First Phase III results for FTY720, a novel oral therapy for MS, show superior efficacy compared to interferon beta-1a

* FTY720 significantly reduced annualized relapse rates by 52% (0.5 mg dose) and 38% (1.25 mg) vs. interferon beta-1a in one-year TRANSFORMS study[1]

* FTY720 generally well-tolerated and safety profile in line with previous experience[1]

* Regulatory submissions for FTY720 in US and EU on track for end of 2009; FREEDOMS and FREEDOMS II placebo-controlled Phase III studies continuing

* Multiple sclerosis, a devastating disease causing progressive disability, affects up to 2.5 million people worldwide including many young adults[2]

Basel, December 12, 2008 - Initial results from the one-year Phase III TRANSFORMS study show the investigational oral compound FTY720 (fingolimod) has superior efficacy to a current standard of care for patients with relapsing-remitting multiple sclerosis (MS). Patients on oral FTY720 experienced significantly fewer relapses than those treated with the injectable medicine interferon beta-1a (Avonex®*)[1].

The study, the first one-year head-to-head Phase III trial against a standard of care in MS, met its primary endpoint for both doses of FTY720.

The annualized relapse rate at one year for patients given FTY720 0.5 mg was 0.16, representing a 52% reduction compared to a relapse rate of 0.33 for interferon beta-1a (p<0.001). The FTY720 1.25 mg dose also showed a significant reduction in relapses with a rate of 0.20 representing a 38% reduction against interferon beta-1a (p<0.001). No statistically significant difference was seen between the two FTY720 doses[1].
Comprehensive analyses of the TRANSFORMS study data are ongoing, and detailed results are planned to be presented at a leading scientific congress in 2009. Regulatory submissions remain on track to be completed in the US and EU at the end of 2009.
"We are encouraged by the early results from TRANSFORMS, which represent a major step towards delivering an effective oral treatment for people with relapsing-remitting MS," said Trevor Mundel, MD, Global Head of Development at Novartis Pharma AG. "These positive results reinforce the potential for FTY720 to provide a significant advance in the future treatment of this devastating disease."

MS is a chronic autoimmune neurodegenerative disease of the central nervous system associated with irreversible progression of disability[3]. As many as 2.5 million people worldwide are affected by the condition[2] that typically begins in early adulthood between the ages of 20 and 40 years when patients are in the prime of life[4].

TRANSFORMS (TRial Assessing injectable interferoN vS FTY720 Oral in RrMS) is the first of three studies to report results in one of the largest Phase III clinical programs ever conducted in MS, involving more than 3,400 patients around the world.
As a head-to-head trial against interferon beta-1a, TRANSFORMS was designed to assess the efficacy of FTY720 compared to an established disease-modifying therapy in reducing relapse rates in patients with relapsing-remitting MS, the most common form of the disease. Two other studies - FREEDOMS and FREEDOMS II - are two-year placebo-controlled Phase III studies to assess the impact of FTY720 in reducing the frequency of relapses and slowing the progression of disability, and to further characterize the benefit-risk profile. Data from these studies to support regulatory submissions are expected in 2009.

TRANSFORMS was a one-year worldwide double-blind, double-dummy study that enrolled 1,292 patients. The study had three arms: oral FTY720 0.5 mg and 1.25 mg once-daily, and the active comparator interferon beta-1a given once-weekly by intra-muscular injection. The patient population in TRANSFORMS was consistent with the demographics and disease state seen in Phase III clinical trials for other disease-modifying treatments for relapsing-remitting MS[5].

The safety profile of FTY720 seen in TRANSFORMS was in line with previous clinical experience. The compound was generally well-tolerated with 87% of FTY720-treated patients completing the study on treatment. The proportion of patients discontinuing therapy was 10% in the FTY720 0.5 mg group, 15% in the FTY720 1.25 mg group, and 12% in the interferon beta-1a group[1].

The most commonly reported adverse events, seen in more than 10% of patients in all three study arms, were headache, nasopharyngitis and fatigue. Influenza-like symptoms were reported in 37% of patients treated with interferon beta-1a and in 4% of patients treated with FTY720[1].

Adverse effects seen in FTY720-treated patients included transient reductions in heart rate at the start of treatment, minor increases in blood pressure, and elevations in liver enzymes (also seen with interferon beta-1a). Macular edema (swelling of the center of the retina) was detected in less than 1% of FTY720-treated patients[1]. Seven cases of localized skin cancer were diagnosed in FTY720-treated patients (four basal cell carcinoma and three melanoma), while one case of squamous cell carcinoma was seen in the interferon beta-1a group. All of these localized skin lesions were successfully removed[1].

As previously reported, two fatal herpes infections occurred in patients treated with FTY720 1.25 mg. Both cases involved confounding factors impacting the outcome, but a role for FTY720 could not be excluded given its immunosuppressive effect.

In general, the safety profile of the FTY720 0.5 mg dose appeared to be better than that of the 1.25 mg dose, including lower rates of infections and bradycardia. Further analyses of the TRANSFORMS data and results from the ongoing Phase III studies will help to provide a more comprehensive assessment of FTY720's benefit-risk profile.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by terminology such as "on track," "planned," "encouraged," "potential," "to assess," "to further characterize," "expected," "appeared to be," "will," or similar expressions, or by express or implied discussions regarding potential regulatory submissions or marketing approvals for FTY720 or regarding potential future revenues from FTY720. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with FTY720 to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that FTY720 will be submitted for approval in any market by the end of 2009 or at any time. Nor can there be any guarantee that FTY720 will ever be approved for sale in any market. Neither can there be any guarantee that FTY720 will achieve any particular levels of revenue in the future. In particular, management's expectations regarding FTY720 could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data (including the upcoming results of the FREEDOMS and FREEDOMS II trials) and unexpected additional analysis of existing clinical data (including the results of the ongoing additional analyses of the TRANSFORMS clinical data); unexpected regulatory actions or delays or government regulation generally; competition in general; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; government, industry and general public pricing pressures; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis
Novartis AG provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines, diagnostic tools and consumer health products. Novartis is the only company with leading positions in these areas. In 2007, the Group's continuing operations (excluding divestments in 2007) achieved net sales of USD 38.1 billion and net income of USD 6.5 billion. Approximately USD 6.4 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 97,000 full-time associates and operate in over 140 countries around the world. For more information, please visit http://www.novartis.com.

References

[1.] Novartis. Data on file.
[2.] World Health Organization. Neurology atlas, 2004. http://www.who.int/mental_health/neurology/neurogy_atlas_review_references.pdf (Accessed 30 November 2008).
[3.] Confavreux C, Vukusic S. Accumulation of irreversible disability in multiple sclerosis: from epidemiology to treatment. Clin Neurol Neurosurg 2006;108:327-32.
[4.] Confavreux C, Aimard G, Devic M. Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 1980;103:281-300.
[5.] Cohen J, et al. Oral fingolimod (FTY720) versus interferon beta-1a in relapsing-remitting multiple sclerosis: baseline patient demographics and disease characteristics from a Phase III trial (TRANSFORMS). Abstract at WCTRIMS, April 2008.
[*] Avonex® is a registered trademark of Biogen Idec.

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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.

FTY720, a novel oral therapy in development for MS, shows sustained benefits for the majority of patients after three years of treatment

Phase II study extension shows 68-73% of patients with multiple sclerosis remained relapse-free after three years of treatment with oral FTY720[1]

New data demonstrate 89% of patients free from active brain lesions - the injury caused by MS - three years after starting treatment[1]

MS, a devastating disease causing progressive disability, affects 2.5 million people worldwide including many young adults[2]
FTY720 regulatory filings planned before end of 2009 in US and EU

Basel, April 15, 2008 - The investigational oral therapy FTY720 (fingolimod) continues to demonstrate sustained benefits in patients with multiple sclerosis (MS) after three years of treatment, according to new clinical data presented today from an ongoing Phase II study extension[1].

Results showed that 73% of patients who began the study on FTY720 5 mg remained free from relapses after three years, and 68% of those who began the study on FTY720 1.25 mg remained relapse-free[1]. The figures after two years of treatment were 77% and 75% respectively[3]. On the basis of comparable efficacy and a better safety profile, all patients have been transferred to FTY720 1.25 mg in the study extension.

The 36-month data also showed an average annualized relapse rate of 0.20[1], equivalent to one relapse in five years, while 89% of patients were free of the active brain lesions characteristic of MS as measured by magnetic resonance imaging (MRI)[1] three years after starting treatment.

The results were presented at the 60th annual meeting of the American Academy of Neurology (AAN) in Chicago, USA.

"These new data demonstrate the exciting potential for FTY720 to reduce relapse rates in MS patients with a convenient once-daily pill," said Professor Giancarlo Comi, Professor of Neurology at the University Vita-Salute San Raffaele in Milan, Italy. "An effective oral treatment would be a significant breakthrough in the management of MS. That is why these results are encouraging - because we are seeing substantial benefits of FTY720 maintained over time in this clinical trial."

FTY720 is a novel, once-daily, oral treatment in worldwide Phase III clinical development for the treatment of relapsing-remitting MS, the form of the disease that affects approximately 85% of people diagnosed with MS[4].

More than 2.5 million people worldwide are affected by MS[2], the most common non-traumatic cause of neurological disability in young people[5]. Regulatory filings for FTY720 are expected in the US and EU before the end of 2009.

"The FTY720 Phase III program is the largest conducted in MS to date, and demonstrates our long-term commitment to the field of MS therapy," said Trevor Mundel, MD, Head of Global Development Functions at Novartis Pharma AG. "It is especially encouraging to see that FTY720 continues to demonstrate sustained efficacy by helping the majority of patients to remain free of relapses as the study progresses."

FTY720 has the potential to be the first in a new class of therapies for MS that act on inflammation by modulating sphingosine-1-phosphate receptors (S1P-R), reducing the number of inflammatory immune cells, called lymphocytes, from reaching the brain. In addition, FTY720 reaches the brain and S1P-Rs are present on central nervous system (CNS) tissue, so FTY720 may have a direct beneficial effect on MS within the CNS. This additional potential mechanism of action is supported by new preclinical data being presented at AAN[6],[7].

The Phase II study presented at AAN began with a six-month placebo-controlled phase in which 281 patients with relapsing MS received placebo, FTY720 1.25 mg or FTY720 5 mg once-daily. This was followed by a long-term extension in which all patients took FTY720. At the end of three years, 173 patients were in the extension, which is still ongoing. The study has been conducted in Canada and 10 European countries.

Results from the six-month placebo-controlled trial showed that FTY720 reduced relapse rates by more than 50% compared to placebo[5]. Current first-line therapies for MS reduced relapse rates by 30-35% on average in two-year studies[5].
Among patients originally on placebo who converted to active therapy in the extension, 51% were free of relapses at three years[1]. The figure at two years was 57%[3].

FTY720 has been generally well tolerated throughout the three years of the Phase II study and its extension, with the most common adverse events being nasopharyngitis, headache, fatigue and influenza[1]. Increases in alanine aminotransferase (liver enzymes) were observed in 16% of patients. Dermatological screening of patients was implemented in the extension after a small number of cases of localized skin malignancies were reported.

Novartis continues to study FTY720 in an ongoing, blinded Phase III clinical trial program. This program includes comprehensive monitoring that will further assess and characterize the safety profile of FTY720.

MS is caused by the destruction of myelin, which helps neurons carry electrical signals in the brain[8]. The disease causes problems with muscle control and strength, vision, balance, sensation and mental function[8]. MS typically presents in relapsing forms involving acute self-limiting attacks of neurological dysfunction (or "relapses") followed by complete or partial restoration of functions.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by terminology such as "planned", "potential", "would", "encouraging", "expected", "commitment", "may", "continues", "will", or similar expressions, or by express or implied discussions regarding potential future regulatory filings or marketing approvals for FTY720 or regarding potential future revenues from FTY720. Such forward-looking statements reflect the current views of the Company regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with FTY720 to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that FTY720 will be submitted to regulatory authorities for approval, or will be approved for sale in any market. Nor can there be any guarantee that FTY720 will achieve any particular levels of revenue in the future. In particular, management's expectations regarding FTY720 could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis
Novartis AG provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on growth areas in healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, and consumer health products. Novartis is the only company with leading positions in these areas. In 2007, the Group's continuing operations (excluding divestments in 2007) achieved net sales of USD 38.1 billion and net income of USD 6.5 billion. Approximately USD 6.4 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 98,200 full-time associates and operate in over 140 countries around the world. For more information, please visit http://www.novartis.com.

References
[1.] Comi G et al. Oral FTY720 (fingolimod) in patients with relapsing multiple sclerosis. 3-year extension shows sustained low relapse rate and MRI activity. Abstract presented at 60th annual meeting of American Academy of Neurology, Chicago 12-19 April 2008.
[2.] National Multiple Sclerosis Society website.
http://www.nationalmssociety.org/about-multiple-sclerosis/who-gets-ms/index.aspx Accessed March 11, 2008.
[3.] Kappos L. et al. Oral fingolimod (FTY720) in relapsing MS: 24-month results of the Phase II study. ECTRIMS 2006.
[4.] National Multiple Sclerosis Society website.
http://www.nationalmssociety.org/about-multiple-sclerosis/what-is-ms/index.aspx Accessed March 11, 2008.
[5.] Kappos L et al. Oral Fingolimod (FTY720) for Relapsing Multiple Sclerosis. N Engl J Med 2006;355, p. 1130.
[6.] Barske C et al. FTY720 (Fingolimod) and S1P-Receptor 1 and 5 specific Agonists Increase the Number of Oligodendrocytes in Vitro. Abstract presented at 60th annual meeting of American Academy of Neurology, Chicago 12-19 April 2008.
[7.] Schubart A et al. FTY720 suppresses ongoing EAE and promotes a remyelinating environment preventing axonal degeneration within the CNS. Abstract presented at 60th annual meeting of American Academy of Neurology, Chicago 12-19 April 2008.
[8.] National Multiple Sclerosis Society website.
http://www.nationalmssociety.org/about-multiple-sclerosis/symptoms/index.aspx Accessed March 11, 2008.

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New Preclinical Data Suggests FTY720 May Repair or Reduce Damage Caused by Multiple Sclerosis Through a Direct Effect in the Brain

· Potential beneficial impact on central nervous system in addition to well established action on immune cells

· Recruitment complete for two of three pivotal Phase III trials; recruitment for third study is ongoing and on track

· MS most common neurological disorder in young adults, affecting more than an estimated 2.5 million people worldwide

EAST HANOVER, NJ, October 12, 2007- New preclinical data presented at European Committee for Treatment and Research of Multiple Sclerosis (ECTRIMS) in Prague suggests that FTY720 (fingolimod) directly reduces neurodegeneration and enhances repair of the central nervous system (CNS) damage caused by multiple sclerosis (MS) by interacting with sphingosine-1-phosphate receptors (S1P-R) expressed on brain cells. This mechanism of action may be in addition to the established anti-inflammatory role of FTY720 that is mediated by the reduction of inflammatory immune cells, called lymphocytes, from reaching the brain.

FTY720 is a novel, once-daily, oral treatment currently in worldwide Phase III clinical development to test its safety and efficacy as a disease modifying therapy for relapsing-remitting MS, which affects approximately 85% of people with multiple sclerosis.

The potential direct beneficial effect of FTY720 in the CNS is supported by the results of several preclinical experiments being presented at ECTRIMS, including research in animal models of MS and in vitro studies on CNS cells called oligodendrocytes.

In an animal model of MS (experimental autoimmune encephalomyelitis in rats), the administration of FTY720 directly into the CNS resulted in a statistically significant reduction in disease severity. This decrease in disease activity was seen in the absence of a reduction of lymphocytes in the bloodstream, suggesting that the favorable effect of FTY720 seen in this model is due to a direct effect in the CNS that is independent of the effects on peripheral lymphocytes.

In two experiments presented at ECTRIMS, the modulation of S1P-R by the addition of FTY720 resulted in an increase in the number, growth and survival of oligodendrocytes in cell culture. This effect of FTY720 on oligodendrocytes may help limit destruction of myelin and promote its repair and, thus, may contribute to the effectiveness of FTY720 in MS. Oligodendrocytes are cells in the CNS that make a fatty tissue, called myelin, which is necessary for normal signal transfer along nerve fibers in the CNS. Myelin and oligodendrocytes are typically damaged in MS.

"FTY720 crosses the blood-brain barrier and the drug's target - S1P receptors - are present on brain cells, including oligodendrocytes as shown in animal cell studies," said Jack Antel, Professor, Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. "We are able to confirm that FTY720 directly modulates the S1P receptors on human oligodendrocyte progenitor cells."

FTY720 is currently being investigated in the largest worldwide Phase III clinical trial program to be conducted in MS to evaluate further its efficacy and safety as a disease modifying therapy for relapsing-remitting MS. This comprehensive program includes trials referred to as FREEDOMS, FREEDOMS II and TRANSFORMS. Recruitment is complete for FREEDOMS and TRANSFORMS. Recruitment is ongoing and on track for FREEDOMS II and FTY720 regulatory filing is planned for the second half of 2009. For more information about the clinical trial program, including eligibility criteria and location of U.S. study sites, patients can call the following toll-free number: 866-788-3930, or visit www.MSClinicalTrials.com.

"Novartis has a significant long-term investment and commitment to multiple sclerosis and neuroscience through its extensive research and development program," said Ludwig Hantson, PhD, Senior VP for Commercial Development & Specialty Businesses at Novartis Pharmaceuticals Corporation. "We believe oral FTY720 is an exciting and promising experimental therapy for MS as shown by the compelling Phase II data. As an oral therapy with a novel mechanism of action and promising efficacy, FTY720 has the potential to be a significant and innovative therapeutic advance."


Phase II Study Results

The six-month, placebo-controlled Phase II study conducted in 281 patients with relapsing MS in 11 countries (Europe and Canada) showed that oral FTY720, taken once-daily, reduced relapse rates by more than 50% compared to placebo and reduced MRI (magnetic resonance imaging) measures of inflammation with approximately 80% of patients free of active brain lesions.

In patients continuously treated with FTY720 for up to two years (placebo-controlled study plus the extension trial), up to 77% of patients were relapse-free and more than 80% of patients were free of active brain lesions at two years.

In the six-month placebo-controlled phase of the Phase II study, the most frequent adverse events reported for FTY720 were dose-dependent upper respiratory tract infections (mainly nasopharyngitis) and dyspnea, plus diarrhea and nausea. FTY720 treatment was associated with initial dose-dependent decreases in heart rate and expiratory air flow. Clinically asymptomatic increases in alanine aminotransferase (liver enzyme) and an increase in blood pressure were also observed. No unexpected adverse events emerged in patients treated for up to 24 months compared with the six-month placebo-controlled phase. There was no further elevation of blood pressure with continued treatment beyond the effect seen at six months.

The ongoing Phase III study program includes comprehensive monitoring, which will provide further characterization of the safety profile of FTY720.


Multiple Sclerosis

MS is the most common disorder of the CNS in young adults, affecting more than an estimated 2.5 million people worldwide. It is a progressive and debilitating disorder caused by the destruction of myelin, which helps neurons carry electrical signals in the brain. MS causes problems with muscle control and strength, vision, balance, sensation and mental function. MS typically presents in relapsing forms involving acute self-limiting attacks of neurological dysfunction (or "relapses") followed by complete or partial restoration of functions.


Disclaimer

This release contains certain forward-looking statements relating to Novartis' business, which can be identified by the use of forward-looking terminology such as "may," "suggests," "suggesting," "potential," "promising," "planned" or similar expressions, or by express or implied statements regarding the potential approval of FTY720 by health authorities for marketing, whether or not FTY720 will be the first orally effective MS treatment, the potential health effects or long-term impact of a patient's use of FTY720, or potential future revenue from FTY720. Such forward-looking statements reflect the current views of Novartis regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with FTY720 to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that FTY720 will be approved for any indications or labeling in any market. Neither can there be any guarantee that, if approved, it will be the first orally effective MS treatment. Neither can there be any guarantee regarding the health effects or long-term impact of a patient's use of FTY720. Neither can there be any guarantees that FTY720 will reach any particular levels of revenue. In particular, management's expectations regarding FTY720 could be affected by, among other things, unexpected clinical trial results, including new clinical trial results and additional analysis of existing results; unexpected regulatory actions or delays or government regulation generally; competition in general; Novartis' ability to obtain or maintain patent or other proprietary intellectual property protection; government, industry and general public pricing pressures, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.


About Novartis

Novartis has been a leader in the neuroscience area for more than 50 years, having pioneered early breakthrough treatments for Alzheimer's disease, Parkinson's disease, Attention Deficit Hyperactivity Disorder, epilepsy, schizophrenia and migraine, many of which continue to be regarded as "gold standards" to this day. Novartis continues to be at the forefront of research and development of new compounds and is committed to addressing unmet medical needs and to supporting patients and families affected by these disorders.

Novartis Pharmaceuticals Corporation develops, manufactures markets and sells leading innovative prescription drugs used to treat a number of diseases and conditions, including those in the cardiovascular, metabolic, cancer, organ transplantation, central nervous system, dermatological, gastrointestinal and respiratory areas. The company's mission is to improve people's lives by pioneering novel healthcare solutions.

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG (NYSE: NVS), a world leader in offering medicines to protect health, cure disease and improve well-being. Our goal is to discover, develop and successfully market innovative products to treat patients, ease suffering and enhance the quality of life. We are strengthening our medicine-based portfolio, which is focused on strategic growth platforms in innovation-driven pharmaceuticals, high-quality and low-cost generics, human vaccines and leading self-medication OTC brands. Novartis is the only company with leadership positions in these areas. In 2006, the Group's businesses achieved net sales of USD 37.0 billion and net income of USD 7.2 billion. Approximately USD 5.4 billion was invested in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 100,000 associates and operate in over 140 countries around the world. For more information, please visit http://www.novartis.com .


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Oral Tysabri steps up to the plate

By Anna Lewcock

27/06/2007 - With a number of companies competing in the race to develop the first oral treatment option for multiple sclerosis, UCB and Biogen Idec's oral version of the infamous Tysabri has entered Phase II trials.

The two companies' candidate, currently going by the name CDP323, is an oral VLA-4 antagonist (as is Tysabri) intended for the treatment of relapsing-remitting multiple sclerosis (MS). The Phase II trials are expected to yield results by the end of 2008.

Biogen Idec hopped on board to partner with UCB in developing and commercialising the small molecule compound back in October last year, following encouraging Phase I trials. The two companies are initially investigating the compound for the treatment of MS, but will also be considering its use in treating other autoimmune disease indications.

UCB and Biogen are co-developing and co-commercialising the compound, with all commercialisation costs and profits to be shared equally. Over $200m (€149m) will be added to UCB's coffers courtesy of the Biogen deal.

CDP323 is one of the few oral alpha-4 integrin antagonists according to UCB, and it's hoped that by tapping Biogen's expertise in multiple sclerosis the two companies can come up with a competitive product.

Biogen is already responsible for the market-leading MS drug worldwide, Avonex (interferon beta-1a), which brought the company revenues of around $1.7bn over 2006. However, the company ahs taken a few punches over the last few years regarding an existing injectable MS treatment, Tysabri (natalizumab).

Tysabri, also a VLA-4 antagonist, was approved by the US Food and Drug Administration (FDA) for relapsing-remitting forms of MS back in 2004, however was hastily withdrawn three months later after several cases of patients developing a life-threatening viral infection of the brain.

The occurrence of progressive multifocal leukoencephalopathy (PML) in certain patients held Tysabri of the market for a significant period of time, only returning with stringent guidelines in June last year.

Damage to Biogen and Tysabri partners Elan's potential revenues was significant, with original analyst estimates for the treatment predicting annual revenues of up to $3bn, but following its withdrawal and late relaunch the drug only managed to generate $74m over 2006 - split between Elan and Biogen.

Although the companies have initiated risk management plans in the US and Europe to facilitate the correct use of Tysabri, the firms clearly recognise that the damage have may have already been done, with Biogen foreseeing "many rumours and speculation regarding Tysabri and suspected cases of PML" in the future.

Despite the unfavourable aura surrounding the existing version of Tysabri, a spokesperson for UCB told in-PharmaTechnologist.com that the two companies "strongly believe an oral solution is worthwhile exploring," and that the product could potentially become one of the firm's bigger products.

A 24-hour oral formulation of the drug could have significant advantages over the current monthly version of Tysabri in that it could reduce the likelihood of PML taking hold in a patient, as well as the more obvious non-invasive aspect of drug administration.

It's perhaps unsurprising that Biogenis hoping to catch the next big wave in MS treatment by successfully producing an oral formulation whilst simultaneously reaffirming its position in the MS market and hopefully demonstrating the safety of a Tysabri-like treatment option.

In addition to this, the MS market is growing fairly rapidly, and the first non-invasive oral treatment to become available would earn itself a particularly favourable position and at least a temporary monopoly while competitors catch up.

Several firms are fighting to be the first on the market with a non-invasive treatment option for MS sufferers. Only earlier this month Teva and partners Active Biotech announced their oral candidate was entering Phase II trials, and Novartis' hotly tipped oral MS treatment (FTY720, fingolimod) is on track for submissions in 2009.

Preclinical Studies Suggest FTY720 Mechanisms In Multiple Sclerosis May Include Direct Activity In The Brain

New preclinical data, presented at the American Academy of Neurology (AAN) annual meeting in Boston, reflect the expanding understanding of FTY720's (fingolimod) mechanism of action in multiple sclerosis (MS), suggesting direct beneficial effects in the brain. The data suggest that FTY720 may have the potential to reduce neurodegeneration and enhance repair of the central nervous system (CNS) by modulating S1P receptors expressed on brain cells. Separately, new clinical data presented from the six-month Phase II study found that the proportion of patients with clinical depression was significantly lower in the FTY720 groups compared to placebo.

These new preclinical data add to a growing body of evidence that FTY720 has multiple, specific mechanisms of action. The ongoing Phase III clinical development program includes comprehensive monitoring to further understand the clinical and safety implications of these mechanisms of action.

MS is a progressive and debilitating disorder of the CNS that frequently affects young people, women twice as often as men. It is caused by the destruction of myelin, which helps neurons carry electrical signals in the brain. MS is the most common inflammatory and neurodegenerative disorder of the CNS, causing problems with muscle control and strength, vision, balance, sensation and mental function. MS typically presents in relapsing forms involving acute self-limiting attacks of neurological dysfunction (or "relapses") followed by complete or partial restoration of functions.

Preclinical studies

FTY720's previously known activity is based on its ability to bind to the sphingosine 1-phosphate receptor-1 (S1P-R1) on circulating lymphocytes (white blood cells). This activity reversibly traps a proportion of lymphocytes in the lymph nodes, reducing the number of inflammatory T-cells circulating in the bloodstream and in the CNS.

One of the preclinical studies presented at AAN evaluated FTY720's ability to activate S1P receptors on astrocytes in cell culture. Astrocytes are known to play an active role in nervous tissue repair, and to regulate the permeability of the blood brain barrier. The study findings indicate that FTY720 activates S1P receptors on astrocytes, stimulating intracellular pathways that regulate a variety of functions, such as cell proliferation and migration. (Muellershausen et al)

A second study, also conducted in cell culture, demonstrated that FTY720 improved the survival and increased the number of immature and mature oligodendrocytes - cells that help form myelin in the CNS. Stimulation of S1P receptors on oligodendrocytes may help limit demyelination and/or promote myelin repair. (Barske et al)

In the third study, conducted in an established animal model of MS [experimental autoimmune encephalomyelitis (EAE) in rats], researchers found that FTY720 directly administered in the rat brain significantly suppressed the severity of clinical EAE, suggesting additional mechanisms of action independent of lymphocyte depletion. In imaging studies, enhanced myelination and axonal protection associated with the clinical effects were confirmed in animals receiving oral FTY720. (Schubart et al)

Clinical results in depression (Kappos et al)

Data from the six-month placebo-controlled Phase II study of once-daily oral FTY720 in patients with MS found that the proportion of patients with clinical depression was significantly lower in the FTY720 groups at six months compared to placebo. Depression is a common co-morbid condition in people with MS; the presence of depression in MS may reduce adherence to disease-modifying therapy and lead to higher rates of treatment discontinuation.

The Phase II study included 281 patients, randomized to receive FTY720 1.25 mg, FTY720 5 mg, or placebo. Depression was evaluated in 239 patients using the Beck Depression Inventory - Second Edition (BDI-II). BDI-II scores of 14 or more suggest clinical depression. At baseline, mean BDI-II scores were 9.3 for patients randomized to receive FTY720 1.25 mg, 8.0 for patients randomized to receive FTY720 5 mg, and 9.1 for patients randomized to receive placebo. At month six, patients receiving FTY720 1.25 mg had the most improvement in depression symptoms (BDI-II = 7.9, mean change from baseline = -1.45). Patients receiving FTY720 5 mg had no change in mean BDI-II scores, and patients receiving placebo showed worsening (BDI-II=10, mean change from baseline = +0.94). The proportions of patients with BDI-II scores indicating clinical depression were significantly lower in both FTY720 groups when compared with the placebo group at month six: 33% of patients receiving placebo versus 17% of patients receiving FTY720 1.25 mg (p=0.0176) and 19% of patients receiving FTY720 5 mg (p=0.0407).

About FTY720

FTY720 is a novel oral drug that is currently in a worldwide Phase III clinical development program as a once-daily, disease modifying therapy for relapsing MS. Previously reported Phase II results showed that patients treated with FTY720 had a significant reduction in relapses and in inflammation as measured on Magnetic Resonance Imaging (MRI) compared to placebo at six months and that low disease activity was maintained over two years. Up to 77% of patients remained relapse free and more than 80% of patients were free from lesions showing active inflammation on MRI after two years of continuous FTY720 treatment. Patients who received placebo for the first six months of the study also experienced a marked improvement after switching to FTY720 in the extension, and low disease activity was sustained through month 24.

The Phase III clinical trials program includes FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis), a 24-month, randomized, double-blind, placebo-controlled study program that plans to include over 2,000 patients worldwide with the relapsing-remitting form of MS, and TRANSFORMS (TRial Assessing injectable interferoN vS FTY720 Oral in RrMS), an international 12-month, randomized, double-blind study comparing FTY720 to Interferon-beta-1a (Avonex®, i.m. once weekly). For more information about the clinical trial program, including eligibility criteria and location of U.S. study sites, patients can call the following toll-free number: 866-788-3930, or visit www.MSClinicalTrials.com.

In the six-month placebo-controlled phase of the Phase II study, the most frequent adverse events reported for FTY720 were dose-dependent upper respiratory tract infections (mainly nasopharyngitis) and dyspnea, plus diarrhea and nausea. FTY720 treatment was associated with initial dose-dependent decreases in heart rate and expiratory air flow. Clinically asymptomatic increases in alanine aminotransferase (liver enzyme) and an increase in blood pressure were also observed. No unexpected adverse events emerged in patients treated for up to 24 months compared with the six-month placebo-controlled phase. There was no further elevation of blood pressure with continued treatment beyond the effect seen at six months. The ongoing Phase III study program includes comprehensive monitoring, which will provide further characterization of the safety profile of FTY720.

Disclaimer

This release contains certain forward-looking statements relating to Novartis' business, which can be identified by the use of forward-looking terminology such as "may," "suggest," "suggesting," "potential," "growing body of evidence," "plans to include" or similar expressions, or by express or implied statements regarding the potential approval of FTY720 by health authorities for marketing, whether or not FTY720 will be the first orally effective MS treatment, the potential health effects or long-term impact of a patient's use of FTY720, or potential future revenue from FTY720. Such forward-looking statements reflect the current views of Novartis regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with FTY720 to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that FTY720 will be approved for any indications or labeling in any market. Neither can there be any guarantee that, if approved, it will be the first orally effective MS treatment approved. Neither can there be any guarantee regarding the health effects or long-term impact of a patient's use of FTY720. Neither can there be any guarantees that FTY720 will reach any particular levels of revenue. In particular, management's expectations regarding FTY720 could be affected by, among other things, unexpected clinical trial results, including new clinical trial results and additional analysis of existing results; unexpected regulatory actions or delays or government regulation generally; competition in general; Novartis' ability to obtain or maintain patent or other proprietary intellectual property protection; government, industry and general public pricing pressures, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis

Novartis Pharmaceuticals Corporation develops, manufactures, markets and sells leading innovative prescription drugs used to treat a number of diseases and conditions, including those in the cardiovascular, metabolic, cancer, organ transplantation, central nervous system, dermatological, gastrointestinal and respiratory areas. The company's mission is to improve people's lives by pioneering novel healthcare solutions.

Novartis has been a leader in the neuroscience area for more than 50 years, having pioneered early breakthrough treatments for Alzheimer's disease, Parkinson's disease, Attention Deficit Hyperactivity Disorder, epilepsy, schizophrenia and migraine, many of which continue to be regarded as "gold standards" to this day. Novartis Neuroscience continues to be at the forefront of research and development of new compounds, is committed to addressing unmet medical needs and to supporting patients and families affected by these disorders.

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG (NYSE: NVS), a world leader in offering medicines to protect health, treat disease and improve well-being. Our goal is to discover, develop and successfully market innovative products to treat patients, ease suffering and enhance the quality of life. Novartis is the only company with leadership positions in both patented and generic pharmaceuticals. We are strengthening our medicine-based portfolio, which is focused on strategic growth platforms in innovation-driven pharmaceuticals, high-quality and low-cost generics, human vaccines and leading self-medication OTC brands. In 2006, the Group's businesses achieved net sales of USD 37.0 billion and net income of USD 7.2 billion. Approximately USD 5.4 billion was invested in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 101,000 associates and operate in over 140 countries around the world.

New Oral Agents for Multiple Sclerosis, Including Novartis/Mitsubishi Pharma's Novel Drug, Will Capture 25% of Market Share by 2020

Concerns Over Safety and Efficacy Will Prevent Emergence of a Blockbuster Drug Through 2020, According to a New Report from Decision Resources

WALTHAM, Mass., March 28 /PRNewswire/ -- Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that emerging oral therapies for multiple sclerosis, including a new drug from Novartis/Mitsubishi Pharma, will capture 25% of the market share by 2020 in the United States, Japan, France, Germany, Italy, Spain, and the United Kingdom.

The new Pharmacor report Multiple Sclerosis 2005-2020: Will Emerging Oral Agents Unseat Current Therapies? finds that Novartis/Mitsubishi Pharma's new agent, currently known as fingolimod (also called FTY-720) will outperform other emerging therapies because of its oral formulation, superior efficacy, and acceptable safety profile, although experts temper
their excitement with caution because the drug's side-effect profile has not yet fully emerged.

Physicians' and experts' wariness concerning drug safety was prompted by the development of serious infections (three of which proved fatal) in five patients who received Biogen Idec/Elan's Tysabri, which launched in the U.S. market in 2004. For safety concerns, Tysabri was pulled from shelves in 2005 -- following a safety review, the drug was re-approved by the Food and Drug Administration in 2006.

"The history of serious side effects associated with Tysabri has not only impaired its once-promising market potential but also negatively influenced physician opinion of emerging therapies," said Decision Resources Analyst Bethany Kiernan, Ph.D. "As a result of overarching concerns over safety and efficacy, we forecast that no emerging therapies will obtain blockbuster status through 2020."

About Pharmacor from Decision Resources
Pharmacor is a unique family of studies that assesses a host of market-impacting factors and analyzes the commercial outlook for drugs in research and development.

About Decision Resources
Decision Resources (http://www.decisionresources.com) is a world leader in market research publications, advisory services, and consulting designed to help clients shape strategy, allocate resources, and master their chosen markets.

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For more information, contact:
Elizabeth Marshall
Decision Resources, Inc.
781-296-2563
emarshall@dresources.com


SOURCE Decision Resources, Inc.