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MS treatment hopes

Promising fast-track drug developments and a candidate to restore lost function

Man looking through Microscope Multiple sclerosis (MS) is a non-fatal neurological disorder that causes progressive disability over the course of a patient's life. The typical new patient is a young adult woman: two to three times more women than men are diagnosed with this disorder, and onset is most commonly between 20 and 40 years of age. The disease course can take two forms: relapsing-remitting and progressive. The relapsing-remitting form is when periods of worsened function (known as attacks or relapses) are followed by a degree of recovery; the progressive form is a gradual worsening of function in the absence of acute attacks. Additionally, relapsing-remitting MS can change its pattern and become progressive, and in this case it is termed secondary progressive MS.

Patients experience a diverse range of symptoms as a result of MS attacks. Fatigue and parasthesias are among the most common, but pain, disturbances in vision, and sexual, emotional and cognitive dysfunctions are all frequently reported. Spasticity, poor bladder control and mobility problems characterise later stages of the disease. Symptoms are the result of central nervous system (CNS) demyelination, caused by the patient's own immune system attacking the myelin sheaths of nerve cells in the CNS. The types of symptoms experienced are contingent upon which nerves have been damaged.

In addition to observing these symptoms, diagnosis of MS is primarily made by MRI examination of the central nervous system. Neurologists look for multiple lesions (scleroses), which are indicative of demyelination. Gadolinium-enhancing lesions are the most strongly indicative of MS, but others, such as T1 and T2 hyperintense lesions, are also associated with the disorder.

Much pharmacological treatment for MS focuses on treating symptoms and ameliorating relapses, using symptom-specific drugs and intravenous corticosteroids, although disease-modifying treatments have been available since late last century. Clinicians may recommend one of three interferons (Biogen Idec's Avonex or EMD Serono/Pfizer's Rebif, which are both formulations of interferon ß-1a, or Bayer's Betaseron, an interferon ß-1b), glatiramer acetate (Teva's Copaxone), mitoxantrone (EMD Serono's Novantrone), or natalizumab (Biogen Idec/Elan's Tsyabri).

None of these, however, has been the 'silver bullet' to multiple sclerosis. While they have been shown to have efficacy in decreasing relapses and accumulated disability, tolerability profiles leave something to be desired. Mitoxantrone is only approved in the US, and its use must be monitored as it can cause cardiomyopathy. Natalizumab carries a small but perturbing risk of progressive multifocal leukoencephalopathy.  Interferons must be injected once a week or more frequently, with the attendant discomfort of flu-like symptoms. Glatiramer acetate seems the most tolerable, but it must be injected three times per week. For these reasons, research into new, better disease-modifying MS drugs is a burgeoning area of development, with oral formulations being a strong trend.

On the fast track
Three drugs are currently in fast-track development for MS. Biogen Idec is developing BG 12 (dimethyl fumarate) as an oral capsule for the treatment of relapsing-remitting MS. BG 12 appears to have a dual mechanism of action as both an immunosuppressive/anti-inflammatory compound and a cytoprotectant. In a phase II trial published in the Lancet, significantly fewer new gadolinium-enhancing lesions were found in patients receiving 360 or 720 mg/day of BG 12 compared with placebo. This drug is now in two large phase III trials. Both will assess the effect of BG 12 on relapse rates over two years; the DEFINE study will compare relapse versus placebo, and the CONFIRM study will compare it versus glatiramer acetate (Teva's Copaxone). Results for both two-year studies are expected in 2010.

In September 2008, BioMS was granted fast-track status by the US Food and Drug Administration (FDA) for their drug dirucotide, an intravenous treatment aimed at secondary progressive MS. Dirucotide is a T-cell activation inhibitor, and works by reducing production of the antibodies that target myelin, causing an attack, in patients with human leukocyte antigen (HLA) haplotypes DR2 or DR4. A five-year follow-up to a phase II trial found a significantly longer time to progression in DR2 and DR4 carriers who received dirucotide, compared with placebo (6.5 vs 1.5 years). The two-year, pivotal, phase III MAESTRO-03 trial of dirucotide will assess time to disease progression as its primary endpoint. This trial has passed three reviews by the Data Safety and Monitoring Board, and, like the trials of BG 12, results are expected in 2010.

In February, the FDA granted fast-track status to Teva for laquinimod, a once daily oral immunomodulator under investigation for relapsing-remitting MS. Phase II results were promising, with patients treated with 0.6 mg/day of laquinimod having a significantly lower mean number of gadolinium-enhancing lesions on MRI scans over 24, 28, 32 and 36 weeks, compared with those treated with placebo. Teva is now running two pivotal phase III trials of laquinimod: the two-year, three-armed BRAVO trial, which will compare relapse rate across patients treated with laquinimod, interferon ß-1a or placebo, and the similar, two-armed (laquinimod versus placebo) ALLEGRO trial. The latter trial has finished accrual and should complete in March 2011; the former is still recruiting and is expected to finish in quarter four of the same year.

Merck Serono's cladribine, an antilymphocytic immunosuppressant approved for leukaemia and lymphoma, is a candidate oral therapy for MS. The two-year, phase III 'CLARITY' study investigated cladribine as monotherapy for relapsing-remitting MS. The primary endpoint, reduction in relapse rate, was met; registration submission in this indication is planned for mid-2009.

Sanofi-aventis' oral immunomodulator teriflunomide acts to block NF-кB, a transcription factor which may be involved in autoimmunity. Phase II results show significantly fewer unique T1 and T2 enhancing lesions in patients who received teriflunomide compared with those who received placebo, and significantly fewer patients with increased disability among those who received the 14 mg/day dose of teriflunomide, compared to placebo. Most interestingly, rates of adverse events were not significantly different from placebo. Sanofi-aventis aims to confirm these results in the four-year phase III TEMSO (TEriflunomide Multiple Sclerosis Oral) study, which has finished patient accrual and is due to complete in 2010.

Fingolimod, a lysosphingolipid receptor modulator, is being developed by Novartis for relapsing-remitting MS. Phase II results reported that patients receiving fingolimod showed significantly fewer new or persistent gadolinium-enhancing lesions over six months of treatment compared with placebo recipients; this response was sustained for the full year of the trial. Fingolimod is currently being studied in four phase III trials: 'INFORMS' (currently recruiting), which will assess time to disability progression as the primary endpoint; FREEDOMS (in progress) and FREEDOMS-II (recruiting), which will both assess relapse rates, and TRANSFORMS (in progress), which will compare the drug with interferon ß-1a (Biogen Idec's Avonex). Preliminary results of the TRANSFORMS trial suggest that fingolimod's efficacy is superior to interferon ß-1a with regard to relapse rate.

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Potential cure
One exciting option in development is high-dose cyclophosphamide. This differs markedly from other current or potential MS drugs in that, rather than aiming to ameliorate symptoms or relapses, it is designed actually to restore lost function and eliminate autoimmunity. Very high dosages of cyclophosphamide are given by four-hour infusions over four consecutive days. This destroys the peripheral immune system, allowing the patient's stem cells to create a new peripheral immune system over the following two to three weeks, at home. Cyclophosphamide is an approved cytotoxic chemotherapeutic agent and is likely to begin phase III testing in refractory MS, under the trade name Revimmune (Accentia and Biovest). Accentia intends to apply for fast-track status for Revimmune.

New hope
Myriad other drugs are in, or have completed, phase II trials. Monoclonal antibodies, novel interferons and immunomodulators, vaccines, and even an oestrogen pill are being developed to treat MS. With the plethora of options under investigation, sufferers can take new hope.

The Author
Pipeline was written by Josephine Ogle at Adis International (Wolters Kluwer Health), using data derived from Adis R&D Insight and Clinical Trials Insight. For further information on Adis services, please contact Camille Scot-Smith on 020 7981 073.
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12th May 2009


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