German pharmaceutical and chemicals company Merck KGaA has announced that the U.S. Food and Drug Administration accepted a new drug application for its oral multiple sclerosis treatment Cladribine with a priority review designation, after Merck's initial submission was rejected last fall.

Priority review status is applied to drugs that have the potential to provide significant advances in treatment and means the FDA will complete its review in six months rather than the usual 10. Merck expects a decision in the fourth quarter.

Cladribine tablets are a therapy for relapsing forms of multiple sclerosis.

Merck resubmitted its application for U.S. regulatory approval for the oral treatment Cladribine in June, after the FDA rejected the company's initial submission in November.

Merck received approval for Cladribine in Russia in early July.

Source: ADVFN Copyright 1999-2010 ADVFN PLC (28/07/10)

Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that surveyed neurologists have low awareness of Novartis/Mitsubishi Tanabe's FTY-720 (Gilenia) among the surveyed oral emerging therapies for the treatment of multiple sclerosis (MS).

According to the new report, Brand Perception Series: Physician Segmentation in Multiple Sclerosis, just over one-third of surveyed physicians have heard of FTY-720 (Gilenia) compared with three-quarters of surveyed physicians who are aware of Merck Serono/EMD Serono's oral cladribine and half of surveyed physicians who are aware of Teva/Active Biotech's laquinimod.

The majority of surveyed physicians indicate that they will use the surveyed emerging oral agents in relapsing/remitting MS patients who have failed therapy with interferon betas and Teva's Copaxone.

Only a small percentage (10 percent or less) will use the surveyed emerging oral agents in treatment-naive patients. Surveyed physicians report they will most likely prescribe these emerging oral agents for patients who cannot tolerate the side effects of their current therapy or who are unwilling to risk the side effects of Biogen Idec/Elan's Tysabri.

Thirty percent of physicians surveyed fall into the high-volume, cost-conscious prescriber segment, and value out-of-pocket cost to the patient and reimbursement restrictions more than the other segments in this analysis.

"Among the three physician segments identified in this analysis, the high-volume, cost-conscious prescribers are the most-likely to prescribe FTY-720 (Gilenia) if approved. Survey results indicate the majority of these physicians will reserve prescribing the agent to patients who have failed both interferon-betas and Copaxone, or to those who have failed Tysabri," said Decision Resources Analyst Cindy Fung, Ph.D. "While FTY-720 may be reserved as a later-line therapy, high-volume, cost-conscious physicians are not as concerned about familiarity with an agent, so they may be more willing to adopt a novel emerging agent, provided it is priced competitively."

About Brand Perception Series: Physician Segmentation

Brand Perception Series: Physician Segmentation identifies key physician segments to uncover targeted opportunities for current and emerging drug brands. This series offers a fresh look at a competitive drug market by analyzing physician perception of current and emerging drugs using unique physician profiles that will help biopharmaceutical companies understand and size market opportunities.

Source: Medical News Today © 2010 MediLexicon International Ltd (19/07/10)

Cladribine Tablets will be available in Russia under the trade name Movectro(R).

"This approval for Cladribine Tablets means that people with Relapsing/Remitting multiple sclerosis in Russia will benefit soon from this effective oral treatment", said Elmar Schnee, President of Merck Serono. "This is an important milestone reinforcing Merck Serono's leadership position and ongoing commitment to fight against the devastating disease of multiple sclerosis. We expect other regulatory approvals in the near future."

Merck Serono initiated its global filings in mid-2009 and, to date has submitted regulatory applications for Cladribine Tablets in about 40 countries.

"The availability of Cladribine Tablets in Russia will represent a key milestone for people with multiple sclerosis as this is the first approval of an orally-administered disease-modifying therapy for relapsing-remitting multiple sclerosis", said Professor Alexey Boyko, Department of Neurology and Neurosurgery at the Russian State Medical University, Moscow. "This approval is an important step toward optimizing medical care in multiple sclerosis."

"The approval of Cladribine Tablets will transform the way Russian patients with relapsing-remitting multiple sclerosis and physicians approach therapy options", said Professor Gavin Giovannoni, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, United Kingdom, and principal investigator of the CLARITY study. "I hope that this new therapeutic option will also be available soon for people living with multiple sclerosis in other countries."

Merck Serono will now apply for the listing of Cladribine Tablets within the Russian State Federal drug reimbursement program. The Company expects to launch Movectro(R) in Russia in early 2011

Russian registration was supported by the results from the CLARITY⁽¹⁾ study, the largest placebo-controlled Phase III clinical trial in relapsing-remitting MS completed to date. A total of 1,326 patients with relapsing-remitting MS were randomized at 155 centers in 32 countries, including 23 centers in Russia. The CLARITY study results, recently published in The New England Journal of Medicine⁽²⁾, show that short-course treatment with Cladribine Tablets significantly reduced relapse rates (the primary endpoint), the risk of disability progression (a key secondary endpoint), and MRI measures of disease activity (other key secondary endpoints) at 96 weeks. Adverse events that were more frequent in the Cladribine Tablets groups included lymphopenia and herpes zoster.

¹ CLARITY: CLAdRIbine Tablets Treating MS OrallY

² Giovannoni G et al. A Placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis; N Engl J Med 362:416, February 4, 2010

About the CLARITY study design

The CLARITY study was a two-year (96-week), randomized, double-blind, placebo-controlled, international trial. It randomized 1,326 patients with relapsing-remitting MS according to the revised McDonald criteria. Study participants were randomized to one of three different treatment groups consisting of two different dose regimens of Cladribine Tablets or matching placebo tablets (1:1:1 ratio). Cladribine Tablets were given in two (3.5 mg/kg total dose) or four (5.25 mg/kg total dose) treatment courses in the first year, with each course consisting of once daily administration for four to five consecutive days (depending on patient weight), which means study patients took Cladribine Tablets for 8 to 20 days during the year. In the second year, two treatment courses were administered to all patient groups, meaning that patients took Cladribine Tablets for 8 to 10 days during the year.

The primary endpoint of the CLARITY study was the relapse rate over 96 weeks. Secondary endpoints included MRI endpoints, proportion of subjects relapse-free and disability progression at 96 weeks.

About Cladribine Tablets

Merck Serono's oral formulation of cladribine (Cladribine Tablets) is an investigational treatment for patients with relapsing-remitting multiple sclerosis (MS). Cladribine is a small molecule that may interfere with the behavior and the proliferation of certain white blood cells, particularly lymphocytes, which are thought to be involved in the pathological process of MS. Merck Serono has applied for marketing approval of Cladribine Tablets in the European Union, the United States and other regions.

Source: Merck Serono (12/07/10)

Cladribine, an oral drug already marketed for hematologic cancers under the trade name Leustatin, was superior to placebo in reducing progression and other signs of MS disease activity, researchers reported at CMSC-ACTRIMS.

Freedom from any disease activity, including relapse, disability progression, or MRI progression, was experienced by 44.3% of patients treated with a high-dose of cladribine, and 43% of patients randomized to a low-dose regimen compared with 16% of placebo patients (P<0.001), said Gavin Giovannoni, PhD, from the Blizard Institute of Cell and Molecular Science at the Barts and the London School of Medicine and Dentistry in London, England.

That finding emerged from a post-hoc analysis of data from a randomized, placebo-controlled study of more than 1,300 MS patients. Giovannoni reported the results of the analysis at the Joint Consortium of Multiple Sclerosis Centers and America's Committee on Treatment and Research in Multiple Sclerosis.

"Disease activity-free outcome is a composite efficacy parameter that may become the gold standard for measuring remission," he said.

"We are looking for more sensitive disease outcomes in MS trials," Patricia Coyle, MD, of the State University of New York at Stony Brook, told MedPage Today.

"I think freedom from disease activity is a very appealing primary outcome in future relapsing trials to replace attack rate," which, she said, is "way down, even in placebo arms." She said there were multiple reasons for the decline in attack rate, including earlier treatment.

That success has made it more difficult to assess disease modifying drugs. The appeal of freedom from disease activity as an endpoint, Coyle said, "is that first, it is a composite outcome, combining clinical and MRI activity, and second, it is setting the bar higher. It's a much more demanding outcome, but it is a very reasonable one."

Cladribine is an immunomodulator which preferentially reduces long-term numbers of CD4+ and CD8+ T cells, and transiently reduces B cells, Giovannoni explained.

The new results were from the recently published CLARITY study, a phase III trial of oral cladribine versus placebo. The primary endpoints in that study indicated cladribine's ability to reduce the relapse rate by more than 50%, MRI lesions by up to 88%, and the risk for three-month disability progression by more than 30%.

The composite measure of freedom from all disease activity was not a prespecified endpoint of CLARITY.

Patients in the study had relapsing-remitting MS, with no more than one disease modifying treatment failure, and no disease-modifying treatment within the past three months. Patients were randomized to either placebo or cladribine doses 3.5 mg/kg or 5.25 mg/kg over the 96-week trial.

Freedom from disease activity was defined as having no relapse, no sustained three-month disease progression, and an absence of T1 gadolinium-enhancing lesions and active T2 lesions over the course of the trial.

The percent of patients free from relapses was 60.9% versus 79.7% for low-dose cladribine and 78.9% for high dose cladribine (P<0.01).

Freedom from three-month disease progression was 85.9% for the low-dose and 84.9% for the high dose cladribine versus 79.4% for placebo (P<0.01).

Roughly nine of every ten patients in the high dose cladribine arm (91.0%) were free from T1 Gd+ lesions versus 86.8% in the low dose arm and just 48.3% of the controls (P<0.01). And absence of active T2 lesions was 62.5% for the high dose group, 61.7% for the low-dose arm, and 28.4% in controls (P<0.01).

The odds ratio of being disease activity-free compared with placebo was 3.99 (95% confidence interval 2.89 to 5.49) for the low dose, and 4.24 (95% CI 3.09 to 5.82) for the high dose.

Similar findings were observed in patients with quiescent T1 Gd+ lesions at baseline -- 46.6% of high dose and 51.5% of low dose patients in this subset were disease-free after treatment versus 21% of controls (P<0.001) as well as for among those with active Gd+ lesions at baseline (39.%% of high dose and 24.6% of low dose patients were disease free after three months versus 3.9% of the placebo patients [P<0.001]).

"Together with the observed tolerability and safety [reported elsewhere], these results suggest that annual short-course treatment with cladribine tablets may provide an important new option in MS therapy," Giovannoni said.

Late last year, Merck Serono said it had received a refuse to file letter from the FDA in response to its New Drug Application for cladribine tablets as a therapy for relapsing forms of MS. The company said at the time that it was working with the FDA to complete the necessary information for a successful filing of the NDA.

The study was supported by Merck Serono.

Giovannoni reported receiving compensation from Merck Serono, Bayer-Schering Pharma, Biogen Idec, and Teva-Aventis.

Coyle received research support from Bayer HealthCare Pharmaceuticals, Novartis Pharmaceutical, and sanofi-aventis. She has also received grants for educational activities from Bayer HealthCare Pharmaceuticals, Biogen Idec, Merck Serono, Pfizer, and Teva Neuroscience.

And she has served as an adviser or consultant for Bayer HealthCare Pharmaceuticals, Biogen Idec, Merck Serono; Novartis Pharmaceuticals , Pfizer, sanofi-aventis, and Teva Neuroscience.

Primary source: International Journal of MS Care
Source reference:
Giovannoni G, et al "Disease activity-free outcome with cladribine tablets during the CLARITY study" International J MS Care 2010; 12(suppl1): 88.

Source: Medpage Today © 2004-2010 MedPage Today, LLC (09/06/10)

German pharmaceutical and chemicals company Merck KGaA said Tuesday it resubmitted its application for U.S. regulatory approval of oral multiple sclerosis treatment cladribine--seven months after the Food and Drug Administration rejected its initial submission.

The FDA last November refused to file Merck's application for approval and the German group's management has since been working with the U.S. drug regulator to address the issues that led to the refusal. A Merck spokeswoman Tuesday declined to say what additional information it provided to the FDA as part of the resubmission.

Analysts at Merck Finck & Co. expect the FDA to approve the drug, saying the company has communicated closely with authorities to amend its filing since the refusal.

The delay has given rival drug Gilenia - FTY720 from Swiss firm Novartis AG  a lead on approval in the U.S. Analysts say Gilenia could be on the U.S. market in the second half of this year, with the FDA advisory committee set to deliberate on the drug on June 10.

Cladribine aims to reduce relapses in people with relapsing forms of MS. The two treatments raise the possibility for the first time that oral treatments might become available alongside the more cumbersome injections and infusions currently used to treat MS.

Merck is also awaiting approval for cladribine in Europe, which it expects to come in the third quarter of this year.

Source: ADVFN Copyright 1999-2010 ADVFN PLC (09/06/10)

Germany's Merck KGaA still sees its application for European approval of multiple sclerosis pill cladribine on track, while regulatory clearance in the United States remains uncertain.

The head of Merck's drug unit Elmar Schnee said at the group's annual shareholder meeting that advisors to EU regulators would probably issue an assessment of the drug in the third quarter, adding he was confident about an approval.

Merck filed for European approval in July 2009.

It has previously said that in an ideal scenario, cladribine could win European approval in the fourth quarter.

Merck has slipped behind Swiss rival Novartis in the race to get the first oral multiple sclerosis treatment to market after the U.S. Food and Drug Administration (FDA) held up its application to bring cladribine to market. 

Novartis has since submitted its pill, FTY720 or Gilenia, for approval in the United States and Europe while investors have been kept wondering what Merck has to do to get its U.S. application back on track.

The German company also said on Friday it was still in talks with the FDA to refile cladribine application as soon as possible.

In February Novartis won U.S. priority review status for its oral treatment, Gilenia (FTY720), for multiple sclerosis.

Source: Reuters  Copyright 2010 Thomson Reuters (09/04/10)

A major trial of the oral drug Cladribine – results of which are published in the New England Journal of Medicine on 20 January 2010 – has shown that it significantly reduces relapse and deterioration of the disease, and goes a long way to eliminating the unpleasant side effects associated with existing therapies.

Cladribine is vying to be the first ever treatment in tablet form for MS, and only needs be taken for between 8 to 10 days a year, eliminating the need for regular injections and intravenous infusions otherwise endured by sufferers. The ease with which Cladribine tablets can be administered, combined with its relatively few side effects, make it a hugely exciting development in the world of MS.

Multiple sclerosis is a disabling neurological condition which usually starts in young adulthood. It results from the body's own immune system damaging the central nervous system. This interferes with the transmission of messages between the brain and other parts of the body and leads to problems with vision, muscle control, hearing and memory. Cladribine tablets work by suppressing the immune system thus compromising its ability to further attack the central nervous system.

Led by Professor Gavin Giovanonni at Barts and The London School of Medicine and Dentistry, the new study involved over 1,300 MS patients who were followed up for nearly two years and monitored using MRI scans. Patients were given either two or four short treatment courses of Cladribine tablets per year, or a placebo. Each course consists of one or two tablets per day for four or five days, adding up to just eight to 20 days of treatment each year.

Compared to patients who were taking a placebo, those taking Cladribine tablets were over 55 per cent less likely to suffer relapse, and 30 per cent less likely to suffer worsening in their disability due to MS.

Professor Giovanonni said: "The introduction of an oral therapy, particularly one that has no short term side effects and is as easy to use as oral Cladribine, will have a major impact on the treatment of MS.

"However, the use of this drug as a first line therapy will have to be weighed up against the potential long term risks which have yet to be defined."

Source: Queen Mary, University of London © Disabled World 2010 (21/01/10)

Oral Therapy for Multiple Sclerosis — Sea Change or Incremental Step? William M. Carroll, M.B., B.S., M.D., F.R.A.C.P.

The long-awaited arrival of oral formulations for the treatment of relapsing-remitting multiple sclerosis is welcome news for the estimated 2.5 million people worldwide who have this chronic, disabling disease. Since the publication of the first pivotal trial of interferon beta-1b in 1993,¹ practitioners and patients alike have been anticipating the approval of oral therapies because of the relative ease of administration, which should improve adherence and reduce restrictions on lifestyle.

In this issue of the Journal, researchers report the results of three well-conducted trials of the first two oral agents, cladribine and fingolimod, in the treatment of multiple sclerosis. The researchers studied cladribine in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial² and fingolimod in the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) trial³ and the Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS).⁴ Although these two drugs differ in their mechanisms of action, both reduce the number of potentially autoaggressive lymphocytes that are available to enter the central nervous system. The articles, which report that the agents are effective and have manageable adverse-effect profiles, raise three questions: How do these therapies measure up against the existing treatments? Are all the longer-term adverse effects known? What do these drug trials tell us about multiple sclerosis and our treatment goals?

Both cladribine (in the CLARITY trial) and fingolimod (in the FREEDOMS trial) were highly effective against placebo over a 2-year period, and fingolimod was more effective than intramuscular interferon beta-1a over a 12-month period (in the TRANSFORMS trial). Each of the three studies involved more than 130 centers in up to 32 countries, and the enrollments of 1272 to 1326 patients ensured that the trials were sufficiently powered to detect an effect of two doses of the active oral agent. Patients had active relapsing disease with durations of 7 to 9 years. On the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), patients had a median score of 2.0 in the fingolimod trials and mean scores ranging from 2.9 to 3.0 in the cladribine trial.

All three studies used the annualized rate of relapse as the primary end point, and high and low doses of cladribine and fingolimod were shown to be superior to both placebo and interferon beta-1a. For cladribine versus placebo, the relative risk reduction in the annualized relapse rate was 57.6% for the group receiving 3.5 mg per kilogram of body weight and 54.5% for those receiving 5.25 mg per kilogram. For fingolimod versus placebo, the relative risk reduction was 54% for the 0.5-mg dose and 60% for the 1.25-mg dose. For fingolimod versus interferon beta-1a, the relative risk reduction was 52% for the 0.5-mg dose and 39% for the 1.25-mg dose. Both agents were superior to the comparators with respect to secondary end points, including measures on magnetic resonance imaging and a number of clinical end points, including the time to the progression of sustained disability at 3 months.

Furthermore, although only fingolimod was tested against the widely used interferon beta-1a, it is likely that the two oral therapies will be at least as effective as other currently available disease-modifying therapies. In this regard, head-to-head trials of subcutaneous interferon beta-1b⁵ and interferon beta-1a⁶ versus intramuscular interferon beta-1a showed advantages of both subcutaneous regimens over the latter. More recent trials were unable to separate the clinical efficacy of the two subcutaneously administered forms of interferon beta from that of glatiramer acetate.⁷

Adverse effects were similar in all three trials of cladribine and fingolimod, and rates of events leading to discontinuation of a study drug were low but still at least twice as frequent with high-dose cladribine (7.9% for the 5.25-mg dose) and fingolimod (10% and 14% for the 1.25-mg dose). Herpetic infections occurred among patients receiving both cladribine and fingolimod. The rate of herpes infections among patients receiving the 1.25-mg dose of fingolimod was 5.5%; such infections were serious in three of these patients, two of whom died. Twenty cases of cutaneous herpes zoster were recorded among patients receiving cladribine, three of which were serious. Three solid tissue cancers (pancreatic, ovarian, and melanoma) occurred among patients receiving low-dose cladribine (3.5 mg per kilogram). Basal-cell carcinoma, melanoma, and breast cancer were all more common among patients receiving fingolimod than among those receiving interferon beta-1a. Macular edema was confirmed in 13 patients, 11 of whom received high-dose fingolimod (7 in the FREEDOMS trial and 4 in the TRANSFORMS trial). Of these 13 patients, 11 recovered within 1 to 6 months after discontinuation of therapy, and the condition of the other 2 patients stabilized. Transient bradycardia and first- and second-degree heart block occurred more frequently among patients receiving high-dose fingolimod than in the comparator groups. Lymphocytopenia was frequent in patients receiving both agents, more so with higher doses. Clinicians and patients will need to evaluate the risks and benefits of each of these drugs. Given the recent studies documenting the development of progressive multifocal leukoencephalopathy among patients receiving natalizumab, a monoclonal antibody against 4-integrin,8 close postmarketing surveillance will be important to detect any increase in these or other unexpected adverse effects.

The mechanism of action of both oral agents represents a major change from those of currently available drugs for multiple sclerosis. Among a number of actions that are claimed for current therapies is that they change the emphasis of the immune response from activation of proinflammatory type 1 helper T cells to activation of antiinflammatory type 2 helper T cells. Even though cladribine is administered in two or four short courses annually, whereas fingolimod is given daily, both drugs were associated with persistent lymphocytopenia. Cladribine is resistant to the enzyme adenosine deaminase, which causes an accumulation of toxic deoxyribonucleotides in lymphocytes, resulting in relatively selective long-term depletion of CD4+ and CD8+ T cells.9 Fingolimod is a synthetic analogue of myriocin that is derived from a fungus (Isaria sinclairii). Once phosphorylated, the drug acts to down-regulate the sphingosine-1-phosphate receptor required for antigen-activated lymphocytes to egress, effectively locking them in the nodes.10 Thus, both cladribine and fingolimod are targeting inflammation, the key driver of immune injury in multiple sclerosis. Similarly, both natalizumab, which blocks lymphocyte access to endothelium in the central nervous system, and the anti-CD52 monoclonal antibody alemtuzumab, which destroys T and B cells, have shown impressive reductions in disease activity.11 Insights from these trials and others treating the initial stages of disease12 suggest that early direct targeting of the immune system offers the best hope for the prevention of later disability.

The studies in this issue of the Journal provide a new horizon for patients with relapsing–remitting multiple sclerosis and a welcome increase in the range of treatment options. Although current therapies remain very effective, particularly when they are administered early, and have well-defined side-effect profiles, oral therapies further support a change in treatment approach to directly prevent immune-mediated injury. This approach will probably be followed until the next step in the therapeutic advance occurs, but such a change in strategy highlights the final question: What are the long-term goals of this new phase of therapy? The question will not be fully answered until the underlying cause of multiple sclerosis is better understood, but the lack of a definable end point remains a contentious issue for clinicians and health care funders alike. Time will determine the long-term effectiveness of these treatments in delaying the development of irreversible disability, and as ongoing, real-life experiments, they will contribute to our understanding of this enigmatic disease.

References

The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655-661.
Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010. DOI: 10.1056/NEJMoa0902533.
Kappos L, Radue E-W, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010. DOI: 10.1056/NEJMoa0909494.
Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010. DOI: 10.1056/NEJMoa0907839.
Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 2002;359:1453-1460. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the Evidence Trial. Neurology 2002;59:1496-1506. 
Achiron A, Fredrikson S. Lessons from randomised direct comparative trials. J Neurol Sci 2009;277:Suppl 1:S19-S24. 
Iaffaldano P, D'Onghia M, Trojano M. Safety profile of Tysabri: international risk management plan. Neurol Sci 2009;30:Suppl 2:S159-S162.
Sipe JC. Cladribine for multiple sclerosis: review and current status. Expert Rev Neurother 2005;5:721-727.
Massberg S, von Andrian UH. Fingolimod and sphingosine-1-phosphate -- modifiers of lymphocyte migration. N Engl J Med 2006;355:1088-1091. 
The CAMMS223 Trial Investigators. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008;359:1786-1801. 
Goodin DS, Bates D. Treatment of early multiple sclerosis: value of treatment initiation after a first clinical episode. Mult Scler 2009;15:1175-1182.

Source: The New England Journal Of Medicine (10.1056/NEJMe0912019) © 2010 Massachusetts Medical Society. (21/01/10)

U.S. regulators rejected as incomplete Merck KGaA's application to sell the oral treatment multiple sclerosis.

Merck, the  German based drugmaker will seek a meeting with the U.S. Food and Drug Administration after the agency refused to accept its application for the medicine, cladribine, spokesman Gangolf Schrimpf said.

“Our next step is to request a meeting with the FDA,” Schrimpf said in a telephone interview. “We’re not in a position to discuss the details of the FDA letter.”

Merck, which is vying with Novartis AG to market the first oral MS drug, asked the FDA in September to approve cladribine.

“This will certainly delay market entry, the amount of time depending on the full nature of the required actions,” DZ Bank AG analysts Elmar Kraus and Thomas Maul said in a research note today. Merck’s lead over Novartis “should now be gone.”

A refusal to file indicates “important information” was missing from the application, according to regulations dated 1993 that are posted on the FDA’s Web site. Minor omissions that wouldn’t significantly delay an application shouldn’t be grounds for refusal, according to the FDA rules.

Compete

Unlike existing injected medicines for multiple sclerosis, the Merck drug, approved more than a decade ago to fight leukemia, is taken for a few weeks out of the year in pill form. The drug works by suppressing the immune system, blunting its attack on nerve cells. Merck’s pill could compete with Novartis’s experimental multiple sclerosis pill FTY720, which disrupts the movement of immune cells into the bloodstream.

Cases of cancer in people who took cladribine during a clinical trial appear “relatively non-threatening,” and the drug is likely to be adopted gradually by patients with severe forms of multiple sclerosis, Sanford C. Bernstein Ltd. analysts concluded after data was presented at the European Committee for Treatment and Research in Multiple Sclerosis congress in Dusseldorf, Germany, in September.

In January, Merck said four patients were diagnosed with cancer during a final-stage trial of cladribine. An independent monitoring board was aware of the cases but didn’t consider them a safety concern, Merck said at the time.

Cancer

Each of the four cancer cases in the trial affected a different organ. Patients were diagnosed with early stage cervical cancer, melanoma, ovarian cancer and pancreatic cancer. Another patient developed choriocarcinoma, a cancer of the placenta, after becoming pregnant six months after she finished the study. No malignancies were reported in the placebo group.

Merck asked EU regulators to approve cladribine in July. Sales of the medicine could reach 700 million euros ($1.05 billion) a year, according to an estimate by DZ Bank.

Novartis has said it would ask U.S. and European regulators to approve its MS pill at the end of this year. The Swiss drugmaker has said it aims for at least $1 billion in sales for its multiple sclerosis franchise.

Source: Bloomberg © 2009 Bloomberg LP (30/11/09)

Merck Serono, a division of Merck KGaA, Darmstadt, Germany, announced today the submission of a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for Cladribine Tablets, Merck Serono’s proprietary investigational oral formulation of cladribine, as a therapy for reducing relapses in people with relapsing forms of multiple sclerosis (MS).

Cladribine Tablets has the potential to be the first orally administered disease-modifying therapy available for people living with relapsing MS, as all disease-modifying therapies currently approved for the treatment of MS are parenteral therapies.

“As a leader in the area of neurodegenerative diseases, we continue to focus on making a positive difference in the lives of people living with MS, and their families,” said Fereydoun Firouz, President and CEO of EMD Serono, Inc., the US subsidiary of Merck Serono. “If approved, short-course therapy with Cladribine Tablets could transform the way people approach their treatment options, and meet an unmet need as an oral, disease-modifying drug available for MS. We look forward to working with the FDA during the course of the regulatory process.”

Commenting on the study, Helen Yates, Multiple Sclerosis Resource Centre Chief Executive said, "To see yet another oral therapy moving ever closer to the market is superb news for people affected by MS.  The CLARITY study has shown good results in both its primary and secondary endpoints and Cladribine offers another choice for people with MS that does not involve injections which has huge significance for individuals who find injecting difficult."

The NDA submission is supported by results from the CLARITY^(a) study, a two-year, randomized, double-blind, placebo-controlled Phase III trial of Cladribine Tablets in people with relapsing-remitting MS. The NDA also shows that all primary and secondary endpoints of the CLARITY trial were met. The CLARITY data were presented at the 61st Annual Meeting of the American Academy of Neurology (AAN) in April 2009 and at other recent international scientific meetings.

Merck Serono submitted a marketing authorization application to the European Medicines Agency (EMEA) for Cladribine Tablets in July 2009.

^(a) CLARITY: CLAdRIbine Tablets Treating MS OrallY

About the CLARITY study

The CLARITY study was a two-year (96-week), randomized, double-blind, placebo-controlled, international trial. It randomized 1,326 patients with relapsing-remitting MS according to the revised McDonald criteria. Study participants were randomized to one of three different treatment groups consisting of two different dose regimens of Cladribine Tablets or matching placebo tablets (1:1:1 ratio). Cladribine Tablets were given in two or four treatment courses in the first year, with each course consisting of once daily administration for four to five consecutive days, which means study patients took Cladribine Tablets for 8 to 20 days during the year. In the second year, two treatment courses were administered to all patient groups. The primary endpoint of the CLARITY study was the relapse rate at 96 weeks. Secondary endpoints included MRI endpoints, proportion of subjects relapse-free and disability progression at 96 weeks. Out of the 1,326 randomized patients, 90% of patients treated with Cladribine Tablets completed the study (92% in the lower total dose group and 89% in the higher total dose group) compared to 87% in the placebo group.

About Cladribine Tablets

Merck Serono’s proprietary oral formulation of cladribine (Cladribine Tablets) is currently being evaluated in Phase III as a treatment for patients with relapsing forms of multiple sclerosis (MS). Cladribine is a small molecule that may interfere with the behaviour and the proliferation of certain white blood cells, particularly lymphocytes, which are thought to be involved in the pathological process of MS.

The clinical development program for cladribine tablets includes:

- The CLARITY extension study: a two-year placebo-controlled extension of the CLARITY study, designed to provide data on the long-term safety and efficacy of extended administration of Cladribine Tablets for up to four years - The ORACLE MS study: a two-year Phase III placebo-controlled trial designed to evaluate the efficacy and safety of Cladribine Tablets as a monotherapy in patients at risk of developing MS (patients who have experienced a first clinical event suggestive of MS). This trial was announced in September 2008 and is ongoing. - The ONWARD study: a Phase II placebo-controlled trial designed primarily to evaluate the safety and tolerability of adding Cladribine Tablets treatment to patients with relapsing forms of MS, who have experienced breakthrough disease while on established interferon-beta therapy. This trial was announced in January 2007 and is ongoing.

Cladribine Tablets has been granted a fast track designation by the US Food and Drug Administration based on the need for an oral therapy in a subset of patients with relapsing forms of multiple sclerosis.

Source: Merck Serono and MSRC (01/10/09)

A new analysis of data from a clinical trial of Merck KGaA's oral drug cladribine has underscored its potential as a treatment for multiple sclerosis, researchers said on Friday.

The fresh finding from the Phase III trial -- headline results of which were first presented in April -- showed a short course of cladribine tablets significantly increased the proportion of patients without disease activity after two years.

Commenting on the study, Helen Yates, Multiple Sclerosis Resource Centre Chief Executive said, “The work that is being undertaken on oral therapies is very important to people with MS.  Removing the need for weekly or even daily injections is a goal that is understandably significant.  Cladribine seems to be producing good results in trials and it is hoped that this drug makes the final part of its journey to market and becomes available to people with MS for whom it is appropriate!"

Research presented at the European Committee for Treatment and Research in Multiple Sclerosis congress in Duesseldorf found 43 and 44 percent of patients treated with two different doses of cladribine had absence of disease activity, compared with 16 percent of those on placebo.

Lead investigator Peter Rieckmann of Germany's Bamberg Hospital said achieving such long-term remission was a very important goal in treating the condition.

The German drugmaker is leading the race to develop the first multiple sclerosis drug that can be taken orally, rather than by injection or infusion.

Cladribine, like rival oral drug FTY720 from Swiss drugmaker Novartis appears more effective than current leading treatments.

But both experimental drugs cause side effects because they interfere with the body's immune system. As a result, the companies must persuade physicians and investors that the balance of risk and benefit stacks up.

Merck submitted a marketing application for cladribine in Europe in July and expects to file in other countries, including the United States, during the third quarter of 2009.

Source: Reuters © Thomson Reuters 2009 and MSRC (11/09/09)

Owing to its infrequent dosing and positive efficacy, nearly 90 percent of surveyed neurologists indicate they will prescribe Merck Serono/EMD Serono's oral cladribine for the treatment of multiple sclerosis.

The new Physician & Payer Forum report entitled Multiple Sclerosis: How Will Clinician Attitudes and Reimbursement Issues Determine How Orals Will Compete with Current Disease-Modifying Drugs in this Dynamic Landscape? finds that the percentage of surveyed neurologists willing to prescribe oral cladribine is higher than the percentage willing to prescribe the emerging oral therapies Biogen Idec's BG-12 and Novartis/Mitsubishi Tanabe's FTY-720 (fingolimod).

The report also finds that emerging oral therapies will likely be prescribed most often to patients with relapsing-remitting multiple sclerosis and as second-line therapies.

"Neurologists we surveyed indicate that oral cladribine, FTY-720, and BG-12 will each be prescribed to patients with any disease subtype but that these therapies will be preferentially prescribed to approximately one-quarter of patients with relapsing-remitting disease," said Decision Resources Analyst Bethany Kiernan, Ph.D. "This is likely due to these agents' ongoing clinical trials involving relapsing-remitting multiple sclerosis patients. Additionally, surveyed neurologists will prescribe emerging oral therapies to about one-fifth of secondary progressive multiple sclerosis patients. Yet despite the similarities in projected prescribing patterns among these therapies, our findings indicate that oral cladribine will be favoured over FTY-720 as well as BG-12, suggesting that clinicians have begun to differentiate these oral agents from one another."

The report also finds that the majority of surveyed MCO pharmacy directors will give emerging oral therapies non-preferred tier status on their commercial plans. More than half of surveyed MCOs expect to place oral cladribine, FTY-720 and BG-12 on tier 3 of their commercial plans' formularies. Surveyed pharmacy directors cite the high cost of these agents as the main reason for their non-preferred status. However, about one-quarter of surveyed pharmacy directors expect to place these therapies on tier 2 of their formularies, which is likely due to their perceived advantages in efficacy, safety, and/or convenience compared with current drugs.

Multiple Sclerosis: How Will Clinician Attitudes and Reimbursement Issues Determine How Orals Will Compete with Current Disease-Modifying Drugs in this Dynamic Landscape? is based on a U.S. survey of 102 neurologists and 20 MCO pharmacy directors. Their responses were compared to assess similarities and differences of opinion regarding clinical, economic and scientific factors.

Source: Decision Resources (10/09/09)

Merck KGaA asked European regulators to approve its pill for multiple sclerosis, the next step in the German drugmaker’s race against Novartis AG to market the first oral medicine for the debilitating nerve disease.

Merck submitted a marketing authorization application for the pill, cladribine, to the European Medicines Agency and plans an application to U.S. regulators this quarter, the Darmstadt, Germany-based maker of drugs and chemicals said in an e-mailed statement today.

The application “brings us closer to the possibility of providing an oral short-course treatment to patients with multiple sclerosis,” Roberto Gradnik, an executive vice president in Merck’s Serono division, said in the statement.

Merck presented clinical trial data at the American Academy of Neurology conference in April showing that cladribine halved the risk of relapse, with a side effect in some patients of depleting the white blood cells that protect the body from infection. Patients who took cladribine were less likely to see their multiple sclerosis progress and more likely not to relapse at all than those on a placebo, the two-year trial showed.

Five people were diagnosed with cancer, including one case of choriocarcinoma, a cancer of the placenta, in a woman who became pregnant six months after she finished the study.

Unlike existing injected medicines for multiple sclerosis, cladribine, approved to fight leukemia more than a decade ago, is taken for a few weeks out of the year in pill form. The medicine works by suppressing the immune system, blunting its attack on nerve cells. Merck’s pill could compete with an experimental pill from Novartis, FTY720, which disrupts the movement of immune cells into the bloodstream.

“A market entry in Europe beginning of 2010 seems feasible, as should be the case for the U.S.,” Elmar Kraus and Thomas Maul, analysts for DZ Bank AG, wrote in a note to investors.

Source: Bloomberg © Bloomberg L.P (24/07/09)

The Effect of Short-course Oral Treatment With Cladribine Tablets on Annualized Relapse Rate was Significant as Early as 12 Weeks After Initiation of Treatment and Sustained Through to the 96 Weeks of the Study

Merck Serono, a division of Merck KGaA, Darmstadt, Germany, announced today new data from post-hoc analyses of the 2-year (96-week) placebo-controlled CLARITYa Phase III trial using Cladribine Tablets (Merck Serono's proprietary investigational oral formulation of cladribine) to treat patients with relapsing-remitting multiple sclerosis. These data show that short-course oral treatment with Cladribine Tablets resulted in rapid and sustained improvements in clinical and magnetic resonance imaging (MRI) outcomes, which were accompanied by rapid and sustained effects on blood-cell subtypes implicated in the pathogenesis of multiple sclerosis. The data will be presented at the 19th Meeting of the European Neurological Society (ENS) in Milan, Italy. ^(1,2,3,4)

"The early impact on relapse reduction, together with the evidence for sustained benefits over 96 weeks as shown in the CLARITY study, support the short-course annual dosing regimen for Cladribine Tablets," said Prof. Giancarlo Comi, Professor of Neurology at the University Vita-Salute San Raffaele in Milan, Italy and an investigator for the CLARITY study. "Short-course oral treatment with Cladribine Tablets has the potential to make a meaningful difference in the lives of people with multiple sclerosis and their families."

A total of 1,326 patients were randomized to one of three different arms of the CLARITY study, consisting of two different dose regimens of Cladribine Tablets or matching placebo tablets (1:1:1 ratio). Cladribine Tablets were given in two (low-dose regimen) or four (high-dose regimen) treatment courses in the first year, with each course consisting of once daily administration for four to five consecutive days (depending on patient weight), which means study patients took Cladribine Tablets for 8 to 20 days during the year. In the second year, two treatment courses were administered to all patient groups, meaning that patients took Cladribine Tablets for 8 to 10 days during the year.

In the CLARITY study, Cladribine Tablets significantly reduced the annualized relapse rate compared with placebo (primary endpoint). This effect was significant (as indicated by non-overlap of 95% confidence intervals versus placebo) as early as 12 weeks after initiation of treatment for patients treated with the low-dose regimen of Cladribine Tablets (low-dose regimen: 0.20; placebo: 0.49), and 16 weeks after initiation of treatment for both Cladribine Tablets treatment groups (low-dose regimen: 0.19; high-dose regimen: 0.21; placebo: 0.44). Effects were sustained through to the 96 weeks of the study with relative reductions in annualized relapse rates greater than 50% for patients treated with Cladribine Tablets with respect to placebo (low-dose regimen: 0.14; high-dose regimen: 0.15; placebo: 0.33 , p<0.001 for both treatment groups).

Lower mean numbers of different types of brain lesions (as measured by pre-specified key MRI endpoints) were observed for both Cladribine Tablets treatment groups by the first assessment point (24 weeks) and were sustained through the 96-week evaluation period, achieving high levels of statistical significance (all p<0.001). The pre-specified key MRI secondary endpoints were T1 gadolinium-enhanced, active T2 lesions and combined unique lesions.

The effects of Cladribine Tablets on clinical and MRI measures were accompanied by rapid and sustained effects on blood-cell subtypes implicated in the pathogenesis of multiple sclerosis, such as T cells (CD3+, CD4+ and CD8+), and more transiently B cells (CD19+).

Overall, the frequencies of adverse events by MedDRA System Organ Class in both Cladribine Tablets treatment groups from the CLARITY study were comparable to those observed in the placebo group. The most commonly reported adverse events were headaches, upper respiratory tract infection, nasopharyngitis and nausea. Lymphopenia, an expected event based on the presumed mechanism of action of cladribine, occurred more frequently in the Cladribine Tablets treatment groups (low-dose regimen: 21.6%; high-dose regimen: 31.5%; placebo: 1.8%). The overall rate and incidence of infections in patients treated with Cladribine Tablets and placebo were similar. Herpes zoster infections were reported in 2.3% of patients treated with Cladribine Tablets. These herpes infections were localized to the skin and responded appropriately to treatment.

Merck Serono plans to submit Cladribine Tablets for registration to the European Medicines Agency (EMEA) and to the US Food and Drug Administration (FDA) during summer 2009.

References:

⁽¹⁾ G. Giovannoni et al. Clinical efficacy of cladribine tablet therapy in patients with relapsing-remitting multiple sclerosis: results from the CLARITY study, a 96-week, Phase III, double-blind, placebo-controlled trial

⁽²⁾ P. Soelberg-Sørensen et al. Haematological profiles in patients treated with cladribine tablets for relapsing-remitting multiple sclerosis: results from the CLARITY study, a 96-week, Phase III, double-blind, placebo-controlled trial

⁽³⁾ G. Comi et al. Magnetic resonance imaging (MRI) outcomes in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets: results from the CLARITY study, a 96-week, Phase III, double-blind, placebo-controlled trial

⁽⁴⁾ P. Vermersch et al. Rapid and sustained efficacy with cladribine tablet treatment in relapsing-remitting multiple sclerosis: results from the CLARITY study, a 96-week, Phase III, double-blind, placebo-controlled trial

Source: Cloud Computing Journal © 2009 SYS-CON Media, Inc (22/06/09)

Merck KGaA reported late-stage data showing that its cladribine tablets significantly cut the rate of clinical relapses, disability progression and brain lesions in patients suffering from relapsing remitting multiple sclerosis, echoing preliminary data reported earlier this year.

But a handful of cancer cases in the study may raise some safety concerns for physicians that must choose cladribine over alternative therapies that have longer safety data in larger patient populations.

Merck, based in Germany, is currently leading the race to bring an oral therapy to patients with the debilitating disease and plans to use the data to file for regulatory approval in Europe and the U.S. in mid-2009. Currently, the leading MS therapies sold by Biogen Idec Inc. are once-daily injections.
"When you have the possibility to be first, you have the possibility to shape the market," said Elmar Schnee, head of Merck's pharmaceuticals business and member of its executive board, in an interview.

In January, Merck reported that the company-run trial, involving 1,326 patients and lasting two years, met its primary goal of reducing the annualized relapse rate in comparison to placebo, cutting that rate by between 55% and 58% depending on the dosage.

The full data, presented at the American Academy of Neurology meeting in Seattle, show that the relative relapse risk in cladribine was about half of that seen in patients on placebo.

Over two years, 80% of the patients in the low-dose group and 79% of those in the high-dose group experienced no clinical relapse, compared to 61% of those on placebo.

In another secondary goal of the trial, cladribine treatment cut the risk of disability progression by more than 30%. Both doses also reduced different types of brain lesions in MS patients, according to the study.

Notably, four patients in the cladribine group developed cancer during the study and another case emerged six months after the study ended. One of the patients eventually died.

There were no occurrences of cancer in the placebo arm.

The cancers were "isolated cases" in different organ systems, Merck said, and expects that ongoing studies may shed more light on the issue.

"I think this will help in trying to understand if there is, or there is not, a relationship between cladribine and the occurrence of malignancies," said Bruno Musch, head of global clinical development for neurodegenerative diseases at Merck.

"So far, there is no element to conclude that there is a relationship," he said.

Lymphopenia, a decrease in a type of white blood cells called lymphocytes, occurred more frequently in the cladribine groups - 22% of patients in the low dose and 31% in the high dose. The development was expected because the drug disrupts certain white blood cells that are thought to play a role in MS.

No related increase in patient infections was reported in the study.

Helen Yates, Chief Executive of the Multiple Sclerosis Resource Centre (MSRC) said,:

"It is very encouraging news that Cladribine seems to not only reduce relapse rate but also seems to have a positive impact on disability progression.  However we would like to see the issues and concerns about the potential carcinogenic factors addressed as soon as possible so that people affected by MS can consider this treatment without the concern of cancer causing agents. Nevertheless, any oral therapy that demonstrates efficacy is very welcome as injectable therapies cause concerns and discomfort for so many"

Merck expects that it can gain approval for cladribine using only the one Phase III study, and has spoken with European and U.S. regulators about the issue.

Cladribine is taken very infrequently when compared to many MS drugs that are taken daily. In the study, patients were given two or four treatment courses in the first year, with each course being a daily pill for four to five consecutive days. In the second year, two treatment courses were administered to all patient groups.

Despite its infrequent dosing and being a pill, rather than a biologic, Merck will likely be aggressive in pricing the drug.

"I think that pricing has to be in line with the benefits that the drug brings to the patient," Schnee said. "It doesn't differ if you have an injectable or if you have a tablet."

Biogen's Avonex, the MS market leader, is currently sold for about $30,000 a year.

Although Merck is aiming to be the first oral therapy, Novartis AG is hot on its heels.

Earlier Wednesday, the Swiss drug giant said data on its own MS pill, FTY720, showed that 80% to 83% of patients remained free of relapses during the one-year study - compared to 69% of those who took Avonex.
Novartis also disclosed a patient death, highlighting concerns about the drug's safety profile. The company plans to file for regulatory approval in Europe and the U.S. at the end of 2009.

Biogen, which has a product portfolio focused on MS, is developing BG-12, an oral drug in late-stage trials with data likely in 2011.

Source: Marketwatch © 2009 MarketWatch, Inc (30/04/09)

- Two-Year Primary Efficacy Endpoint of CLARITY Trial met: 58% Relative Reduction in Annualized Relapse Rate in the low Total Dose Treatment Group and 55% in the High Total Dose Treatment Group

- Submission for Registration of Cladribine Tablets Planned for mid-2009

- Cladribine Tablets are the First Oral Investigational Multiple Sclerosis Treatment to Complete a Two-Year Pivotal Study

Merck Serono, a division of Merck KGaA, Darmstadt, Germany, announced today that the CLARITY⁽¹⁾ Phase III pivotal trial of its proprietary oral formulation of cladribine (cladribine tablets) met the two-year primary endpoint of clinical relapse rate reduction in patients with relapsing-remitting multiple sclerosis (MS).

The two cladribine tablet treatment groups of the study, assessing different dose regimens, demonstrated a statistically significant reduction in the annualized rate of relapses compared to placebo. Patients from the lower total dose group experienced a 58% relative reduction in annualized relapse rates with respect to placebo (0.14 versus 0.33 for the placebo group; pOverall, the frequencies of adverse events were low in the cladribine tablet treatment groups and were comparable to that observed in the placebo group. Lymphopenia, an expected event based on the presumed mechanism of action of cladribine, occurred more frequently in the cladribine tablet treatment groups. With the exception of lymphopenia, the most frequently reported adverse events in the three study groups were headaches and nasopharyngitis.

"We believe the CLARITY data mark an important milestone in the assessment of investigational oral treatments for multiple sclerosis and that cladribine tablets have the potential to make a real difference in the lives of patients," said Elmar Schnee, President of Merck Serono. "Based on the successful completion of the CLARITY study, we plan to submit cladribine tablets for registration to the EMEA and to the FDA for mid-2009."

Secondary endpoints of the CLARITY study were also met, including reduction of lesion activity as measured by magnetic resonance imaging (MRI), proportion of subjects relapse-free and disability progression. Full study results will be submitted for presentation at an upcoming scientific meeting.

The CLARITY study was a two-year (96 weeks), randomized, double-blind, placebo-controlled, international trial. It enrolled 1,326 patients with relapsing-remitting MS according to the revised McDonald criteria⁽²⁾. Study participants were randomized to one of three different treatment groups consisting of two different dose regimens of cladribine tablets or matching placebo tablets (1:1:1 ratio). Cladribine tablets were given in two or four treatment courses in the first year, with each course consisting of once daily administration for four to five consecutive days, which means study patients took cladribine tablets for only 8 to 20 days during the year. In the second year, two treatment courses were administered to all patient groups. The primary endpoint of the CLARITY study was the qualifying relapse rate at 96 weeks. Secondary endpoints included MRI endpoints⁽³⁾, proportion of subjects relapse-free and disability progression at 96 weeks. Out of the 1,326 randomized patients, 90% of patients treated with cladribine tablets completed the study (92% in the lower total dose group and 89% in the higher total dose group) compared to 87% in the placebo group.

About cladribine tablets
Merck Serono's proprietary oral formulation of cladribine (cladribine tablets) is currently being evaluated in Phase III as a treatment for patients with relapsing forms of multiple sclerosis (MS). Cladribine is a small molecule that may interfere with the behavior and the proliferation of certain white blood cells, particularly lymphocytes, which are thought to be involved in the pathological process of MS.

The clinical development program for cladribine tablets includes:

- The CLARITY (CLAdRIbine Tablets Treating MS OrallY) extension study: a two-year placebo-controlled extension of the CLARITY study, designed to provide data on the long-term safety and efficacy of extended administration of cladribine tablets for up to four years

- The ORACLE MS (ORAl CLadribine in Early MS) study: a two-year Phase III placebo-controlled trial designed to evaluate the efficacy and safety of cladribine tablets as a monotherapy in patients at risk of developing MS (patients who have experienced a first clinical event suggestive of MS). This trial was announced in September 2008.

- The ONWARD (Oral Cladribine Added ON To Rebif New Formulation in Patients With Active Relapsing Disease) study: a Phase II placebo-controlled trial designed primarily to evaluate the safety and tolerability of adding cladribine tablets treatment to patients with relapsing forms of MS, who have experienced breakthrough disease while on established interferon-beta therapy. This trial was announced in January 2007.

Cladribine tablets have been granted a fast track designation by the US Food and Drug Administration based on the need for an oral therapy in a subset of patients with relapsing forms of multiple sclerosis.

^1. CLARITY: CLAdRIbine Tablets Treating MS OrallY

^2. The McDonald criteria are diagnostic criteria for MS. In April 2001 an international panel in association with the National Multiple Sclerosis Society (NMSS) of America recommended revised diagnostic criteria for MS. They make use of advances in MRI imaging techniques and are intended to replace the Poser criteria. The new criteria facilitate the diagnosis of MS in patients who present with signs and symptoms suggestive of the disease. The McDonald criteria for the diagnosis of multiple sclerosis were revised in 2005 to simplify and speed diagnosis, while maintaining adequate sensitivity and specificity.

^3. The exact correlation between MRI findings and the current or future clinical status of patients, including disability progression, is unknown.

Source: Merck Serono (23/01/09)

ORACLE MS Phase III Trial Will Assess Effectiveness of Cladribine Tablets in Preventing Conversion to Definite Multiple Sclerosis in Addition to the Fully Enrolled Phase III Pivotal Trial - the CLARITY Study - for Treatment of Relapsing Forms of Multiple Sclerosis

Merck Serono, a division of Merck KGaA, Darmstadt, Germany, announced today the initiation of a Phase III trial to evaluate the therapeutic effects of its proprietary oral formulation of cladribine (cladribine tablets) in patients at risk of developing multiple sclerosis (MS).

The trial, called ORACLE MS (ORAl CLadribine in Early MS) will evaluate the safety and efficacy of two dosage regimens of cladribine tablets versus placebo in the treatment of patients who have experienced a first clinical event suggestive of MS. Cladribine tablets are currently also being evaluated in a fully enrolled Phase III pivotal trial - the CLARITY(¹) study - for treatment of relapsing forms of MS. As announced in January 2007, CLARITY was the first pivotal trial among all Phase III oral compounds in development for MS to complete enrollment. Cladribine tablets have been granted a fast track designation by the US Food and Drug Administration.

"There is increasing evidence supporting the initiation of treatment with a disease-modifying drug in patients who have experienced a first clinical event suggestive of multiple sclerosis, an initial stage of the disease when clinical manifestations are not necessarily pronounced but where the potential exists for irreversible neurological damage to take place," said Dr. Thomas Leist, Associate Professor of Neurology and Director of the Comprehensive MS Center at Thomas Jefferson University, Philadelphia, PA, and an investigator in the ORACLE MS study. "The ORACLE MS study will evaluate the effectiveness and safety of cladribine tablets in preventing conversion to definite multiple sclerosis."

"As a leader in multiple sclerosis treatments, we are committed to providing new options that can further improve the course of the disease and the quality of life for people living with this disease," said Dr. Richard Douge, Executive Vice President, Global Marketing, Merck Serono. "The initiation of the ORACLE MS study further demonstrates our commitment to continue to build a solid portfolio of products for use in a broad multiple sclerosis patient population. We believe that our proprietary oral formulation of cladribine has the potential to address an important unmet medical need at a critical time of disease development."

The ORACLE MS study is a randomized, double-blind, placebo-controlled, international trial. It will involve more than 600 patients considered at risk of developing MS due to a recently experienced isolated demyelinating event (e.g. optic neuritis, myelopathy or brainstem syndrome) and having MRI brain scans consistent with early signs of MS. Study participants will be randomized in one of the three arms of the study to receive one of two different dosage regimens of cladribine tablets or matching placebo tablets (1:1:1 ratio).

Patients will be treated for a period of two years (96 weeks), or up to the time when they experience a second attack leading to a diagnosis of clinically definite MS, in which case they would be offered open-label treatment with Rebif(R) 44 mcg three times a week for a 96-week maintenance treatment period. Patients who do not convert to clinically definite MS within the initial 96-week period of the study will be eligible to enroll in a 96-week long-term follow-up treatment period. These maintenance and long-term follow-up periods of the study are intended to assess the effect of early treatment with cladribine tablets on relapses and subsequent treatment response to disease-modifying therapy for relapsing-remitting MS and to evaluate the sustained effect of cladribine tablets in delaying the development of definite MS.

In the study, cladribine tablets are given in two or four treatment cycles in the first year, with each cycle consisting of once daily administration for four to five consecutive days, which means study patients take cladribine tablets for only 8 to 20 days during that year. In the second year, two treatment cycles are administered to all patient groups.

The primary endpoint of the ORACLE MS trial is time to conversion to MS, according to the McDonald criteria. Other endpoints include time to conversion to clinically definite MS according to the Poser criteria (the main secondary endpoint), assessments of MRI brain scans, and disability progression.

Approximately 200 medical centers globally are expected to participate in this trial.

⁽¹⁾ CLARITY: CLAdRIbine Tablets Treating MS OrallY

Source: Merck Serono International S A (18/09/08)

Merck Serono announced today that it has begun the ONWARD (Oral Cladribine Added ON To Rebif New Formulation in Patients With Active Relapsing Disease) Phase II study. The ONWARD study will evaluate the safety, tolerability and efficacy of two dose regimens of Merck Serono's proprietary oral formulation of Cladribine when added to the new formulation of Rebif(R) (interferon beta-1a) in multiple sclerosis (MS) patients with active disease despite treatment with Rebif(R). Oral cladribine is currently also evaluated as a monotherapy in a fully enrolled Phase III pivotal trial (the CLARITY study) for first-line treatment of relapsing forms of MS. The new formulation of Rebif(R) is under regulatory review by the European Medicines Agency, the US Food and Drug Administration and other healthcare authorities.

"Multiple sclerosis patients with signs of active disease while on treatment with a disease modifying drug may benefit from adding another agent with a different mechanism of action, to complement and increase the overall efficacy while maintaining an acceptable safety and tolerability profile," said Bruno Musch, Merck Serono's Head of Neurology Clinical Development. "The different mechanism of action and the oral intermittent administration of oral cladribine make it a potentially useful add-on therapy to Rebif(R) at a critical time of disease progression."

"Oral cladribine is currently being evaluated as a monotherapy in the CLARITY Phase III pivotal study and is on track to become the first oral therapy for first-line treatment of multiple sclerosis", said Franck Latrille, Merck Serono's Head of Product Development. "We are now initiating the ONWARD study as we believe that oral cladribine also has a great potential as an add-on therapy, for patients who have signs of active relapsing disease while on a treatment."

The ONWARD study is a two-year (96 weeks), randomised, double-blind, placebo-controlled, international trial. The trial will be conducted in 40 sites located in the United States and in Europe. It will involve 260 MS patients who have experienced at least one relapse while taking Rebif(R) during the year prior to study enrollment. Study participants will be randomised in one of the three arms of the study to receive one of two different dose regimens of oral cladribine or matching placebo tablets, in addition to the new formulation of Rebif(R) 44 micrograms subcutaneous three times a week. In the study, oral cladribine is given in two or four treatment cycles in the first year, with each cycle consisting of daily administration for four or five consecutive days, which means study patients take oral cladribine therapy for only 8 to 20 days during that year. In the second year, two treatment cycles are administered in all dose regimens.

The primary safety endpoints of the ONWARD study consist of a wide range of safety and tolerability parameters measured during 96 weeks of treatment. The primary efficacy endpoint is the mean change in the number of new T1 gadolinium-enhanced lesions per subject per magnetic resonance imaging (MRI) scan from baseline to 96 weeks.

About oral Cladribine

Merck Serono's proprietary oral formulation of cladribine is currently being evaluated in Phase III as a treatment for patients with relapsing forms of multiple sclerosis (MS). Cladribine is a small molecule that interferes with the behaviour and the proliferation of certain white blood cells, particularly lymphocytes, which are involved in the pathological process of MS. Through its differentiated mechanism of action, oral cladribine may offer a safe and effective new option to patients with MS.

SOURCE Serono International S A (24/01/07)

Merck Serono announced today that patient enrollment has been completed in the CLARITY (CLAdRIbine Tablets Treating MS OrallY) study, a Phase III pivotal clinical trial evaluating the efficacy and safety of Merck Serono's proprietary oral formulation of cladribine for the treatment of relapsing forms of multiple sclerosis (MS).

"The completion of patient enrollment into the CLARITY pivotal trial is a major milestone in the development program of oral cladribine," said Franck Latrille, Merck Serono's Head of Product Development. "It brings us one step closer to our objective of offering patients the first oral therapy for first line treatment of multiple sclerosis, with the convenience of short courses of therapy given intermittently."

The CLARITY study is a two-year (96 weeks), randomised, double-blind, placebo-controlled, international trial. It enrolled more than 1,300 patients and will provide data on key endpoints including clinical relapses, disability progression and magnetic resonance imaging (MRI). Study participants have been enrolled in one of the three arms of the study to receive one of two different dose regimens of oral cladribine or matching placebo tablets. In the study, oral cladribine is given in two or four treatment cycles in the first year, with each cycle consisting of daily administration for five consecutive days, which means study patients take oral cladribine therapy for only 10 or 20 days during the year. In the second year, two treatment cycles are administered.

The increased convenience resulting from the oral intermittent administration of oral cladribine has the potential to address an important unmet medical need in patients with MS.

Oral cladribine was designated a Fast Track product by the US Food and Drug Administration (FDA) in September 2006. Under Fast Track designation, oral cladribine is eligible for Priority Review and the FDA may consider portions of the marketing application for review before the New Drug Application (NDA) is completed.

About oral Cladribine

Merck Serono's proprietary oral formulation of Cladribine is currently being evaluated in Phase III as a treatment for patients with relapsing forms of multiple sclerosis (MS). Cladribine is a small molecule that interferes with the behavior and the proliferation of certain white blood cells, particularly lymphocytes, which are involved in the pathological process of MS. Through its differentiated mechanism of action, oral cladribine may offer a safe and effective new option to patients with MS.

Source: Serono International S A. (16/01/07)

Serono's proprietary oral formulation of cladribine for the treatment of multiple sclerosis is currently being evaluated in a multi-center, multi-national Phase III study, CLARITY (CLAdRIbine Tablets Treating MS OrallY) . It is a two-year, double-blind, placebo-controlled study involving over 1,200 patients. Patient enrollment into this pivotal trial is planned to be completed by the end of 2006.

"We are very pleased that oral cladribine has been designated a Fast Track product," said Ernesto Bertarelli, CEO of Serono. "As a leader in multiple sclerosis, we are committed to providing new treatment options that can further improve the quality of the lives of people with this serious disease and our objective is to bring to them the first oral disease modifying treatment."

"Thanks to decades of research, there are injectible drugs available to treat some forms of MS, but there is certainly a need for more and even better therapies to treat all forms of the disease. Having an effective oral therapy for MS would be a major step forward in improving quality of life for people with MS," said Dr. John Richert, Vice President, Research and Clinical Programs, at the National Multiple Sclerosis Society.

Fast Track programs are designed to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. Under Fast Track designation oral cladribine is eligible for Priority Review and FDA may consider for review portions of the marketing application before the New Drug Application (NDA) is completed.

About Cladribine

Cladribine is a purine nucleoside analogue that interferes with the behavior and the proliferation of certain white blood cells, particularly lymphocytes, which are involved in the pathological process of multiple sclerosis. Through its differentiated mechanism of action, oral cladribine may offer an alternative option to patients with multiple sclerosis.

Source: Serono International S A(21/09/06)

Serono announced today that recruitment in the U.S. is beginning for the Phase III CLARITY study (CLAdRIbine Tablets in Treating MS OrallY Study) of oral cladribine for the treatment of patients with relapsing forms of multiple sclerosis (MS). This multi-national study was successfully initiated outside the U.S. in 2005, and will now expand to include 17 clinical trial sites in the U.S. The study is one of the largest MS trials ever conducted, and enrollment is on track to be completed in 2006.

CLARITY is a two-year, double-blind, placebo-controlled Phase III study of more than 1,200 patients. It is designed to assess patients' clinical relapses, disability progression and MRI (magnetic resonance imaging) brain activity. Previous clinical trials using cladribine administered by injection in patients with MS showed positive effects in reduction of new lesion development in the brain as seen on MRI scans; reductions in relapses were also observed.

"The Phase III CLARITY trial is enrolling at a strong pace, and the addition of US sites will accelerate this pace and bring us one step closer to our goal of making the first oral MS therapy available for people living with this debilitating condition, underscoring our fundamental and long-term commitment to the MS community," said Dr. Paul Lammers, Chief Medical Officer at Serono, Inc. "The formulation of oral cladribine, combined with the proposed short dosing regimen, should help patients to be more compliant with their MS therapy and lighten the patient's treatment burden associated with chronic MS."

"We all are looking forward to the day when there is an FDA approved oral therapy that can affect the underlying disease process in MS," said Dr. John Richert vice president research and clinical programs at the National MS Society. "Clinical studies, such as CLARITY, are an important part of the process leading to the development of these new medications. Those interested in determining whether they are eligible to participate in the clinical trial should speak with their healthcare provider."

Trial Recruitment Taking Place in 15 States

Currently, there are 17 clinics, medical centers, universities and hospitals recruiting patients to participate in the study in 15 major cities across the country.

"We are excited to further evaluate oral cladribine for the treatment of MS," said Dr. Dusan Stefoski, M.D., associate professor of the Rush Multiple Sclerosis Center and a clinical investigator for the CLARITY trial. "From my clinical experience, the addition of an oral therapy for MS could improve compliance among patients and potentially change the MS treatment paradigm."

Source: Serono Press Release (04/05/06)

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