Drugs

Here, you can read about the latest research into new drugs for MS and it's symptoms.

More news can be found in New Pathways Magazine, our bi-monthly publication, and also check daily at MSRC: Latest MS News.

• Disease Modifying Drugs 
• Low Dose Naltrexone 
• Sativex® 
• Ampyra (Fampyra) 
• Gilenya®
• Movectro® (Cladribine) 
• Aimspro (Goats Serum)
• Azathioprine 
• Trimesta (Oral Estriol)
• Mitoxantrone and Copaxone Combination Therapy 
• Laquinimod 
• Teriflunomide (Aubagio™)
• MBP8298 
• NeuroVax 
• Tovaxin 
• BHT - 3009 
• HiCy & Revimmune 
• CHR-1103 
• BG-12 
• Zenapax (daclizumab) 
• Rituximab (Rituxan) 
• Cyclophosphamide 
• Novantrone (Mitoxantrone) 
• Lemtrada (Campath) 
• MN-166 (Ibudilast) 
• RPI-78M 
• ATX-MS-1467 
• RTL-1000
• Further possible MS Drugs and Treatments 
• Cannabis and Cannabinoid Research 
• Minocycline
• Statins 
• Modafinil 
• Pycnogenol
• Viagra (sildenafil) 
• Possible Drugs For The Treatment Of MS Symptoms
• Genetically Modified Drugs And Components 
• Prokarin
• PEGylated interferon beta
• Masitinib

Success of immunomodulators in MS shifts discovery focus to neuroprotection

With six immunomodulatory agents in late-stage development for relapsing–remitting multiple sclerosis, this area of the therapeutic space has become highly competitive. Could remyelination therapies that provide neuroprotection be the next frontier?

Close on the heels of the approval last year of the first oral disease-modifying drug for multiple sclerosis (MS), Novartis's fingolimod, six more late-stage contenders — including novel oral agents and monoclonal antibodies (mAbs) — are next up. As a result, the landscape for immunomodulatory agents is becoming increasingly crowded.

The latest clinical trial results for these relapsing–remitting MS (RRMS) treatment contenders were presented in October at the joint ECTRIMS–ACTRIMS meeting in Amsterdam. A highlight was data for Biogen Idec's BG-12 (dimethyl fumarate), an orally available small molecule (with a relative molecular mass of <150) that is thought to act in part by modulating the activity of the transcription factors nuclear factor-κB and NRF2, which have important roles in inflammation. Results from the Phase III DEFINE trial of the drug showed that the drug met its primary end point, significantly reducing the proportion of patients who relapsed at 2 years. Top-line data from the CONFIRM trial — which included Teva's injectable immunomodulator glatiramer acetate as an active comparator — were reported days after the meeting and provided similarly positive results.

BG-12 so far appears to have a clean safety profile, with flushing and diarrhoea as the main side effects. It also reduced disease progression significantly in the DEFINE trial, although not in the CONFIRM trial. Based on these data, Biogen Idec says it plans to file the drug for regulatory approval next year. The efficacy and safety findings, combined with the ease of use of the oral agent, have led some analysts to propose that BG-12 could be set to become the best of the oral immunomodulators.

Another promising immuno-modulatory agent, administered by injection rather than orally, is Genzyme/Sanofi's alemtuzumab, which has already been approved for chronic lymphocytic leukaemia. The CD52-specific mAb — which was one of the first mAbs to be created in the laboratory of Nobel prize winner César Milstein — depletes both T and B lymphocytes, temporarily reducing key inflammatory players and potentially leading to the reconstitution of cell populations that are less prone to engage in autoimmune attack. In CARE-MS I, a Phase III trial in treatment-naive patients, the mAb met its primary end point, significantly improving the annualized relapse rate compared with the active comparator, Merck Serono's subcutaneous interferon-β1a.

The CARE-MS II trial, which tested the mAb in a treatment-experienced patient setting, also recently reported positive data, potentially paving the way for a filing early next year.

The other Phase III candidates include Sanofi's oral dihydroorotate dehydrogenase inhibitor teriflunomide, Roche/Biogen Idec's injectable CD20-specific mAb ocrelizumab and Biogen Idec's injectable interleukin-2-specific mAb daclizumab. Teva's Phase III immunomodulator laquinimod failed to meet the primary end point in a first pivotal trial, and the company now says it may delay plans to file early next year and could instead initiate another pivotal trial.

Promisingly, all the different approved and experimental therapies offer patients considerable options. Each exerts its effect via a different mechanism of action — in the periphery, at the blood–brain barrier or in the brain — providing a unique safety–efficacy profile and the possibility of personalization if ongoing biomarker efforts prove fruitful. Yet, despite these advances, the successes are also united by a common theme that highlights an outstanding unmet need in MS: they act by modulating the immune aspects of MS, but do not induce the repair of damaged tissue. “We've pretty much sorted the inflammatory phase of MS, with whatever drug,” says Alasdair Coles, a neurologist at Cambridge University, UK, and investigator on the CARE-MS I trial. “The big challenge now is neuroprotection.”

The remyelination challenge

In the early stages of RRMS, it is thought that demyelination of axons through autoimmune processes compromises neuronal conduction, resulting in the early neurological deficits. Although endogenous remyelination pathways work to repair axonal damage, this process seems to slow down as the disease progresses. In the more progressive stages of disease, the hallmarks of inflammation fade away even as the rate of neurodegeneration increases. How then can neurodegeneration be delayed?

“The most fruitful avenue for preventing axonal degeneration in MS, most of us would agree, is to induce remyelination itself,” says Timothy Vartanian, a neurologist at Weill Cornell Medical College, New York, USA. Although there has been some work to protect oligodendrocyte precursors — which generate the cells that are responsible for laying down the myelin sheaths — accumulating evidence suggests that a shortage of these is not typically the problem, he adds.

And so efforts are underway to enhance the efficacy of the endogenous remyelination process. One of the lead remyelination candidates is Biogen Idec's BIIB033 (also known as anti-LINGO1) — a monoclonal antibody that targets LINGO1, a negative regulator of oligodendrocyte differentiation and myelination. In 2007 Biogen Idec and collaborators showed that gene knockout and antibody antagonism of LINGO1 activity aided the recovery of mice with experimental autoimmune encephalomyelitis, a widely accepted inflammatory model of disease that, despite limitations, has given rise to both glatiramer acetate and Biogen Idec's natalizumab (Nature Med. 13, 1228–1233; 2007). The same study also suggested that inhibition of LINGO1 activity improved axonal integrity. The mAb is now in Phase I trials.

Another potential remyelination approach that is in the clinic is GlaxoSmithKline's mAb GSK1223249, which targets Nogo-A, a neurite growth inhibitor. Although the candidate is in Phase I trials for amyotrophic lateral sclerosis, it has been proposed by some as a potential remyelination therapeutic for MS as well.

Yet, although there are few candidates in the clinic, advances in the understanding of the basic biology underpinning remyelination may provide new fodder for translational research. “The field has rumbled along the ground for many years, but in the past 5 years it has really taken off,” says Robin Franklin, a neuroscientist at the University of Cambridge. “I think a lot of companies are dipping their toes in the water here,” he adds.

Industry experts agree. “I've noticed that people are starting to take the remyelination approach up,” says Alfred Sandrock, Senior Vice President of Research and Development at Biogen Idec. Mike Panzara, Therapeutic Area Head for Multiple Sclerosis at Genzyme, moreover notes that Genzyme has a “very active business development and internal efforts to bolster neurorepair and remyelination efforts”.

Neither Biogen Idec nor Genzyme would comment on which targets or pathways they are prioritizing for preclinical research, but several avenues of exploration have recently emerged. Franklin and his colleagues published a paper on the retinoid X receptor-γ (RXRγ) signalling pathway earlier this year, for example (Nature Neurosci. 14, 45–53; 2011). Knockdown or inhibition of the pathway blocked oligodendrocyte differentiation, and administration of RXRγ agonists increased axon remyelination in an aged rat model of demyelination. “We are now pursuing strategies to develop isoform-specific agonists that can target RXRγ,” says Franklin. Other pathways that are getting attention include the WNT pathway, chemokine receptor pathways, the Notch pathway and growth factors for oligodendrocytes (FEBS Lett. doi:10.1016/j.febslet.2011.08.017).

Sandrock points out that recent advances in genetics are providing hints for new pathways too. A recent paper in Nature identified 29 new susceptibility loci for MS and replicated many of the previously identified associations (Nature 476, 214–219; 2011). “We now have more than 50 polymorphisms that increase the risk of MS,” says Sandrock. “Many of these are in the immune pathways, but many are not. These could provide clues as to how to prevent neurodegeneration.”

While drug discoverers search for suitable targets — and work towards developing animal models that better replicate the neurodegenerative aspects of disease — drug developers have their hands full with the clinical challenges of testing remyelination therapies. Two key questions plague the space: which patients are most likely to respond, and how can you measure remyelination?

On the patient population front, explains Vartanian, there are a couple of difficult questions. If you enrol patients with RRMS who are at an early stage of the disease and look for remyelination either specifically within lesions or across the whole brain, then there may not be a large enough signal-to-noise ratio to detect an effect if endogenous remyelination processes are active in these patients. However, if you take patients with more progressive disease — who will have the most marked demyelination and are in most need of new treatments — then the extensive glial scarring and modification of the extracellular matrix around damaged axons may not be conducive to remyelination. “I think in reality you are probably going to want to test both types of patients,” he suggests.

In regard to an end point for success in these trials, as yet there are no non-invasive surrogate markers for quantifying myelin in the human brain and/or spinal chord. But, says Vartanian, progress is being made. In particular, he points to the advances in positron emission tomography scanning and magnetic resonance imaging tools — including the myelin water fraction, the magnetization transfer ratio and DESPOT post-processing approach — as leading possibilities. “I think we are very close to the place where we can come up with a quantitative measure,” he says.

And so despite the hurdles, the view that remyelination therapies are the way forward is becoming increasingly widespread. “The MS treatment of the future is a drug to treat inflammation and stop relapses, plus another drug to provide neuroprotection,” says Coles. And although the immunomodulatory space is increasingly crowded, the remyelination approach remains wide open.

Source: Nature Reviews © 2011 Nature Publishing Group (02/12/11)

Newer MS compounds impacting on use of current disease modifying drugs

While Biogen Idec's Avonex and Teva's Copaxone continue to capture the majority of multiple sclerosis (MS) patients first starting on a disease-modifying agent (DMA), the introduction of Novartis' Gilenya, the only oral DMA currently on the market, appears to have impacted the average length of the time that patients remain on their first-line therapy before a switch may be initiated.

Gilenya, typically prescribed as a second or later-line DMA, has also negatively impacted the overall market share of certain DMAs compared to the 2010 audit fielded prior to the Gilenya launch, with Pfizer / EMD Serono's Rebif and Biogen Idec's Avonex, taking the greatest hit.

In addition to the introduction of Gilenya, another recent event impacting the MS market is the commercial availability of the anti-JC virus antibody assay to help mitigate the PML risk associated with treatment of Biogen Idec's Tysabri. Based upon the patient-level audit data, the percent of patients tested for anti-JC virus antibodies differs based both on brand of DMA at the time of testing and MS disease classification. While patients who test negative for the antibodies are most likely to switch to Tysabri, patients who test positive are most likely to switch to Gilenya.

The majority of DMA-treated patients experience at least some MS-related symptoms with the most common including fatigue, abnormal sensory perceptions, and balance issues. Since there are currently very few FDA-approved symptomatic agents, the agents most often prescribed to help control MS-related symptoms are typically products without a formal indication for MS. Acorda's Ampyra, the first FDA-approved symptomatic agent for a MS-related symptom, is used by neurologists to treat walking impairment, spasticity, and / or fatigue. A number of important differences exist between patients treated with Ampyra and those who are not, including the severity of the disease at DMA initiation and current disease classification.

When asked to hypothetically switch audit patients to one of the DMAs in late stage clinical development, neurologists identify the greatest opportunity for Biogen Idec's PEG-Avonex and Teva's laquinimod. A number of patient characteristics appear to help identify the types of patients who are perceived by neurologists as more likely to be switched to a specific DMA in development upon approval.

Source: BioTrends Research Group, LLC (07/11/11)

Oral drugs offer easier way to treat MS

A number of new multiple-sclerosis medications are beginning to hit the market that promise to make it easier for patients to control flare-ups of the disease and slow its progression.

The drugs, designed to be taken orally, represent a new generation of treatment for MS. Currently, people with the disease can choose from a range of drugs that are administered by injection.

Physicians say many people are reluctant to stick themselves with a needle and would be more comfortable taking a pill once or twice a day. This could encourage a greater number of MS patients to take medication as needed and could spur earlier treatment, which is important since disability from MS is cumulative.

Cost of the new drugs is expected to be high. Novartis AG's Gilenya, so far the only oral MS drug on the market, is priced at about $48,000 a year; the drugs still being developed are expected to cost about the same. That's higher than injectable drugs currently in use, which cost roughly $40,000 a year. Health insurers often pick up most of the expense of MS drugs.

There is a "tremendous desire" among MS patients to begin using oral treatments because of their ease of use, says Joseph Herbert, director of the MS Care Center at NYU Langone Medical Center. Still, he says, many physicians are being cautious about prescribing the oral drugs because their side effects can't be fully assessed until they are used widely for an extended period of time.

Among its side effects, Gilenya can increase a person's risk of infection and potentially lead to toxicity of the liver and an eye disease called macular edema, clinical trials have shown. Some of the oral drugs still in development are expected to have somewhat milder side effects.

The current injectable drugs have generally less severe side effects, including injection-site irritation and flu-like symptoms, although some patients incur more serious problems such as liver damage.

Elizabeth Fuchs, an MS patient on Staten Island, N.Y., began taking Gilenya about two months ago. The 49-year-old was diagnosed with MS about 12 years ago and had tried several injectable medications. Avonex, made by Biogen Idec Inc., required weekly intramuscular injections. She later switched to Copaxone, from Teva Pharmaceutical Industries, which is administered with a daily subcutaneous injection.

"It is just much easier to put a pill in your mouth and take a glass of water," Ms. Fuchs says. Not having to inject herself has made her feel more positive about having MS and even allows her to forget she has the disease, she says.

There is no cure for MS, a chronic, inflammatory condition that occurs when the body's immune system attacks its own central nervous system.

MS, which affects about 400,000 people in the U.S., is marked by symptoms such as vision problems, limb numbness and paralysis. Women are more likely to get the disease than men, and genetic factors may make certain individuals more susceptible, according to the National Multiple Sclerosis Society.

Gilenya, which received Food and Drug Administration approval last fall, is thought to work by reducing the quantity of circulating immune cells that can cause damage in an MS attack. More than 6,500 patients are taking the drug, according to the most recent Novartis data.

Recent data from large clinical trials of other drugs being developed, including Biogen Idec's BG-12, Teva Pharmaceutical's laquinimod, and teriflunomide, from Sanofi-Aventis SA, show they are also effective at controlling MS flare-ups and slowing the progression of disability from the disease. More data on the drugs are expected later this year and, assuming FDA approval, they could all be on the market in late 2012.

The success of any of these drugs isn't guaranteed. Another oral MS drug, Merck KGaA's cladribine, was rejected by U.S. and European regulators earlier this year amid long-term safety-related questions, including an increased cancer rate in patients taking the drug. The company says it remains committed to gaining approval.

Another drug, Biogen's Tysabri, was approved in 2004 but was later temporarily pulled from the market after it was linked to a rare brain infection. Tysabri, administered by intravenous infusion, became available again in 2006 but is limited mainly to patients who don't respond to other treatments.

A recent analysis by Novartis showed that Gilenya reduced relapses among MS patients by 54%. Disability progression was reduced by 30%, using a standard measurement of this process.

Biogen's BG-12 drug reduced MS flare-ups by a similar amount as Gilenya, but with fewer side effects. Smaller reductions in flare-ups were seen in trials with patients using laquinimod (23%) and teriflunomide (31%).

By comparison, Avonex, one of the leading injectable drugs, has been shown to reduce MS flare-ups by 32% and disability progression by 37% over two years.

Physicians say MS cases vary greatly and some drugs won't work for certain patients. Also, it is difficult to directly compare two different clinical trials.

NYU's Dr. Herbert says it is a challenge to get patients to use prescribed injectable therapies. Oral medications' ease of use should increase the number of patients who use the drug as required, he says. This also is expected to encourage some patients, especially those in the initial stages of MS, to begin therapy before the disease advances significantly.

"The data certainly suggest that starting therapy earlier does slow down the progression of the disease," says Timothy Coetzee, chief research officer for the National Multiple Sclerosis Society.

Doctors say they aren't likely to recommend a patient switch to one of the new oral drugs if an injectable drug currently in use is working. Although the ease of taking a pill, rather than an injection, is important, effectiveness of a given drug takes precedence. Patients who switch treatments run the risk of the new drug not being the right fit for them, says Mayo Clinic neurologist Mark Keegan.

Source: Wall Street Journal Copyright ©2011 Dow Jones & Company, Inc. (17/05/11)

New oral drugs hailed for treating MS

For decades, research into treatments for multiple sclerosis has plodded forward, making slow but significant gains in improving the lives of people with the degenerative nerve disorder.

That steady but slow pace made the speed at which progress occurred in the past year nearly breathtaking, with the U.S. Food and Drug Administration approving a number of new breakthrough drugs for people with MS.

Nicholas LaRocca, vice president of health-care delivery and policy research for the National Multiple Sclerosis Society, said that 2010 was "an unprecedented year for MS, both in terms of the many developments that are in the pipeline as well as drugs that have come to market."

The new medications broke new ground not only through the therapy they provide but also in the way they are administered. The drugs can be taken orally, a break from past MS treatments that had to be given by either injection or IV.

They include:
Gilenya (fingolimod), the first oral medication designed to reduce relapses and delay the progression of MS.

Ampyra (dalfampridine), the first drug approved to treat a specific symptom of MS -- in this case, improving people's ability to walk.

Nuedexta, a two-drug combination designed to treat people with MS who have lost emotional control because of a symptom known as pseudobulbar affect, a severe emotional consequence of the disorder that causes uncontrollable laughing or crying.

Other oral therapies are in the pipeline. One now under FDA review is cladribine, a drug aimed at reducing relapses that could further improve convenience for people with MS, LaRocca said.

"It is taken orally but in discrete blocks of time over the course of the year," he said. "It's a couple of very short courses of oral therapy, as opposed to taking it constantly."

LaRocca said that these and other new drugs that have hit the market or on the verge of FDA approval will make it much easier for those with MS to find relief.

"People respond differently to different therapies," he said. "The more treatments we have, the higher the likelihood that a person will find a treatment that works best for them. We're going to see a steady stream of options for people with MS, providing people with the choices they need."

The new oral therapies also help people regain some small sense of control by allowing them to more easily take their medications, said Dr. Ron Cohen, chief executive and founder of Acorda Therapeutics, the company that developed Ampyra.

"It's certainly a more convenient form of the type of therapy that's already been available as an injection," Cohen said. "What's not known right now is, of all the orals, the relative efficacy of these orals versus the best of the injectables. With the injectables, there's a pretty good sense of what to expect in terms of efficacy and safety. It will take several years to develop such a track record for oral medications."

With the approval of the new drugs, eyes are turning toward the future and the next potential advance in MS treatment. Both Cohen and LaRocca said that treatments that repair the neural damage caused by multiple sclerosis are the next frontier for researchers.

Multiple sclerosis is now believed to be an autoimmune disorder in which the body damages the nervous system by attacking myelin, the fatty substance that surrounds and protects nerve fibres, according to the National Multiple Sclerosis Society.

The drug Ampyra works by restoring the conductive power of nerves that have lost their myelin, Cohen said.

"Right now, there's nothing that can repair the damage once it's been done," he said. "If we had something that could restore the myelin, you could potentially dial back the damage done by the disease."

The National Multiple Sclerosis Society supports four research centers, two in the United States and two in the United Kingdom, that are focused on neural protection and repair, LaRocca said.

"We have drugs that can slow or stop the progression of MS," he said. "We don't have treatments that can repair the damage to the nervous system caused by MS. That's really the next frontier. That's what we hope to see in the pipeline in the future."

Source: Yahoo! News Copyright © 2011 Yahoo! Inc (01/02/11)

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