NEDA Is Central to Current MS Treatment

WASHINGTON, DC—Although treatment algorithms for multiple sclerosis (MS) cannot be adopted formally yet, FDA approval of nearly a dozen new therapies in recent years has yielded enough data to support several useful treatment strategies. At the center of current approaches for using these newer disease-modifying therapies (DMT), including the induction and escalation treatment paradigms, is the concept of no evidence of disease activity (NEDA), according to a presentation at the 67th Annual Meeting of the American Academy of Neurology.

“NEDA may be a viable goal and may be attainable with many [treatment] options,” said Timothy West, MD, a neurologist at the Sansum Clinic in Santa Barbara, California. It is unclear which patients will achieve NEDA, however. “We cannot yet predict response to therapy, so therapeutic risk probably should be a factor [in treatment decisions]. If I can give you a much lower-risk medicine and you get a really good clinical response … that would make us think that [clinicians] might want to do that first, which would support the escalation model.”

Recent data have helped establish several clinical and radiologic markers of poor prognosis that may help neurologists choose among available therapies. “If you see an African American male with 30 lesions, and 10 of them are enhancing, and he’s got an [Expanded Disability Status Scale (EDSS) score] of 4 … that person’s not going to do well,” he said. “You may [now] think about that person differently, and that’s a good thing.”

When a treatment fails, data can suggest which therapy clinicians should try next. These data, which are somewhat limited, derive largely from studies involving the modified Rio Score and the Bermel approach to DMT failure—both of which are based on interferon data alone—as well as the consensus-based Canadian Treatment Optimization Model. “That’s where we are right now as far as an algorithm and data,” said Dr. West. “We’re really basing this off of a small portion of our DMT arsenal…. You might get a little bit more of a bang for your buck if you switched to something in the same efficacy class. You might get a lot more bang for your buck if you jump to that next level of efficacy.”

How Can Patients Achieve NEDA?
Eleven DMTs have received FDA approval since 1993. “The current therapies … have varying mechanisms of action. They have varying efficacies. They have varying safety profiles, and it’s hard to know where to use which medicine and what is the right patient for each medicine.”

The concept of NEDA is based on the idea that clinicians can define and attain a target in patients. The concept was first identified in the AFFIRM study, which sought to analyze the effect of natalizumab, in an effort to define composite measures for use in clinical practice. The study goal of clinical disease-free status, which was defined as no activity on clinical measures (ie, no relapses and no sustained disability progression), was combined with radiologic disease-free status (ie, no gadolinium-enhancing lesions and no new enlarging T2-hyperintense lesions on cranial MRI) into the larger goal of combined disease-free status, which came to be known as NEDA.

NEDA has proven to be achievable. In the AFFIRM study, 37% of patients on natalizumab achieved this goal, versus 7% on placebo, and Dr. West cited more than a half dozen other trials involving various treatments in which a sizable percentage of patients achieved NEDA. Maintaining NEDA, however, is another matter. In a seven-year longitudinal cohort of 215 patients with MS, Rotstein et al found that 46% of patients on DMT reached NEDA at one year, but 8% of the patients maintained NEDA for seven years.

“There wasn’t any difference between early or established MS in this metric, which argues a little bit against [the concept of a] window of opportunity,” said Dr. West. “It’s also worth noting that NEDA can predict itself, which is helpful [in the] long term. NEDA, two years later, had a positive predictive value of 78% for no progression in seven years—and this speaks to possibly that window of opportunity.” A patient with active MS who achieves NEDA for two years has a chance of maintaining NEDA for seven years, added Dr. West.

Induction Versus Escalation
Given that roughly one-third of patients on any approved MS medication are likely to achieve this goal, the questions for clinicians are how to enable a patient to attain NEDA and how to assess it. The induction and escalation treatment paradigms are relevant to these questions. The induction paradigm involves maximizing therapeutic benefit while tolerating increased therapeutic risk, based on the assumption that the risk of MS outweighs the risk of the treatment. The escalation paradigm involves minimizing therapeutic risk while maximizing therapeutic benefit, based on the assumption that one can decrease the risk of MS sufficiently while exposing the patient to less therapeutic risk.

The goal of the induction model is to stop MS activity as soon as possible. This goal is based on the assumption that a window of opportunity early in the disease warrants the increased therapeutic risk despite an unclear prognosis. “If there’s no window of opportunity, we can wait to induce [patients] a few years down the road,” said Dr. West. “But if there is really a narrow window at the beginning … then the induction model makes a lot of sense.”

The idea of the window of therapeutic opportunity arose from studies of alemtuzumab in the late 1990s and early 2000s in patients with severe MS. In a 2006 article that examined EDSS change following alemtuzumab therapy, Coles et al found that while most patients with secondary progressive MS got worse, those in the relapsing-remitting arm achieved significant and striking improvement. “Not only did they stabilize … they actually gained multiple points on their EDSS score,” said Dr. West.

One caveat with the induction paradigm is that because one gets a variable response from available DMTs, clinicians can achieve NEDA with any of these medicines, but often at a high cost: they all raise significant safety and tolerability concerns. These concerns provided the rationale for the escalation paradigm.

Data indicate that a Caucasian patient with features such as monofocal onset, a low relapse rate in the first two to five years, or good recovery after the first relapse likely has a better prognosis than an African American or other nonwhite patient with features such as multifocal onset, a high relapse rate in the first two to five years, or poor recovery after the first relapse. A patient with a good prognosis may limit a clinician’s tolerance of risk and incline him or her toward the escalation model, said Dr. West.

“The idea here is: can we basically work through medicines in a quick way to get [patients] to a NEDA status while also limiting the risk? The assumption here is that sometimes the risk of treatment is greater than that of the MS.... We can define and identify what constitutes treatment failure … and then the next DMT might be more effective.

“We have a lot of tools with which to fight this disease,” Dr. West continued. “Our goal should be to stop the illness as soon as we can…. Both the escalation model and the induction model are trying to get to that goal—they’re just doing it a little bit differently.”

—Fred Balzac

WASHINGTON, DC—Although treatment algorithms for multiple sclerosis (MS) cannot be adopted formally yet, FDA approval of nearly a dozen new therapies in recent years has yielded enough data to support several useful treatment strategies. At the center of current approaches for using these newer disease-modifying therapies (DMT), including the induction and escalation treatment paradigms, is the concept of no evidence of disease activity (NEDA), according to a presentation at the 67th Annual Meeting of the American Academy of Neurology.

“NEDA may be a viable goal and may be attainable with many [treatment] options,” said Timothy West, MD, a neurologist at the Sansum Clinic in Santa Barbara, California. It is unclear which patients will achieve NEDA, however. “We cannot yet predict response to therapy, so therapeutic risk probably should be a factor [in treatment decisions]. If I can give you a much lower-risk medicine and you get a really good clinical response … that would make us think that [clinicians] might want to do that first, which would support the escalation model.”

Recent data have helped establish several clinical and radiologic markers of poor prognosis that may help neurologists choose among available therapies. “If you see an African American male with 30 lesions, and 10 of them are enhancing, and he’s got an [Expanded Disability Status Scale (EDSS) score] of 4 … that person’s not going to do well,” he said. “You may [now] think about that person differently, and that’s a good thing.”

When a treatment fails, data can suggest which therapy clinicians should try next. These data, which are somewhat limited, derive largely from studies involving the modified Rio Score and the Bermel approach to DMT failure—both of which are based on interferon data alone—as well as the consensus-based Canadian Treatment Optimization Model. “That’s where we are right now as far as an algorithm and data,” said Dr. West. “We’re really basing this off of a small portion of our DMT arsenal…. You might get a little bit more of a bang for your buck if you switched to something in the same efficacy class. You might get a lot more bang for your buck if you jump to that next level of efficacy.”

How Can Patients Achieve NEDA?
Eleven DMTs have received FDA approval since 1993. “The current therapies … have varying mechanisms of action. They have varying efficacies. They have varying safety profiles, and it’s hard to know where to use which medicine and what is the right patient for each medicine.”

The concept of NEDA is based on the idea that clinicians can define and attain a target in patients. The concept was first identified in the AFFIRM study, which sought to analyze the effect of natalizumab, in an effort to define composite measures for use in clinical practice. The study goal of clinical disease-free status, which was defined as no activity on clinical measures (ie, no relapses and no sustained disability progression), was combined with radiologic disease-free status (ie, no gadolinium-enhancing lesions and no new enlarging T2-hyperintense lesions on cranial MRI) into the larger goal of combined disease-free status, which came to be known as NEDA.

NEDA has proven to be achievable. In the AFFIRM study, 37% of patients on natalizumab achieved this goal, versus 7% on placebo, and Dr. West cited more than a half dozen other trials involving various treatments in which a sizable percentage of patients achieved NEDA. Maintaining NEDA, however, is another matter. In a seven-year longitudinal cohort of 215 patients with MS, Rotstein et al found that 46% of patients on DMT reached NEDA at one year, but 8% of the patients maintained NEDA for seven years.

“There wasn’t any difference between early or established MS in this metric, which argues a little bit against [the concept of a] window of opportunity,” said Dr. West. “It’s also worth noting that NEDA can predict itself, which is helpful [in the] long term. NEDA, two years later, had a positive predictive value of 78% for no progression in seven years—and this speaks to possibly that window of opportunity.” A patient with active MS who achieves NEDA for two years has a chance of maintaining NEDA for seven years, added Dr. West.

Induction Versus Escalation
Given that roughly one-third of patients on any approved MS medication are likely to achieve this goal, the questions for clinicians are how to enable a patient to attain NEDA and how to assess it. The induction and escalation treatment paradigms are relevant to these questions. The induction paradigm involves maximizing therapeutic benefit while tolerating increased therapeutic risk, based on the assumption that the risk of MS outweighs the risk of the treatment. The escalation paradigm involves minimizing therapeutic risk while maximizing therapeutic benefit, based on the assumption that one can decrease the risk of MS sufficiently while exposing the patient to less therapeutic risk.

The goal of the induction model is to stop MS activity as soon as possible. This goal is based on the assumption that a window of opportunity early in the disease warrants the increased therapeutic risk despite an unclear prognosis. “If there’s no window of opportunity, we can wait to induce [patients] a few years down the road,” said Dr. West. “But if there is really a narrow window at the beginning … then the induction model makes a lot of sense.”

The idea of the window of therapeutic opportunity arose from studies of alemtuzumab in the late 1990s and early 2000s in patients with severe MS. In a 2006 article that examined EDSS change following alemtuzumab therapy, Coles et al found that while most patients with secondary progressive MS got worse, those in the relapsing-remitting arm achieved significant and striking improvement. “Not only did they stabilize … they actually gained multiple points on their EDSS score,” said Dr. West.

One caveat with the induction paradigm is that because one gets a variable response from available DMTs, clinicians can achieve NEDA with any of these medicines, but often at a high cost: they all raise significant safety and tolerability concerns. These concerns provided the rationale for the escalation paradigm.

Data indicate that a Caucasian patient with features such as monofocal onset, a low relapse rate in the first two to five years, or good recovery after the first relapse likely has a better prognosis than an African American or other nonwhite patient with features such as multifocal onset, a high relapse rate in the first two to five years, or poor recovery after the first relapse. A patient with a good prognosis may limit a clinician’s tolerance of risk and incline him or her toward the escalation model, said Dr. West.

“The idea here is: can we basically work through medicines in a quick way to get [patients] to a NEDA status while also limiting the risk? The assumption here is that sometimes the risk of treatment is greater than that of the MS.... We can define and identify what constitutes treatment failure … and then the next DMT might be more effective.

“We have a lot of tools with which to fight this disease,” Dr. West continued. “Our goal should be to stop the illness as soon as we can…. Both the escalation model and the induction model are trying to get to that goal—they’re just doing it a little bit differently.”

—Fred Balzac

WASHINGTON, DC—Although treatment algorithms for multiple sclerosis (MS) cannot be adopted formally yet, FDA approval of nearly a dozen new therapies in recent years has yielded enough data to support several useful treatment strategies. At the center of current approaches for using these newer disease-modifying therapies (DMT), including the induction and escalation treatment paradigms, is the concept of no evidence of disease activity (NEDA), according to a presentation at the 67th Annual Meeting of the American Academy of Neurology.

“NEDA may be a viable goal and may be attainable with many [treatment] options,” said Timothy West, MD, a neurologist at the Sansum Clinic in Santa Barbara, California. It is unclear which patients will achieve NEDA, however. “We cannot yet predict response to therapy, so therapeutic risk probably should be a factor [in treatment decisions]. If I can give you a much lower-risk medicine and you get a really good clinical response … that would make us think that [clinicians] might want to do that first, which would support the escalation model.”

Recent data have helped establish several clinical and radiologic markers of poor prognosis that may help neurologists choose among available therapies. “If you see an African American male with 30 lesions, and 10 of them are enhancing, and he’s got an [Expanded Disability Status Scale (EDSS) score] of 4 … that person’s not going to do well,” he said. “You may [now] think about that person differently, and that’s a good thing.”

When a treatment fails, data can suggest which therapy clinicians should try next. These data, which are somewhat limited, derive largely from studies involving the modified Rio Score and the Bermel approach to DMT failure—both of which are based on interferon data alone—as well as the consensus-based Canadian Treatment Optimization Model. “That’s where we are right now as far as an algorithm and data,” said Dr. West. “We’re really basing this off of a small portion of our DMT arsenal…. You might get a little bit more of a bang for your buck if you switched to something in the same efficacy class. You might get a lot more bang for your buck if you jump to that next level of efficacy.”

How Can Patients Achieve NEDA?
Eleven DMTs have received FDA approval since 1993. “The current therapies … have varying mechanisms of action. They have varying efficacies. They have varying safety profiles, and it’s hard to know where to use which medicine and what is the right patient for each medicine.”

The concept of NEDA is based on the idea that clinicians can define and attain a target in patients. The concept was first identified in the AFFIRM study, which sought to analyze the effect of natalizumab, in an effort to define composite measures for use in clinical practice. The study goal of clinical disease-free status, which was defined as no activity on clinical measures (ie, no relapses and no sustained disability progression), was combined with radiologic disease-free status (ie, no gadolinium-enhancing lesions and no new enlarging T2-hyperintense lesions on cranial MRI) into the larger goal of combined disease-free status, which came to be known as NEDA.

NEDA has proven to be achievable. In the AFFIRM study, 37% of patients on natalizumab achieved this goal, versus 7% on placebo, and Dr. West cited more than a half dozen other trials involving various treatments in which a sizable percentage of patients achieved NEDA. Maintaining NEDA, however, is another matter. In a seven-year longitudinal cohort of 215 patients with MS, Rotstein et al found that 46% of patients on DMT reached NEDA at one year, but 8% of the patients maintained NEDA for seven years.

“There wasn’t any difference between early or established MS in this metric, which argues a little bit against [the concept of a] window of opportunity,” said Dr. West. “It’s also worth noting that NEDA can predict itself, which is helpful [in the] long term. NEDA, two years later, had a positive predictive value of 78% for no progression in seven years—and this speaks to possibly that window of opportunity.” A patient with active MS who achieves NEDA for two years has a chance of maintaining NEDA for seven years, added Dr. West.

Induction Versus Escalation
Given that roughly one-third of patients on any approved MS medication are likely to achieve this goal, the questions for clinicians are how to enable a patient to attain NEDA and how to assess it. The induction and escalation treatment paradigms are relevant to these questions. The induction paradigm involves maximizing therapeutic benefit while tolerating increased therapeutic risk, based on the assumption that the risk of MS outweighs the risk of the treatment. The escalation paradigm involves minimizing therapeutic risk while maximizing therapeutic benefit, based on the assumption that one can decrease the risk of MS sufficiently while exposing the patient to less therapeutic risk.

The goal of the induction model is to stop MS activity as soon as possible. This goal is based on the assumption that a window of opportunity early in the disease warrants the increased therapeutic risk despite an unclear prognosis. “If there’s no window of opportunity, we can wait to induce [patients] a few years down the road,” said Dr. West. “But if there is really a narrow window at the beginning … then the induction model makes a lot of sense.”

The idea of the window of therapeutic opportunity arose from studies of alemtuzumab in the late 1990s and early 2000s in patients with severe MS. In a 2006 article that examined EDSS change following alemtuzumab therapy, Coles et al found that while most patients with secondary progressive MS got worse, those in the relapsing-remitting arm achieved significant and striking improvement. “Not only did they stabilize … they actually gained multiple points on their EDSS score,” said Dr. West.

One caveat with the induction paradigm is that because one gets a variable response from available DMTs, clinicians can achieve NEDA with any of these medicines, but often at a high cost: they all raise significant safety and tolerability concerns. These concerns provided the rationale for the escalation paradigm.

Data indicate that a Caucasian patient with features such as monofocal onset, a low relapse rate in the first two to five years, or good recovery after the first relapse likely has a better prognosis than an African American or other nonwhite patient with features such as multifocal onset, a high relapse rate in the first two to five years, or poor recovery after the first relapse. A patient with a good prognosis may limit a clinician’s tolerance of risk and incline him or her toward the escalation model, said Dr. West.

“The idea here is: can we basically work through medicines in a quick way to get [patients] to a NEDA status while also limiting the risk? The assumption here is that sometimes the risk of treatment is greater than that of the MS.... We can define and identify what constitutes treatment failure … and then the next DMT might be more effective.

“We have a lot of tools with which to fight this disease,” Dr. West continued. “Our goal should be to stop the illness as soon as we can…. Both the escalation model and the induction model are trying to get to that goal—they’re just doing it a little bit differently.”

—Fred Balzac