Roche Pharmaceuticals, the owner of Genentech, announced positive phase III study results of their anti-CD20 monoclonal antibody called Ocrelizumab yesterday. Ocrelizumab is a humanized monoclonal antibody targeting CD20 on mature B cells, whereas Rituximab is a Chimeric antibody (part mouse and part human) with the same target. This clears the way for FDA approval of Ocrelizumab by late 2015 or early 2016. The two phase III studies involved 1656 relapsing MS patients (both relapsing remitting and secondary progressive) randomized to either an Ocrelizumab infusion every 6 months (600 mg) or Rebif 44 mcg three times a week. Ocrelizumab significantly reduced relapse rates, new lesion formation on MRI and disability progression during the two years of the study compared to Rebif. Amazingly, serous adverse events associated with Ocrelizumab were not more common than serious adverse events with Rebif, a drug considered very safe and a first line therapy for MS. The most common adverse events with Ocrelizumab were infusion related reactions, which can be controlled with premedication. A phase III study of Ocrelizumab in primary progressive MS is still underway.

Why is this important?

1. Many people with MS who have benefited from Rituximab in the past or could benefit from it now are no longer able to receive it because of  insurance restrictions. These study results open the way for FDA approval of this class of medication

2. Only one other MS medication (Lemtrada) has shown significant benefits on relapse rates, disability progression and MRI activity over 2 years when compared to a highly active first line DMT (Rebif). Remember, it is relatively easy to be better than placebo treatment. Not only is Ocrelizumab better than Rebif, it is relatively safe and well tolerated over 2 years of treatment. A full understanding of the relative benefits and risks of Ocrelizumab awaits final release of the actual study data for us to review, but the statements in their press release are very exciting. 

3. Any treatment that can be administered as infrequently as every 6 months will be welcome to most MS patients

4. Depending on our review of the study data, this drug may benefit certain secondary progressive MS patients

All are cause for celebration.

Revere (Rip) Kinkel MD
Director of the Multiple Sclerosis Program
University of California San Diego

There has been a lot of chatter and excitement this month about the potential benefits of high dose statin therapy in Secondary Progressive MS. Jeremy Chataway and colleagues reported this month in the online edition of Lancet (March 2014) that high dose statin therapy (Simvastatin 80 mg orally once a day) reduced the rate of whole brain atrophy by 43% over 2 years with benefits observed during both the first and second year of the study.

Brain Atrophy was chosen as the primary outcome in this study. This means that changes in the size or volume of the entire brain as measured on MRI scans at yearly intervals were used to determine if there was a difference between the 70 patients treated with Simvastatin and the 70 patients treated with placebo. This outcome was justified based on prior studies showing a relationship between the development of brain atrophy and the development of worsening disability in MS patients. By using brain atrophy as the primary outcome the study investigators were able to observe a treatment effect of simvastatin with fewer study patients and a shorter study time interval. In contrast a study to determine if simvastatin reduced the development of sustained disability in MS would require many hundreds of patients potentially for a longer interval. Interestingly, the investigators did report a possible benefit on two clinical disability measures at 2 years, though the significance of this benefit is unclear at this time.

These are very hopeful preliminary results but caution must be advised until further studies are completed for the following reasons:

1. Statin therapy has already been studied in early relapsing forms of MS with mixed results
2. Statin therapy can have significant adverse effects in some patients although no significant problems were observed in this study
3. This is a phase II study in a relatively small number of patients (140 to be exact) and must be confirmed in a later phase III study; it is not unusual for a phase III study to show negative results even though a prior phase II study was positive
4. The mechanism of benefit from high dose statin therapy is unclear and this could guide us in the selection of the most appropriate patients for this therapy. For instance, there does not appear to be a significant effect on relapses or new MRI lesions. Therefore, is the drug neuroprotective or is it having an effect on vascular comorbidity (a known benefit of statins) that is indirectly limiting brain atrophy in some patients?
5. We do not know if the reduction in atrophy is affecting the white matter or the gray matter from the published study results. A reduction in gray matter atrophy would be far more compelling, since gray matter atrophy seems to the main driver of disability in MS
   

So what should you do with these results if you have secondary progressive MS? After all, the simvastatin was well tolerated in this group of patients. I suggest talking it over with your physician and certainly consider this drug and dosing schedule if you require statin therapy to lower cholesterol or if you have other accepted cardiovascular or cerebrovascular risk factors known to be benefited by statin therapy. I would also encourage you to participate in any Phase III trials of statin therapy that you may hear about in the coming months

It seems fitting that on Valentine’s Day I should write about new hope for an MS treatment that may even benefit those with progressive disease!  Better yet, this treatment may even target the cause of the disease instead of simply suppressing inflammatory responses within the central nervous system.

Researchers in Australia have published a case report documenting the rather dramatic response of a severe progressive MS patient to immunotherapy which was designed to boost a specific type of immune response against B Cells latently infected with Epstein Barr Virus, the cause of mononucleosis and a possible cause of MS.  The patient experienced:

·      A dramatic reduction in inflammatory MRI lesions
·      Improvement in symptoms and neurological findings
·      A reduction in the production of immunoglobulins within the spinal fluid

The reduction in immunoglobulin being produced within the nervous system and measured in spinal fluid was perhaps the most remarkable finding, as it suggests that this treatment eliminated intrathecal (meaning within the spinal fluid) B cells latently infected with Epstein Barr Virus.

There is a wealth of direct and indirect evidence that Epstein Barr Virus plays an important role in causing MS.  Pathological studies reveal nodules of inflammatory cells scattered across the surface of the brain, often in clusters resembling tiny lymph nodes. Many of these cells are a type of lymphocyte, called a B cell, that are infected with Epstein Barr virus. These inflammatory cells appear to directly damage the underlying cortex of the brain, which may trigger an inflammatory response that spreads throughout the nervous system over many years. It is these same B cells that mature to become the type of cells (called plasma cells) that produce the immunoglobulins in the spinal fluid (CSF) that we use to help diagnose MS. We call these immunoglobulins in the CSF oligoclonal bands.

The therapy given to this patient was designed to boost the cytotoxic immune response against EBV infected B Cells.  The immune system depends on cytoxic or CD8+ T immune cells to destroy cells infected with viruses, but this cytotoxic response is often lacking in MS patients. They used a novel approach to stimulate a sample of the patient’s blood with AdE1-LMPpoly, a recombinant adenovirus vec­tor that boosts cytotoxic CD8+ T cell responses against Epstein Barr virus proteins expressed by infected B Cells, and then re-injected these boosted cells back into the patient. The patient tolerated the treatment well and improved.

Clearly, these results require confirmation in well designed and controlled clinical trials, but for the first time we seem to have a path forward to finding an effective therapy for MS that is based on a reasonable hypothesis regarding the cause of the disease.  I wouldn’t be surprised to find a therapy like this available within 5 years if confirmed by additional studies.

Happy Valentine’s Day

--Dr. Kinkel