Medicine & Research

Fingolimod Trial for PPMS Does Not Meet Primary Endpoint

Novartis’ Phase III INFORMS study in primary progressive multiple sclerosis did not show a significant difference between fingolimod and placebo on a combination of disability measures in clinical trials. The safety results were consistent with the well-characterized safety profile of fingolimod in relapsing MS.
PPMS is different from relapsing MS in terms of its basic disease process, near-absence of acute relapses, and fewer active MRI lesions. There are no approved treatments that have been shown to change the course of this disease, and management focuses mainly on the treatment of symptoms.

The INFORMS study was based on the knowledge that fingolimod enters the central nervous system and can interact with damage-causing cells residing in the CNS. As opposed to the consistently strong efficacy seen in relapsing MS, the results of the INFORMS study seem to suggest that PPMS and relapsing forms of MS have different underlying mechanisms.

Dr. Thrower: Unfortunately, we still have no FDA-approved option for slowing the progression of primary-progressive MS. This is largely due to the different nature of PPMS vs. relapsing-remitting MS. PPMS tends to be slowly progressive with much less active inflammation. Most of our MS disease-modifying therapies are designed to lessen inflammation. So, with PPMS, the major target for most DMTs may be harder to hit because the target is smaller than in RRMS. What follows is my personal take on PPMS, the negative clinical trial results, and dealing with PPMS in real life.

1: Less inflammation does not mean no inflammation. Many people with PPMS still have active or enhancing lesions on MRI. While treatment results may not be as dramatic with DMTs in PPMS as they can be in RRMS, some benefit may still be there. Trials of Copaxone and Rituxan in PPMS were technically negative, but closer examination shows that some slowing may have still been there with these drugs in PPMS.

2: We are not very good at measuring disability in MS. For years, our gold standard for disability measurement in MS has been the EDSS or Expanded Disability Status Scale. This measure is heavily weighted towards walking ability and does a poor job of measuring other issues such as arm function and fatigue. More recent studies, including the INFORM trial of fingolimod, also use the MSFC or MS Functional Composite. This looks at memory, upper extremity function, and walking speed; and may be more sensitive to the big picture of how a person with MS is doing.

3: Maybe we need to target something other than inflammation. If PPMS is more of a neurodegenerative condition than an inflammatory one, alternative strategies such as antioxidants would be a better fit. Tecfidera is a DMT that is proposed to work through such antioxidant pathways and will likely be tested in PPMS. The biggest target for the future remains neural repair.

4: Finally, don’t forget the role of wellness and symptom management. Even if we don’t have the magic bullet to stop and/or reverse progression in PPMS yet, we do have a myriad of options to manage symptoms and improve quality of life through rehabilitation and medications.

Stem Cell Therapy May Hold Key to MS Treatment

A new study shows that after three years, an experimental stem cell treatment was effective for creating sustained remission of active relapsing-remitting multiple sclerosis and was linked to improvements in neurologic function. The treatment was shown to have few serious early complications or unexpected adverse events.

The study followed 24 patients who received high-dose immunosuppressive therapy. Using a patient’s own cells, the researchers found that the overall rate of survival was 78.4 percent at three years. Progression-free survival was 90.9 percent and clinical relapse-free survival was 86.3 percent. Patients showed improvement in neurologic disability, quality of life, and functional scores. While researchers encountered hematological and gastro-intestinal side effects, they were both expected and reversible.
The study was published online by JAMA Neurology.

Dr. Thrower: MS involves a person’s immune system attacking something that it should not be. In MS, the immune attack is directed against the myelin in the brain and spinal cord. This abnormal immune response is the result of both environmental and genetic factors. What if we could reprogram the immune system in a way that would have it not attack myelin? This is the idea behind an autologous hematopoietic stem cell transplant. Autologous means the stem cells come from the patient as opposed to a matched donor. The appeal of using autologous cells is that the body should not reject them. An allogeneic transplant is one using a matched donor. Even with modern matching techniques, there is the risk of the body rejecting the transplant (host versus graft disease) or the transplant actually fighting the recipient’s body (graft versus host disease) when using allogeneic cells. This means recipients of allogeneic cells need to be on medications to help prevent these complications.

Before a person can get their autologous or allogeneic stem cells, the existing immune system must be wiped out. Autologous stem cells are obtained from the patient and frozen for later use. Then, high-dose immunosuppressive therapy is given, using a combination of chemotherapeutic drugs to kill the existing immune system. The patient is then given their own stem cells back to generate a fresh immune system, one that does not know how to attack myelin. As shown in the reported study, the results can be encouraging. Still, this is a very aggressive procedure, and there can be significant risks. The results appear to be most encouraging in people with aggressive RRMS, much less so for
progressive forms of MS.

Studies Weaken MS, Vaccination Link

A pair of studies calls into question links between vaccines and multiple sclerosis. In particular, neither study found long-term associations with the human papillomavirus vaccine and MS.

In the first study, a research team, led by Dr. Annette Langer-Gould, of Kaiser Permanente, Southern California, in Pasadena, Calif., looked at the complete health records of Kaiser Permanente, Southern California, members to determine whether vaccines, particularly those for hepatitis B and human papillomavirus (HPV), increase the risk of MS. They identified 92 cases and 459 controls of females ages 9 to 26 years. They found no associations between HepB vaccination, or any vaccination and the risk of acquired central nervous system demyelinating syndromes (CNS ADS) up to three years later.

Vaccination of any type was associated with an increased risk of CNS ADS onset within the first 30 days after vaccination only in younger individuals. They found that short-term increase in risk suggests that vaccines may accelerate the transition from subclinical to overt autoimmunity in patients with existing disease. Their findings, published in the December issue of JAMA Neurology, however, do not suggest a need for a change in vaccine policy.

The second study, led by Nikolai Madrid Scheller of Statens Serum Institut, in Copenhagen, Denmark, wanted to know if the quadrivalent human papillomavirus (qHPV) vaccination is associated with an increased risk of multiple sclerosis. Identifying a cohort of all females ages 10 to 44 years in Denmark and Sweden, followed up from 2006 to 2013, researchers found no link between the qHPV vaccination and the development of multiple sclerosis. Their findings, published in the January issue of JAMA, did not support concerns about a causal relationship between qHPV vaccination and demyelinating diseases.

Dr. Thrower: The topic of vaccine safety in MS has been around for years. Two recent studies shed some light on the relationship between certain vaccines and the risk of a demyelinating condition like MS. The first study looked at people who had developed a demyelinating condition and another group who did not. The researchers then looked at whether the subject had recently gotten any vaccination, especially those for hepatitis B or HPV. No correlation was seen between vaccination and the risk of a demyelinating condition.

The second study looked at all women receiving the human papillomavirus vaccine in Sweden or Denmark between 2006 and 2013. The HPV vaccine is given to women to diminish the risk of acquiring human papillomavirus. The vaccine is also offered to men to lessen the likelihood that they may transmit HPV to women. 99.7 percent of cases of cervical cancer are due to chronic infection with HPV. While cervical cancer was once a major cause of death in women, rates decreased drastically when routine Pap smears began. Still, in 2014, 12,360 women in the U.S. were diagnosed with cervical cancer and 4,020 died from it. HPV vaccinations will hopefully reduce these rates even further. In 2009, there were five reports of women developing a demyelinating condition within weeks of getting the HPV vaccine. This most recent large study failed to show any correlation between the risk of developing MS and having gotten the HPV vaccine. This study does not address the safety of the HPV vaccine in a person already diagnosed with MS. Given that the HPV vaccine is not a live virus, one would not expect any risk of an MS relapse after receiving this vaccine.