Immunotherapy for MS succeeds in trial

 
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PostPosted: Tue Jul 09, 2013 6:25 pm    Post subject: Immunotherapy for MS succeeds in trial Reply with quote

From MedPage Today, July 1, 2013:



Quote:
Immunotherapy for MS succeeds in trial

By John Gever, Deputy Managing Editor, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
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A skin patch delivering peptides derived from the presumed autoimmune target in multiple sclerosis reduced relapse frequency and brain lesions in a pilot clinical trial, researchers said.

In 30 patients with relapsing-remitting MS enrolled in the 1-year, placebo-controlled trial, those receiving the myelin skin patches containing 1 mg of peptides had an annualized relapse rate of 0.43 versus 1.4 in patients treated with a placebo patch (P=0.007), according to Krzysztof Selmaj, MD, PhD, of the Medical University of Lodz in Poland, and colleagues.

The mean cumulative number of gadolinium-enhancing brain lesions per patient was lower with the 1 mg patch by 66.5% compared with controls (0.0085 versus 0.0255, P=0.02), they reported online in JAMA Neurology.

However, a 10-mg patch appeared to be substantially less effective than the lower-dose patch. Brain lesion counts and volumes in this group (which had only four patients) were similar to those in the placebo group, even as the mean annualized relapse rate was lower at 0.25 than in either of the other two treatment arms (P not reported).

Selmaj and colleagues speculated that the higher peptide dose in the 10-mg patch may have triggered increased pathological immune cell activity, potentially "induc[ing] a number of specific T cells to differentiate into effector cells," they wrote.

No serious adverse events were reported. Patch-site reactions of "modest intensity" were seen in four of the 20 patients receiving the myelin patches. Other adverse effects occurred at similar rates in all three arms.

In an accompanying commentary, Lawrence Steinman, MD, of Stanford University, called the results "promising" and added that they were consistent with what many in the field have considered the Holy Grail in MS: the induction of immunological tolerance.

MS is widely believed to result from an autoimmune attack on myelin, the principal component of the sheathing that surrounds nerve fibers. When the myelin sheaths become sufficiently degraded, nerve function is impaired as well.

But, compared with the drug-development effort industry has expended toward agents that interfere with some aspect of immune function, comparatively little has focused on persuading the immune system to stop attacking myelin in the first place, Steinman indicated.

"It is clear that the pharmaceutical industry is taking the safer approach, the 'well-traveled road,' when they redirect drugs with a major impact on immune function, drugs often already approved for other diseases," he wrote, alluding to drugs such as anti-CD20 drugs including rituximab (Rituxan) and ocrelizumab and the anti-CD52 agent alemtuzumab (Lemtrada).

Hitting those targets "results in massive perturbation and deletion of major components of the immune system, an approach well worth taking in malignancy, but an approach that could prove problematic in the long run for chronic autoimmune diseases of the nervous system," Steinman wrote.

In the current study, Selmaj and colleagues selected three myelin-based peptides (without industry funding or participation) that could be delivered transdermally from patches placed on the upper arm. These peptides included epitopes that earlier studies had suggested were targeted for immune attack in MS patients.

The patches were formulated to deliver 1 or 10 mg of these peptides or saline -- 10 patients received the saline patches, 16 the 1-mg patch, and four the 10-mg patch. The patches were changed weekly during the first 4 weeks and then monthly for 11 months. Patients and clinical staff were blinded to treatment assignments; the patches were visually identical.

Reflecting the clinical MS population, most patients were women. The mean age was about 37, with duration of MS symptoms averaging about 8 years and baseline EDSS disability scores averaging 2.6. Mean annualized relapse rate prior to enrollment was 1.1.

After one year in the study, the number of relapse-free patients and the number showing disability progression in each treatment group were as follows:

Placebo: relapse free, 1/10; progressive disability, 7/10

1 mg myelin: relapse free, 10/16; progressive disability, 3/16

10 mg myelin: relapse free, 3/4; progressive disability, 1/4

Mean EDSS scores increased by 0.75 in the placebo group versus 0.08 and 0.00 in the 1- and 10-mg patch groups, respectively.

MRI results showed a more mixed picture, especially with respect to the 10-mg group. The mean cumulative number of gadolinium-enhancing lesions with 10 mg was actually higher than in the placebo group (0.0341 versus 0.0255), and the volume of those lesions was nearly doubled with the 10-mg patch versus placebo.

But the mean cumulative number of new T2 lesions was lower with both the 1- and 10-mg patches (0.75 and 1.25, respectively) than in the placebo group (2.4).

Mean T1 lesion volume decreased in both of the myelin patch arms whereas it increased with placebo, yet mean T2 lesion volume decreased only with the 1-mg patch.

Overall, Selmaj and colleagues concluded that "the efficacy and safety profiles that have emerged from this study make the transdermal application of a mixture of three myelin peptides, an attractive and promising therapeutic approach in patients with relapsing-remitting MS."

And, in line with Steinman's cautions about untoward immune effects of other treatment strategies, Selmaj and colleagues suggested that myelin peptide delivery would "spar[e] other mechanisms critical for immune protection."

Steinman suggested that the same approach could also yield good results in other neuroimmunological diseases thought to have single-antigen autoimmune targets -- specifically, neuromyelitis optica and myasthenia gravis. The self-antigen damaged in the former is aquaporin 4, while in the latter it's the acetylcholine receptor molecule.

__________________________

The study had no external funding.

Selmaj and colleagues reported relationships with Novartis, Biogen Idec, ONO Pharma, Genzyme, Roche, Synthon, Teva, and Merck Serono.

Steinman reported serving as founder of a company, Tolerion, aimed at developing antigen-specific tolerance therapies.


The article can be seen here.
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PostPosted: Fri Jul 12, 2013 5:28 pm    Post subject: Reply with quote

More on this here.
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PostPosted: Sat Aug 31, 2013 6:42 pm    Post subject: From Rocky Mountain MS Center Reply with quote

From the Rocky Mountain MS Center eMS News, August 30, 2013:

Quote:
Putting a patch on MS?

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system. In people with MS, specific immune system cells (T-cells) misidentify elements of the brain and spinal cord as foreign and try to destroy them. Myelin has long been thought to be a target—the red flag to the bull—that ignites this attack process. Over the years, different strategies have been used to try to limit this immune attack. One of these is to retrain the immune system so it is tolerant to myelin. In that case, the attacking cells would simply ignore myelin and leave it alone. That is the logic underlying a recent study by Polish researchers. The goal of their study was to induce myelin tolerance and thereby reduce myelin destruction and MS attacks.

In this recent small study, researchers in Poland used a skin patch to administer small amounts (1.0 mg) of myelin particles (peptides) to 20 people with relapsing-remitting MS. In the following year, these 20 people showed significant reductions in MRI disease activity and clinical relapses when compared to ten people who were given an inactive placebo patch, and when compared to four people who received a much larger dose (10 mg).

According to Dr. Leila Jackson, Rocky Mountain MS Center immunologist and researcher, “There is a ton of work that has been done in the past on treatment of MS patients with myelin antigens—different vaccine strategies, all sorts of different things. All of the other vaccines have not been approved due to lack of efficacy or other issues. This one is exciting because they appear to have some positive results. One interesting thing about this study is that there appears to be a positive effect at the lower dose but not at the higher dose. Another is that the route of administration is different. The immune cells in the skin that would take up this antigen are completely different that those that would be targeted in an IM injection and with other vaccine strategies. They activate, and ultimately educate, different immune cells.”

The study results were positive. For those using the 1.0mg patch, the annual relapse rate was reduced by nearly 70 percent compared with the placebo group. The proportion of those with worsening disability was decreased by 51 percent. No serious adverse events were noted in the study.

This was a preliminary study involving a very small group of patients. Larger studies will need to be done to prove both safety and efficacy, but the approach is novel and the results are encouraging.
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