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Alemtuzumab is a monoclonal antibody that selectively targets CD52, a protein abundant on T and B cells. Treatment with alemtuzumab results in the depletion of circulating T and B cells thought to be responsible for the damaging inflammatory process in MS. Alemtuzumab has minimal impact on other immune cells. The acute anti-inflammatory effect of alemtuzumab is immediately followed by the onset of a distinctive pattern of T and B cell repopulation that continues over time, rebalancing the immune system in a way that potentially reduces MS disease activity.
There was good news for French drug giant Sanofi this week as data from an extension study backed the long-term efficacy of its multiple sclerosis drug Lemtrada.
Interim data from the first 12 months of the extension trial showed that relapse rates and sustained accumulation of disability were low among patients previously treated with Lemtrada (alemtuzumab) in either of the two-year Phase III CARE-MS I or CARE-MS II studies.
In both these Phase III trials, Lemtrada was was given as an IV administration on five consecutive days, and the second course was administered on three days 12 months later.
After the first year of the extension arm, more than 80% of patients did not need further treatment with the drug, and more than half remained relapse-free through the first year of the extension study, the drugmaker said.
Alemtuzumab (marketed as Campath, MabCampath or Campath-1H and currently under further development as Lemtrada) is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma. It is also used in some conditioning regimens for bone marrow transplantation, kidney transplantation and Islet cell transplantation.
Alemtuzumab binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. After treatment with alemtuzumab, these CD52-bearing lymphocytes are targeted for destruction.
Alemtuzumab is used as second-line therapy for CLL. It was approved by the US Food and Drug Administration for CLL patients who have been treated with alkylating agents and who have failed fludarabine therapy. It has been approved by Health Canada for the same indication, and additionally for CLL patients who have not had any previous therapies.
It is also used under clinical trial protocols for treatment of some autoimmune diseases, such as multiple sclerosis, in which it shows promise. Alemtuzumab was withdrawn from the markets in the US and Europe in 2012 to prepare for a higher-priced relaunch aimed at multiple sclerosis.
A complication of therapy with alemtuzumab is that it significantly increases the risk for opportunistic infections, in particular, reactivation of cytomegalovirus.
- Drug may reverse MS brain damage”. 22 Oct 2008.
- “Sanofi and Genzyme Report New Positive Data from First Phase III Study with MS Drug”. 24 Oct 2011.
- “Sanofi withdraws Campath in US and EU”. Pharma Times Online. August 21, 2012.
Laquinimod is an experimental immunomodulator developed by Active Biotech and Teva. It is currently being investigated as an oral treatment for multiple sclerosis (MS).
Laquinimod is the successor of Active Biotech’s failed experimental immunomodulator linomide.
The compound has been investigated in two Phase II trials using successive magnetic resonance scans (MRI). Laquinimod seems to be able to reduce the MS disease activity on MRI. However, the response to a given dose was discrepant between both studies.
Phase III studies for MS started in December 2007. In 2011, Teva announced its clinical trials involving laquinimod had failed, being unable to significantly reduce relapses into MS among patients beyond a placebo. However, the final results of above mentioned phase III trial proved oral laquinimod administered once daily slowed the progression of disability and reduced the rate of relapse in patients with relapsing–remitting multiple sclerosis 
Mar 6, 2013 –
CONCERTO Study Enrolling Patients Globally to Evaluate Impact of Laquinimod on Disability Progression
Teva Pharmaceutical Industries Ltd. and Active Biotech announced today enrollment of the first patient in the CONCERTO study – the third Phase III placebo-controlled study designed to evaluate the efficacy, safety and tolerability of once-daily oral laquinimod in patients with relapsing-remitting multiple sclerosis (RRMS). The primary outcome measure of CONCERTO will be confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS).
“Previous Phase III studies in more than 2,400 people with RRMS suggest a unique profile of laquinimod, directly affecting the neurodegenerative processes that lead to disability progression, the main concern in the treatment of RRMS,” said CONCERTO principal investigator, Dr. Timothy Vollmer, Professor of Neurology, University of Colorado Denver, Medical Director of the Rocky Mountain Multiple Sclerosis Center, and Co-Director of the RMMSC at Anschutz. “We are currently enrolling patients in this third pivotal study to further examine the clinical benefits of laquinimod on disability progression, the primary endpoint of the CONCERTO trial, and brain atrophy, at both the previously studied 0.6 mg dose, and now a higher 1.2 mg dose.”
The multinational, randomized, double blind placebo-controlled study will aim to enroll approximately 1,800 patients at more than 300 sites globally (http://clinicaltrials.gov/show/NCT01707992). Along with the primary endpoint of time to confirmed disability progression, the study will also examine the impact of laquinimod on endpoints such as percent change in brain volume and other clinical and MRI markers of disease activity.
“For nearly 30 years, Teva has been focused on improving the lives of people with multiple sclerosis by delivering innovative treatment options that address this complex disease,” said Dr. Michael Hayden, President of Global R&D and Chief Scientific Officer at Teva Pharmaceutical Industries Ltd. “The CONCERTO study demonstrates our commitment to collaborating with MS communities worldwide to further develop laquinimod and address unmet patient needs.”
Laquinimod is an oral, once-daily CNS-active immunomodulator with a novel mechanism of action being developed for the treatment of MS. In animal models laquinimod crosses the blood brain barrier to potentially have a direct effect on resident CNS inflammation and neurodegeneration. The global Phase III clinical development program evaluating oral laquinimod in MS includes two pivotal studies, ALLEGRO and BRAVO.
In addition to the MS clinical studies, laquinimod is currently in clinical development for Crohn’s disease and Lupus.
CONCERTO is a multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled study followed by an active treatment phase, to evaluate the efficacy, safety and tolerability of two doses of oral administration of laquinimod 0.6 mg/day or 1.2 mg/day in subjects with RRMS. This third Phase III laquinimod study will evaluate laquinimod in approximately 1,800 patients for up to 24 months, after which patients will continue to an active treatment period with laquinimod for an additional 24 months. The primary outcome measure will be time to confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS). The study will also examine the impact of laquinimod on endpoints such as percent change in brain volume, as well as other clinical and MRI markers of disease activity.
ABOUT MULTIPLE SCLEROSIS
MS is the leading cause of neurological disability in young adults. It is estimated that more than 400,000 people in the United States are affected by the disease and that two million people may be affected worldwide. Multiple sclerosis is a degenerative disease of the central nervous system in which inflammation and axonal damage and loss result in the development of progressive disability.
Teva Pharmaceutical Industries Ltd. (NYSE: TEVA) is a leading global pharmaceutical company, committed to increasing access to high-quality healthcare by developing, producing and marketing affordable generic drugs as well as innovative and specialty pharmaceuticals and active pharmaceutical ingredients. Headquartered in Israel, Teva is the world’s leading generic drug maker, with a global product portfolio of more than 1,000 molecules and a direct presence in about 60 countries. Teva’s branded businesses focus on CNS, oncology, pain, respiratory and women’s health therapeutic areas as well as biologics. Teva currently employs approximately 46,000 people around the world and reached $20.3 billion in net revenues in 2012.
ABOUT ACTIVE BIOTECH
Active Biotech AB is a biotechnology company with focus on autoimmune/inflammatory diseases and cancer. Projects in or entering pivotal phase are laquinimod, an orally administered small molecule with unique immunomodulatory properties for the treatment of multiple sclerosis, TASQ for prostate cancer as well as ANYARA for use in cancer targeted therapy, primarily of renal cell cancer. In addition, laquinimod is in Phase II development for Crohn’s and Lupus. Further projects in clinical development comprise the two orally administered compounds, 57-57 for SLE & Systemic Sclerosis and RhuDex(TM) for RA. Please visit http://www.activebiotech.com for more information.
- Tan IL, Lycklama à Nijeholt GJ, Polman CH et al. (April 2000). “Linomide in the treatment of multiple sclerosis: MRI results from prematurely terminated phase-III trials”. Mult Scler 6 (2): 99–104. PMID 10773855.
- Comi G, Pulizzi A, Rovaris M et al. (June 2008). “Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study”. Lancet 371 (9630): 2085–2092. doi:10.1016/S0140-6736(08)60918-6. PMID 18572078.
- Polman C, Barkhof F, Sandberg-Wollheim M et al. (March 2005). “Treatment with laquinimod reduces development of active MRI lesions in relapsing MS”. Neurology 64 (6): 987–91. doi:10.1212/01.WNL.0000154520.48391.69. PMID 15781813.
- Keegan BM, Weinshenker BG (June 2008). “Laquinimod, a new oral drug for multiple sclerosis”. Lancet 371 (9630): 2059–2060. doi:10.1016/S0140-6736(08)60894-6. PMID 18572062.
- ClinicalTrials.gov NCT00509145 Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (RRMS) (ALLEGRO)
- Kresege, Naomi (1 August 2011). “Teva’s Copaxone Successor Fails in Latest Clinical Trial”. Bloomberg. http://www.bloomberg.com/news/2011-08-01/teva-s-oral-multiple-sclerosis-drug-fails-to-meet-goal-of-clinical-trial.html. Retrieved 2 August 2011. “Teva Pharmaceutical Industries Ltd. (TEVA)’s experimental multiple sclerosis pill failed to reduce relapses more than placebo in a clinical trial, dealing a blow to the company’s effort to find a successor to an older drug.”
- (Comi et al. N Engl J Med 2012;366:1000).
EP 1073639; JP 2002513006; US 6077851; WO 9955678
5-Chloroisatoic anhydride (I) is alkylated with iodomethane and NaH to afford (II). Subsequent condensation of anhydride (II) with the malonic monoamide (III) in the presence of NaH in hot DMA furnishes the target quinoline carboxamide.
Reaction of 2-amino-6-chlorobenzoic acid (I) with phosgene and NaHCO3 in dioxane gives 5-chloroisatoic anhydride (II), which is methylated by means of iodomethane and NaH in DMF to yield 5-chloro-1-methylisatoic anhydride (III). Finally, anhydride (III) is condensed with the malonic monoamide (IV) by means of NaH in hot dimethylacetamide. Alternatively, condensation of anhydride (III) with ethoxy malonyl chloride (V) by means of NaOMe and triethylamine in dichloromethane affords 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3- carboxylic acid ethyl ester (VI), which is finally condensed with N-ethylaniline (VII) in refluxing toluene. Alternatively, ester (VI) is hydrolyzed by means of concentrated HCl in hot Ac2O to give the carboxylic acid (VIII), which is finally condensed with N-ethylaniline (VII) by means of SOCl2 and TEA in dichloromethane