Sequencing Disease-Modifying Therapies in Relapsing Remitting MS

Transcription

1 Sequencing Disease-Modifying Therapies in Relapsing Remitting MS Flavia M. Nelson, MD Assistant Professor of Neurology University of Texas Medical School at Houston Associate Director, MRI Analysis Center Multiple Sclerosis Research Group Houston, Texas Introduction Hello, I m Dr. Flavia Nelson, associate professor of Neurology and associate director of the MRI Analysis Center with the MS Research Group at the University of Texas Medical School in Houston. Our center, although highly focused on research, has a large clinical practice with over 3000 patients actively followed for the management of their disease. I d like to welcome you to this MedImage case entitled, Sequencing Disease-Modifying Therapies in Relapsing-Remitting MS, during which I will discuss how to use efficacy, safety, and tolerability considerations to formulate individualized treatment strategies&46; I would like to thank Dr. Leorah Freeman, MD, for her valuable contribution to this presentation. She comes from the Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié Salpêtrière in Paris, and is currently a fellow and NMSS grantee at our institution. Let&3146;s begin our case. Case Presentation Mrs. Newman comes to the neurology clinic for a routine follow-up. She s a 36-year-old female diagnosed with relapsing-remitting MS at age 26. She was started on glatiramer acetate soon after diagnosis and has done well. Her last exacerbation was two years ago with a total of three exacerbations requiring steroid treatments since diagnosis. Her current EDSS is 3, which means minimal neurological deficits. Her more recent MRI shows a moderate lesion load and no enhancements. Please refer to image one, which shows a T2-weighted FLAIR image that shows a moderate lesion load and the corresponding T1-weighted post-gadolinium images with no enhancements representing active lesions or obvious atrophy, and one black hole. Mrs. Newman has two children&344; ages seven and nine, and she does not plan to extend her family. Her neurologist is pleased with her current state, but the patient complains of being tired of injections and having significant lipoatrophy in her arms and legs to the point that she s unable to wear short-sleeved blouses or short pants and feels very self-conscious about wearing a bathing suit. She has heard of the new oral disease- Page 1 of 12

2 modifying therapies and would like to know if she s a good candidate for them. Switch Considerations: Efficacy, Safety, and Tolerability So switch considerations: let s talk about efficacy, safety, and tolerability. In the U.S., there are currently ten DMTs approved for the treatment of relapsing-remitting MS. One of them is also indicated in secondaryprogressive MS; this is mitoxantrone, which is an immunosuppressant. The three most recently approved by the FDA are the first orals in the market: fingolimod, teriflunomide, and BG-12, also known as dimethyl fumarate. Prior to these, all DMTs were injectable and referred to as platform therapies, with the exception of natalizumab, which is an IV infusion. Fingolimod was originally approved by the FDA in May 2010, followed by teriflunomide in late 2012, and followed by BG-12, or dimethyl fumarate, in early Today, we will discuss the three recently FDA-approved oral DMTs on the market, their efficacy, safety, monitoring needs, and approach to selection, and we will also discuss natalizumab, which is in a category of its own. So these four options were discussed with our patient, who, as you may remember, complained of injection fatigue and injection-site side effects. The following background information should be kept in mind when having a discussion with a patient on the newest available DMTs. The current state of the recently approved therapies is that treatments primarily affect both T and B cell function. The exact mechanism of action of these DMTs. aside from being different for each drug and not completely understood, in general, plays a minimal-to-no role when choosing a DMT for a specific patient. It is important to point out that comparisons among drugs are difficult to make as there are no head-to-head trials for natalizumab, fingolimod, teriflunomide, and dimethyl fumarate, or BG-12, and there are no multicenter cooperatives similar to those for hematologic malignancies available. So the key to choosing the next best option for a patient who is either having breakthrough disease or side effects from the injectable DMTs is to evaluate the risks versus the benefits (which is the efficacy), evaluate the side effects, and also, if possible, evaluate the long- and short-term toxicity of the new DMT. It is also important to make the decision on a case-by-case basis. Approved Options for This Patient s Next Therapy So let s review the efficacy, side effects, and safety, as well as monitoring needs for these oral DMTs. Fingolimod is a once-a-day oral drug that has an efficacy of approximately 54% reduction in annualized relapse rate, which we ve seen in the phase III clinical trial against placebo. The main side effects that are seen with fingolimod are macular edema, cardiac conduction issues, and infection. In terms of safety, it is Page 2 of 12

3 considered approximately a three-plus because of what we mentioned in the cardiac conduction issues, and in terms of convenience it would be considered a four-plus. Monitoring is somewhat cumbersome, especially at the beginning of the therapy. An EKG, an evaluation by an ophthalmologist including ocular coherence tomography, as well as liver function test and CBC need to be obtained prior to starting fingolimod. The first dose needs to be administered under supervision with pulse and blood pressure taken every hour for the first six hours, and an EKG needs to be obtained at the end of the first six hours after the administration of the first dose After that, labs can be obtained every three to six months at the physician s discretion. Teriflunomide is a once-a-day drug that in phase III clinical trials showed a 31% reduction in annualized relapse rate and good data on disability. The main side effects are LFT elevation; some hair thinning; very rarely, neuropathy; and occasional diarrhea. It is a Category X for pregnancy. So in terms of safety it s considered approximately a three-plus, but in terms of convenience, it s high as five-plus. Monitoring is slightly cumbersome the first six months of therapy as liver function tests need to be obtained once a month for the first six months, then every three months for the next six months, and then every six months to a year at the physician s discretion. Fumarate, or BG-12, is a twice-a-day oral drug that has shown a 44% to 53% reduction in annualized relapse rate in phase III clinical trials. The main side effects, which can be mild to severe, are flushing and GI problems, as well as occasionally lymphopenia. In terms of safety, it s considered a three- to four-plus, and, in terms of convenience, approximately a four-plus. There are no official recommendations for monitoring, but at the physician s discretion a recent CBC prior to starting fumarate should be obtained, and monitoring every six months to a year. Natalizumab is perceived as the most effective DMT; therefore, we will discuss it in more detail. The annualized relapse rate reduction versus placebo at year one has been one of the highest reported in phase III clinical trials; a 68% reduction. Despite its efficacy, natalizumab is used with caution due to its association with the development of progressive multifocal leukoencephalopathy, which is seen in patients with previous exposure to the JC virus which is approximately 50% to 55% of the population and more frequently seen in patients with previous exposure to immunosuppressants. In the first two years, month one to month 24, patients that have no prior immunosuppressant use have a risk of PML of less than one in a thousand. If there is immunosuppressant use prior to natalizumab, the risk goes up to two in a thousand in the first two years. Once we move to the year two to year four, with that immunosuppressant exposure we have a risk of five in a thousand, and with immunosuppressant exposure goes up to 11 in a thousand for year two to year four. It is also important to know that the titers of the JC virus antibodies are important in terms of incidence of PML. So in the first two years, month one to month 24, the PML risk, depending on the titer, if the titer is less than 0.9, the risk is 0.1 in a thousand. If the titer is less than 1.5, the risk continues to be 0.1 in a thousand, but Page 3 of 12

4 at a titer of over 1.5, the risk goes up to one in a thousand in the first two years of treatment. Now, if we look at the year two to year five, the risk is 0.3 if the titer is less than 0.9, 1.2 if the titer is less than 1.5, and jumps up to 8.1 if the titer is above 1.5 again, in years two to five. Emerging Therapeutic Options Now that we have discussed the new DMTs, let s switch gears and talk about emerging therapeutic options for multiple sclerosis. Most new therapies have shown a significant effect on the inflammatory component of the disease by decreasing the annualized relapse rate. However, their effect on neuroprotection and repair remains questionable. Consequently, it is of great interest to develop therapies that can potentially affect these processes and slow disability progression. Three drugs with such potential are laquinimod, daclizumab, and alemtuzumab. Laquinimod is a once-a-day oral drug currently under evaluation for treatment of MS and it has been proposed for its neuroprotective potential. Indeed, phase III trials in relapsing-remitting MS showed that laquinimod not only slowed the progression of disability, but also decreased the rate of gray matter atrophy and reduced the aggressive destructive lesions visible as persistent hypointensities on T1-weighted scans, also called persistent black holes. The possibility that laquinimod could exert a neuroprotective role in MS was further supported by animal studies that demonstrated its ability to modulate neuronal excitability and limit cytotoxic damage in experimental autoimmune encephalitis. However, laquinimod s efficacy on the reduction of annualized relapse rate has been below what is seen with current DMTs, which is why the drug was refused approval by both the FDA and the European Medicines Agency, or EMA. A new multinational randomized double-blind placebo-controlled study is currently recruiting patients to evaluate higher doses of oral laquinimod at 0.6 milligrams a day or 1.2 milligrams per day. This will further assert its neuroprotective effect on the time to confirm disease progression, which will be the primary endpoint of this trial. In summary, despite a favorable adverse effect profile, the role of laquinimod in this MS therapeutic landscape remains uncertain. Daclizumab is a new form of a humanized monoclonal antibody that binds to CD25, which is a receptor subunit on T cells that become abnormally activated in MS. Daclizumab modulates interleukin-2 signaling without causing general immune cell depletion. It is believed to work by decreasing abnormally-activated T cells and pro-inflammatory lymphoid tissue inducer cells and increasing CD56 natural killer cells that help regulate the immune system. Page 4 of 12

5 Recent results of a phase III trial, DECIDE, were released in June 2014 and showed that treatment with daclizumab was superior to weekly interferon beta-1a on the study s primary endpoint, with a statistically significant 45% reduction in annualized relapse rate. Also, positive results of the first phase III trial of this agent, known as SELECT, show that administered monthly in a dose of 150 milligrams reduced the annualized relapse rate by 54%. The reduction was comparable in the 300 milligram dose group at 50%. The effect of the drug seen on disability progression was unexpected, as in only 52 weeks of follow-up the drug reduced disability versus placebo by 57% in the 150-milligram daclizumab group and by 43% with the 300-milligram dose. Safety results showed that adverse events were comparable between groups, but there was an increase in liver enzymes seen with treatment, and one death occurred in the treated group possibly related to infection. Phase II trial outcomes have also demonstrated daclizumab s efficacy on several clinical measures. However, safety concerns were raised during initial testing. Rates of serious infections, respiratory tract infections, and recurring oral herpes were increased in daclizumab-treated subjects. Skin reactions, often compatible with hypersensitivity were found in up to 20% of patients and severe in as many as 1%. Elevation of liver enzymes was also a frequent occurrence for patients treated with daclizumab in phase II/III trials. Of more concern, serious autoimmune adverse effects have been reported, including CNS vasculitis, Crohn s disease, thyroiditis, glomerulonephritis or Goodpasture s syndrome, autoimmune hepatitis, ITP, infusion reactions, and possibly malignancies. These may limit the future use of the drug. It is important to note that no opportunistic infections have been reported and should not be expected, as daclizumab does not hamper transmission of immune cells into the brain. An ongoing phase III trial extension should clarify the longer-term tolerance of daclizumab and offer insights into the place of this drug in the treatment of MS. It appears that this compound is promising in terms of efficacy and attractive for its once-a-month subcutaneous administration, but its risk benefit profile may only be favorable in patients with aggressive disease. Also, a rigorous safety monitoring program would need to be implemented should daclizumab be prescribed in clinical practice. Alemtuzumab; results for the still investigational alemtuzumab versus standard therapy with interferon beta-1a from a second phase III trial in patients with relapsing-remitting MS were reported in The CARE-MS II trial met both co-primary endpoints of reductions in relapse rate and sustained accumulation of disability in treated patients with relapsing-remitting MS. Results of the CARE-MS I, a similar phase III comparison of alemtuzumab and interferon beta-1a, had shown a significant reduction in relapse rates at three years but no significant effect on sustained accumulation of disability with alemtuzumab, an effect the researchers attributed in part to an unexpectedly low number of disability events in the comparator group. Patients in CARE-MS I were treatment-naive, whereas participants were required to have experiencd a relapse while on prior therapy to be eligible for the CARE-MS II. Some of the patients in CARE-MS II had already failed interferon. The safety profile observed in the trial was consistent with previous alemtuzumab use in MS, and adverse Page 5 of 12

6 events continued to be manageable. The most common types of adverse events associated with alemtuzumab in CARE-MS II were infusion-associated reactions, including headache, rash, nausea, hives, fever, itching, insomnia, and fatigue. Infections were common in both groups with a higher incidence in the alemtuzumab group. The most common infections in patients treated included upper respiratory and urinary tract infections, sinusitis, herpes, and herpes simplex infection. Infections were predominantly mild to moderate in severity, and there was no treatment-related, life-threatening, or fatal infection. Approximately 16% of alemtuzumabtreated patients developed an autoimmune thyroid-related adverse event, and approximately 1% developed immune thrombocytopenia during the second-year study period. These cases were detected early through a monitoring program and were managed using conventional therapies. Patient monitoring for immune cytopenias and thyroid or renal disorder is incorporated in all trials. Monthly monitoring for autoimmune thyroid disease or immune thrombocytopenic purpura will be required with alemtuzumab treatment. Alemtuzumab was granted fast-track designation by the U.S. Food and Drug Administration, but approval was denied in early More recently, alemtuzumab was resubmitted for FDA consideration. The drug was approved by EMA in MRI Technique in Assessing Treatment Outcomes Now that we ve discussed not only the new FDA-approved but the current medications in the pipeline, let s talk about assessing treatment outcomes and disease monitoring using MR imaging. MRI is currently utilized as a surrogate marker of treatment efficacy in clinical trials. MRI outcomes are not used as a primary endpoint except in phase II trials. In phase III trials, the main secondary endpoints that are used are number of gadolinium-enhancing lesions, number of new or enlarged T2 lesions, and more recently, T2 and T1 lesion volume, as well as total lesion volume, which is the sum of the T2 plus T1 lesion volume. Whole brain atrophy and more sophisticated measures, such as gray and white matter atrophy, are generally evaluated either as tertiary or as exploratory endpoints. Supporting data for the use of MRI as a surrogate marker of clinical activity was seen in an important metaanalysis of 23 randomized placebo-controlled trials in relapsing-remitting MS with a total of around 6500 patients. Results identify a strong correlation between the effect of treatment on relapses and MRI lesions measured. More than 80% of the variance in treatment effect on relapses was explained by the variance in MRI measures. Gadolinium enhancement in new or newly enlarging lesions identified on T2 have greater utility in evaluating effectiveness of treatment. However, MRI metrics have weak predictive value for future disability and poorly correlate with disability in progressive disease. Let s look at image two in which we see a T2 FLAIR showing periventricular lesions and a T1 postgadolinium image showing one corresponding enhancing lesion as well as one hypointense lesion. Page 6 of 12

7 An example of enlarging T2 lesions can be seen on image three, and here we see a scan obtained in 2012 and a follow-up scan obtained in 2014 with a significantly enlarged T2 lesion. An example of an increase in the number of T2 lesions can be seen on image four; again, this is a scan obtained in 2012 followed by a scan obtained two years later in 2014 that shows a significant increase in the number of T2 lesion loads. So in clinical practice, a noticeable increase in size and/or number of T2 lesions, or also of T1 hyperintense lesions, also called black holes, as well as the presence of gadolinium-enhancing lesions on an MRI obtained at random and not during a relapse, are all suggestive of breakthrough disease or disease activity in the absence of relapses or disability progression. It is important to remember that the utility of MRI metrics to predict treatment response for approved therapy has yet to be evaluated. Also, despite data demonstrating surrogacy of MRI metrics in clinical trials, the utility of routine MRI evaluation in the clinical setting is still controversial. So obtaining a follow-up MRI is reasonable for unexpected clinical worsening and reassessment of treatment initiation or modification. Persistent hypointensities on T1-weighted images may correlate with tissue damage and have been utilized as a secondary outcome measure in clinical trials. Of note, true black holes are T1 hypointense lesions that persist for at least six months. However, some studies have shown that only a small proportion of T2 lesions evolve to black holes. On image five we see a T1-weighted image with periventricular black holes shown by the yellow arrows, and on the right we see a T2-weighted FLAIR with the corresponding hyperintensity where the black holes are. Brain atrophy is noted to occur at all stages of MS and occurs at a greater rate when compared to healthy controls. However, the various mechanisms involved in measures of atrophy and the lack of such automated tools in the clinical setting make this MRI metric less useful in making day-to-day patient decisions. Again, we can look at image five and see an important enlargement of the ventricles, which is difficult to evaluate in the clinical setting unless we can follow MRIs serially. In summary, caution must be used when making a decision to switch DMTs on the basis of MRI activity alone. These findings should be taken in the context of lesion behavior over the last few years and lesion load for each particular patient. The patient s previous MRIs should be used as their own baseline. It is also important to note that there are no correct criteria on how many or what amount of lesion enlargement constitutes disease activity. Another suggestion is to confirm that disease activity observed in one scan is sustained and seen not only once but preferably again in a scan repeated at least three to six months after the one showing an increase in lesion activity. In summary, examples of MRI activity that alone or in combination with clinical activity should prompt a physician to consider a DMT change include presence of gadolinium-enhancing lesions, increase in the size and the number of T2 lesions, obvious atrophy, and increase in black holes. Page 7 of 12

8 Clinical Application Now, let s talk about recommendations when considering treatment options in a naive patient. First, let s go to image six in which we see a suggested treatment approach for patients with relapsing-remitting MS. When the patient is first diagnosed, the first-line agents, including the interferons or glatiramer acetate, can be considered. Also, BG-12 or teriflunomide could be considered. Now, if the patient fails the initial treatment or it s perceived as not effective, then we can move to the second-line treatment, which could be either dimethyl fumarate (or BG-12), fingolimod, or natalizumab. Now, on the other hand, if the treatment is not tolerated, another first-line agent could be chosen. Now, once we re on the second-line, if the second-line agent is not tolerated again, another second-line agent could be considered. But if instead, the patient is having breakthrough disease on the second-line agent or the agent is perceived as not effective, then a third-line agent should be considered. In this category, we can find rituximab; potentially, alemtuzumab if it gets approved; or other cytotoxic agents. Now, safety and efficacy is important to consider when choosing a DMT. In terms of safety and efficacy, every agent has a different degree of safety and efficacy that has to be taken into account when making a decision. Now there are still some unresolved issues of MS therapy. For example: how severe is MS in this patient, and is more risk worth taking? Another issue: what are the long-term risks of new therapies, which we still don t know? What about if the treatment effect is greatest early in the course of MS should we administer the most effective therapy first? And could aggressive treatment inhibit CNS repair by harming the good immune cells and progenitor cells? How do we follow the course of disease, especially for cognition and personality changes? And how much should we rely on the MRI scan for disease assessment, which we have discussed in some detail? Last but not least, the question remains: can we ever stop therapy? And some of these questions will hopefully be answered as time goes by and with extension trials from the new DMTs. Conclusion Let s return to our case. After a discussion, which included data on efficacy from phase III clinical trials, safety issues, monitoring needs, and side effects, the patient was prescribed teriflunomide. The decision was based on the following: she s responding well to her current immunomodulator therapy has no breakthrough disease therefore, she does not necessarily need a higher efficacy DMT. Second, the side effect profile, in the patient s opinion, would be easy to tolerate. Third, the ease of administration being a once-a-day pill and not requiring special monitoring other than lab work once a month looks preferable to the patient as well. Last but not least, there is no concern on the patient becoming pregnant, which makes teriflunomide a good option. Every patient has different needs, so the above rationale may not apply to everyone. Page 8 of 12

9 The takeaway messages are: maximum impact on disease is with early treatment; any disease activity, whether it s clinical or by MRI, appears to be a bad sign; individualized risk assessment and management is key; targeted therapy, according to disease course, previous response to therapy, adherence, symptoms, and MRI behavior is important; and for now, balancing safety with efficacy is mostly a clinical art. Thank you for listening to this case today, and I hope that you will join us for future cases as well. Suggested Readings Brex PA, Ciccarelli O, O'Riordan JI, Sailer M, Thompson AJ, Miller DH. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med. 2002;346: Comi G, Jeffery D, Kappos L, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366: Coyle PK. Switching therapies in multiple sclerosis. CNS Drugs. 2013;27: Fazekas F, Soelberg-Sorensen P, Comi G, Filippi M. MRI to monitor treatment efficacy in multiple sclerosis. J Neuroimaging. 2007;17 Suppl 1:50S-55S. Filippi M, Rocca MA, Pagani E, et al. Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psychiatry Sep 12. [Epub ahead of print] Giovannoni G, Gold R, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial. Lancet Neurol. 2014;13: Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 2013;381: ,br> Page 9 of 12

10 Li DK, Held U, Petkau J, et al. MRI T2 lesion burden in multiple sclerosis: a plateauing relationship with clinical disability. Neurology. 2006;66: Molyneux PD1, Filippi M, Barkhof F, et al. Correlations between monthly enhanced MRI lesion rate and changes in T2 lesion volume in multiple sclerosis. Ann Neurol. 1998;43: Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354: Ruffini F, Rossi S, Bergamaschi A, et al. Laquinimod prevents inflammation-induced synaptic alterations occurring in experimental autoimmune encephalomyelitis. Mult Scler. 2013;19: Sormani MP, Bonzano L, Roccatagliata L, Cutter GR, Mancardi GL, Bruzzi P. Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: a meta-analytic approach. Ann Neurol. 2009;65: Vollmer TL, Sorensen PS, Selmaj K, et al. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol. 2014;261: Wynn D, Kaufman M, Montalban X, et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol. 2010;9: Page 10 of 12

11 Page 11 of 12

12 Page 12 of 12