From Clinical Trials to Treatments: 0 → → 9 and Counting…

Outline for today The clinical trial process How clinical trials are changing Progress to date: from 0 options to 9 and counting… A closer look at Aubagio and BG-12 Thumbs up and thumbs down examples from clinical trials Introducing a valuable resource Questions – comments – concerns It wasn’t very long ago that we wouldn’t have been having this conversation at all. Within our lifetime, the treatment landscape in MS has gone from being empty and bleak to being full of options and full of promise. This presentation is designed to describe the clinical trial process and important ways the process is changing; review the nine available disease modifying therapies with a closer look at the recently-approved Aubagio and the anticipated BG-123; examine a few examples of positive and negative outcomes from clinical trials, and talk about resources that can assist with treatment decisions. With options, however, come choices. And our goal is to help make the decision-making process as informed and comfortable as it can be for people living with MS and their family members. Today we’ll be talking about the treatment decisions people are making and the factors that make those decisions increasingly complex and challenging. We will look at the valuable lessons we are learning from Tysabri in terms of understanding relative benefits and risks – and the different ways in which people with MS, family members, clinicians, and government regulatory agencies may interpret risk. Finally, we will consider some strategies for making personal medical decisions.

Why large-scale, multicenter, placebo-controlled trials are the gold-standard MS is a highly variable disease Symptoms/disease course vary Responses to treatment vary Outcomes may differ from one center to another Large-group data overcome variability The placebo response is powerful 70% of people with MS who are treated with a placebo will demonstrate improvement – at least for a while A new treatment must show sustained benefit beyond that placebo effect This slide – which is self-explanatory – helps to demonstrate why clinical trials are so essential to the process of identifying effective treatment. It also helps to explain why anecdotal reports of miraculous recoveries are not sufficient evidence of any product’s efficacy or safety.

The clinical trial process Pre-clinical phase – animal studies Phase I (evaluating safety in humans) small, unblinded, open-label studies Phase II (evaluating efficacy + safety in humans) small, double-blind Phase III (required for FDA approval) large, multi-center, randomized, double-blind, placebo-controlled /comparator studies Phase IV – Post-Marketing Real-world experience after a drug comes to market The purpose of this slide is to demonstrate the time and investment required to bring a drug to market. It also shows the purpose of each step in the process.

The benefits and challenges of Phase IV The benefits gained from post-marketing data We learn how drugs “behave” in the real world Patients are more heterogeneous Prescribers are more heterogeneous Patients are not as carefully screened Treatment is not as carefully monitored We broaden our knowledge of short- and long-term benefits and risks Trials are short; real-life has no time limit Gilenya and cardiac issues Tysabri and PML Novantrone and leukemia . Even large-scale, multi-center clinical trials involve a relatively small number of people over a relatively short period of time. The data collected in Phase IV, after the drug has come to market, provides much more information about a drug’s efficacy and safety. Gilienya, Tysabri, and Novantrone provide excellent examples of situations in which important new safety information emerged once these medications were available outside the controlled setting of a clinical trial. This new information can then be incorporated into recommendations for clinicians and their patients.

The benefits and challenges of Phase IV, cont’d The challenges of post-marketing data Phase IV data are uncontrolled and anecdotal Events reported by patients and doctors may or may not be related to the medication – and without a randomized, control group comparison, there is no way to tell Different people report the same experience differently; people report different experiences in the same way It can take time for important patterns to emerge Phase IV data also pose challenges because they emerge in an uncontrolled environment. With time and experience with large numbers of people, patterns begin to emerge that tell us more about a drug’s benefits and potential risks.

How clinical trials are changing Placebo-controlled trials pose ethical issues Can we deprive people with MS of the established standard of care? Comparator trials are becoming more common FDA may require comparison with existing standard of care A placebo-controlled trial typically involves one group that receives the study treatment and one group that receives a placebo or “dummy” medication. Now that several medications are approved to treat MS, it may be considered unethical to randomize an MS patient to a group that is not receiving an effective MS treatment through the course of the trial. Many of the newer trials are beginning to include a comparator arm, which means that the new treatment is being compared against an existing treatment that has already demonstrated its efficacy and safety.

Declaration of Helsinki – 2000 The risks, benefits, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists. Most people are unaware of the Declaration of Helsinki or of the thinking that has gone into the ethical issues related to clinical trial design and implementation.

International Advisory Committee on Clinical Trials of New Agents in MS (National MS Society 2006) Placebo-controlled trials may be considered: In forms of the disease for which there is no effective treatment (PPMS and PPMS without relapses) For subjects who are unwilling/unable to take an available medication For subjects who have not benefited from available medications For subjects in areas where effective treatments are not available When every effort has been made to ensure that patients have access to effective treatments and are fully aware of their options outside of the trial The National MS Society convened a group to examine these ethical issues in MS clinical trials. The group identified certain specific situations in which placebo-controlled trials continue to be appropriate.

How clinical trials are changing, cont’d Almost all trials are international Increasing the pool of untreated subjects Larger pool of subjects without access to existing treatments Trials need greater diversity Disease course variation between racial groups Medication trials are needed in pediatric MS patients Because the number of people with MS is relatively small, and the number of untreated people with MS is (fortunately) also small, researchers have to broaden their reach into order to find clinical trial participants. Research has also demonstrated that people from different racial groups experience somewhat different disease courses and rates of progression. This means that it’s critically important to ensure that clinical trials of a new treatment include adequate representation of all of the groups of people who may take the medication in the future so that doctors and patients know how to evaluate the potential value of the treatment. Clinical trials typically do not involve patients below the age of 18. To date, pediatric MS patients have been treated with the same medications that are used by adults with MS. As is true in other diseases, an effort is being made to conduct clinical trials in children below the age of 18 to determine the safety and efficacy of treatments in the younger age range.

How clinical trials are changing, cont’d FDA: Patient-focused drug development To assess a drug’s benefits and risks we must: Understand the severity of condition Review the available treatment options Patients who live with a disease; Have a direct stake in the drug review process Have a unique perspective on disease severity and unmet medical needs Impact on activities of daily living Impact on quality of life Involving patients in the drug development process is a new priority for the FDA. People living with a disease have important experiences and perspectives that can and should inform the development process.

The Role of PDUFA V 1993 – Prescription Drug User Fee Act (PDUFA) Required drug manufacturers to help pay the cost of the drug review process As of 2011, these fees made up 62% of drug review budget Reduced the waiting time for drug review/approval from two years to one. PDUFA V (2013-2017) – provides resources for including patients in the review process Patient Focused Drug Development Process is underway Patient-reported outcomes to be evaluated for inclusion with traditional types of outcome measures This slide provides a brief history of the Prescription Drug User Fee Act of 1993, including the most recent version that includes patients in the review process. PDUFA has helped pay for the cost of drug review and significantly speeded the process – both of which are reassuring for people with MS and other diseases who are impatient with the length of time it takes to bring new treatments to market.

Where have clinical trials gotten us so far?

A long way in a relatively short period of time Prior to 1993 – “Diagnose and Adios” is the norm For the fortunate few: Relapse management Symptom management Rehabilitation Emotional support 1993 to 2005 – five DMT options interferon beta medications (Avonex, Betaseron, Rebif) glatiramer acetate (Copaxone) mitoxantrone (Novantrone) Although we are all impatient for more effective treatments and, ultimately, a cure for MS, this timeline demonstrates just how quickly the MS treatment landscape has change in a very short period of time.

Still looking at the big picture 2006 to 2010 – three additional DMT options natalizumab (Tysabri) interferon beta-1b (Extavia) fingolimod (Gilenya) 2010 to 2011 – three new sx management medications dalfampridine (Ampyra) – walking dextromethorphan/quinidine (Nuedexta) – PBA* onabotulinumtoxinA (Botox) – upper limb spasticity; urinary incontinence *pseudobulbar affect

And the even bigger picture 2012 – one new oral teriflunomide (Aubagio) 2013 and beyond – the sky’s the limit BG00012 (dimethyl fumarate) expected in March alemtuzumab (Lemtrada) – submitted to the FDA ocrelizumab – RRMS trial; PPMS trial recruiting; comparison trial recruiting natalizumab – phase II PPMS/SPMS trial – completed rituximab – phase II/III PPMS – completed daclizumab – phase II RRMS trial -- completed ponesimod -- phase II trial completed simvastatin (Zocor) – phase II completed in progressive MS And more… This slide was current as of November, 2012.

A closer look at our newest option Teriflunomide (Aubagio) Approved in 2012 to treat relapsing forms of MS Taken orally once per day – 7 mg or 14 mg dose Reduces the spread of T and B immune cells; stops the production of immune messenger chemicals by T cells. Benefits demonstrated in clinical trials: Reduction of relapses in both doses vs. placebo Slowed disability progression vs. placebo; statistically significant only at the higher dose Greater benefit on all MRI measures in both groups vs. placebo; but greater in higher dose group Fewer side effects in the lower dose group

Teriflunomide, cont’d Most common side effects Abnormal liver functions, hair thinning (alopecia), diarrhea, influenza, nausea and unusual numbness or tingling in the hands or feet (paresthesias) “Black box warnings” Liver damage Birth defects [Category X rating – the medication must be completely out of a man’s or woman’s body prior to conception] For more detailed information, go to www.ms-coalition.org/EmergingTherapies Teriflunomide typically remains in a person’s body for an average of 8 months and may remain for as long as two years. Before trying to conceive, both women and men should stop taking the medication and undergo an accelerated elimination process to ensure that the level of medication in the body has been reduced to a sufficiently safe level.

FDA- Defined Pregnancy ratings A – controlled studies show no risk B – no evidence of risk in humans but remains a possibility [GA] C – evidence suggests chance of fetal harm but the benefits may outweigh the risks [all interferons and natalizumab] D – positive evidence of risk from studies or post-marketing data but benefits may outweigh the risks [mitoxantrone] X – positive evidence of animal or human fetal abnormalities from studies or post-marketing data with risks outweighing any possible benefit [teriflunomide] Because medications are not tested in pregnant woman, A ratings are rare. The X rating for teriflunomide was based on animal data and clinical experience with leflunomide, a related medication used to treat rheumatoid arthritis. No fetal deaths or significant abnormalities have occurred to date (as of November, 2012) with teriflunomide.

A closer look at the next probable option BG-12 (dimethyl fumarate) FDA decision expected in 1st quarter of 2013 Capsule taken orally – 240 mg taken 2 or 3 times daily Benefits reported in DEFINE trial: both doses vs. placebo: 49% and 50% reduction in risk of relapse 48% and 53% relative reduction of annualized relapse rate 38% and 34% reduction in risk of disability progression Fewer new, enlarging or active lesions on MRI These two slide provide a brief summary of what we know so far (as of November, 2012) about BG-12.

BG-12, cont’d Benefits reported in CONFIRM trial: both doses vs. placebo: Lower annualized relapse rate Reduced disease activity on MRI Smaller proportion of people experienced relapses No benefit on disease progression vs. placebo Most common side effects of BG-12 in both trials: Flushing and gastrointestinal events Reduced white blood cell counts but no reports of opportunistic infections Liver enzymes elevated in the DEFINE study, but no reports of significant liver injury or liver failure.

And one more… Alemtuzumab (Campath) Humanized monoclonal antibody: reduces or eliminates selective lymphocytes (T cells and/or B cells) Intravenous infusion for 5 days; 3 days one year later In phase III trials compared to Rebif® [Care I: treatment-naïve patients; Care II; patients who experienced relapses on Rebif] Significantly reduced relapse rate May significantly reduce worsening of disability More likely to be relapse-free for two years These two sides provide a brief overview of what we know so far (as of November, 2012) about alemtuzumab.

Alemtuzumab, cont’d Infusion side effects: headache, rash, nausea, fever Complications: Mild-moderate infections Up to 1% developed immune thrombocytopenic purpura (ITP) – detected early through safety monitoring program and treated with conventional treatments. Less than 20% had autoimmune thyroid problems that were managed with conventional treatments Idiopathic thrombocytopenic purpura is a bleeding disorder in which the immune system destroys platelets, which are necessary for normal blood clotting. Persons with the disease have too few platelets in the blood.

Other trials that have given us a thumbs up Complementary therapies that are entering the mainstream through careful, controlled research: Exercise Cooling Vitamin D

Trials that have given us a “thumbs down” Ginkgo biloba – did not improve cognition in a randomized controlled trial Donepezil (Aricept) – did not improve memory in a randomized controlled trial St. Johns wort – was not effective with serious depression; may be helpful in milder depression Bee sting therapy – shown not be effective in treating MS A variety of DMT wanna-be’s

Some reasons why trials fail The cause of MS is still unknown so the treatment target may be incorrect Benefits in animals may not translate into benefits for humans Some possible candidates actually worsen MS Some possible candidates cause major side effects Some short-term benefits may disappear over time Some trials aren’t designed correctly to see benefit Every negative trial has something valuable to teach us Fortunately, more negative trials are being published in peer-reviewed publications, which allows researchers and clinicians to learn from them. This sharing of information helps to speed the drug development process by allowing investigators to focus on products with greater potential, design better trials and avoid unnecessary pitfalls.

The good news is… People with MS have 9 treatment options and more on the way More clinical trials are in process than ever before. Progressive forms of MS are getting the international attention they deserve. The International Collaborative on Progressive MS has set the following priorities: Identification of experimental models for progressive MS Identification and validation of therapeutic targets Strategies for proof of-concept clinical trials Clinical outcome measures Symptom management and rehabilitation The International Collaborative on Progressive MS, a group of researchers and representatives of MS patient societies from Europe and North America, has the ultimate goal of expediting the development of disease-modifying and symptomatic treatments for people living with progressive forms of MS. In order to find effective treatments for progressive MS, researchers need to identify potential drug candidates, identify animal models of progressive MS on which to test these candidates, design the kinds of trials that would best demonstrate their potential in MS, and determine the most effective measures for evaluating their potential benefit in humans. And while all this is going on, we need to ensure that ongoing attention is being paid to providing optimal symptom management and rehabilitation strategies to those who are living with progressive MS.

Clinical Trial Resources National MS Society http://nationalmssociety.org/research/clinical-trials/index.aspx U.S. National Institutes of Health www.ClinicalTrials.gov NARCOMS www.mscare.org/cmsc/CMSC-NARCOMS-Information.html The Center for Information and Study on Clinical Research www.searchclinicaltrials.org/ NIH Clinical Trials and You www.nih.gov/health/clinicaltrials/index.htm CenterWatch www.centerwatch.com/

Emerging Therapies Collaborative – www. ms-coalition Emerging Therapies Collaborative – www.ms-coalition.org/EmergingTherapies Unique partnership “to promote optimal, individualized treatment …by facilitating effective communication and medical decision-making” Multiple Sclerosis Coalition* American Academy of Neurology Multiple Sclerosis VA Centers of Excellence East/West Americas Committee for Treatment & Research in MS Downloadable information for professional and lay readers: Developed by members of the Collaborative Approved by all participating organizations Evidence-based Two helpful resources have been developed recently to help address some the challenges discussed in this presentation In 2010, the Society reached out to our sister organizations to find out if they were interesting in collaborating on an effort to promote effective doctor patient communication and decision-making. The Emerging Therapies Collaborative is the product of this outreach. All of the member organizations of the MS Coalition (listed on the next slide), are working with the Academy of Neurology, the MS VA Centers of Excellence and ACTRIMS to produce co-branded evidence-based information for people with MS and their physicians. For each medication, corresponding information is available in language suitable for clinicians and in language for lay readers. The information sheets link people to the FDA labeling information as well as to abstracts of articles describing the pivotal trials. No pharma funding has been used to support this project. This is the very first collaboration of its kind in the MS community – and it will hopefully lead to many more. With such complex issues confronting people with MS, they need to be able to turn to consistent, unbiased messaging from MS advocacy groups and other MS organizations.

*Multiple Sclerosis Coalition Accelerated Cure Project for Multiple Sclerosis Can Do Multiple Sclerosis Consortium of Multiple Sclerosis Centers International Organization of Multiple Sclerosis Nurses Multiple Sclerosis Association of America Multiple Sclerosis Foundation National Multiple Sclerosis Society United Spinal Association

S.E.A.R.C.H.™ Model from MSAA Developed by Multiple Sclerosis Association of America (MSAA) to help people evaluate treatment options: S. = Safety E. = Effectiveness A. = Affordability R. = Risks C. = Convenience H. = Health Outcomes (overall wellness/quality of life) Information and toolkit available at www.MSAssociation.org/programs/Search The Multiple Sclerosis Association of America (MSAA) has created the SEARCH tool to help people think carefully about their treatment options. The helpful acronym highlights the important issues that a person needs to consider relative to each option and discuss with her or his physician and family members.