Special Report:
Panel Recommends Weighing Efficacy, Safety, and Costs of MS Therapies

The Bottom Line:

  • UK's National Institute for Health and Clinical Excellence (NICE) issued a final decision in which it backed the use of fingolimod (Gilenya, Novartis) for certain MS patients.
  • No US payors outright refuse to cover fingolimod, which has FDA approval, but limitations are in place.
  • A Delphi panel recommends: both glatiramer acetate (GA) and a preferred IFN be on formulary; Access to nonpreferred IFNs should be restricted by step therapy or first use of a preferred agent. A preferred highdose/ high-frequency IFN should be on formulary.
  • The panel recommends use of prior authorizations or a requirement of failure of IFN or GA therapy in order to gain access to natalizumab.
  • Access to both fingolimod and dalfampridine should be limited through use of prior authorizations.

“Health plans should consider efficacy, effectiveness, and safety, as well as patient preference, when evaluating MS therapies for formulary placement,” a new consensus statement from managed care experts concludes (J Manag Care Pharm. 2012;18(1):54-62). “Cost and contracting should be considered if efficacy and safety are judged to be comparable between agents.” This conclusion is derived from a recent modified Delphi process involving eight pharmacy directors and six medical directors from managed care companies in the US.

According to study co-author Kellie L. Meyer, PharmD, MPH, Director, Global Value Strategies at Xcenda, the Delphi process was initiated in light of the increased MS competitive treatment landscape and the fact that payors in the United States are faced with constrained healthcare resources , “Mostly to better understand the value and benefit of various treatments.”

The publication is timely, as costs of MS care continue to capture the attention of patients, physicians, payors, policy makers and other interested parties. Costs of care are a worldwide concern. Just weeks after the Delphi consensus publication, the UK's National Institute for Health and Clinical Excellence (NICE) issued a final decision in which it backed the use of fingolimod (Gilenya, Novartis) for certain MS patients. Last year, the agency had rejected fingolimod, even after Novartis offered pricing discounts. Now NICE says the oral agent may be appropriate for highly active relapsing MS only if the patient's relapse rate is unchanged or increased from the previous year or the patient is experiencing ongoing severe relapses despite treatment with other drugs. Access to fingolimod in the UK is contingent on Novartis maintaining special pricing in a patient access program.

No US payors outright refuse to cover fingolimod, which has FDA approval, but limitations are in place. The Managed Care publication affirms restrictions on the drug, among others.

The Recommendations

The Delphi panel recommends that all health plans have both glatiramer acetate (GA) and a preferred IFN on formulary and that access to nonpreferred IFNs should be restricted by step therapy or first use of a preferred agent. Health plans should have a preferred high-dose/high-frequency IFN on formulary, as well, according to the panel. The panel recommends the use of prior authorizations or a requirement of failure of IFN or GA therapy in order to gain access to natalizumab.

Access to both fingolimod and dalfampridine should be limited through use of prior authorizations, the panel says. In the case of dalfampridine, the panel encourages use only in accordance with the FDA indication. The panel further warns against use of fingolimod in combination with other agents until studies are available. The full paper, including all recommendations, is available online at http://www.amcp.org/JMCP/2012/January- February/14484/1033.html.

A Perspective on PAs

Prior authorizations are a key aspect of the recommendations for managing access to MS therapies. “Patients and providers may perceive prior authorizations as a tool by payors to restrict access to treatment,” Dr. Meyer acknowledges, but she notes that PAs are important to assure longterm appropriate access to medications. “PAs can really help ensure there is safe and appropriate use of drugs,” she says.

Generally in the US, if a drug is approved by the FDA, it will be covered in some capacity by payors, Dr. Meyer observes. However, PAs are used to help direct the use of those therapies and associated resources.

One common use for PAs is to ensure that agents are used according to FDA indications, as is recommended for dalfampridine specifically in the current Delphi panel statement. This is an example of “a way payors are using prior authorizations to ensure appropriate use of drugs,” Dr. Meyer maintains.

Dr. Meyer also notes that practicing clinical neurologists who treat patients with multiple sclerosis may have different opinions from those expressed by the health plan pharmacists and medical directors involved in the panel. However, the panel process is important to “help determine the value of therapy to the patient, physician, and payor.” Processes such as this one highlight the reality that “all of those involved in patient care, including the patient, really need to be cognizant of and appropriately consider the cost of therapy and the overall cost of the patient's care so that patients may have access to innovative therapies,” she adds.

Health plans recognize and the current panel recommendations consider the fact that “treatment decisions should be based on the characteristics of the available products and the individual needs of the patient,” Dr. Meyer says. Therefore, prescribers should not view PAs and other tools as absolute barriers to therapy. Instead, these are tools that permit decisions to be made on case-by-case bases, considering the specific needs of individual patients, the way all treatment decisions should be made, Dr. Meyer suggests.

The Delphi panel recommendations are non-binding and subject to change. To react to the panel recommendations, log on to PracticalNeurology.net and comment on this story.

Research Round-up: Stroke

Here are summaries of some key posters presented at the 2012 International Stroke Conference in New Orleans.

Ultra Rapid Brain Attack Team MRI Found Useful

Researchers at the University of South Carolina Palmetto Health Richland Stroke Center developed an ultra-rapid, 10 minute MRI called the “Brain Attack Team MRI” (BAT MRI) to allow accurate and expeditious diagnoses. Believing BAT MRI could be a useful clinical tool to select or exclude patients for IV TPA who present acutely with stroke-like symptoms, researchers looked at 31 consecutive patients who presented <4.5 hours from symptom onset.

Of these 31 BAT MRIs, 13 were read as abnormal (11 acute ischemia, one hemorrhage, one ischemia with hemorrhage). The hemorrhage was in the pons on BAT MRI and was not detected by CT, and this finding excluded using IV TPA in this patient. The authors say two cases where BAT MRI demonstrated AIS met NINDS/ECASS-III criteria and received IV TPA. Of the 18 in whom BAT MRI was read as normal, nine had a discharge diagnosis of TIA, two MRI-negative strokes, three conversion disorders, one CNS neoplasm, one respiratory failure and one peripheral vertigo.

Stroke risk factor analysis showed no “significant correlation between BAT MRI findings and gender, race, prior stroke/TIA, coronary artery disease, diabetes, hyperlipidemia, hypertension, or smoking.” Patients with AIS on BAT MRI were older (68.2 ± 17.5) than those without (58.6 ± 9.7), although it bordered on statistical significance (p=0.08), the authors note.

They concluded that, “in patients with AIS-like symptoms, BAT MRI may be used to confirm AIS, exclude stroke mimics and assess candidacy for IV TPA. Atrial fibrillation correlated with AIS on BAT MRI; therefore, these patients may be more likely to be IV TPA candidates.” (Abstract 2199)

Simvastatin and TPA Combo Decreases Brain Swelling in Rats

Using a rat embolic stroke model, researchers found “that simvastatin in combination with TPA may attenuate brain swelling in acute stroke and, thus, may be a viable adjuvant agent with TPA.” One middle cerebral artery each in young adult male Wistar rats (300g) was embolized with a day-old fibrinrich blood clot. The six groups were injected with [14C] α-aminoisobutyric acid and the brains were processed for Nissl histology and quantitative autoradiography (QAR) at 48 hours post-clot induction. Brain hemispheric and stroke lesion volumes from Nissl-stained brain sections and BBB lesion volumes from QAR images were measured using an image analysis system. Data were expressed as mean ± standard deviation of the ratios to the contralateral hemisphere volumes. Compared to controls, simvastatin, or TPA treatments alone, combination treatment at both two and three hours post-ictus was effective in reducing brain swelling, stroke- and BBB-lesion volumes. Treatment at two hours post-ictus seemed to be more effective than at three hours, researchers said. (Abstract 3983)

Sex Differences, Hemoglobin Levels in Relation to Stroke Outcomes

Sex differences in stroke outcome may be mediated in part by lower hemoglobin levels, a potentially modifiable predictor, according to new research. Retrospectively studying 274 patients (121 women, 153 men) enrolled in a prospective study, study authors explored the relationship of hemoglobin with clinical outcome at six months, as measured by the modified Rankin Scale. The researchers found that women had a lower hemoglobin level (11.7 +/- 1.8 g/dL) compared to men (13.3 +/- 1.7 g/dL; P < 0.001). Low hemoglobin was correlated with worse six-month mRS outcome in univariate analysis (P < 0.001). “Lower hemoglobin remained independently associated with poorer outcome after adjustment for age, sex, blood glucose, NIH stroke scale score, hypertension, smoking and diabetes mellitus,” they write. The inclusion of hemoglobin in the model eliminated the independent effect of sex on outcome. (Abstract 2977)

More Neuroscience Providers; Lower Stroke Death Risk

A higher density of specialist neuroscience providers is associated with significant reduction in deaths from stroke, researchers found in a retrospective analysis. The primary independent variable was the combined density of neurosurgeons and neurologists per million population in the year 2006. Multiple regression analysis was performed, and researchers adjusted for density of general practitioners, urbanicity of the county, and socioeconomic status of the county. Each increase of one neuroscience provider per million population was associated with 0.71 fewer deaths from stroke per million population. On multivariate adjusted analysis, each increase of one neuroscience provider per million population was associated with 0.38 fewer stroke deaths per million population. “Rural location and density of general practitioners, were associated with significant increases in the rate of stroke deaths, while persistent poverty and low educational levels were not significant,” the authors write. The median number of annual stroke deaths per million population in the 3,139 counties analyzed was 586 (IQR 449-754). The median number of neuroscience providers (neurologist or neurosurgeon) per million population was 0 (IQR 0-26), while the median number of general practitioners per million population was 274 (IQR 175-410). (Abstract 2637)

Early Dual Therapy with Clopidogrel and Aspirin Beneficial

Early dual therapy with clopidogrel and aspirin reduces micro-embolic signals at day 7 among patients with predominant intracranial atherosclerosis who had minor ischemic stroke or TIA, without causing significant bleeding complications, according to new research. Researchers investigated the efficacy and safety of early dual antiplatelet use by performing a post-hoc analysis of CLAIR study. The study was a randomized, open-label, blinded-endpoint study in patients who had symptomatic large artery atherosclerosis, in whom MES were present on transcranial doppler monitoring.

The researchers found 65 of 100 patients had TIA or minor stroke (NIHSS 0-3); 30 received dual therapy (aspirin 75-60mg daily and clopidogrel 300mg day 1 then 75mg daily) and 35 received aspirin alone (75-160mg daily) for seven days. Further, 93 percent of patients had intracranial stenosis. At day seven, nine of 29 patients in the dual therapy group and 18 of 34 patients in the monotherapy group for whom data were available had 1 MES (relative risk reduction 41.4%, 95% CI 29.8-51.1, p<0.001). The median number of MES on day seven was 0 in the dual therapy group and 1.0 in the monotherapy group (p=0.02). (Abstract 2743)

Research Briefs and News

UCB's Neupro Gets RLS, Advanced PD Indications

Neupro (rotigotine transdermal system, UCB) received FDA approval for the treatment of the signs and symptoms of advanced stage idiopathic Parkinson's disease (PD) and as a treatment for moderate-to-severe primary Restless Legs Syndrome (RLS). Neupro was previously approved for the signs and symptoms of early stage idiopathic PD.

Five parallel group, randomized, double-blind placebocontrolled trials conducted in the US and abroad confirmed the efficacy of Neurpo in the treatment of the signs and symptoms of idiopathic PD. Patients underwent a weekly titration of Neupro in 2mg/24 hours increments to either the randomized dose or optimal dose. In three trials, Neupro treatment provided statistically significant improvements in the combined scores on the Unified Parkinson's Disease Rating Scale (UPDRS) in early stage PD patients compared with placebo. Two trials of Neupro in patients with advanced PD showed statistically significant changes in off-times among treated patient compared with controls.

The efficacy of Neupro in the treatment of RLS was primarily evaluated in two fixed-dose, randomized, doubleblind, placebo-controlled trials with six-month maintenance periods. Patients received Neupro doses ranging from 0.5mg/24 hours to 3mg/24 hours, or placebo, once daily. Treatment was associated with statistically significant improvements in sum scores on the International RLS Rating Scale (IRLS Scale) and the Clinical Global Impression - Improvement (CGI-I) assessment, compared with placebo.

In clinical trials, the most common adverse reactions (≥5% greater than placebo) for the highest recommended doses of Neupro for treatment of Parkinson's disease were nausea, vomiting, somnolence, application site reactions, dizziness, anorexia, hyperhidrosis, and insomnia. The most common adverse reactions (≥5% greater than placebo) for the highest recommended dose of Neupro for treatment of Restless Legs Syndrome were application site reactions, nausea, somnolence, and headache.

Dalfampridine Provides Positive Data for Potential Use in Chronic Stroke

Acorda Therapeutics presented data showing that treatment with dalfampridine improved motor function in a preclinical model of stroke, with treatment initiated at least four weeks following the ischemic event. These are the first preclinical data to show an oral pharmacologic treatment can improve function in chronic or long-term stroke, according to the company.

The presentation, entitled “Dalfampridine Improves Sensorimotor Function in Rats with Chronic Deficits Following Middle Cerebral Artery Occlusion,” reviewed data from three study groups that received treatment beginning four weeks after a permanent middle cerebral artery occlusion (pMCAO). The neurological impairments that result are expected to be permanent by four weeks, which represents the chronic stage of stroke. Each group received three treatment phases over the course of the study: high and low doses of dalfampridine, and placebo. The order of the treatment phases was different for each group, with a 10-day washout period between each phase. Researchers assessed functional improvement using a battery of standard motor function tests in both the forelimbs and hind limbs. In each of the three study groups, treatment with dalfampridine resulted in significant improvement in function compared to placebo across all measures during the respective treatment periods. Improvements in the high dose phase were consistently better than those seen in the low dose phase.

Dalfampridine, also known as 4-aminopyridine, is the active chemical ingredient in Ampyra (dalfampridine) Extended Release Tablets, 10mg.

FDA Requests Additional Data, May Give Boxed Warning to Northera

FDA has requested additional clinical efficacy data regarding the new drug application for Northera (droxidopa) Capsules and made a preliminary recommendation to include a boxed warning related to supine hypertension. The letter stated that “the warning could be reconsidered if suitable data demonstrating a lack of severe hypertension in a fully prone position versus the 30-degree head-up tilt, the standard of care and criteria used in the Chelsea clinical program, were provided,” according to drug developer Chelsea Therapeutics.

Chelsea is seeking the approval for treatment of symptomatic neurogenic orthostatic hypotension (known as Neurogenic OH or NOH) in patients with primary autonomic failure (Parkinson's disease, multiple system atrophy and pure autonomic failure), dopamine beta hydroxylase deficiency, and non-diabetic autonomic neuropathy. They say the application “was supported by the highly statistically significant (p=0.003) outcome of Study 301,” according to Chelsea.

Chelsea believes that data from their trial Study 306 could potentially meet the criteria for clinical efficacy and durability of effect identified in the Complete Response Letter, and the company pointed out the complete response letter did not identify any outstanding concerns. Study 306 is an ongoing 10-week double-blind, placebocontrolled trial evaluating Northera in patients with symptomatic neurogenic OH associated with Parkinson's disease.

In addition to the clinical requests, FDA said that additional bioequivalence work would be needed to support the approval of a 300mg capsule that company was considering making commercially available to complement availability of the 100mg and 200mg capsules utilized in Chelsea's clinical program, but would not require this for approval of the NDA.

Stroke Still Not Viewed as an Emergency

Just 51 percent of adults diagnosed with stroke in emergency departments across the US arrived via ambulance— a figure that has remained relative consistent for 11 years, new research shows. Analyzing data collected by the National Hospital Ambulatory Medical Care Survey (NHAMCS) between 1997 and 2008, researchers at NewYork-Presbyterian Hospital/Weill Cornell Medical College concluded that most patients still are not calling 911 for symptoms of a stroke and may instead be calling primary care doctors or other healthcare providers. The study appears in JAMA.

EMA Reviewing Teriflunomide

The European Medicines Agency (EMA) is currently reviewing once-daily oral teriflunomide for the treatment of relapsing forms of multiple sclerosis (MS), following acceptance of the marketing authorization application (MAA) from Genzyme, a Sanofi company. The application is based on data from two completed pivotal Phase III trials, TEMSO and TENERE. These are two of five efficacy studies of teriflunomide in MS that are completed or underway, making the clinical program one of the largest and broadest of any MS therapy in development, according to Genzyme. The FDA is also currently reviewing an application to market teriflunomide in the US.

Bristol-Myers Squibb and Meso Scale Discovery Announce Assays Partnership

Bristol-Myers Squibb and Meso Scale Discovery are partnering to develop diagnostic assays to measure cerebrospinal fluid biomarkers related to Alzheimer's disease, the companies announced. The agreement will allow the companies to develop assays based on the Meso Scale Discovery MULTI-ARRAY technology platform. They plan to launch the assays for disease research and drug development later this year.