Clinical Trials in MS—Achievements and Challenges

AMSTERDAM—R­ecent clinical trials for several multiple sclerosis (MS) treatments have yielded promising results and insights into the disease pathogenesis and have provided direction for future research and diagnostic criteria, Ludwig Kappos, MD, reported at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Prof. Kappos, Professor in the Departments of Neurology and Biomedicine, University of Basel, Switzerland, reviewed the safety and efficacy profiles of fingolimod, natalizumab, teriflunomide, and other potential therapies for MS in development, while highlighting the advancements that have been achieved through clinical trials.

Clinical trials helped to introduce more and more effective compounds and treatment algorithms for the management of relapsing MS and clinically isolated syndromes,” Prof. Kappos said. “Clinical results and effects stimulate new directions, be they diagnostic observations or therapeutic successes…. [They] have played an ever-increasing role in shaping our armamentarium against this still enigmatic disease.”

Improvements in Pathogenesis Understanding
According to Prof. Kappos, one of the main achievements of developing new therapies for MS is the increased insight into disease pathogenesis. “We have detected or found out about the effects of compounds whose modes of action we initially misunderstood,” he said. “Through exploring this mode of action, we are also learning much about the pathogenesis of MS.”

Recent research has validated the role of the immune system in disease pathogenesis and also opened new pathways for developing drugs that address the blood-brain barrier, T and B cells, regulatory cells, and cytokines. “Based on currently completed or ongoing studies, a large number of new compounds, especially oral immunomodulators and monoclonal antibodies, are waiting to enter our pharmacology within the next two to four years,” Prof. Kappos said.

Monoclonal Antibodies
Natalizumab, a humanized monoclonal antibody, has proven effective in reducing relapse rates in MS, but it also has been linked to an increased risk for progressive multifocal leukoencephalopathy (PML), Prof. Kappos noted. The drug does not seem to have any additional immunosuppressive effect, and “it is difficult to understand the selectivity of this risk for PML that is created by this compound,” he said. “Other risks have not really occurred, so it must be something specific that we have to explore in more detail.”

Prof. Kappos also discussed rituximab and ocrelizumab, two anti-CD20 monoclonal antibodies that exert their neuroprotective effect through B cell depletion. Rituximab, when compared with interferon-beta, was shown to significantly reduce relapse rates, and was well tolerated, with approximately 90% of study participants remaining in the study for two years. “At the end of this two-year period, all but two patients on this treatment did not have any active new lesions and were free of disease activity as dictated by the MRI scan,” he reported. In a phase II, placebo-controlled study, ocrelizumab was shown to reduce the number of gadolinium-enhancing lesions in patients with relapsing-remitting MS.

Oral Immunomodulators
Fingolimod, an immunomodulator that has achieved “very encouraging results” in phase III studies, “expands on the lessons we learned in the development of ocrelizumab,” Prof. Kappos explained. “One unexpected finding that emerged out of the phase III studies … was a 30% reduction of atrophy or loss of brain volume,” he added. “Fortunately, although it has so many possible interactions in the body, the comprehensive safety program did not yield real issues of concern over the first course [of treatment]. There remain a few questions about long-term safety and efficacy and better understanding of the mode of action, and the profile of the responders.”

Another immunomodulatory compound that has completed phase III studies is teriflunomide, a metabolite of leflunomide. “It’s a more conservative approach to treatment, as it is an immunomodulator with some more selective effects,” Prof. Kappos said. “The effects were less pronounced if you look at the increase in relapse rates … and less pronounced, but dose-dependently increased, regarding T2 and gadolinium MRI criteria.” He reported that the adverse event profile for teriflunomide was “quite reassuring.”

“Laquinimod, another compound that has now finished two studies, is an immunomodulator whose mode of action we have just started to understand,” Prof. Kappos stated. “What is very clear, both in experimental animal and human trials, is that it didn’t exert any immunosuppressive effect.” Patients on this treatment did not experience an increase in infections, and there was evidence that laquinimod exerted some neuroprotective properties by reducing brain atrophy.

Prof. Kappos also discussed the compound dimethyl fumarate as a therapeutic agent for MS, whose mechanism of action is related to its anti-inflammatory effect. “It may be the first drug that acts both on psoriasis and MS,” he noted. “However, it also may interact with pathways that protect the CNS.” Clinical trials showed a reduction in the annualized relapse rate and disability progression, “but there was an impact on the quality of life,” Prof. Kappos noted.

Current Challenges and Future Directions
“At the moment, we are faced with different treatment options that will probably be in daily practice within the next two to four years,” Prof. Kappos stated. “Much of the evidence is not yet published or peer reviewed, but still there are some indications that may help us to define a profile of these compounds…. [Through clinical trials] we learned about the importance of early intervention and—mainly through negative studies—that later MS stages and progressive disease courses respond in a different way to treatments and need different study designs and more advanced outcome measures.”   

Many achievements have been made as a result of successful clinical trials in MS therapy, including new treatment algorithms and diagnostic MRI criteria, but several challenges remain, according to Prof. Kappos. “We have to adapt and further develop our concepts, we have to develop criteria for phase- and cause-adaptive differential indications, and we have to further explore benefits and risks of new compounds … with additional phase III-B and IV studies…. Future research will focus on the interactions of microglia and their role in the development of disability and deficits in MS.

“Investigator-initiated and publicly funded prospective and comprehensive observational and cohort studies must increasingly complement the current paradigm of mostly corporate-sponsored clinical trials,” Prof. Kappos concluded.  

—Ariel Jones  

AMSTERDAM—R­ecent clinical trials for several multiple sclerosis (MS) treatments have yielded promising results and insights into the disease pathogenesis and have provided direction for future research and diagnostic criteria, Ludwig Kappos, MD, reported at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Prof. Kappos, Professor in the Departments of Neurology and Biomedicine, University of Basel, Switzerland, reviewed the safety and efficacy profiles of fingolimod, natalizumab, teriflunomide, and other potential therapies for MS in development, while highlighting the advancements that have been achieved through clinical trials.

Clinical trials helped to introduce more and more effective compounds and treatment algorithms for the management of relapsing MS and clinically isolated syndromes,” Prof. Kappos said. “Clinical results and effects stimulate new directions, be they diagnostic observations or therapeutic successes…. [They] have played an ever-increasing role in shaping our armamentarium against this still enigmatic disease.”

Improvements in Pathogenesis Understanding
According to Prof. Kappos, one of the main achievements of developing new therapies for MS is the increased insight into disease pathogenesis. “We have detected or found out about the effects of compounds whose modes of action we initially misunderstood,” he said. “Through exploring this mode of action, we are also learning much about the pathogenesis of MS.”

Recent research has validated the role of the immune system in disease pathogenesis and also opened new pathways for developing drugs that address the blood-brain barrier, T and B cells, regulatory cells, and cytokines. “Based on currently completed or ongoing studies, a large number of new compounds, especially oral immunomodulators and monoclonal antibodies, are waiting to enter our pharmacology within the next two to four years,” Prof. Kappos said.

Monoclonal Antibodies
Natalizumab, a humanized monoclonal antibody, has proven effective in reducing relapse rates in MS, but it also has been linked to an increased risk for progressive multifocal leukoencephalopathy (PML), Prof. Kappos noted. The drug does not seem to have any additional immunosuppressive effect, and “it is difficult to understand the selectivity of this risk for PML that is created by this compound,” he said. “Other risks have not really occurred, so it must be something specific that we have to explore in more detail.”

Prof. Kappos also discussed rituximab and ocrelizumab, two anti-CD20 monoclonal antibodies that exert their neuroprotective effect through B cell depletion. Rituximab, when compared with interferon-beta, was shown to significantly reduce relapse rates, and was well tolerated, with approximately 90% of study participants remaining in the study for two years. “At the end of this two-year period, all but two patients on this treatment did not have any active new lesions and were free of disease activity as dictated by the MRI scan,” he reported. In a phase II, placebo-controlled study, ocrelizumab was shown to reduce the number of gadolinium-enhancing lesions in patients with relapsing-remitting MS.

Oral Immunomodulators
Fingolimod, an immunomodulator that has achieved “very encouraging results” in phase III studies, “expands on the lessons we learned in the development of ocrelizumab,” Prof. Kappos explained. “One unexpected finding that emerged out of the phase III studies … was a 30% reduction of atrophy or loss of brain volume,” he added. “Fortunately, although it has so many possible interactions in the body, the comprehensive safety program did not yield real issues of concern over the first course [of treatment]. There remain a few questions about long-term safety and efficacy and better understanding of the mode of action, and the profile of the responders.”

Another immunomodulatory compound that has completed phase III studies is teriflunomide, a metabolite of leflunomide. “It’s a more conservative approach to treatment, as it is an immunomodulator with some more selective effects,” Prof. Kappos said. “The effects were less pronounced if you look at the increase in relapse rates … and less pronounced, but dose-dependently increased, regarding T2 and gadolinium MRI criteria.” He reported that the adverse event profile for teriflunomide was “quite reassuring.”

“Laquinimod, another compound that has now finished two studies, is an immunomodulator whose mode of action we have just started to understand,” Prof. Kappos stated. “What is very clear, both in experimental animal and human trials, is that it didn’t exert any immunosuppressive effect.” Patients on this treatment did not experience an increase in infections, and there was evidence that laquinimod exerted some neuroprotective properties by reducing brain atrophy.

Prof. Kappos also discussed the compound dimethyl fumarate as a therapeutic agent for MS, whose mechanism of action is related to its anti-inflammatory effect. “It may be the first drug that acts both on psoriasis and MS,” he noted. “However, it also may interact with pathways that protect the CNS.” Clinical trials showed a reduction in the annualized relapse rate and disability progression, “but there was an impact on the quality of life,” Prof. Kappos noted.

Current Challenges and Future Directions
“At the moment, we are faced with different treatment options that will probably be in daily practice within the next two to four years,” Prof. Kappos stated. “Much of the evidence is not yet published or peer reviewed, but still there are some indications that may help us to define a profile of these compounds…. [Through clinical trials] we learned about the importance of early intervention and—mainly through negative studies—that later MS stages and progressive disease courses respond in a different way to treatments and need different study designs and more advanced outcome measures.”   

Many achievements have been made as a result of successful clinical trials in MS therapy, including new treatment algorithms and diagnostic MRI criteria, but several challenges remain, according to Prof. Kappos. “We have to adapt and further develop our concepts, we have to develop criteria for phase- and cause-adaptive differential indications, and we have to further explore benefits and risks of new compounds … with additional phase III-B and IV studies…. Future research will focus on the interactions of microglia and their role in the development of disability and deficits in MS.

“Investigator-initiated and publicly funded prospective and comprehensive observational and cohort studies must increasingly complement the current paradigm of mostly corporate-sponsored clinical trials,” Prof. Kappos concluded.  

—Ariel Jones  

AMSTERDAM—R­ecent clinical trials for several multiple sclerosis (MS) treatments have yielded promising results and insights into the disease pathogenesis and have provided direction for future research and diagnostic criteria, Ludwig Kappos, MD, reported at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Prof. Kappos, Professor in the Departments of Neurology and Biomedicine, University of Basel, Switzerland, reviewed the safety and efficacy profiles of fingolimod, natalizumab, teriflunomide, and other potential therapies for MS in development, while highlighting the advancements that have been achieved through clinical trials.

Clinical trials helped to introduce more and more effective compounds and treatment algorithms for the management of relapsing MS and clinically isolated syndromes,” Prof. Kappos said. “Clinical results and effects stimulate new directions, be they diagnostic observations or therapeutic successes…. [They] have played an ever-increasing role in shaping our armamentarium against this still enigmatic disease.”

Improvements in Pathogenesis Understanding
According to Prof. Kappos, one of the main achievements of developing new therapies for MS is the increased insight into disease pathogenesis. “We have detected or found out about the effects of compounds whose modes of action we initially misunderstood,” he said. “Through exploring this mode of action, we are also learning much about the pathogenesis of MS.”

Recent research has validated the role of the immune system in disease pathogenesis and also opened new pathways for developing drugs that address the blood-brain barrier, T and B cells, regulatory cells, and cytokines. “Based on currently completed or ongoing studies, a large number of new compounds, especially oral immunomodulators and monoclonal antibodies, are waiting to enter our pharmacology within the next two to four years,” Prof. Kappos said.

Monoclonal Antibodies
Natalizumab, a humanized monoclonal antibody, has proven effective in reducing relapse rates in MS, but it also has been linked to an increased risk for progressive multifocal leukoencephalopathy (PML), Prof. Kappos noted. The drug does not seem to have any additional immunosuppressive effect, and “it is difficult to understand the selectivity of this risk for PML that is created by this compound,” he said. “Other risks have not really occurred, so it must be something specific that we have to explore in more detail.”

Prof. Kappos also discussed rituximab and ocrelizumab, two anti-CD20 monoclonal antibodies that exert their neuroprotective effect through B cell depletion. Rituximab, when compared with interferon-beta, was shown to significantly reduce relapse rates, and was well tolerated, with approximately 90% of study participants remaining in the study for two years. “At the end of this two-year period, all but two patients on this treatment did not have any active new lesions and were free of disease activity as dictated by the MRI scan,” he reported. In a phase II, placebo-controlled study, ocrelizumab was shown to reduce the number of gadolinium-enhancing lesions in patients with relapsing-remitting MS.

Oral Immunomodulators
Fingolimod, an immunomodulator that has achieved “very encouraging results” in phase III studies, “expands on the lessons we learned in the development of ocrelizumab,” Prof. Kappos explained. “One unexpected finding that emerged out of the phase III studies … was a 30% reduction of atrophy or loss of brain volume,” he added. “Fortunately, although it has so many possible interactions in the body, the comprehensive safety program did not yield real issues of concern over the first course [of treatment]. There remain a few questions about long-term safety and efficacy and better understanding of the mode of action, and the profile of the responders.”

Another immunomodulatory compound that has completed phase III studies is teriflunomide, a metabolite of leflunomide. “It’s a more conservative approach to treatment, as it is an immunomodulator with some more selective effects,” Prof. Kappos said. “The effects were less pronounced if you look at the increase in relapse rates … and less pronounced, but dose-dependently increased, regarding T2 and gadolinium MRI criteria.” He reported that the adverse event profile for teriflunomide was “quite reassuring.”

“Laquinimod, another compound that has now finished two studies, is an immunomodulator whose mode of action we have just started to understand,” Prof. Kappos stated. “What is very clear, both in experimental animal and human trials, is that it didn’t exert any immunosuppressive effect.” Patients on this treatment did not experience an increase in infections, and there was evidence that laquinimod exerted some neuroprotective properties by reducing brain atrophy.

Prof. Kappos also discussed the compound dimethyl fumarate as a therapeutic agent for MS, whose mechanism of action is related to its anti-inflammatory effect. “It may be the first drug that acts both on psoriasis and MS,” he noted. “However, it also may interact with pathways that protect the CNS.” Clinical trials showed a reduction in the annualized relapse rate and disability progression, “but there was an impact on the quality of life,” Prof. Kappos noted.

Current Challenges and Future Directions
“At the moment, we are faced with different treatment options that will probably be in daily practice within the next two to four years,” Prof. Kappos stated. “Much of the evidence is not yet published or peer reviewed, but still there are some indications that may help us to define a profile of these compounds…. [Through clinical trials] we learned about the importance of early intervention and—mainly through negative studies—that later MS stages and progressive disease courses respond in a different way to treatments and need different study designs and more advanced outcome measures.”   

Many achievements have been made as a result of successful clinical trials in MS therapy, including new treatment algorithms and diagnostic MRI criteria, but several challenges remain, according to Prof. Kappos. “We have to adapt and further develop our concepts, we have to develop criteria for phase- and cause-adaptive differential indications, and we have to further explore benefits and risks of new compounds … with additional phase III-B and IV studies…. Future research will focus on the interactions of microglia and their role in the development of disability and deficits in MS.

“Investigator-initiated and publicly funded prospective and comprehensive observational and cohort studies must increasingly complement the current paradigm of mostly corporate-sponsored clinical trials,” Prof. Kappos concluded.  

—Ariel Jones