Improving Therapeutic Options for Multiple Sclerosis

Improving Therapeutic Options for Multiple Sclerosis: An Interview With Edward Fox, MD, PhD

Elizabeth Samander, PhD

Medscape Neurology & Neurosurgery. 2008; ©2008 Medscape
Posted 10/16/2008

Editor's Note

New data from key trials in multiple sclerosis (MS) regarding novel therapeutic approaches were presented at the World Congress on Treatment and Research in Multiple Sclerosis held from September 17-20, 2008, in Montreal, Canada. Medscape Scientific Director Elizabeth Samander, PhD, interviewed Edward Fox, MD, PhD, about the results of these trials and what implications these results may have on clinical practice and the future management of patients with MS.

Medscape: Dr. Fox, in your opinion, what were the most compelling research findings presented at the World Congress on Treatment and Research in Multiple Sclerosis (WCTRIMS) meeting this year?

Dr. Fox: The overall message from the meeting this year was that a number of medications are currently being investigated that hold great promise for the treatment of multiple sclerosis (MS). Research was presented from numerous trials involving novel therapies, including monoclonal antibody and oral products. There was a substantial amount of evidence presented on both of those categories, including further data from completed phase 2 trials and descriptions of ongoing phase 3 trials. The number of medications that we have under current investigation is really quite large, so it is difficult to see the timeline for these medicines actually being brought to market. We had hoped that these studies would fully enroll quickly, so that we would have finalized data coming within the next few years. However, it is likely that there will be some delays because of the large number of competing trials with slower-than-expected enrollment.

Monoclonal antibody agents discussed at the meeting included alemtuzumab, rituximab, and daclizumab.[1-6] Those antibodies have certainly been well-tested in phase 2 trials, and plans are ongoing for phase 3 trials in relapsing-remitting MS. There was also a phase 3 trial regarding rituximab[1,5,7] for the treatment of primary progressive MS. The primary endpoint of time to confirmed disease progression did not show a statistically significant difference between rituximab and placebo. However, subcohort analysis suggested a benefit for those patients with active magnetic resonance imaging (MRI) at entry into the study. I think that the overall feeling about B-cell depletion in the treatment of MS is very positive. We are looking forward to other studies, including ones on ocrelizumab,[8] another monoclonal antibody, which can selectively deplete B cells and thereby reduce MS disease activity.

The data presented on the alemtuzumab trial was further information from the phase 2 trial, which showed a highly significant decrease in the number of relapses seen in patients on alemtuzumab compared with patients receiving interferon beta-1a subcutaneously 3 times weekly.[4] The data presented were on a 3 year follow-up trial designed to evaluate the percentage of patients who were clinically disease-free. These were patients who did not have relapses and did not have a progression of disability during the course of the trial. The superiority of alemtuzumab compared with beta-interferon was sustained throughout the 3 years on study. Within the third year it was found that 71% of the patients who were on alemtuzumab were clinically disease-free compared with 38% of those who were receiving interferon beta-1a. These findings have led to the development of 2 phase 3 trials currently enrolling patients.

Medscape: What other novel therapeutic approaches are undergoing clinical trials?

Dr. Fox: The oral medications discussed at this meeting included cladribine,[9-11] fingolimod,[12-14] BG-00012,[15,16] teriflunomide,[1,13,17] and laquinimod.[18] All of these oral agents, as well as several others, are showing promise for the treatment of MS. It may be that any or all of these products will have success in the treatment of MS, but at this time we're still in the discovery phase for the safety as well as for the efficacy of these medications.

The phase 2 trials that have been performed have primarily been based on looking for a reduction in new MRI activity in patients with multiple sclerosis. They all have shown various degrees of benefit in reducing gadolinium-enhancing lesions on MRIs during the course of the phase 2 trials. However, these trials were rather short and generally were not powered to show significant clinical outcomes. An exception was the phase 2 trial on fingolimod, which did show a substantial reduction in relapse rate as well.

The phase 3 trials are going to be looking not only at reduction in MRI activity, but will also be looking at the important clinical measures that will be required for these medications to be licensed. Those include a reduction in relapse rate and prevention of sustained accumulation of disability compared with placebo. These clinical outcome measures may or may not be found despite the MRI evidence that has been seen in the past, because there has been a disconnect between MRI activity and clinical activity seen in several previous agents tested for MS.

Medscape: There is evidence that disease-modifying treatments, although partially effective, are associated with injection-related side effects and suboptimal patient adherence. These findings may suggest that novel therapeutic strategies, including oral therapies, monoclonal antibodies, symptomatic treatments, and combination regimens, are warranted. What is the role of these novel agents in the therapeutic armamentarium with respect to first-line use, add-on treatment for failed first-line therapy, or as an effective induction agent?

Dr. Fox: Certainly our hope is that there's going to be an increased number of agents available for the treatment of MS, but it's going to be necessary to determine at what stage of disease we would use these medications.[19] The strategy of phase 3 trials is typically in first-line treatment of relapsing-remitting MS, in a placebo-controlled trial evaluating medication over a period of 2 years. This certainly gives us an idea as to what its overall effectiveness can be, and the newer treatments will be evaluated for the ability to reduce relapses and accumulation of disability. Phase 3 trials will also have to show an acceptable safety profile and risk management plan. The first-line agents that we currently have on the market, glatiramer acetate and the beta interferons, will likely continue to have a role in first-line therapy when we look at long-term efficacy and safety measures of the newer medicines. It will likely take a number of years to determine the true safety of the monoclonal and oral agents, and their overall use as first-line therapies will depend on these data.

The concern that we have about using any of the new agents as an add-on treatment for failed first-line therapy is again, a safety issue. If it's being used in a combination with other immunomodulatory or immunosuppressive therapy, we cannot currently define the safety of such an approach. This has been a major concern lately with the findings of opportunistic infections such as progressive multifocal leukoencephalopathy in patients who are immunosuppressed. Switching from ineffective first-line therapy to a new therapy is going to be the most likely use in clinical practice soon after these agents reach the market.

Using any of these agents as an effective induction agent is going to require more data from trials where this has been specifically tried. Older medications such as mitoxantrone have been tested as induction therapies with some very favorable results, but the novel agents that are being investigated right now have not been similarly tested.[20-24] Therefore, I believe that the novel agents are likely to be used as first-line or second-line agents rather than initially as induction agents.

Medscape: What is the evidence for agents optimized for neuroprotection and neurorepair?

Dr. Fox: Ideally, any medication that we use as a preventive medicine for MS would have neuroprotective and neurorepair abilities. Research has shown a frequent association of better clinical outcomes if there's prevention of atrophy. The concept of neuroprotection is that we are preventing axonal loss and neuronal loss during the early stages of MS prior to the onset of disability. All of the trials that are looking at atrophy measures are addressing this issue to some degree, but we would like to have advanced imaging metrics to look more directly at the preservation of axonal and neuronal function.

The World Congress and Treatment for Research of Multiple Sclerosis Meeting had a substantial amount of data that were presented regarding these advanced imaging metrics, including magnetic resonance spectroscopy (MRS) and magnetization transfer imaging (MTR). Measurement of neuronal loss by optical coherence tomography (OCT) is also a very promising method of evaluating the degree of atrophy seen in MS.[25] It is likely that the novel therapies currently being investigated will also be tested in a similar manner. It is reassuring to know that we are seeing some positive data on neuroprotection. Improving repair mechanisms may require a new type of medication that would stimulate the production of new myelin growth rather than working as an immunosuppressant medication.

Medscape: What are the limitations and benefits of these novel therapeutic agents, with respect to safety and efficacy, compared with long-approved therapies such as interferon beta and glatiramer acetate?

Dr. Fox: The-first line therapies that we are currently using for the treatment of MS have been on the market for a number of years. The users of these medicines have a certain comfort level with these medications now and the understanding that the long-term data have indicated a relatively good safety profile.

Immunomodulating therapies do not appear to cause the degree of risk that the immunosuppressant therapies may cause. We understand the risk-benefit ratios of the medicines that have been on the market for a number of years, but the novel therapies that are currently under investigation will undoubtedly have a higher degree of uncertainty as to their safety for many years to come. It is quite possible that the novel therapies are going to have immunosuppressant activity that could lead to increased risk for opportunistic infections, limiting their use as first-line therapies.

The efficacy measures, on the other hand, may show direct or indirect evidence of superiority to the first-line therapies. If indeed the therapeutic abilities of these novel therapies are great enough, then we may accept a higher risk potential with these medications and use them as first-line therapy. However, I don't think that the true measure of a medication's safety will be known at the time it enters the market.

Medscape: Does the increase of potential therapeutic agents complicate how to choose first-line therapy?

Dr. Fox: I think with the advent of more choices, we're going to have a greater divide among practicing neurologists as to how they approach the disease. Right now there's fairly good uniformity among neurologists in terms of how to treat early MS. There are differences in opinion about the optimal medication strategies for people with aggressive or chronic disease. But early active disease is currently treated by a limited number of agents that have relatively similar outcome measures in terms of their ability to control the disease. If we have new medicines available to us over the next several years that have a much different risk-benefit ratio with greater promise of disease control but increased risk, I feel that there's likely to be a group of neurologists who will use these medications first line. But there will be a number of other neurologists who are much more conservative in their acceptance of the new medications and will limit the new medicines only to those patients who have failed existing therapies.

Medscape: The fields of genetics and proteomics are beginning to play a large part in the discovery of novel therapeutic targets. How do these newly identified targets impact the development of individualized therapeutic strategies?

Dr. Fox: As we understand the pathology of MS better, we may find that certain medications are tailored for some patients more than others. For example, the biomarkers that may eventually be used for MS would determine whether we would want to use therapies that were depleters of B cells, T cells, monocytes, or a wide-spectrum immunosuppressant.[26,27] Critical to this line of thinking is the understanding of the mechanism of action of our current medications, which remains somewhat murky to this day, because MS is a highly variable and unpredictable disease with different pathologies among different patients. If we understood the pharmacogenomics of MS better, we might be able to tailor appropriate therapies much more accurately.

Medscape: What are some of the outstanding challenges in the treatment of MS that need to be addressed in the future?

Dr. Fox: Balancing the risks and benefits of medications in the treatment of MS has become increasingly important in the last few years. The major challenge in understanding the nature of this disease is elucidating the prognostic factors for an individual patient, so that we may prevent the development of permanent disability that at this point cannot be alleviated. If we can determine which patients have early, aggressive MS before the development of axonal loss and atrophy, we stand a much greater chance of being able to appropriately determine who might require stronger immunosuppressant. Our challenge going forward is to address both the inflammatory and the degenerative nature of MS with medications that effectively control the disease. Data presented at the World Congress on Treatment and Research in Multiple Sclerosis suggests we are now closer to that goal.

Medscape: Thank you Dr. Fox for sharing this information and your insights with us today.

This activity is supported by an independent educational grant from Teva.
References

1. Linker RA, Kieseier BC, Gold R. Identification and development of new therapeutics for multiple sclerosis. Trends Pharmacol Sci. 2008 Sep 17. [Epub ahead of print].
2. Gasperini C, Cefaro LA, Borriello G, et al. Emerging oral drugs for multiple sclerosis. Expert Opin Emerg Drugs. 2008;13:465-477. Abstract
3. Burton JM, O'Connor P. Novel oral agents for multiple sclerosis. Curr Neurol Neurosci Rep. 2007;7:223-230. Abstract
4. Brinar V for the CAMMS223 Study Group. Alemtuzumab Phase 2 Extension Study Design (CAMMS223): assessing long-term outcomes and potential benefits of additional alemtuzumab treatment in patients with relapsing-remitting multiple sclerosis. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P17.
5. Naismith R, Trinkaus K, Fairbairn M, Lauber J, Piccio L, Cross A. Rituximab as add-on therapy for breakthrough disease: clinical effects over 24 weeks. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P476.
6. Neyer L, Singer R, Wang H, Caras I. Daclizumab exhibits efficacy in multiple sclerosis subjects positive for interferon-beta neutralizing antibodies. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P479.
7. Hawker K. Efficacy and safety of rituximab in patients with primary progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, multicenter trial. Parallel Session 10 of Late Breaking News of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Scientific Program S78.
8. Dörner T, Burmester GR. New approaches of B-cell-directed therapy beyond rituximab. Curr Opin Rheumatol. 2008;20:263-268. Abstract
9. Guarnaccia J, Rinder H, Smith B. Preferential effects of cladribine on lymphocyte subpopulations. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P55.
10. Laugel B, Challier J, Siegfried C, Chvatchko Y, Weissert R, Galibert L. Cladribine exerts a modulatory effect on T-cell activation. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P80.
11. Rieckmann P, Giovannoni G, Cook S, et al, for the CLARITY Study Group. Cladribine tablets in relapsing-remitting multiple sclerosis: study design of the 2-year, phase III b CLA RITY (CLA dRibine tablets Treating multiple sclerosis orallY) extension study. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P453.
12. Kappos L, Radue E, O'Connor P, et al., for the FREEDOMS Study Group. Oral fingolimod (FTY 720) in patients with relapsing multiple sclerosis: 3-year results from a phase II study extension. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P72.
13. Kappos L, Polman C, Radue E, et al. Oral fingolimod (FTY 720) in relapsing-remitting multiple sclerosis: baseline patient demographics and disease characteristics from a 2-year phase III trial (FREEDOMS). Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P73.
14. Montalban X, Comi G, Anel J, et al. Oral fingolimod (FTY 720) in relapsing multiple sclerosis: impact on health-related quality of life in a phase II study Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P400.
15. MacManus D, Miller D, Kappos L, R. Gold, et al. The effect of BG00012 on conversion of gadolinium-enhancing lesions to T1-hypointense lesions. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P459.
16. Gold R, Kappos L, Miller D, et al. Safety profile of BG00012, an oral formulation of dimethyl fumarate for patients with relapsing MS. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P50.
17. Tallantyre E, Evangelou N, Constantinescu CS. Spotlight on terfilunomide. Int MS J. 2008;15:62-68. Abstract
18. Comi G, Abramsky O, Arbizu T, et al., for the LAQ/5062 Clinical Advisory Board and Study Group. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 9-month double-blind active extension of the multi-center, randomized, double-blind, parallel-group placebo-controlled study. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P31.
19. Gold R. Combination therapies in multiple sclerosis. Neurology. 2008;255 Suppl 1:51-60.
20. Vollmer T, Panitch H, Bar-Or A, et al. Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis. Mult Scler. 2008;14:663-670. Abstract
21. Le Page E, Leray E, Taurin G, et al. Mitoxantrone as induction treatment in aggressive relapsing remitting multiple sclerosis: treatment response factors in a 5 year follow-up observational study of 100 consecutive patients. J Neurol Neurosurg Psychiatry. 2008;79:52-56. Abstract
22. Filippi M, Le Page E, Leray E, Edan G, Comi G. Magnetic resonance imaging results of a 3-year randomized trial comparing two therapeutic strategies in aggressive relapsing-remitting multiple sclerosis: mitoxantrone as induction for 6 months followed by interferon-b-1b versus interferon-b-1b. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P254.
23. Perumal J, Hreha S, Caon C, et al. Intense immunosuppression as the initial disease-modifying therapy in clinically active relapsing multiple sclerosis. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P490.
24. Ramathal J, Boggild M. Glatiramer acetate following mitoxantrone induction in relapsing-remitting multiple sclerosis: extended experience. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P498.
25. Balcer L. OCT: window on multiple sclerosis. Parallel Session 5 of Advances in Imaging Techniques of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Scientific Program S43.
26. Garcia-Montojo M, Alvarez-Lafuente R, Dominguez-Mozo M, De las Hera V, Bartolome F, Arroyo R. MxA and MMP-9/TI MP-1 ratio as biomarkers of treatment efficacy and disease activity in multiple sclerosis patients. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster 452.
27. Melnikov A, Scholtens D, Reder A, Balabanov R, Stefoski D, Levenson V. Composite methylation profiles of blood DNA as biomarkers for multiple sclerosis. Disease-modifying therapy-part 2. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P869.


Interviewer: Elizabeth Samander, PhD, Scientific Director, Medscape LLC

Interviewee: Edward J. Fox, MD, PhD, Clinical Assistant Professor, University of Texas Medical Branch, Round Rock, Texas

Disclosure for Interviewer: Elizabeth Samander, PhD, is a member of the professional editorial group at Medscape and has reported no relevant financial relationships.

Disclosure for Interviewee: Edward J. Fox, MD, PhD, has disclosed that he has received grants for clinical research from Biogen-Idec, BioMS, EMD-Serono, Genzyme, Opexa Therapeutics, Sanofi-Aventis, and Teva Neuroscience. Dr. Fox has also disclosed that he has received grants for educational activities from Bayer, Biogen-Idec, EMD-Serono, Pfizer, and Teva Neuroscience. Dr. Fox has also disclosed that he has served as an advisor or consultant to Bayer, Biogen-Idec, EMD-Serono, Genzyme, Opexa Therapeutics, and Teva Neuroscience.

Laquinimod Demonstrated Significant and Sustained Impact on Multiple Sclerosis Disease Activity

New Crossover Data Presented at the World Congress on Treatment and Research in Multiple Sclerosis Shows Significant Reduction of Gadolinium-Enhancing Lesions

Jerusalem, Israel and Lund, Sweden, September 18, 2008 - New data from the extension phase of oral laquinimod in relapsing-remitting multiple sclerosis (RRMS) demonstrated a significant reduction in the mean number of gadolinium-enhancing (GdE) lesions in both patients who switched from placebo to laquinimod and patients who continued with their initial laquinimod dose.

In RRMS patients who switched from placebo to laquinimod, 52 percent reduction in the mean number of GdE lesions was observed (p<0.0007). The reduction was significant for both patients switching to high-dose (p<0.009) and low-dose laquinimod (p<0.03). In addition, the proportion of patients who switched to active treatment from placebo, and remained enhancing lesion-free, increased from 31 percent to 47 percent (p<0.012), further reinforcing the efficacy of laquinimod on magnetic resonance imaging (MRI) measured disease activity.

Patients initially treated with 0.6mg/day and 0.3mg/day during the double-blind trial remained on the same dose during the 36-week extension phase. An additional significant reduction in the mean number of GdE lesions was also observed in these patients (n=94, p=0.0062 and n=80, p=0.0013, respectively), a high proportion of which remained completely free of GdE lesions, demonstrating the sustained effect of laquinimod on MRI disease activity.

"These latest data show the rapid onset and sustainability of laquinimod efficacy in MS patients," said Giancarlo Comi, M.D., University Vita-Salute San Raffaele, Scientific Institute San Raffaele, Milan, Italy, principal investigator of the study. "Just as exciting is the fact that, with increased number of patients exposed to laquinimod, we found no new risks or safety issues. This reinforces earlier results demonstrating the laquinimod safety profile. The MS community looks forward to future data as we continue enrolling patients in the laquinimod Phase III clinical program."

These new data from the extension study build upon the initial 36-week, Phase IIb study results published in The Lancet*, which demonstrated that once-daily, oral 0.6mg laquinimod significantly reduced MRI disease activity by a median of 60 percent, compared to placebo, and was well tolerated.

Teva is currently enrolling patients for Allegro and Bravo, two pivotal Phase III clinical trials of laquinimod. For more information please visit www.TevaClinicalTrials.com.

*Lancet 2008; 371:2085-92

About the Study
In the study, "Oral laquinimod in patients with relapsing�remitting multiple sclerosis: 36 weeks double-blind active extension of the multi-center, randomized, double-blind, parallel-group placebo-controlled study," subjects originally assigned to placebo were equally randomized to receive either 0.3 or 0.6mg/day laquinimod, while others continued their original treatment for a 36-week, double-blind extension. Magnetic resonance imaging (MRI) was performed at the beginning and at the end of the active extension phase. The mean number of GdE lesions in patients who switched from placebo to laquinimod was reduced by 52 percent (from 4.46�6.55 to 2.12�3.73; p<0.0007) from the time patients began receiving active treatment.

Two hundred and fifty seven patients (91 percent) entered the extension phase to receive laquinimod 0.3mg/day or 0.6mg/day. Neither new safety signals nor an increase in the incidence rate of adverse events and laboratory abnormalities have emerged following new or prolonged exposure to laquinimod.

Patients on continuous 18 month laquinimod 0.6mg treatment continued to show low MRI disease activity, with a high proportion remaining free of GdE-lesions. A good tolerability profile was also observed. Treatment effects on MRI activity witnessed during the placebo-controlled phase were reproduced when placebo patients switched to laquinimod.

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 recently 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 480 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 Barr� 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. Teva expects to initiate the clinical development of laquinimod for Crohn's disease and Lupus Nephritis in the near future.

About the Phase III Program
Allegro (assessment of oral laquinimod in preventing progression of MS) is a pivotal, global, 24/30-month, double-blind, Phase III study designed to evaluate the efficacy, safety and tolerability of laquinimod versus placebo in the treatment of RRMS. The enrollment goal is approximately 1,000 patients with RRMS.

Bravo (benefit-risk assessment of Avonex® and laquinimod) is a pivotal, multinational, multi-center, randomized, double-blind, parallel-group, placebo-controlled study designed to compare the safety and efficacy of laquinimod with placebo and to provide risk-benefit data for laquinimod versus a currently available injectable treatment. The enrollment goal is approximately 1,200 patients with RRMS.

The globally conducted clinical program will include centers throughout the United States as well as centers Canada, Europe, and Israel. To learn more about the research please visit www.TevaClinicalTrials.com or call 1-866-550-0614 (Allegro) or 1-800-840-5601 (Bravo).

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 RhuDex® for RA. Please visit www.activebiotech.com for more information.

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.

Teva's Safe Harbor Statement under the U. S. Private Securities Litigation Reform Act of 1995:
This release contains forward-looking statements, which express the current beliefs and expectations of management. Such statements are based on management's current beliefs and expectations and involve a number of known and unknown risks and uncertainties that could cause our future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. Important factors that could cause or contribute to such differences include risks relating to: our ability to successfully develop and commercialize additional pharmaceutical products, the introduction of competing generic equivalents, the extent to which we may obtain U.S. market exclusivity for certain of our new generic products and regulatory changes that may prevent us from utilizing exclusivity periods, competition from brand-name companies that are under increased pressure to counter generic products, or competitors that seek to delay the introduction of generic products, the impact of consolidation of our distributors and customers, potential liability for sales of generic products prior to a final resolution of outstanding patent litigation, including that relating to the generic versions of Allegra®, Neurontin®, Lotrel® and Protonix®, the effects of competition on our innovative products, especially Copaxone® sales, the impact of pharmaceutical industry regulation and pending legislation that could affect the pharmaceutical industry, the difficulty of predicting U.S. Food and Drug Administration, European Medicines Agency and other regulatory authority approvals, the regulatory environment and changes in the health policies and structures of various countries, our ability to achieve expected results though our innovative R&D efforts, our ability to successfully identify, consummate and integrate acquisitions, including the pending acquisition of Barr Pharmaceuticals Inc., potential exposure to product liability claims to the extent not covered by insurance, dependence on the effectiveness of our patents and other protections for innovative products, significant operations worldwide that may be adversely affected by terrorism, political or economical instability or major hostilities, supply interruptions or delays that could result from the complex manufacturing of our products and our global supply chain, environmental risks, fluctuations in currency, exchange and interest rates, and other factors that are discussed in this report and in our other filings with the U.S. Securities and Exchange Commission ("SEC").



Company Contacts:
Elana Holzman
Kevin Mannix

Teva Pharmaceutical Industries Ltd.
Teva North America

972 (3) 926-7554
(215) 591-8912

Teva Enrolls Patients for a Second Large Global Phase III Trial Of Oral Laquinimod

The BRAVO trial, together with the ongoing ALLEGRO trial will investigate oral laquinimod in more than 2,000 RRMS patients worldwide.

Jerusalem, Israel and Lund, Sweden, July 16, 2008 - Teva Pharmaceutical Industries Ltd. (NASDAQ: TEVA) and Active Biotech AB (OMX NORDIC: ACTI) announced today that patients are being enrolled for the BRAVO Phase III pivotal trial. BRAVO is a global, 24-month, double-blind study designed to evaluate the efficacy, safety and tolerability of the oral compound laquinimod versus placebo, and to provide risk-benefit data for laquinimod versus a currently available injectable treatment, Avonex®. The BRAVO trial, which was initiated in April this year, aims to enroll approximately 1,200 patients with relapsing-remitting multiple sclerosis (RRMS). A second global Phase III trial of laquinimod including 1,000 patients, ALLEGRO, is also ongoing and recruiting patients globally.

"All currently approved multiple sclerosis (MS) treatments are administered via injection or infusion. The ability to provide a safe and effective oral treatment option would be a significant advancement for the treatment of MS," said Dr. Timothy Vollmer, Medical Director, Rocky Mountain MS Center, Denver, Colorado, and principal investigator of the BRAVO study. "Additionally, the mode of action for laquinimod is unlike any other MS compound, existing or experimental. We are hopeful that this research will expand our abilities to combat the disease through novel targeting."

Data recently published in The Lancet* demonstrated that oral dose of laquinimod significantly reduced the median magnetic resonance imaging (MRI) disease activity by 60 percent, compared to placebo and was well tolerated in RRMS patients. The majority of patients from the study are still receiving treatment with laquinimod in an open-label extension trial.

The safety profiles of oral therapies are of increasing interest to the MS community; We are hopeful that laquinimod will be both efficacious and safe thus providing patients with an optimal risk-benefit profile," said Dr. Per Soelberg Sorensen, Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital, and principal investigator of the BRAVO study.


* Lancet 2008;371:2085-92

About Multiple Sclerosis
Multiple Sclerosis (MS) is the leading cause of neurological disability in young adults. It is estimated that over four hundred thousand 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 BRAVO
BRAVO (benefit-risk assessment of Avonex® and laquinimod) is a pivotal, multinational, multi-center, randomized, double-blind, parallel-group, placebo-controlled study designed to compare the safety and efficacy of laquinimod with placebo and to provide risk-benefit data for laquinimod versus a currently available injectable treatment, Avonex®. The enrollment goal is approximately 1,200 patients with RRMS. The globally conducted study will include centers in the United States, Europe, and Israel. To learn more about BRAVO visit www.TevaClinicalTrials.com or call 1-800-840-5601.

About ALLEGRO
ALLEGRO is a pivotal, global, 24/30-month, double-blind, Phase III study designed to evaluate the efficacy, safety and tolerability of laquinimod versus placebo in the treatment of relapsing-remitting multiple sclerosis (RRMS). The Allegro trial aims to enroll approximately 1,000 patients with RRMS. The globally conducted study will include centers in the United States as well as centers throughout Canada, Europe, and Israel. To learn more about Allegro, visit www.TevaClinicalTrials.com or call +1 866 550 0614.

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 recently 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. Laquinimod also showed consistent and robust effect on all secondary MRI endpoints. 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 460 MS patients have received laquinimod in various Phase I-II 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 Barr� 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. Teva expects to initiate the clinical development of laquinimod for Crohn's disease and 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 leading generic pharmaceutical company. The company develops, manufactures and markets generic and innovative pharmaceuticals and active pharmaceutical ingredients. Over 80 percent of Teva's sales are in North America and Western Europe. Please visit www.tevapharm.com for more information on Teva Phermaceutical Industries Ltd.

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 RhuDex® for RA. Please visit www.activebiotech.com for more information



Teva's Safe Harbor Statement under the U. S. Private Securities Litigation Reform Act of 1995:

This release contains forward-looking statements, which express the current beliefs and expectations of management. Such statements are based on management's current beliefs and expectations and involve a number of known and unknown risks and uncertainties that could cause Teva's future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. Important factors that could cause or contribute to such differences include risks relating to: Teva's ability to accurately predict future market conditions, potential liability for sales of generic products prior to a final resolution of outstanding patent litigation, including that relating to the generic versions of Allegra®, Neurontin®, Lotrel®, Famvir® and Protonix®, Teva's ability to successfully develop and commercialize additional pharmaceutical products, the introduction of competing generic equivalents, the extent to which Teva may obtain U.S. market exclusivity for certain of its new generic products and regulatory changes that may prevent Teva from utilizing exclusivity periods, competition from brand-name companies that are under increased pressure to counter generic products, or competitors that seek to delay the introduction of generic products, the impact of consolidation of our distributors and customers, the effects of competition on our innovative products, especially Copaxone® sales, the impact of pharmaceutical industry regulation and pending legislation that could affect the pharmaceutical industry, the difficulty of predicting U.S. Food and Drug Administration, European Medicines Agency and other regulatory authority approvals, the regulatory environment and changes in the health policies and structures of various countries, our ability to achieve expected results though our innovative R&D efforts, Teva's ability to successfully identify, consummate and integrate acquisitions (including the pending acquisition of Bentley Pharmaceuticals, Inc.), potential exposure to product liability claims to the extent not covered by insurance, dependence on the effectiveness of our patents and other protections for innovative products, significant operations worldwide that may be adversely affected by terrorism, political or economical instability or major hostilities, supply interruptions or delays that could result from the complex manufacturing of our products and our global supply chain, environmental risks, fluctuations in currency, exchange and interest rates, and other factors that are discussed in Teva's Annual Report on Form 20-F and its other filings with the U.S. Securities and Exchange Commission. Forward-looking statements speak only as of the date on which they are made and the Company undertakes no obligation to update or revise any forward-looking statement, whether as a result of new information, future events or otherwise.




Company Contacts:
Elana Holzman, Investor Relations
Kevin Mannix, Investor Relations
Teva Pharmaceutical Industries Ltd.
Teva North America
+972 3 926 7554
+1215 591 8912

Sven Andreasson, President & CEO
Active Biotech
+46 46 19 20 49

Teva & ANP Announce That Atl/Tv1102, a Novel Drug for The Treatment Of Relapsing Remitting Multiple Sclerosis (Rrms), Demonstrated Significant Reducti

-- Results Demonstrate Impressive Reduction of Disease Activity

-- Teva Intends to Conduct Additional Pre-Clinical and Clinical Research Before Continuing to a Phase III Study with this Unique and Promising Molecule --
Jerusalem, Israel & Melbourne, Australia, June 30, 2008 - Teva Pharmaceutical Industries Ltd. (NASDAQ: Teva) and Antisense Therapeutics Ltd. (ASX: ANP) announced today that ATL/TV1102, a novel, anti-sense drug, significantly reduced disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). A randomized, double-blind, placebo-controlled Phase IIa study met its primary endpoint showing a significant reduction by 54.4% (p=0.01) in cumulative number of new active lesions in patients taking ATL/TV1102 for 8 weeks, compared to placebo, as measured by magnetic resonance images (MRI).

Based on these encouraging results, Teva intends to conduct additional pre-clinical and clinical research before continuing to a Phase III study with this unique and promising molecule.

The Principal Investigator for the trial, Volker Limmroth MD PhD, Chairman of the Department of Neurology, Cologne City Hospitals, Germany, said, "The results of this international multi-center clinical study are very encouraging and demonstrate a highly significant effect for ATL/TV1102 on disease activity in MS patients."
"Following these results, we are planning to continue the development of this new and exciting molecule designed to confirm the efficacy of ATL/TV1102," said Moshe Manor, Teva's Group Vice President, Global Innovative Resources. "Together with COPAXONE®, a market-leading MS therapy and Laquinimod, an oral MS treatment currently in Phase III studies, Teva continues with its commitment to help MS patients and improve their quality of life."

"We are very pleased with the results of this study. Achieving the primary endpoint to such a significant degree vindicates our efforts in developing this unique drug, the first to use antisense technology in the treatment of MS. We now look forward to continuing the development of ATL/TV1102 for MS with one of the leading pharmaceutical companies in the world", said Mark Diamond, Chief Executive Officer of Antisense Therapeutics Ltd.

Teva is responsible for funding and performing future development activities as outlined above for ATL/TV1102. This decision by Teva to move forward with the development of ATL/TV1102 triggers a US$4 million milestone payment in accordance with the license agreement between Teva and ANP.

Study Design and Results
ATL/TV1102 Phase IIa trial was a randomized, double-blind, placebo-controlled clinical trial of ATL/TV1102. Patients received either ATL/TV1102 or placebo injections subcutaneously at a dose of 200 mg three times a week for the first week and twice weekly over additional 7 weeks after which they were monitored for additional 8 weeks. Assessment was done using monthly MRI brain scans. 77 patients were enrolled in the trial, which was conducted at multiple trial sites across six European countries. The goal of the trial was to obtain preliminary evidence of ATL/TV1102's effectiveness in reducing MS-related MRI brain lesions and assess its safety profile.

In the primary endpoint of the study, ATL/TV1102 showed a significant 54.4% reduction in cumulative number of new active MRI lesions on weeks 4, 8 and 12 (p=0.01).

In addition, patients taking ATL/TV1102 experienced a 65% reduced cumulative number of Gadolinium (Gd)-enhancing lesions on weeks 4, 8, and 12 (p=0.0053). ATL/TV1102 was also effective in significantly reducing T1-enhancing lesion volume by 84% at week 12.

ATL/TV1102 demonstrated an increasing effect with time on the reduction of new active lesions over 12 weeks - one month after the completion of dosing. This extended duration of activity post dosing was anticipated based on the drug's long (>3 week) half-life, and would support the proposition of less frequent dosing than the twice weekly dosing employed in the current trial though this would need to be confirmed in future clinical studies.

Data from this study demonstrated that in general, ATL/TV1102 was well-tolerated. Potentially attributable adverse events included injection site reactions which were mild to moderate and thrombocytopenia. Thrombocytopenia was reversible after treatment interruption returning to within normal ranges and was not accompanied with any clinical consequences.

The companies plan to present the results of this study at future scientific meetings.

About Multiple Sclerosis
Multiple Sclerosis (MS) is the leading cause of neurological disability in young adults. It is estimated that 400,000 people in the United States are affected by this disease, and that over two million people are affected worldwide. MS is a progressive, demyelinating disease of the central nervous system affecting the brain, spinal cord and optic nerves.

Patients with MS may experience physical symptoms and/or cognitive impairments, including weakness, fatigue, ataxia, physical dysfunction, bladder and bowel problems, sensory effects, and visual impairment. MS also has a significant impact on the sufferers' social functioning and overall quality of life.

About ATL/TV1102
ATL/TV1102 is a 2nd generation antisense drug discovered by Isis Pharmaceuticals Inc. (NASDAQ: ISIS) and licensed to ANP. Antisense drugs block specifically disease-causing proteins from being produced by interacting with their intended target based on information in the genetic code. ATL/TV1102 is a second generation anti-sense inhibitor of CD49d, a subunit of VLA-4 (Very Late Antigen-4), and is currently in Phase IIa clinical trials as a treatment for MS. In inflammation, white blood cells (leukocytes) move out of the bloodstream into the inflamed tissue, for example, the CNS in MS, and the lung airways in asthma. The inhibition of VLA-4 may prevent white blood cells from entering sites of inflammation, thereby halting progression of the disease. VLA-4 is a clinically validated target in the treatment of MS. Antisense inhibition of VLA-4 has demonstrated positive effects in a number of animal models of inflammatory disease including MS (Myers et al. J Neuroimmunol 160, p12-24, 2005).

About Teva Pharmaceutical Industries
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 Antisense Therapeutics
Antisense Therapeutics Limited (ASX: ANP) is an Australian publicly listed biopharmaceutical drug discovery and development company. Its mission is to create, develop and commercialize antisense pharmaceuticals for large unmet markets. ANP has two drugs in development and two drugs in pre-clinical research. ATL/TV1102 (injection) is in the advanced stages of a Phase IIa trial as a potential treatment of multiple sclerosis. ATL1103 is a second-generation antisense drug designed to lower blood IGF-I levels and is entering pre-clinical development as a potential treatment for acromegaly and vision disorders. ATL/TV1102 (inhaled) is at the pre-clinical research stage as a potential treatment for asthma. ATL1101 is a second-generation antisense drug at the pre-clinical research stage being investigated as a potential treatment for prostate cancer. ATL/TV1102 has been licensed to Teva Pharmaceutical Industries Ltd.

Copaxone® (glatiramer acetate injection) is indicated for the reduction of the frequency of relapses in patients with RRMS.


Teva Safe Harbor Statement under the U. S. Private Securities Litigation Reform Act of 1995:

This release contains forward-looking statements. Such statements are based on management's current beliefs and expectations and involve a number of known and unknown risks and uncertainties that could cause Teva's future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements, including statements relating to the results of the ATL/TV1102 Phase IIa study and the potential efficacy, tolerability and marketability of ATL/TV1102. Additional risks relating to Teva and its business are discussed in Teva's Annual Report on Form 20-F and its other filings with the U.S. Securities and Exchange Commission. Forward-looking statements speak only as of the date on which they are made and the Company undertakes no obligation to update or revise any forward-looking statement, whether as a result of new information, future events or otherwise.




Company Contacts:
Elana Holzman
Kevin Mannix
Teva Pharmaceutical Industries Ltd.
Teva North America
972 (3) 926-7554
(215) 591-8912

Mark Diamond Antisense Therapeutics Ltd
61 (3) 9827 8999

Oral Agent Shows Promise Against Multiple Sclerosis

By Charles Bankhead, Staff Writer, MedPage Today
Published: June 19, 2008

MILAN, Italy, June 19 -- A new type of immumodulatory agent for relapsing-remitting multiple sclerosis led to a 40% reduction in lesions, according to results of a multicenter, placebo-controlled phase IIb trial.

Patients treated with laquinimod at a dose of 0.6 mg a day averaged 2.6 gadolinium-enhancing lesions on MRI compared with 4.2 for the placebo group (P=0.0048), Giancarlo Comi, M.D., of the University Vita-Salute here, and colleagues reported in the June 21 issue of The Lancet.

The between-group difference emerged early in the trial, and follow-up beyond the primary study period demonstrated even larger reductions in MRI-detected lesions with laquinimod versus placebo.

Additionally, the number of new lesions was reduced by 50% in the laquinimod group.

"The decrease of MRI activity during the last part of the study was evidence for both [gadolinium-enhancing] and new T2 lesions, indicating that laquinimod reduces not only the extent of blood-brain barrier opening, but also the accrual of fixed lesions," the authors said.

Available therapies for multiple sclerosis all target inflammatory aspects of the disease. In addition, all of the approved therapies require injection, creating a potential advantage for any oral agent.

Laquinimod is structurally related to linomide, a drug that reduced disease activity in MS but had unacceptable toxicity, the authors said. Preclinical and phase I clinical studies suggested laquinimod had greater activity and a more favorable safety profile compared with linomide.

In a previous 24-week, randomized phase II study, laquinimod 0.3 mg/d suppressed formation of new MS lesions and was well tolerated. Those results led to the current evaluation of two different doses of the drug.

The study involved 306 patients relapsing-remitting multiple sclerosis with who had had one or more relapses in the previous year and at least one gadolinium-enhancing lesion on screening MRI. Investigators at 51 centers in nine countries randomized the patients to placebo or to laquinimod 0.3 mg/d or 0.6 mg/d.

The trial lasted 36 weeks, and the primary outcome was the cumulative total of gadolinium-enhancing lesions from the final four MRI scans at weeks 24, 28, 32, and 36.

Compared with placebo, laquinimod 0.6 mg reduced the average number of lesions per scan on the final four MRI scans by 40.4%.

The 0.3 mg dose did not significantly reduce the number of lesions compared with placebo (3.9 versus 2.6).

Comparison of the median cumulative number of lesions from the last four MRI scans resulted in a 55% reduction in the number of lesions with laquinimod 0.6 mg versus placebo (4.0 versus 9.0).

The number of new T2 lesions on the last four scans was 44% lower with laquinimod 0.6 mg (P=0.0013), and the number of new T1-hypointense lesions was 51% lower in the laquinimod 0.6 mg group (P=0.0064).

Examination of MRI scans from weeks 12 through 36 demonstrated a 51% reduction in the mean number of gadolinium-enhancing lesions with laquinimod 0.6 mg (2.7 versus 4.4) and a 60% decrease in the median number of lesions (6.0 versus 15.0).

Patients in the laquinimod 0.6 mg group had an annualized relapse rate of 0.52 compared with 0.77 for those on placebo which was not statistically significant (P=0.0978). Additionally, 70.8% of laquinimod 0.6 mg patients were relapse-free compared with 62.7% of the placebo group.

Both doses of laquinimod were well tolerated, the authors said. The primary treatment-related effect was a transient, dose-related increase in liver enzymes.

In an accompanying commentary, B. Mark Keegan, M.D., and Brian G. Weinshenker, M.D., of the Mayo Clinic in Rochester, Minn., said the results raised several questions:

* Why was the 0.3 dose effective in the earlier phase II study but not in the current study?
* Was the limited duration the reason for the lack of difference in relapse rate?
* How does laquinimod's efficacy compare with that of other immunomodulatory agents?

They also noted that MRI gadolinium-enhanced lesions are not a perfect surrogate outcome: "The correlation between MRI findings and clinical disease course is, however, imperfect. Gadolinium-enhancing lesions are mildly predictive of relapse rate but not of clinical disability."

The Mayo clinicians also remained circumspect about the generally favorable safety profile of laquinimod.

"Continued vigilance is needed because serious adverse effects are commonly not in evidence until phase III studies are started . . . or until after approval," they said.

Teva Pharmaceutical Industries supported the study.

Dr. Comi reported consulting and speaking relationships with Teva, Novartis, sanofi-aventis, Merck-Serono, Biogen-Dompe, and Bayer Schering. Several coauthors also reported relationships with the pharmaceutical industry.

Dr. Weinshenker disclosed that he is a paid member of the data-safety monitoring committee for another oral agent being evaluated for multiple sclerosis.

Dr. Keegan declared that he has no conflicts.

Primary source: The Lancet

Source reference:
Comi G, et al "Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicenter, randomized, double-blind, placebo-controlled phase IIb study" Lancet 2008; 371: 2085-2092.

Additional source: The Lancet
Source reference:
Keegan BM, Weinshenker BG "Laquinimod, a new oral drug for multiple sclerosis" Lancet 2008; 371: 2059-2060.

SLU Researchers to Test New Oral Medication for Multiple Sclerosis

Apr 29, 2008 - 4:38:53 PM


(HealthNewsDigest.com) - ST. LOUIS – Researchers at Saint Louis University are preparing to test an investigational pill to treat relapsing-remitting multiple sclerosis, the most common form of the potentially disabling neurological disease.

There are currently no oral medications approved to treat MS, which affects some 400,000 people in the United States (with approximately 10,000 new cases diagnosed each year). There are various medications to slow or modify the progression of the disease, but all must be injected into the skin, muscle or veins, making the search for an oral medication a top priority.

SLU will be one of several dozen sites around the world where researchers will study how patients with relapsing-remitting MS respond to the experimental drug laquinimod, which is taken in tablet form once a day. About 1,000 patients will be enrolled worldwide.

MS is a disease in which the body’s immune system attacks the protective coating – called myelin – surrounding the nerves within the central nervous system, as well as the nerve fibers themselves. Symptoms can vary widely from person to person, but they generally include fatigue, muscle weakness, numbness, impaired mobility, balance and cognition and vision disturbances.

About 85 percent of people newly diagnosed with the disease have relapsing-remitting MS. This form of the disease is characterized by periodic attacks or flare-ups (relapses), followed by months or even years of little to no signs of the disease (remission).

“Laquinimod seems to modulate how the immune system works,” said Florian P. Thomas, M.D., Ph.D., professor of neurology at the Saint Louis University School of Medicine and the study’s principal investigator. “In smaller, earlier trials, the drug reduced the likelihood of relapses in patients, as well as the number of MS lesions seen on MRI tests.”

In the randomized, double-blind study – the largest such investigation of the drug to date – half the volunteers will receive laquinimod while the remainder will be given a placebo.

They’ll remain in the trial for up to 30 months, during which time researchers will periodically assess how their disease develops. At various visits throughout the trial, patients will be given complete physical and neurological examinations, as well as an MRI scan to determine the extent of scarring on the brain – a defining characteristic of multiple sclerosis.

For the study, SLU researchers are looking for patients with relapsing-remitting MS between the ages of 18 and 55. Among other criteria, patients must not have taken any immuno-suppressive drugs within the last six months. Women must not be pregnant or breast feeding, and those of child-bearing age must be on at least two forms of birth control.

People wanting more information or to find out whether they qualify to participate in the study should call 314-977-4900.

Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.

www.HealthNewsDigest.com

© Copyright by HealthNewsDigest.com

Initiation Of Enrollment In Pivotal Phase III Clinical Study Of Oral Laquinimod For Relapsing-Remitting Multiple Sclerosis

Jerusalem, Israel and Lund, Sweden, November 7, 2007 - Teva Pharmaceutical Industries Ltd. (NASDAQ: TEVA) and Active Biotech AB (OMX NORDIC: ACTI) announced today the initiation of enrollment in the Allegro trial (assessment of oral laquinimod in preventing progression of multiple sclerosis). Allegro is a global pivotal, 24/30-month, double-blind, Phase III study designed to evaluate the efficacy, safety and tolerability of the oral investigational compound laquinimod versus placebo in the treatment of relapsing-remitting multiple sclerosis (RRMS). The Allegro trial aims to enroll approximately 1,000 patients with RRMS.

"Currently there are several RRMS treatments available; however, they are all administered via injection or infusion. An orally administered therapy brings us one step closer to offering patients and physicians a highly effective, new, convenient and less invasive method of drug delivery," said Doug Jeffery, M.D., Ph.D., Associate Professor, Wake Forest University Baptist Medical Center. "Previous Phase II studies have demonstrated positive results for laquinimod, and we hope that results from this pivotal Phase III trial will further reinforce these findings."

Recently, Teva concluded a 36-week extension of the 36-week Phase IIb core trial, which demonstrated that laquinimod 0.6 mg met its primary endpoint. The data from this extension trial further confirmed and strengthened the results from the initial 36-week Phase IIb trial. The majority of the patients that have participated in the trial are now receiving treatment with laquinimod in a continued open-label extension trial.

"The initiation of Phase III clinical trial is a critical milestone for Teva in our commitment to the MS community," said Moshe Manor, Group Vice President - Global Innovative Resources, of Teva Pharmaceutical Industries Ltd."We are excited about the development of Laquinimod, which together with Copaxone, will broaden our MS platform and position Teva as a leading company in the MS field".

Additional new data, presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on October 13, 2007 in Prague, demonstrated that laquinimod reduced inflammation, demyelination and axonal damage in an animal model experimental autoimmune encephalomyelitis (EAE), indicating that the compound may have both anti-inflammatory and neuroprotective properties.
Based on encouraging results from various animal models, laquinimod is now being investigated for other autoimmune diseases.

"We are very pleased to see how Teva has successfully advanced the laquinimod clinical trial program in order to bring a novel, first-in-class product to the market for the treatment of MS," said Sven Andr�asson, President and CEO of Active Biotech AB.

The efficacy, safety, and tolerability of laquinimod will also be studied in an additional Phase III pivotal trial in RRMS (BRAVO), which is expected to begin enrollment in the first quarter of 2008. This trial is a multinational, multi-center, randomized, parallel-group, placebo-controlled study which will compare the effects of laquinimod to those of placebo, and provide risk-benefit data comparing once-daily orally administered laquinimod to a product presently used for treatment of RRMS (an active comparator). This study plans to enroll approximately 1,200 participants who will be followed for 24 months.

About Multiple Sclerosis
Multiple Sclerosis (MS) is the leading cause of neurological disability in young adults. It is estimated that 400,000 people in the United States are affected by the disease, and that over one million people are 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 Allegro
Allegro is a multinational, multi-center, randomized, double-blind, parallel-group, placebo-controlled study, currently enrolling approximately 1,000 patients with RRMS. The globally conducted study will include centers in the United States as well as centers throughout Canada, Europe, and Israel. To learn more about Allegro, visit www.TevaClinicalTrials.com or call 1-866-550-0614.

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 recent Phase IIb study in 306 patients was presented at the 2007 Annual Meeting of the American Academy of Neurology (AAN). The data demonstrated that an oral 0.6 mg dose of laquinimod, administered daily, significantly reduced magnetic resonance imaging (MRI) disease activity by 40 percent versus placebo (p=0.0048) in RRMS patients, and was well tolerated. Looking into the median data of the primary end point laquinimod 0.6mg reduces disease activity (MRI) by 55% compared to placebo. Laquinimod showed consistent and robust effect (statistical significant) on all secondary MRI end points.
In addition, the study showed a favorable trend toward reducing annual relapse rates and the number of relapse-free patients compared with placebo. Treatment with both 0.3 and 0.6 mg doses were well tolerated with only some transient and dose-dependent increases in liver enzymes reported. To date 460 MS patients have received laquinimod in various clinical trials.

Active Biotech AB
Active Biotech AB (OMX NORDIC: ACTI) is a biotechnology company focusing on research and development of pharmaceuticals. Active Biotech has a strong R&D portfolio with pipeline products focused on autoimmune/inflammatory diseases and cancer. Most advanced projects 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 RhuDex® for RA. In addition, the autoimmunity project I-3D is in preclinical development. www.activebiotech.com

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




Safe Harbor Statement under the U. S. Private Securities Litigation Reform Act of 1995: This release contains forward-looking statements, which express the current beliefs and expectations of management. Such statements are based on management�s current beliefs and expectations and involve a number of known and unknown risks and uncertainties that could cause Teva�s future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. Important factors that could cause or contribute to such differences include risks relating to: Teva`s ability to successfully develop and commercialize additional pharmaceutical products, the introduction of competing generic equivalents, the extent to which Teva may obtain U.S. market exclusivity for certain of its new generic products and regulatory changes that may prevent Teva from utilizing exclusivity periods, competition from brand-name companies that are under increased pressure to counter generic products, or competitors that seek to delay the introduction of generic products, the impact of consolidation of our distributors and customers, potential liability for sales of generic products prior to a final resolution of outstanding patent litigation, including that relating to the generic versions of Allegra®, Neurontin®, Lotrel®, and Famvir®, the effects of competition on our innovative products, especially Copaxone® sales, the impact of pharmaceutical industry regulation and pending legislation that could affect the pharmaceutical industry, the difficulty of predicting U.S. Food and Drug Administration, European Medicines Agency and other regulatory authority approvals, the regulatory environment and changes in the health policies and structures of various countries, our ability to achieve expected results though our innovative R&D efforts, Teva�s ability to successfully identify, consummate and integrate acquisitions, potential exposure to product liability claims to the extent not covered by insurance, dependence on the effectiveness of our patents and other protections for innovative products, significant operations worldwide that may be adversely affected by terrorism, political or economical instability or major hostilities, supply interruptions or delays that could result from the complex manufacturing of our products and our global supply chain, environmental risks, fluctuations in currency, exchange and interest rates, and other factors that are discussed in Teva�s Annual Report on Form 20-F and its other filings with the U.S. Securities and Exchange Commission. Forward-looking statements speak only as of the date on which they are made and the Company undertakes no obligation to update or revise any forward-looking statement, whether as a result of new information, future events or otherwise.
Company Contacts:
Dan Suesskind, Chief Financial Officer
Teva Pharmaceutical Industries Ltd.
972-2-941-1717

George Barrett,
Corp. E. V.P. - Global pharmaceutical Markets
Chief Executive Officer
Teva Pharmaceutical Industries Ltd.
Teva North America
(215) 591-3030

Liraz Kalif / Kevin Mannix,
Investor Relations
Teva Pharmaceutical Industries Ltd.
Teva North America
972-3-926-7281
(215) 591-8912

Sven Andr�asson President & CEO
Active Biotech
+46 46 19 20 49

Tomas Leanderson Chief Scientific Officer
Active Biotech
+46 46 19 20 95

Cecilia Hofvander Manager Corporate Communication
Active Biotech
+46 46 19 11 22

Active Biotech drug could have the edge in oral MS race

By Anna Lewcock

07/06/2007 - A joint effort to develop a winning oral formulation for the treatment of multiple sclerosis (MS) has taken another step towards the finish line with initiation of Phase III trials for the novel laquinimod compound.

Developed by Swedish firm Active Biotech and licensed to pharma giant Teva, laquinimod is just one of the competitors in the race to become the first oral treatment for MS, but according to the two firms there are vital differences between their drug candidate and other oral formulations in development.

The once daily laquinimod therapy differentiates itself by being an immunomodulatory compound (capable of modifying or regulating immune functions), in contrast to some rival oral MS treatments in development which affect the body in a different way.

"Other companies are developing products that are immunosuppressive rather than immunomodulatory," Active Biotech CEO Sven Andréasson explained to in-PharmaTechnologist.com.

"These are fine for the short term, but are not so good in the long term and tend to result in more side-effects."

Trials of laquinimod thus far have shown a very clear safety profile according to Andréasson, suggesting that it could be a more attractive option for long term use. The Phase III trials that the two companies are initiating will help test this theory that the novel oral laquinimod formulation will result in less side effects than its competitors, whilst still proving an effective MS treatment.

The drug itself is in tablet form and will be administered once a day, with the recent Phase II trials evaluating dosages of 0.3mg and 0.6mg, both of which were well-tolerated with only some transient and dose-dependent increases in liver enzymes.

Labelled a "very druggable compound" by Andréasson, the drug is not difficult to manufacture and Active Biotech has secured a substance patent through to 2019 and applied for a method patent that will protect to 2022 or 2024. Teva will take care of production and pricing for the new product.

A non-invasive, oral MS treatment could mean serious revenues for the team that manages to hit the market first. Although other companies are already well on the way with Phase III trials of their compounds, the immunomodulatory mode of action of Active Biotech's drug could give it a critical edge in the market.

The company is set to receive royalties between 12 and 20 per cent on the oral formulation, which could lead to some significant earnings if the product emerges as an MS blockbuster.

Currently valued at almost $6bn (€4.4bn), the MS market is growing rapidly, and has been forecast to reach around $10bn by the time oral laquinimod could hit the shelves in three or four years time.

Teva already has an MS treatment out on the market in the form of Copaxone (glatiramer acetate), which last year brought in around €1.6bn in revenues - a figure which Andréasson expects to be able to match with laquinimod.

"Although there are some products already in Phase 3, like those from Novartis, Merck-Serono or Bayer Schering, they are all immunosuppressive so there is still a clear profile for our drug," he said.

"We believe it should be at least as good as current treatments available, as well as being safe for long-term treatments."

With Active Biotech having dedicated eight years of research to the product thus far, and the Phase III trials expected to start later this year, the final product could offer a much needed non-invasive option to the million people worldwide currently suffering with MS.