Laquinimod – new promising treatment of multiple sclerosis

Laquinimod is a once-daily novel oral immunomodulatory agent developed as a disease modifying treatment for multiple sclerosis, MS, which Active Biotech has licensed to Teva Pharmaceutical Industries Ltd. (2004). Teva also performs a Phase II study of laquinimod in Crohn's disease.

Multiple sclerosis

Multiple sclerosis (MS) is a chronic, progressive disease affecting the central nervous system. The disease affects the central nervous system in the brain and spinal cord. The symptoms are caused by the body’s own immune system attacking and damaging the myelin sheaths surrounding nerve fibers. This causes inflammation within the central nervous system causing the patient to suffer relapses and disease progression. The etiology of the disease is unknown, but is assumed to depend, like other autoimmune diseases, on both genetic and environmental factors. 

There are various forms of MS, the most common is relapsing remitting MS ("RRMS"). It is characterized by unexpected recurring relapses that can last from a few days to a few weeks and are followed by complete or partial remission. For approximately 80 percent of all patients, the disease begins as RRMS but most develop after some ten or so years into secondary progressive MS (“SPMS”), which is characterized by a gradually increasing degree of handicap, without the recovery periods.

MS primarily affects young and middle-aged people. The disease often first appears when the patient is between 20 and 50 years old, and the number of women affected is twice as high as the number of men. A total of about two million people throughout the world suffer from MS. The disease is more common in the northern hemisphere. The Nordic region, the British Isles and North America are regarded as high-risk areas.

There are currently three types of drugs for the treatment of MS: interferons, glatiramer acetate and natalizumab. The drugs reduce the number of relapses and are therefore all approved for treatment of MS patients with relapses. The total market for MS pharmaceuticals amounted to USD 8.8 billion in 2008 (Therapeutic Categories Outlook, Cowen & Co, March 2009). Since MS patients must be on medication throughout their lifetime, an oral treatment creates a substantial advantage compared with existing products in the market, all of which must be injected.

Crohn's disease

Crohn's disease is a chronic inflammatory condition that affects the gastrointestinal tract. The symptoms of Crohn's disease can vary significantly among afflicted individuals. The main gastrointestinal symptoms are abdominal pain, diarrhea, vomiting, or weight loss. Crohn's disease can also cause complications outside of the gastrointestinal tract such as skin rashes, arthritis, and inflammation of the eye.

The precise cause of Crohn's disease is not known. The disease occurs when the immune system attacks the gastrointestinal tract and for this reason, Crohn's disease is considered to be an autoimmune disease. This autoimmune activity produces inflammation in the gastrointestinal tract, and therefore Crohn's disease is classified as an inflammatory bowel disease.

Ongoing research

The Allegro study (assessment of oral laquinimod in preventing progression of multiple sclerosis), which is a global, pivotal, double-blind, Phase III study designed to evaluate the efficacy, safety and tolerability of laquinimod versus placebo in the treatment of RRMS, has been in progress since November 2007. The Allegro study was fully recruited in November 2008 encompassing 1,000 patients. The treatment administered is a 0.6 mg tablet of laquinimod once a day or placebo. The study is scheduled to continue for 24 months with the possibility to extend to 30 months.

A second pivotal Phase III study, Bravo (benefit-risk assessment of Avonex® and laquinimod), which is a global, multi-center, randomized, placebo-controlled 24 months study with parallel groups, was initiated in April 2008. The study will compare the effect of once-daily orally administered laquinimod 0.6 mg with placebo and also provide risk-benefit data in relation to treatment with a product presently established in the market and administered by injection (Avonex®). The Bravo study was fully recruited in June 2009 encompassing 1,200 patients. For further information about the Bravo study, please visit www.tevaclinicaltrials.com/hcp/bravo_info.aspx.

Detailed information regarding the Phase III studies is published on www.TevaClinicalTrials.com and www.clinicaltrials.gov. 

Current results

In February 2009, oral laquinimod received a Fast Track designation from the U.S. Food and Drug Administration (FDA). Drugs designated for Fast Track are intended for the treatment of a serious or life-threatening condition and have demonstrated the potential to address unmet medical needs. Fast Track designation can potentially facilitate development and expedite the review process.  This may allow laquinimod to enter the market as soon as late 2011.

In June 2008, data published in the medical journal The Lancet showed that the treatment using tablet-form laquinimod significantly reduced disease activity in the brain of RRMS patients by 60% (median), measured with magnetic resonance imaging (MRI), compared with placebo, and was well-tolerated. Most of the patients who participated in the study are continuing to receive treatment with laquinimod in an open extension study. The article, entitled “Effect of Laquinimod on MRI-monitored disease activity in patients with RRMS: a multicenter, randomized, double-blind, placebo-controlled phase IIb study,” was published in The Lancet Volume 371, Issue 9630. 

Laquinimod Immunomodulatory Action Confers Both Neuroprotective and Anti-Inflammatory Properties

Results Presented at 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)

JERUSALEM & LUND, Sweden--(BUSINESS WIRE)--Sep 11, 2009 - Teva Pharmaceutical Industries Ltd. (NASDAQ: TEVA) and Active Biotech (NASDAQ OMX NORDIC: ACTI) today presented data further illuminating the novel, dual mechanism of action (MOA) of investigational oral, once-daily, laquinimod for the treatment of relapsing-remitting multiple sclerosis (RRMS), conferring neuroprotective and anti-inflammatory properties. Results from several preclinical studies suggest that laquinimod elicits a protective therapeutic effect by reducing demyelination and inducing axonal protection.

These studies expand upon a growing body of data suggesting the mechanism of oral laquinimod in RRMS patients is targeted immunomodulation, and may help contribute to the favorable benefit-to-risk profile associated with this compound.

“MS patients, and the physicians who treat them, await the availability of an oral agent with an efficacy and safety profile required to address the chronic, lifelong nature of the disease,” explains Prof. Wolfgang Brück, head of the Neuropathology Dept., the Georg-August-Universität, Göttingen, Germany. “The seemingly targeted immunomodulation that appears to be associated with the dual MOA of laquinimod and the favorable benefit-to-risk profile seen in patients studied for up to 3.5 years, make the drug a potential candidate to address this unmet need for an oral therapy.”

Laquinimod received Fast Track designation from the U.S. Food and Drug Administration (FDA) in February 2009. Two global Phase III clinical trials, BRAVO and ALLEGRO, have completed enrollment and are currently ongoing.

ABOUT THE STUDIES

The studies evaluating the properties of laquinimod being presented at ECTRIMS include:

• Laquinimod induces up-regulation of neurotrophins in serum of patients with relapsing-remitting multiple sclerosis (P 783, 15:30 - 17:00 Immunomodulation – 2, September 11, 2009)
  R. Linker, J. Thöne, G. Comi, R. Gold (Bochum, DE; Rome, IT)

596 serum samples from RRMS patients participating in the LAQ/5062 trial were tested for the presence of neurotrophic factors, including neurotrophin (NT)-3, NT-4 and brain derived neurotrophic factor (BDNF). Data on the expression of neurotrophic factors were correlated with their functional activity in a neuronal survival assay. Treatment with 0.6 mg of laquinimod resulted in a significant and specific, up to 11-fold increase in BDNF serum levels as compared to baseline, as well as to placebo treatment after 3 months. Besides an immunomodulatory mechanism of action, laquinimod has the ability to increase levels of neurotrophic factors in vivo possibly contributing to neuroprotection in MS patients.

• Anti-inflammatory pathways activated by laquinimod in CD4+, CD8+, CD14+, CD19+ and NK peripheral blood cells subtypes of relapsing-remitting multiple sclerosis patients (P 264, 15:30-17:00 Immunomodulation – 2, September 10, 2009)
  M. Gurevich, B. Timan, L. Hayardeny, A. Achiron (Ramat Gan, Netanya, IL)

High throughout gene expression analysis of in-vitro incubation of peripheral blood mononuclear cells from RRMS patients with laquinimod demonstrated that laquinimod induced in-vitro immunomodulatory effects that are characterized by activation of anti-inflammatory IL-4 pathway in CD4+ cells, promotion of apoptosis in CD8+ and B cells and suppression of metabolic activity of CD14+ and NK cells.

• Reduced inflammation, demyelination and axonal damage after therapeutic laquinimod treatment in experimental autoimmune encephalomyelitis (P 441, 15:30 - 17:30 Immunomodulation – 1, September 11, 2009)
  C. Wegner, C. Stadelmann, W. Brück (Gottingen, DE)

In animal models of MS, laquinimod inhibits the development of acute and chronic experimental autoimmune encephalomyelitis (EAE). Laquinimod modulates the cytokine balance in favour of anti-inflammatory Th2/Th3 cytokines. Therapeutic treatment with laquinimod is effective in ameliorating the extent of macrophage and T cell infiltration, demyelination and axonal damage. Findings indicate that laquinimod might have an axon-protective effect in addition to its anti-inflammatory properties.

• The effect of laquinimod on the distribution of monocyte subsets (P 808, 15:30 - 17:00 Immunomodulation – 2, September 11, 2009)
  T. Birnberg, S. Jung (Rehovot, IL)

Monocytes are circulating blood leukocytes that play important roles in inflammatory responses. In mice, monocytes originate in the bone-marrow from Macrophages and Dendritic cells precursor. Murine blood monocytes encompass two main Ly6Chi and Ly6Clow subsets. Recent evidence suggests that the ratio of the two monocyte subsets can have effects on the susceptibility of the organism to various disorders, including experimental autoimmune encephalomyelitis (EAE) lesions. These cells are accumulating in the blood and CNS immediately prior to EAE clinical episodes. The results indicate that the effect by which laquinimod exerts its clinical efficacy in autoimmune diseases may be due to its impact on the myeloid precursor cells.

ABOUT MULTIPLE SCLEROSIS

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. MS is a progressive, demyelinating disease of the central nervous system affecting the brain, spinal cord and optic nerves. Demyelination is the destructive breakdown of the fatty tissue that protects nerve endings.

ABOUT LAQUINIMOD

Laquinimod is a novel once-daily, orally administered immunomodulatory compound that is being developed as a disease-modifying treatment for RRMS. Active Biotech developed laquinimod and licensed it to Teva Pharmaceutical Industries, Ltd. in June 2004. A Phase IIb study in 306 patients was published in The Lancet and demonstrated that an oral 0.6 mg dose of laquinimod, administered daily, significantly reduced MRI disease activity by a median of 60 percent versus placebo in RRMS patients. In addition, the study showed a favorable trend toward reducing annual relapse rates and the number of relapse-free patients compared with placebo. Treatment was well tolerated, with only some transient and dose-dependent increases in liver enzymes reported. Over 1,000 MS patients have received laquinimod in various clinical trials.

In addition to the efficacy that laquinimod has shown in Phase II RRMS clinical trials, laquinimod has demonstrated potent therapeutic efficacy in preclinical models of other autoimmune diseases such as rheumatoid arthritis, insulin-dependent diabetes mellitus, Guillain Barré Syndrome, lupus and Inflammatory Bowel Disease. The broad profile of efficacy in animal models of inflammatory diseases suggests that laquinimod affects a pivotal pathway of inflammation and autoimmunity. Laquinimod is currently in Phase II development for Crohn's disease and Teva expects to initiate the clinical development of the compound for Lupus Nephritis in the near future.

ABOUT TEVA

Teva Pharmaceutical Industries Ltd., headquartered in Israel, is among the top 20 pharmaceutical companies in the world and is the world's leading generic pharmaceutical company. The Company develops, manufactures and markets generic and innovative human pharmaceuticals and active pharmaceutical ingredients, as well as animal health pharmaceutical products. Over 80 percent of Teva's sales are in North America and Europe.

ABOUT ACTIVE BIOTECH

Active Biotech AB (OMX NORDIC: ACTI), headquartered in Sweden, is a biotechnology company with R&D focus on autoimmune/inflammatory diseases and cancer. Projects in pivotal phase are laquinimod, an orally administered small molecule with unique immunomodulatory properties for the treatment of multiple sclerosis, as well as ANYARA for use in cancer targeted therapy, primarily renal cancer. Further key projects in clinical development comprise the three orally administered compounds TASQ for prostate cancer, 57-57 for SLE and RhuDexTM for .

NEJM：口服拉喹莫德可有效减少多发性硬化的复发率

基线受试者的临床和人口统计学特征

概念验证临床实验已经为拉喹莫德（laquinimod）减轻复发好转型多发性硬化的有效性提供了充足的证据。意大利米兰神经病学研究所的Giancarlo Comi博士及其同事进行了深入的研究，相关成果发表在国际权威杂志NEJM2012年3月15日在线版。

这项随机，双盲，3期临床实验在24个国家的139个网点同时进行，总共纳入1106名复发好转型多发性硬化患者，按1：1比例随机指定接受每天0.6mg剂量的口服拉喹莫德治疗或安慰剂处理，治疗持续24个月。实验主要结束指标为24个月期限内的年复发率。次要结束指标为确定的残疾恶化程度（失能进展）（以至少持续3个月的残疾状态调查量表得分进行度量），以核磁共振T2显示的钆损伤累积增加量以及新增加或扩大的损伤。

结果显示，与安慰剂组相比，拉喹莫德可以中度减少年复发率(0.30±0.02 vs. 0.39±0.03, P=0.002)均值(±SE)并减少确定的残疾恶化程度(11.1% vs. 15.7%; hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.91; P=0.01)。与安慰剂组相比，核磁共振T2显示的钆损伤积累以及新出现或扩大的损伤在拉喹莫德治疗组患者中程度较轻(1.33±0.14 vs. 2.12±0.22 and 5.03±0.08 vs. 7.14±0.07, respectively; P<0.001 for both comparisons)。观察到的丙氨酸转氨酶水平短暂升高至正常范围阈值上限的3倍的病例数，在拉喹莫德治疗组为24例患者(5%)而安慰剂组则为8例(2%)。

结论：在这一3期临床实验中，每天1次口服拉喹莫德可减缓复发好转型多发性硬化患者的失能进展并减少复发率。