Tuesday, January 31, 2017

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.

Tuesday, January 17, 2017

Ocrelizumab Exclusive: Interview with Pioneering Researcher Dr. Peter Chin

Dr. Peter Chin
Late last month I was contacted via email by a representative for the pharmaceutical company Genentech, asking if I would like to interview one of the researchers who played an instrumental role in the development of the new MS disease modifying drug ocrelizumab. At first I assumed I must’ve received the email as the result of some sort of clerical error, what with my being a mere blogger and all, but I figured if they’re offering, I’m accepting.

Thus, I present the below interview with Dr. Peter Chin, the Group Medical Director of Neuroscience at Genentech. Dr. Chin has been involved with the development of ocrelizumab for well over a decade, and was a pioneer in the study of the role of immune system B cells in multiple sclerosis. This line of thinking has upended much of what had previously been thought about the disease, as the working theory up until very recently was that immune system T cells were the primary culprits that should be targeted when developing drugs aimed at alleviating multiple sclerosis. Ocrelizumab is a very close cousin of rituximab, also known by its brand-name Rituxan, another Genentech product which many neuros have been using off label to treat their MS patients.

Ocrelizumab, an intravenous medication requiring infusions approximately every 6 months, has garnered a tremendous amount of attention of late, as it is the first drug ever to show efficacy in treating progressive MS in a late stage clinical trial and is in the process of being considered for approval for the treatment of PPMS (as well as relapsing multiple sclerosis) by the FDA. The drug has generated blaring headlines and hyperbolic chatter in the medical and mainstream press, and talking directly to Dr. Chin presented a valuable chance to cut through the clutter and get the pertinent info straight from the horse’s mouth. Not to insinuate that Dr. Chin is a horse; au contraire, he proved to be an extremely erudite gentleman during our extensive talk. He was also quite generous with his time, as our scheduled 30 minute interview lasted for nearly an hour.

The following interview is filled with a tremendous amount of important information. It’s been lightly edited for readability. I’ll publish it here without commentary and follow-up next week with my take on the potential promises and pitfalls of ocrelizumab, an intriguing new MS medication.

As you read through the interview, you’ll notice a brand-new feature on these pages called “WK notes”. These are explanations in everyday language of some of the more esoteric medical terminology that cropped up during the interview. And, if anybody’s wondering, “WK” stands for Wheelchair Kamikaze, not Wicked Kool.



WK: Dr. Chin, let me thank you for taking the time to do this interview. To start, could you explain the importance of the relatively recent research into the role of B cells in the Multiple Sclerosis disease process? I understand that when this research first started, it was not in the mainstream of general Multiple Sclerosis research.

Dr. Peter Chin: Genentech started collaborating with leading academic researchers at major universities to look into the possibility that B cells might be important in MS about 15 years ago. To some degree this was not the mainstream line of thinking, but there were researchers who had a scientific hypothesis and believed that B cells might be important because they are the cells that differentiate into cells that secrete antibodies, and antibodies are implicated in the disease pathogenesis (WK note: pathogenesis refers to the conditions that lead to the development of a disease). They are found in lesions and in the cerebral spinal fluid as oligoclonal bands (WK note: more commonly referred to as O-bands, these are one of the primary diagnostic indicators that neurologists look for when examining the spinal fluid of potential MS patients). So there was some rationale, and I think it was an exciting time when the first proof of concept studies unblinded, showing that B cells may play a more important role than anybody thought.

WK: Just to be clear, before this time it was assumed that this was a T cell mediated disease, is that right?

Dr. Chin: That’s correct. The vast majority of efforts in developing new medications up until that point were directed towards T cells.

WK: Genentech was the first to study the use of B cell therapies in MS with the drug Rituxan, whose generic name is rituximab, which was the precursor to ocrelizumab, correct?

Dr. Chin: Yes, that’s right. Genentech developed rituximab a long time ago for oncology, and we learned a lot about the medication from there. Rituximab provided a proof of concept that B cells might be important in MS, but we advanced another molecule that we believe has the best potential for long-term treatment from both the safety and efficacy standpoints for people living with MS, and that’s ocrelizumab. Ocrelizumab is a humanized molecule which is different from rituximab because rituximab is what we call a chimeric antibody, which has a portion of its protein sequence that is derived from mice. (WK note: a chimera is a mythical beast made up of the parts of different animals, such as a winged lion. Chimeric drugs are those that include the DNA of both humans and animals.) Ocrelizumab is a humanized molecule, meaning most of its protein sequence is human. That becomes important, particularly in a chronic disease, because ocrelizumab is hypothetically less likely to generate an immune response against the drug itself than a drug that includes more non-human DNA.

WK: Can you tell us a bit about the proof of concept studies that used rituximab to treat RRMS?

Dr. Chin: Yes, it’s important to recognize that these were small proof of concept studies, with a single dose of rituximab against placebo. It did show a reduction in MRI enhancing lesions, which was the primary endpoint, and also showed about a 50% reduction in relapses against placebo, in a six-month period. So it did provide some preliminary information that targeting CD20 positive B cells might be effective (WK note: CD20 is a protein that appears on the surface of a variety of different types of B cells). Around the same time, ocrelizumab was being studied in rheumatoid arthritis in a dose ranging study. One thing we looked at was multiple doses of ocrelizumab and their effects on B cells as well as efficacy and safety. We also looked at immunogenicity (WK note: immunogenicity is the ability of a substance to provoke a response in the immune system) and found that this was a molecule that had potential for chronic autoimmune conditions, and decided to advance ocrelizumab for Phase II development in RRMS, which led to the Phase III development program which was just published in the New England Journal of Medicine.

WK: PPMS trials were also done with rituximab about 10 years ago, too. Since I am suspected of having PPMS, I was tremendously interested in that particular trial. Can you talk a little bit about that trial?

Dr. Chin: The rituximab PPMS trial is a trial that I was involved in, actually, and it was a Phase II/III study of 439 patients comparing rituximab versus placebo. It was a single study, and it was a negative study. Meaning that the primary endpoint, which was the time to 12 week confirmed disability progression, was not significantly different than placebo.

WK: My understanding is that even though the trial as a whole was negative, when the data was looked at retrospectively there was a subset of patients – primarily those who were younger, less disabled, and had enhancing lesions – that did appear to gain benefit from the drug. Is that correct?

Dr. Chin: That’s right, although this finding was hypothesis generating rather than confirmatory, meaning it was not proven in the study.

WK: Okay, let’s talk about the ocrelizumab MS trials, which are creating chatter all around the MS community. Starting with the RRMS studies, some of the results reported were pretty astounding. Could you describe those results?

Dr. Chin: The phase III RMS studies were called OPERA 1 and OPERA 2 (WK note: RMS refers to both RRMS and Relapsing SPMS). These were two, two-year trials – double-blind, double dummy studies – comparing ocrelizumab head-to-head to the interferon beta 1a drug Rebif. Here the relapse reductions were 46% and 47% compared to interferon. There was also a 40% reduction in confirmed disability progression, and approximately 95% reduction in gadolinium enhancing lesions compared to interferon. These are very promising results from an efficacy standpoint, and have the potential to really change the way that MS is treated.

WK: Yes, those are extremely impressive results. Were there any instances of PML, the potentially fatal brain infection that has been seen in patients taking some of the other MS disease modifying drugs, in any of the patients in the Ocrelizumab trials?

Dr. Chin: No cases of PML have been observed in any of the ocrelizumab development trials.

WK: Okay, let’s move onto the PPMS trial, which is really generating tons of buzz. Could you please summarize the studies and their findings?

Dr. Chin: The ORATORIO study is the Phase III double blinded study, lasting more than 2 and half years, comparing ocrelizumab to a true placebo. The primary result of this study indicated a 24% reduction in the risk of 12 week disability progression. Importantly, there was also a 25% reduction in the risk of 24 week disability progression, which is generally considered a more robust outcome measure for disability progression.

That 25% reduction is the reduction in risk over the entire timeframe for all the patients that were included in the trial, and that’s at least 120 weeks, but there were patients who entered the study early in the treatment period that were on the drug for a longer period of time. So the 25% reduction in the risk of disability progression is the figure for the entire cohort for the entire length of the trial.

WK: Okay, so the data from the trial tells us that this new drug for people with primary progressive MS is not reversing disability or stopping the progression of disability, but it is slowing the accrual of disability. Is that a fair assessment?

Dr. Chin: Yes, the primary result of the study is the 24% reduction in 12 week confirmed disability progression. So that is not a measure of improvement, and you’re correct, it shows a delay in the progression of disability as measured by EDSS (WK note: EDSS is a scale that measures the level of disability in MS patients).

WK: Realistically, then, PPMS patients on ocrelizumab can expect that they probably will keep progressing, but it would be at a slower rate than if they were left untreated?

Dr. Chin: That’s a hard question to answer for any individual, but the overall results for the population of the study show a slowing of disability production as measured by EDSS, there is a slowing of the worsening of the timed 25 foot walk, which is another major end point in progressive MS trials. This is literally a measure of how long it takes to walk 25 foot feet. There is a slowing in the rate of brain volume loss, and, at least over the course of the trial, there appears to be a stabilization of the accumulation of T2 lesion accumulation. On this end point the placebo treated patients continue to accumulate T2 lesion volume and patients on ocrelizumab experienced a small decrease that was stable over the course of the two and half years or more.

WK: You previously noted that ocrelizumab was tested in trials for the treatment of rheumatoid arthritis. Weren’t those trials halted because of opportunistic infections and patient deaths?

Dr. Chin: There were opportunistic and serious infections observed in the Phase III program in rheumatoid arthritis. What’s important here is that rheumatoid arthritis is a different treatment paradigm. These are patients that are also on concurrent immunosuppressants in addition to ocrelizumab. (WK note: many of the rheumatoid arthritis patients in the ocrelizumab trial were taking other immune suppressing drugs in addition to ocrelizumab.)

WK: And ocrelizumab was also being trialed for treating lupus, and those trials also had to be halted for similar reasons, correct?

Dr. Chin: There were 2 studies in lupus. Ocrelizumab was studied in systemic lupus erythematosus (SLE), and that was discontinued primarily because the expectation for efficacy was low based on another study involving B cell targeting. The other study was on lupus nephritis, and there were serious infections that were observed, but the decision to halt was based on an assessment of potential benefits versus risks.

The same is true for the Rheumatoid Arthritis program. The potential for benefit/risk improvements over existing therapies, based on the data that were already on hand, was deemed not to be promising. So the studies were discontinued.

WK: Were any of these same problems – opportunistic infections and patient deaths – seen in either the RRMS or PPMS ocrelizumab trials?

Dr. Chin: The ocrelizumab Phase III safety results for MS overall were very favorable. This is the data that was just published in the New England Journal of Medicine. The proportion of patients in the relapsing study with any adverse event were similar to those who were on beta interferon, and the proportion of patients with any serious adverse event, including serious infections, were also similar to interferons. The same is true with the primary progressive MS trial, which was a slightly longer trial. When compared to placebo the proportion of any adverse event, any serious adverse event, or any serious infection was comparable to placebo.

WK: In looking over the ORATORIO PPMS trial results, it appears that there were higher rates of cancer among the ocrelizumab treated population when compared to the placebo population. I believe the numbers were 2.3% of the ocrelizumab population developed cancers, while .8% of the placebo group developed cancers. Is that of any real concern?

Dr. Chin: There is a numerical imbalance in the number of cases observed, but the overall numbers are small. This is not a confirmed risk, but I will say that patient safety is important to us and we do continue to monitor this in ongoing clinical trials. We don’t believe that the totality of the data supports a causal relationship, but we will continue to monitor this in our ongoing Phase III open label extension studies. So far, in the additional data we’ve accumulated, there is no increase in the rate of cancers being seen.

WK: The earlier rituximab trials demonstrated that there was a subset of the PPMS population on which the drug appeared to be effective – primarily younger patients who were less disabled and had enhancing lesions. In the ocrelizumab PPMS study this group made up about 26% of the test subject population, whereas in the general PPMS population the number of patients displaying those characteristics is thought to be somewhere between 10%-15%. So it would appear that the ocrelizumab study was populated with a higher percentage of patients who might be high responders than are present in the real-life PPMS population. Can you comment on this possible disparity?

Dr. Chin: The first thing I would say is that the study results are designed to assess the efficacy in the entire study population. So this was not a study only of patients of a certain younger age or only of patients who had enhancing lesions or did not have enhancing lesions. I say that because when you look at subgroup results, it’s important to recognize that these studies are not designed to address the efficacy in the subgroups. Also, I would note, that in data that we presented earlier this year that there is a directional consistency, meaning that there is still a reduction in disease worsening in patients who both had enhancing lesions and did not have enhancing lesions at baseline. This was presented at the ACTRIMS meeting in February 2016.

WK: Are there differences between the mechanisms rituximab and ocrelizumab use to eradicate CD20 B cells?

Dr. Chin: There are differences in how they bind to CD20 molecules on the B cells. And there are differences in what we call effector function, and that’s the portion of the antibody that interacts with other elements of the immune system to remove the cells. So, yes, there are differences in the functions of the two molecules.

WK: The mechanism of ocrelizumab in PPMS patients that do have enhancing lesions – which indicate active inflammation within the central nervous system – would presumably be much the same as you would see in the RRMS model, in that the drug clearly reduces inflammation by targeting B cells. Can you propose a mechanism of action for ocrelizumab that would be beneficial for the vast majority patients with PPMS who don’t have signs of enhancing lesions or any other signs of active inflammation in their central nervous systems?

Dr. Chin: That’s a very challenging question, and a good question. I think what you’ve hit on is an area that the entire research community in MS is thinking about. It’s not a question that anyone can answer definitively at this point, because the mechanism of progressive MS and the evolution of progressive MS over time isn’t completely understood. I think there’s a recognition in the research community that the biology has become very complex and how intervening in one way will impact the disease is hard to predict. Genentech is a member of the Industry Forum of the International Progressive MS Alliance, a coalition of organizations that has formed to address the kinds of questions that you’re asking, so we contribute what we can to the understanding of progressive MS. But that’s a really big question that you’re asking.

I think our understanding of B cells currently, which I will acknowledge is ongoing and evolving, is that B cells do interact with T cells, and by removing B cells from circulation we may be breaking that interaction. We also know that B cells differentiate into plasma cells and plasmablasts which create antibodies, which might also be involved. (WK note: plasma cells and plasmablasts are among the more mature types of B cells circulating in the human body.) B cells also create a number of cytokines that also impact and potentially stimulate other parts of the immune system. (WK note: cytokines are chemicals secreted by cells that trigger actions in other cells.) There may be multiple ways that selectively targeting b-cells might be leading to efficacy.

WK: Just a couple of weeks ago we learned that the December 28, 2016 date for and FDA decision on the approval of ocrelizumab had been delayed until March 28, 2017. Can you shed some light on the reasons behind that postponement?

Dr. Chin: We did have an announcement about this extension of the date, and yes it’s March 28, 2017, which is the expected action date by the FDA. The FDA needs more time to review additional data that was submitted during the review, regarding the commercial manufacturing process. What I want to stress is that this is not related to the review of safety or efficacy data. It’s about the manufacturing process and the data regarding that process. This extension of the action date by the FDA is a commonly used procedural tool and they use it to allow more time to evaluate additional information. It’s not uncommon for questions that come up during the review, and as a result of those questions additional data get submitted. It’s just the nature of the process.

WK: As a final question, as a scientist who has devoted a large part of your career to studying MS and progressive MS, what do the trial results from the PPMS ocrelizumab studies indicate to you about the disease, and what can we look forward to in the future for what had previously been an untreatable and rather terrible malady?

Dr. Chin: I think the first thing I’d say is that the data that we just published in the New England Journal are really landmark data for a number of reasons. One, they highlight and confirm that B cells are important in MS, which is still a relatively new concept. That’s a major area of science that Genentech has contributed to that the entire community is continuing to work on. From a clinical trial results standpoint, this is the first molecule that has shown efficacy in both relapsing MS and primary progressive MS. It’s the first molecule under consideration for approval by the FDA for both RRMS and PPMS. It’s an exciting time and an exciting potential new medicine to be working on.

Particularly in regards to primary progressive MS, I want to make the note that Genentech is the only company that has actually done two Phase III studies on primary progressive MS. It’s something that we’ve been very committed to because of the unmet medical needs and the fact that there are no approved therapies. My great hope is that people will start to see that maybe we can do something about primary progressive MS, and build upon this first step with ocrelizumab, which is a very meaningful one.

WK: On behalf of all Wheelchair Kamikaze readers, I’d like to offer a tremendous thank you for doing this interview. On a more personal level, I’d like to thank you for devoting your career to unraveling the mystery of this dreadful disease. It’s tremendously important for a lot of people who suffer from all forms of MS, but especially those who have been without any proven treatment options for so long, who are stuck living with the misery that is progressive MS.

Dr. Chin: Thank you for that, Marc. I think it’s important for you to know that there are hundreds of people at Genentech and Roche who have worked on these primary progressive trials and the RMS trials for many years. I think I can speak for all of them that they do it with a passion for making a difference, understanding the degree of unmet need that’s out there.


I hope readers have found real value in the above interview. I’d love to hear your thoughts in the comments section.

As I stated earlier, I’ll follow this up next week with an essay on my thoughts about all things ocrelizumab, touching on many of the points that I discussed with Dr. Chin. A big thanks goes out to Genentech and Dr. Peter Chin for allowing me the chance to conduct this rather expansive interview.

Until next time…

.

Thursday, January 5, 2017

New Year's Eve Through MS Eyes (repost)

(This essay was first posted about one year ago. Guess this makes it a golden not so oldie, but it's timely and the sentiments expressed will hold true as long as MS remains my unwanted life partner…)

Back in in the days before I got jumped by MS I always loved New Year’s Eve. While many of my fellow habitual night crawlers derided the night’s festivities as “amateur’s hour”, a time when those less accustomed to nocturnal hijinks were apt to get sloppy and make fools of themselves, I embraced the ringing in of the new year con mucho gusto. Never content with just one party for the duration of the night, my friends and I would go on a kind of New Year’s Eve tour, hitting four or five shindigs and nightclubs before heading home well after dawn on January 1. The sentimentality of the holiday, with its tacit promises of sins forgiven and futures bright with hope held me in its thrall, for though I seemed to live in a state of perpetual neurotic dissatisfaction, I also brimmed with expectations that bigger and brighter days were waiting just over the horizon. New Year’s Eve was the one night a year that this heady brew of emotions and expectations were codified into celebration, to be shared with friends and strangers alike.

I suppose my fondness for the holiday has its roots in my early childhood. My mom and dad divorced when I was three, and for several years after the split my mom and I lived with my grandmother and my unmarried aunt. On New Year’s Eve my young, single mom – who herself loved the nightlife – would head out with her friends into the NYC of the swinging 60s, and my grandmother, aunt, and I would watch Guy Lombardo and his Royal Canadians playing old timey big band hits for the well-heeled crowd at the Waldorf Astoria Hotel, broadcast live to our ragged black and white console TV. We didn’t have much money and lived in a building in the Bronx that was closer to a tenement than a high-rise, but our lack of means did nothing to diminish the excitement and expectations of the evening.

Though I was maybe only four or five years old, on New Year’s Eve I was allowed to stay up till midnight to take part in a family tradition that stretched back decades. We didn’t have any fancy noisemakers or horns, but at the stroke of midnight, as confetti and balloons floated down on the well to do at the Waldorf and Guy Lombardo’s boys played “Auld Lang Syne”, my grandmother, aunt, and I grabbed sturdy but well-worn metal pots and pans, and, using big spoons as drumsticks, burst into the hallway of our apartment building, banging with joyous intensity on those old, scarred cooking implements, creating a raucous racket and shouting at the top of our lungs “Happy New Year’s!” Most of the other residents of the building joined us in creating a jubilant and low rent but somehow defiant cacophony, delirious and intoxicating stuff for the very young me. I daresay that for those few moments we had a lot more fun than the swells at the Waldorf.

When I grew older, as a young adult I fully embraced the revelry of the holiday. I had quite a few memorable New Year’s Eves in my late teens through my mid 20s, from seeing the new wave band The Waitresses playing a show at 5 AM at the famous Peppermint Lounge to bumming cigarettes from a then barely known Howie Mandel at an MTV “after party” that rollicked on and on as if it might never end. I recall with great fondness stumbling out of a nightclub with a group of deliriously intoxicated friends and madly howling at the moon as the last seconds ticked away on one long ago year. As I transitioned into full adulthood, mixed in with raucous annual celebrations were the occasional intimate, more romantic New Year’s get-togethers with lovers and close friends. No matter the circumstances, though, the night never passed without champagne and good cheer, and always kindled within me expectations of bigger and better things to come.

Now, nearly 13 years since I was diagnosed with Primary Progressive MS, the night carries with it a much more complex and troublesome mix of emotions. For the first several years after my creeping paralysis struck, while I was still relatively able bodied, my wife and I would host New Year’s Eve parties, more sedate than my revelries of the past but good times nonetheless. Now, with my body increasingly compromised and my stamina waning, even a small gathering of friends can prove taxing. This New Year’s it was just my wife and me watching celebrations from around the world beamed into our living room in high definition on our big-screen TV, images so crisp and detailed it seemed as though I could step right into them. That is, if I could step.

Despite my best efforts to stay fixed in the moment, I soon found it impossible to watch millions of people celebrating without enviously contrasting their situation with my own. With nary a thought given to their tremendous good fortune at simply having limbs and senses intact, the televised multitudes danced and sang, drank and strutted, laughed and hugged and mingled and voiced exuberant expectations about a future brimming with possibilities. Lubricated by flowing booze and the magic of the night, all could convince themselves that the coming days held good fortune that would far eclipse those which now belonged to history.

For the healthy masses, New Year’s Eve encapsulates the reality that the future is but a blank canvas, the images to be painted on it not predetermined but subject to the will of each individual. All but the most intransigent of difficulties will give way to effort, ingenuity, and discipline. Reality is but a construct of the human mind and the emotions it creates, and as such can be born anew once the self-defeating habits of the past are no longer allowed to dictate actions in the present. Not that these kinds of changes are easy, but with sound body and mind anything – anything – is possible. Sadly, it took my getting sick for me to fully understand this, but there is no greater truth.

And there I sat in a wheelchair – a wheelchair, goddamnit – trying my best to not begrudge the healthy, to vicariously share in at least some of the delirium, to laugh along with them and not let the sneaky tears that kept making their way to the corners of my eyes expose the turmoil that roiled within. There is indeed a reason they call progressive disease progressive. Physically, this last year has been a rough one, with old symptoms getting noticeably worse and new ones breaking the surface. Activities that could be accomplished with relative ease just a year ago are now at times tortuously difficult, and some of those that had been difficult have become damn near impossible. And by activities I don’t mean anything as devilishly complicated as walking or tying a shoe, but rather firmly gripping a fork, or struggling into a sweater, or on bad days, even just staying out of bed for more than four or five hours at a time. My strange and thus far indecipherable mix of endocrine dysfunctions, creeping paralysis, and hideously painful deteriorating joints (courtesy avascular necrosis, a very rare side effect of the intravenous steroids once used to try to beat back the creeping paralysis) has become more intractable than ever, defying all efforts, mainstream and alternative alike, to slow things down.

Unlike those healthy New Year’s Eve revelers on TV, no amount of willpower or change of habits will arrest this bitter physical decline. I continue to fight my disease on all fronts, employing a dizzying array of supplements and medicines to lessen the impact of some symptoms, and undergoing treatments both holistic and traditional at which my condition seems simply to sneer. Though for the most part my spirit stays strong, in the face of this insidious physical onslaught and its accompanying indignities I find it impossible to not at times give way to the weight of it all, having my breath taken away daily by the shocking realization that this is no dream that I can wake from, but instead a concrete reality in which I am being forced to watch myself slowly wither away. My mantra of “staying in the moment” does still help to keep me grounded, but there are also times when the moment just sucks, no two ways about it. Though I can and do fantasize about a future free from illness, my utter conviction to stare this bastard straight in the eyes lands such fantasies well into the realm of the far-fetched, right there alongside my old dreams of becoming the next Mick Jagger or Philip Roth.

New Year’s Eve is a time to look back and project forward, and for the healthy this shedding of the old and embracing of the new can be cathartic, if even just for a few hours. This New Year’s brought me no such respite, though, as a look back illuminated the losses suffered these past 12 months, and peering too deep into the future can be perilous, a glimpse at the dark at the end of the tunnel, a glance at an unthinkable void.

Yet I am not without hope. I keep myself immersed in the latest research and MS news, and though much of it is, quite frankly, garbage, there are approaches that do show promise. Perhaps I am delusional, but even through this morass of illness and increasing disability my resolve to not back down sometimes bends but doesn’t break, even as I acknowledge that merely stabilizing my disease state is at this point quite a longshot. But I know for a fact that sometimes longshots do come in. After all, I’m a guy who once won $15,000 in the Florida lottery, so I’m proof positive that you’ve got to be in it to win it.

And even as I sat there watching the partiers on TV, wrestling with my complicated and disconcerting mass of emotions, when the clock struck midnight I chugged some champagne and kissed my wife, while my inner five-year-old banged on pots and pans and screamed at the top of his lungs, “Happy New Year’s!”…