In The News
Study Investigates Pediatric Stroke
The first study to gauge the variation between hemorrhagic and ischemic stroke in children finds “an urgent need for more rapid identification of stroke symptoms in children,” and says the lack of valid pediatric stroke recognition tools for emergency physicians and paramedics contributes to delays in treatment.
Published online February 2 in Annals of Emergency Medicine, the study examined the records of 81 pediatric stroke patients, 47 with acute ischemic stroke (AIS), three with transient ischemic attack (TIA), and 31 with hemorrhagic stroke (HS). The vast majority of patients (81 percent) experienced a sudden onset of symptoms. Almost two thirds of AIS patients had weakness in their limbs (62 percent) and/or face (70 percent). Just shy of three-quarters (73 percent) of HS patients had headache, and more than half had vomiting (58 percent).
Computer tomography identified all cases of HS but only half of AIS cases, leading researchers to suggest that magnetic resonance imaging may be the best tool for diagnosing AIS. “The symptoms and signs of acute ischemic and hemorrhagic stroke are similar in adults and children, but in children stroke is not considered early enough and patients do not receive brain imaging early enough,” says study author Franz Babl, MD.
Previous pediatric stroke studies have focused on acute ischemic stroke, despite hemorrhagic stroke accounting for roughly half of all pediatric strokes.
MS Drug Hits Road Bump
The FDA did not approve the supplemental New Drug Application (sNDA) for a lower-volume (0.5mL) injection of glatiramer acetate, according to a release from Teva. The FDA reportedly said that although the 0.5mL formulation contained the same active ingredient as the currently marketed Copaxone, because the mechanism of action of glatiramer acetate is not fully understood, even a formulation change could impact clinical outcomes.
“Unless you can provide a convincing argument that the new higher concentration/lower volume formulation does not have an impact on efficacy, an adequate and well controlled efficacy study will be needed to support efficacy of this new formulation,” the FDA said. The sNDA was based on the SONG trial that studied a lower-volume injection of Copaxone containing 20mg of glatiramer acetate— the currently approved dose—in a 0.5mL injection. The trial was intended to explore whether a reduced-volume injection enhances the patient injection experience.
In all, 148 patients enrolled in the open-label, randomized, two-arm, single crossover study. Half of the patients injected 20mg/1.0mL daily for the first 14-day period (Period 1). The other half injected 20mg/0.5mL daily during the same period. During the second 14-day period (Period 2), the groups switched their injection volume formulation. The first group injected 20mg/0.5mL glatiramer acetate daily and the second group injected 20mg/1.0mL glatiramer acetate daily.
Personalized T-cell Therapy for MS Patients?
Opexa Therapeutics reached an agreement with the FDA on the design of a late-stage trial for its experimental MS drug Tovaxin after two meetings with the agency. “We are very pleased with the outcome of our two recent FDA meetings regarding Tovaxin, the first ever personalized T-cell therapy for MS patients, as we believe we now have a well defined path forward for phase III clinical studies,” commented Neil K. Warma, President and Chief Executive Officer of Opexa.
The company reports that the FDA concurred with Opexa regarding its proposed clinical trial protocol, including the patient population, end points, patient numbers, and trial design. The FDA also offered several recommendations to further enhance a phase III trial, they note.
The phase III clinical trial protocol presented to the FDA was based in part on a recently conducted analysis of data from the previous phase IIb TERMS trial in a sub-population of patients that were naïve to disease modifying agents (i.e., patients who had not previously used any drugs other than steroids to treat their disease). “The analysis,” they comment, “produced encouraging results which showed that these patients, when treated with Tovaxin, had a 64 percent reduction in annualized relapse rate versus placebo (p=0.046, n=70). This statistically significant efficacy result, coupled with the ‘superior safety profile’ of Tovaxin, was highlighted during the FDA meeting to emphasize what the Company believes to be a promising benefit-to-risk profile for Tovaxin, according to the company.”
New Site Helps Focal Dystonia Patients
People affected by certain focal dystonias, as well as caregivers, family and friends, can learn more about the conditions and access helpful resources at the new website: FocalDystoniaExchange.com.
Launched by Merz Pharmaceuticals, the site offers educational information about the symptoms and effects of focal dystonias, including cervical dystonia and blepharospasm. There are articles of interest and downloadable materials, such as a treatment journal, and even an online patient journal written by Beka Serdans, RN, founder of the non-profit Care4Dystonia, Inc. (www.Care4Dystonia.org).
Butrans Patch Now Available
For the management of moderate to severe chronic pain, Butrans (buprenorphine) Transdermal System CIII is now available by prescription. The Butrans Transdermal System (Purdue Pharma L.P.) is the first opioid analgesic on the market that delivers continuous release of buprenorphine for seven days. Three strengths of are available: 5mcg/hour (NDC code 59011-750-04); 10mcg/hour (NDC code 59011-751-04); and 20mcg/hour (NDC code 59011- 752-04). The maximum dose of Butrans is 20mcg/hour.
Butrans is a Schedule III product and can be abused in a manner similar to other opioid agonists, legal or illicit, Purdue notes. Working with the FDA, the company developed a Risk Evaluation and Mitigation Strategy (REMS) for Butrans that includes a Medication Guide, Elements to Assure Safe Use, such as healthcare providers training, and a timetable for submitting assessments of the REMS. This information is available at www.butransrems.com.
Concussion Study Underway
Vicor Technologies, Inc. will begin a study to assess concussions in competitive athletes using its PD2i Analyzer™ with its partners, the University of Mississippi Medical Center (UMMC) and Belhaven University. “Being able to effectively assess the extent of a concussion and risk of follow-on pathological events in athletes will enable all involved in assessing the extent of harm incurred during competitive play to better determine player need for advanced care and/or player ability to continue to play unharmed,” says David H. Fater, CEO of the company.
Vicor Technologies is a biotechnology company focused on the development of innovative, noninvasive medical devices using its patented, proprietary PD2i® nonlinear algorithm and software.
Bad News, Good News for Alzheimer's Imaging Agent
An advisory committee for the FDA recently recommended against approval of the radiotracer florbetapir (Amyvid, Avid Radiopharm/Eli Lilly). But in a second unofficial vote, the committee reversed course 16 to 0 in favor of florbetapir, a diagnostic to detect the presence of β-amyloid in the brain, if the company increases education initiatives for imaging readers.
According to the Dow Jones Newswire, “One FDA reviewer said images for only five of 29 patients were rated identically by three readers used in the study, raising concerns about reader consistency. The agency noted that in a real-world setting that just one person would likely interpret a scan.”
Eli Lilly completed its purchase of Avid Radiopharm for $300 million upfront, plus a potential $500 million in milestone payments.
Stroke Patients Fare Better at Stroke Centers
According to a study in the January 26 issue of JAMA, ischemic stroke patients admitted to hospitals designated as primary stroke centers had a modestly lower risk of death at 30 days, compared to patients admitted to non-designated hospitals.
Mortality data from the New York Statewide Planning and Research Cooperative System for patients admitted with acute ischemic stroke (n=30,947) between 2005 and 2006 were compared at designated stroke centers and nondesignated hospitals. Data for stroke were also compared against those for gastrointestinal hemorrhage (n=39,409) or heart attack (n=40,024).
Among the patients with acute ischemic stroke, about 50 percent (n=15,297) were admitted to designated stroke centers (n=104). “The overall 30-day all-cause mortality rate was 10.1 percent for patients admitted to designated stroke centers and 12.5 percent for patients admitted to nondesignated hospitals, with analysis indicating that admission to a designated stroke center hospital was associated with a 2.5 percent absolute reduction in 30-day all-cause mortality,” according to JAMA. The use of thrombolytic therapy was 4.8 percent for patients admitted at designated stroke centers and 1.7 percent for patients admitted at nondesignated hospitals (adjusted difference in use, 2.2 percent). Among patients surviving to hospital discharge, there was no disparity in rates of 30-day all-cause readmission and discharge to a skilled nursing facility.
"Differences in mortality also were observed at one-day, seven-day, and one-year follow-up. The outcome differences were specific for stroke, as stroke centers and nondesignated hospitals had similar 30- day all-cause mortality rates among those with gastrointestinal hemorrhage or acute myocardial infarction," the authors write.
Highlights of New Epilepsy Data
Following are a few highlights from data presented at the American Epilepsy Society Annual Meeting in San Antonio last December.
Adenosine A1 Receptors and Ketogenic Diet. Seizure reduction provided by the ketogenic diet appears to be linked to increased A1R-mediated inhibition attributable to the low carbohydrate nature of the diet. Masino, et al. showed that in transgenic mice with spontaneous recurrent seizures due to an adenosine deficiency but with intact A1Rs (Adk-tg), a ketogenic diet nearly eliminated all spontaneous seizures and significantly reduced the duration of seizures that did occur. In contrast, in mice whose seizures were triggered by reduction or deletion of A1Rs, the ketogenic diet had little or no effect on seizure frequency.
AED Retention Rates Measured. Among 185 patients prescribed lacosamide since June 3, 2009 at one clinic, the overall retention rate was 79.34 percent. The agent was prescribed as an adjunct in every case. Compared to other six-month AED retention rates from the same clinic, lacosamide retention was similar to that for lamotrigine (78.5 percent) and better than that for levetiracetam (62.2 percent), oxcarbazepine (68.0 percent), topiramate (56.4percent), or zonisamide (65.6 percent. Lacosamide discontinuation was mainly due to inefficacy (36 percent), dizziness (28 percent), and lethargy (24 percent), Schusse, et al. report.
Rufinamide Effective for Adult Epilepsy. A retrospective chart review of the first 48 adult outpatients prescribed rufinamide at the Columbia University Comprehensive Epilepsy Center show that the agent can be a useful adjunctive agent for adult patients with refractory epilepsy, both on- and off-label. Efficacy was evident across epilepsy syndromes. Mean age was 41 (18 to 70 years). Patients consisted of 13 (27 percent) with Symptomatic Generalized Epilepsy, 20 (42 percent) with Primary Generalized Epilepsy (PGEN), 13 (27 percent) Focal Epilepsy, and two (four percent) Focal and PGEN. Among responders, improvement occurred most often at 1600mg/day (four patients), with maximum dose at 3200mg/day (three), and final dose at 1600mg/day (four). The total retention on rufinamide, which was high at six months (71 percent), dropped considerably by 12 months (29 percent). Only a third of patients reached the maximum recommended dose, with maximum benefit most commonly seen at 1600mg/day. Adverse effects were mild, transient, and consistent with previous studies.
Long-term Lacosamide Improves Seizure and HRQoL. Long-term therapy with lacosamide is associated with significant improvements in all aspects of seizure severity, as well as in most aspects of HRQoL, results of a phase III open-label extension trial show. At week 48, patients had an average improvement of -0.64 on the Overall SSQ score, a rating combining overall seizure severity and bother. More than 35 percent of patients had an improvement on all measures of HRQoL. About half of patients showed clinically meaningful improvement on seizure worry and social functioning.
Levetiracetam-ER Pharmacokinetics Similar in Adults and Children. The pharmacokinetic profile for levetiracetam-ER is similar in children and adults with epilepsy, according to results of a multicenter, open-label, two-arm study of patients with localization- related or generalized epilepsy on one to three AEDs. Twelve children (6M/6F; mean [range] age 14.9 y [13-16]) and 13 adults (5M/8F; 41.8 y [24-52]) were enrolled in the study. In both children and adults, median time to peak levetiracetam extendedrelease plasma concentration was six hours, while mean Cmax,D were 17.3 and 14.9g/mL for children and adults. Corresponding mean AUC24h,D were 265 and 236g h/mL. Variability on mean AUC24h and Cmax were similar between children and adults. In both groups, 25 percent of the patients reported TEAEs, the most frequent of which were somnolence, nausea and vomiting, each occurring in two (eight percent) patients. Drug-related TEAEs were reported by 16 percent of patients, all of which were mild except for one case of severe vomiting.
A reader pointed out incosistency on the part of our editorial staff in the Nov/Dec issue, where we referred to botulinum toxin as both a preventive and preventative treatment for headache. Our reader points out that the words have been debated in the literature (JAMA. 1964;189(9):700); Preventive is preferred.
In the Pipeline
Laquinimod, an investigational, once-daily oral immunomodulator under investigation for the treatment of relapsing remitting multiple sclerosis, demonstrated a sustained positive benefit-risk profile and was shown to reduce Gd-enhancing (GdE) T1 lesions, while maintaining a good safety profile. In a new study, published online in Multiple Sclerosis, 239 (93 percent) patients completed the extension phase and 222 (87.1 percent) had a final scan. Researchers found that GdE lesions were significantly reduced for patients switching from placebo to 0.3 or 0.6mg doses (52 percent, p=0.0006).
In patients first randomized to 0.6mg, “the reduction of MRI activity observed in the placebo-controlled phase was maintained in the extension. The proportion of GdE-free patients for those who switched from placebo increased from a baseline of 31 percent to 47 percent at the end of the extension phase (p = 0.01),” according to the publication. There were no new adverse events during the extension study. The incidence rate of liver enzymes elevation observed in the LAQ/5062 core study decreased in the extension phase. The study was a multinational, double-blind, 36-week extension of the placebo-controlled phase IIb laquinimod study and was conducted in nine countries at 51 sites.
The study’s lead author, Giancarlo Comi, Professor in the Department of Neurology at the Scientific Institute San Raffaele in Milan, Italy, detailed the study further in a Q&A with Practical Neurology.
How should neurologists interpret the results of this
study? How do findings compare with earlier studies and
what do you feel was uncovered by this latest study?
This nine-month study is an extension of the core nine-month placebo-controlled LAQ/5062 study which showed that laquinimod reduced MRI-disease activity as measured by MRI. As such, it was designed to address three main issues:
1.) whether the beneficial effects of oral laquinimod compared with placebo seen on MRI-measured disease activity in the core study are reproduced in patients switching from placebo to active treatment,
2.) whether the effects of oral laquinimod on MRI parameters of disease activity are sustained in those who continued active treatment and
3.) additional long-term safety and tolerability data on laquinimod in patients with RRMS.
Although the extension study is devoid of a control group, it managed to show reproducibility and sustainability of the effects in similar magnitudes to those seen in the core study and in a statistically significant manner. The favorable safety profile seen in the core study was also strengthened, with incidence of adverse events declining over time.
Laquinimod’s predecessor, linomide, resulted in serious
cardiovascular events in MS patients (Multiple Sclerosis
6(2):99-104.) Has this been an issue or have there been
Laquinimod was developed following a thorough structure-activity relationship screening program [with Linomide], which was aimed to produce a molecule with a better safety profile than its predecessor. Preclinical data have shown that laquinimod has substantially lower pro-inflammatory effects than Linomide. Currently, with the openlabel extension of this study (presented last ECTRIMS), phase II studies with laquinimod (and their extensions) sum up to a total exposure of more than 500 patient years, with patients treated with laquinimod for more than four years. No cases of myocardial infarction/ischemia have been reported thus far. The MI cases in Linomide phase III trials appeared as early as two weeks after initiation of the drug, so we believe that the exposure to laquinimod we have so far is sufficient to rule out the similarity between the two drugs in this regard.
What’s next? What is the focus of the phase III studies and
what do you hope to learn, or what issues do you hope will
The two phase II studies were designed as proof-ofconcept, with MRI serving as a biomarker for disease activity. However, the only valid endpoints in RRMS are clinical, i.e., reduction of frequency of relapses and slowing the progression of disability. In order to measure these, one needs large, multinational, well-controlled phase III trials with patients being treated for at least two years. The ALLEGRO trial is assessing these endpoints (as well as other MRI endpoints and quality of life measures) in more than 1,100 RRMS patients equally randomized to either laquinimod 0.6mg daily or placebo. The BRAVO study has similar endpoints,and contains a comparative arm of more than 400 patients treated with weekly injections of interferonβ-1a (Avonex) in order to compare laquinimod to a currently available therapy. The results of these two studies are expected during 2011.
Data presented at the International Congress of the World Muscle Society suggested that the investigational new drug ataluren slowed the loss of walking ability in patients with nonsense mutation dystrophinopathy, a disease continuum comprising Duchenne and Becker muscular dystrophy. These results suggest that, for the first time, a therapy addressing the underlying cause of a disease can slow down a patient’s loss of walking ability. Jay Barth, MD, VP of Clinical Development at PTC Therapeutics, explains the findings further.
How should neurologists interpret the results of this
study? How do these findings compare with your earlier
studies and what do you feel was uncovered by this latest
We believe that this phase IIb clinical trial in nonsense mutation Duchenne/Becker muscular dystrophy (nmDMBD) was a landmark study. It was the first registration-directed trial in this disorder and was designed to evaluate ataluren's potential to treat the underlying cause of the disease. The phase IIb trial results showed that ataluren slowed the loss of walking ability in patients with nmDBMD. The primary endpoint was the change in 6-minute walk distance (6MWD) from baseline to 48 weeks. The data showed a 29.7 meter difference in the average change in 6MWD when comparing the low-dose ataluren (10-, 10-, 20-mg/kg TID) and placebo arms. This result is consistent with the study hypothesis of a 30-meter difference and is consistent with the average change in 6MWD observed in registration-directed trials of approved drugs for other diseases. The 6MWD results were further supported by positive trends in muscle function, as measured by timed function tests, in patients receiving ataluren (10-, 10-, 20-mg/kg) compared to those receiving placebo.
This trial also established an appropriate ataluren dose. While the 6MWD results showed a treatment effect at the low-dose of ataluren (10-, 10-, 20-mg/kg TID), there was no difference between a high-dose of ataluren (20-, 20-, 40-mg/kg TID) and placebo. The finding of improvement over placebo at the low dose but not at the high dose is consistent with nonclinical data which suggest a bell-shaped dose response curve.
Furthermore, the trial employed outcome measures that previously had not been used in a therapeutic trial in DBMD. The study demonstrated the feasibility and reliability of the 6-minute walk test as a measure of disease progression in patients with DBMD. However, variability in the change in 6MWD was greater than anticipated, indicating substantial heterogeneity in the rate of disease progression by the end of the 48-week study. These new data support understanding of the disease natural history and may assist researchers to optimally design and power future therapeutic trials in DBMD.
An evaluation of dystrophin protein expression was
included in this study as an exploratory endpoint; however,
due in part to technical limitations of the assay, no relationship could be established by 6MWD and dystrophin
expression. Could you talk a little about the theory
behind this possible relationship? Will it be explored
in any future studies?
An investigational new drug, ataluren is a protein restoration therapy designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation. A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein, such as the dystrophin protein in nmDBMD. Restoration of functional dystrophin protein may enable ataluren to address the underlying cause of nmDBMD and change the course of the disease.
The phase IIb trial was the first long-term, multinational, placebo-controlled study to evaluate muscle biopsies for dystrophin expression with the goal of correlating protein levels with clinical efficacy outcomes. The results showed that the analysis was compromised by the technical limitations of the method (such as low sensitivity), poor sample quality due to procedural complexity, and high variability in disease pathology. Due in part to these issues, no correlation between muscle dystrophin and 6MWD at baseline or in changes from baseline to Week 48 was observed.
Given available data from clinical trials of multiple investigational drugs, the international research community has recognized that current methods are inadequate to validate muscle dystrophin as a biomarker for drug response. PTC Therapeutics is supporting an effort led by TREAT-NMD and the Children's National Medical Center to identify, validate, and standardize a reliable and reproducible method for the analysis of muscle dystrophin in therapeutic clinical trials.
What is next? What is the timeline in terms of interactions
with the U.S. FDA?
Discussions with the U.S. Food and Drug Administration regarding the path forward for ataluren in nmDBMD are underway, and PTC Therapeutics expects to provide an update on the U.S. regulatory timeline in the first half of 2011.