widely from patient to patient suffering from progressive MS, and can sometimes temporarily “plateau” or even cease entirely, predicting disease progression can be quite difficult, even for patients themselves. Using myself as an example, my wife likes to chide me that I’ve been telling her that I’ll probably be bedridden in six months for the last five years. In order to properly assess the effectiveness of any treatment for progressive MS using disability scores as markers, studies would need to last much longer than the 2-3 years typical MS trials generally run, which is among the reasons why so few trials on progressive MS have been conducted. Even in the recent, much talked about successful study involving the use of biotin to treat progressive MS patients (click here), it was shown that after one year only 13% of patients taking placebo showed evidence of disease progression (compared to 4% taking biotin). I certainly hope that the patients with nonenhancing progressive MS reporting benefit do turn out to be success stories and that some form of HSCT does demonstrably prove effective on noninflammatory multiple sclerosis, but so far, at least, the data is lacking.

Also lacking is long-term data on the durability of HSCT derived benefits on patients of all stripes. One older study (click here) looked at patients with aggressive multiple sclerosis 15 years after treatment and found that 44% of patients who had exhibited enhancing lesions before treatment and 10% who didn’t remained progression free. It should be noted that the patients included in this study were treated with earlier, much harsher forms of chemotherapy, and one would hope that the refinements made in the technique more recently would increase durability.

Although all of the studies reported on in this article are considered early to mid-stage trials, they do suggest that HSCT is an extremely promising and potentially game changing treatment for multiple sclerosis. Further trials will be necessary before HSCT receives any kind of official approval for the treatment of multiple sclerosis. Although the treatment is being offered to patients in quite a few clinics around the world, the cost is quite high and most insurance companies will not cover the expense. Given the exorbitant cost of multiple sclerosis drugs, though, as more reliable data is released this situation should change. Paying $100,000 for a one-time treatment that keeps the disease at bay for even 5-7 years is far more cost-effective than paying the roughly $50,000-$60,000 per year currently charged for the FDA approved disease modifying drugs, a point that I’m sure will not be lost on the insurance company bean counters. It should be interesting to see how the pharmaceutical companies react to the HSCT threat to their bottom lines.

Those patients currently considering HSCT therapy should limit their choice of treatment centers to those which have extensive experience administering HSCT, as study after study has shown that safety and efficacy increases exponentially with the number of procedures done. This treatment is not to be taken lightly, and cutting corners for cost or convenience could prove quite the egregious mistake.

Given the current quickening pace of HSCT research, I would guess that the treatment could approach widespread acceptance sometime within the next five years, as long as the financial considerations of the pharmaceutical companies don’t get in the way (and that may prove to be a mighty big if). Based on the latest data, once approved HSCT should prove to be the most effective treatment available for patients with very aggressive active inflammatory multiple sclerosis, but will likely be reserved for those patients who have first failed current frontline therapies. As for patients with nonenhancing progressive disease, though objective hard data supporting the use of HSCT is lacking, given the anecdotal evidence I hope and expect expect future research will be done on such patients in an attempt to clarify the matter. The stakes are quite high for these patients, and even if the odds of success seem slight, the potential gains warrant further investigation. With neuroregenerative and neuroprotective compounds now in the research pipeline, and with HSCT offering so much promise, there is much reason for MSers to harbor hope for a brighter future.

Stay strong, my friends…

Geez, what was that I said about this article not becoming as long as a Russian novel? Maybe I should change my name to Tolstoy (many apologies to Tolstoy)…

Bits and Pieces: Writer's Block Edition (Also: Tecfidera, Crying Jags, the Price of MS Drugs, Underwater Wheelchairs, Asinine Research, and Some Funky Stuff)

Cover of Gojira [Blu-ray]

(For those who receive Wheelchair Kamikaze via email, this post contains videos that can be viewed on the Wheelchair Kamikaze website – click here. They're really good videos, so I encourage you to check them out.)

I usually start these Bits and Pieces posts with thoughts and/or observations that have been rattling around inside my brain pan for the last several days or weeks, but somehow as I sit down to write this I’m experiencing nary a rattle. Truth be told I've been struggling with some writers block these last few weeks, pretty much for the first time since I started writing this blog over five years ago. I suppose it might only be expected after all of these posts, but geez, writer’s block sucks.

I suppose I could jabber on about how disappointed I am in the Boston Red Sox the season, or how much I’m looking forward to the new season of fantastic zombie TV show The Walking Dead (which doesn’t start until October, ugh), or how bummed I am that I missed seeing the new Godzilla movie in 3-D at the IMAX theater which is one block away from my apartment. Can you believe it? I LOVE Godzilla, and I missed the chance to see the beast from the deep in three dimensions on a screen 30 feet tall! How could I be so stupid?

Now, I don’t expect the new Godzilla movie to be anywhere near as good as the original 1954 Godzilla, and by original I mean the Japanese version, not the Americanized one that intercut scenes of Raymond Burr playing an American reporter in Tokyo during Godzilla’s onslaught into the sublime Japanese film, which is actually very introspective (well, as introspective as a movie about a prehistoric beast eating Tokyo can be), filled with nuanced references to Japan’s national angst about World War II, the horrors of atomic warfare, and the potential dangers of science run amok.

Speaking of Raymond Burr, did you know that he once owned his own private island in Fiji? I knew he was a successful actor who starred in some very popular TV series (Perry Mason, Ironsides) and had a very clandestine private life, but go know he had enough money to buy a private island. I sure would like a private island, although these days I guess a private island wouldn’t be much use to me, given my heat sensitivity issues and the fact that I don’t think sand and my wheelchair would get along very well. God, I hate having MS.

Okay, I guess that’s enough writing about nothing, so I might as well get to my latest collection of MS news items and other bits of info that have caught my attention and/or fancy over the past month or so. Hope you find them interesting, informative, entertaining, and worthwhile…

♦ The oral MS drug Tecfidera has been on the market here in the US for a little bit over a year, and a new study provides encouraging news about Tecfidera’s efficacy, while another furnishes some disconcerting data regarding the drug’s side effects. A paper released just this week demonstrates that Tecfidera is remarkably effective on newly diagnosed RRMS patients who have not previously been on other MS drugs (click here). Patients in the study took the drug either two or three times a day, and researchers found that Tecfidera reduced relapse rates by 56% and 60% in these groups, reduced the risk of relapse by 54% and 57%, reduced the number of new or enlarging lesions by 80% and 81%, and reduced Gadolinium enhancing lesions by 92%, when compared to patients taking a placebo. These numbers place Tecfidera amongst the most effective MS drugs available. No word yet on the effectiveness of the drug on patients who have had the disease for a longer duration, or who have already been on other treatments, but one would imagine that similar rates of effectiveness should be expected.

On the downside, another study looking at Tecfidera’s side effects found that gastrointestinal problems and flushing were reported by large numbers of patients taking the drug (click here). Although more serious side effects (such as opportunistic infections) were not reported, researchers found that gastrointestinal problems were severe enough to force roughly 10%-25 % of Tecfidera patients to stop taking the drug, depending on the MS clinic providing the data. Over 50% of Tecfidera patients required some kind of over-the-counter medications to help combat the initial side effects of taking the drug, although the majority of patients noted that these side effects subsided within three months of starting the drug. Seems that similar percentages of patients (10%-25%) experienced few if any side effects, and physicians are trying to find ways to ameliorate the incidence of side effects in their Tecfidera patients.

So, definitely a mixed bag on the Tecfidera front. Highly effective on the one hand, problematic side effects on the other (although no deadly side effects so far, thank heavens). As with all things MS, it seems it’s never easy…

♦ On one of the Internet MS forums I occasionally visit, a member was worried that they might be “cracking up” because they found themselves laughing or crying – sometimes uncontrollably – at the drop of a hat, and often at inappropriate moments. A little light bulb went off in my head (yes, I have light bulbs in my head, and they’re all of the old-fashioned incandescent variety) and I remembered a little known and talked about MS symptom called the pseudobulbar affect (click here). PBA, as it is called, is a symptom seen across a wide variety of disorders of the central nervous system which makes those afflicted with it highly prone to laughing and/or crying fits, usually completely beyond their control.

As might be expected, pseudobulbar affect can be very disturbing to those MS patients who suffer from it, especially if they don’t know that their out of whack emotions might be a symptom of their disease. A recent study found that about 10% of people with MS suffer from PBA (click here), so it’s more common than might be expected. Here is a little online quiz to check if you might have PBA (click here), thoughtfully provided by the drug company that (surprise!) makes a pill to combat it. Yes, there’s a pill for that! It’s called Nuedexta (click here). Now, this is just a guess, but I bet the pill is obscenely expensive. Hey, I just did a little googling (honestly, I did) and found that Nuedexta costs a mere $600 a month. Yikes! Yes, the price of MS meds forces one to laugh to keep from crying, and that has nothing to do with pseudobulbar affect.

♦ Speaking of the high price of MS drugs, five multiple sclerosis medications landed on a list of the 73 drugs whose prices have increased the most since 2007 (click here). Since that time, the price of Copaxone as increased 157%, Rebif 154%, Avonex 147%, Betaseron 133%, and Tysabri 102%. Given the fact that the first four of these drugs (the CRAB drugs) are the oldest MS “disease modifying therapies” and have been on the market for at least 15 years, one would expect their price to have decreased with time rather than increase. Apparently, though, logic plays no role when it comes to pricing MS drugs (and most other drugs, for that matter), as drug companies try to squeeze as much profit as possible out of their older drugs before patents expire and generic alternatives become available. Can’t say this isn’t a winning strategy for the drug companies, since Copaxone generated $4,000,000,000 (!) in sales last year and was the highest grossing MS drug on the market. Is it any wonder that more progress towards finding a cure hasn’t been made when huge gobs of money are being pocketed by keeping MS patients dependent on drugs that only “modify” the disease and most medical research is funded by the companies pocketing those gobs of money? An old saying about geese and golden eggs springs to mind.

♦ Okay, enough about drugs and drug companies, let’s move on to other vistas. How about some underwater ones? In this video (part of the terrific TED Talks series), artist Sue Austin takes my Wheelchair Kamikaze concept to new heights, or, more correctly, depths. After an extended illness left her disabled, Ms. Austin found the world shrinking, a feeling many of those with MS know all too well. As she eloquently expresses in the below video, before getting her wheelchair and exploring all of the potential it presented, she had internalized the limitations and dependencies that society seems subconsciously to want to impose on the disabled. When she got her powerchair, though, her world and all the possibilities contained within it suddenly burst wide open. The chair allowed her to explore unexpected directions in her visual artwork, and ultimately led her to take this new mode of creative expression under the sea. Yes, Sue Austin scuba dives in her wheelchair, and with style. Incredible, beautiful, and inspirational…




♦ The folks at the Made Strong company (click here) offer T-shirts and other items bearing their “Made Strong” credo, and they donate 10% of their profits to worthy causes (for MS, these monies go to the Race to Erase MS). I’m typically turned off by feel-good slogans and platitudes, especially when they have to do with the disease that has taken a wrecking ball to my life. The phrase “I Have MS but MS Doesn’t Have Me” makes me want to poke my eyeballs out with red-hot knitting needles. But there’s something about “Made Strong” that strikes a chord. There’s very little good I care to say about multiple sclerosis, but I do have to admit that struggling with MS and all the BS that goes along with it has made me a mentally stronger person even as the disease has whacked away at my physical self. I’m no longer the neurotic, anxiety riddled person that I used to be back in my healthy days. Dealing with this illness has led me to me confront some of my darkest fears and even my own mortality, forcing to the surface a mettle I honestly didn’t know I possessed. So, yeah, Made Strong, an MS slogan I can live with.

The Made Strong people have generously offered a 10% discount to Wheelchair Kamikaze readers. Just use the promo code WCK10 when ordering. (Full disclosure: Made Strong sent me a free T-shirt to introduce me to their products. Does this make me guilty of accepting a bribe? Maybe, but I promise that I wouldn’t have given them a word on this blog if I didn’t appreciate the sentiment expressed on their goods. I guess everybody has their price, but I’d hate to think that mine is as cheap as a T-shirt. Note to other product manufacturers: sending me free stuff will NOT guarantee you a place on these pages, but, on the offhand chance you’re interested, I do like cameras, vintage NYC World's Fair memorabilia, and exotic chocolates. Also, I really enjoy giving my wife jewelry, so diamonds 1.5 carats or larger set in white gold or platinum might get you a Wheelchair Kamikaze shout out. Just saying.)

♦ Okay, time for another installment of… asinine research (the crowd roars)! I’ve come across yet another study having to do with MS patients falling down (click here). What is it about multiple sclerosis and falling down that so fascinates researchers around the world? Seems to me that the two go hand-in-hand, MS and falling down, sex and pregnancy, beans and cornbread. This has to be the third or fourth “falling down” study I’ve featured here on WK, and I’ve passed up a few along the way.

Okay, so, this study compiled the results of a bunch of different studies from Australia, Sweden, United Kingdom, and the United States. Wait a minute, that’s three English-speaking countries out of four, and I’m pretty sure a lot of Swedish people speak pretty good English, so this immediately casts doubts on the validity of these results. Dammit, this study is biased against non-English-speaking multiple sclerosis patients who fall down! What, falling down in other languages doesn’t count? Don’t we all say “ow” when we fall down, no matter what our native tongue? If you prick us, do we not bleed? Must we constantly erect artificial barriers that keep us from seeing ourselves as one big family of man, instead giving way to tribalism and divisiveness, even when researching as eternally perplexing a subject as whether or not people with a potentially crippling disease fall down? Oh, the humanity!

Despite its jingoistic tendencies, this falling study does break some new ground (pun intended) as it defines MS patients who fall down as either “fallers” (those who fell only once during a during a three-month span) or “frequent fallers” (those who fell twice or more during the three-month span). My question is, do frequent fallers get some kind of gifts or rewards, like frequent flyers? Do they have exclusive access to luxurious waiting areas in their neurologists’ offices, replete with thickly padded floors and walls, where their every whim will be catered to as they tumble and crash to the ground? I mean, what good is it to qualify as a “frequent faller” if you can’t rack up those frequent faller points? Does accumulating enough frequent faller points allow for some kind of upgrade, like maybe to a neurologist who actually gives a shit? Of course, this study does nothing to address these issues. Stupid researchers.

What this study does reveal is shocking, simply shocking! “Most falls occur indoors (65%) between 6 AM and 6 PM (75%).” Gee, that couldn’t be because most MSers with mobility issues tend to spend a lot of time indoors, and – I’m guessing here, probably need to research this more fully – most falls don’t happen while sleeping, could it? “Primary progressive MS was associated with significantly increased odds of being a faller.” Who would’ve thought, given the fact that the most common first presenting symptom of PPMS is gait disturbances, that this form of the disease would lend itself to going kerplop? “Fall risk peaked at EDSS levels of 4.0 and 6.0…” Hmmm, EDSS 4.0 is defined as “fully ambulatory… despite relatively severe disability” and EDSS 6.0 calls for “intermittent or constant assistance (cane, crutch, or brace) required to walk about 325 feet”, so this study finds that patients whose disease has progressed far enough to produce “relatively severe disability” but not far enough to put them in a wheelchair face the greatest danger of taking a dive. Is Captain Obvious one of the authors of this paper? For their next research project, I suggest the authors study whether or not hitting yourself hard on the head with a hammer can cause a concussion. Hopefully by testing the hypothesis on themselves.

Seriously, though, the issue of PwMS suffering numerous falls is no joking matter, as I’ve known several folks who have really hurt themselves after taking a tumble. Here’s a page (click here) with some common sense tips on things that can be done to help prevent falls whether or not you have MS. And for all my MS friends out there, I think my best advice is to just use your head, and not as landing gear. I know we can all be very obstinate and loath to “give in” to the disease, but a broken hip or gashed forehead is too high a price to pay for pride. If you need help, ask for it. If doing something that used to be easy has become nearly impossible, just don’t do it, at least not without assistance. Easier said than done, I know, but MS can do enough damage without your giving it a helping hand.

♦ In my last “Bits and Pieces” post I concluded with a video by the musical artist Paolo Nutini, one of the musicians who are part of the neo-soul/retro-soul movement, making music that hearkens back to the funky, soulful sounds of the 1960s and 70s. Lots of readers commented on how much they enjoyed the video, and since I’m absolutely addicted to the stuff, I figured I’d make examples of the genre a regular part of these little compilations. So, feast your ears on Mr. Charles Bradley, who pours his guts out on every track he records. Part of the Daptone Records stable of artists, Charles Bradley may be considered a new artist, but he’s no young pup. He recorded his first album at the age of 62 in 2011, backed by the relentlessly funky Manahan Street Band. Mr. Bradley has lived a life filled with hardship and heartache, and his musical emergence is so unlikely that it’s almost impossible to believe. It’s captured in a terrific documentary called “Charles Bradley: Soul of America” (click here), which can be viewed on Amazon Prime streaming video. Throughout a lifetime spent living a hardscrabble existence, at times practically homeless, Bradley picked up gigs as a James Brown impersonator, an influence unmistakable in his recorded output.

So, without further fanfare, here is the righteous, mighteous, and out of sighteous Charles Bradley…