Promising Developments Suggest New Directions in MS Therapy and Research

The past several weeks have witnessed many promising developments in the field of MS, from data presented at the recent Joint Trienniel Congress of the European Committee for Treatment and Research in MS and the Americas Committee for Treatment and Research in MS (ECTRIMS/ACTRIMS), to recent FDA submissions. Here's a round-up of some pertinent news.

Copaxone Demonstrates Neuroprotection in MS

Preclinical data demonstrate reparative and neuroprotective effects of treatment with Copaxone (glatiramer acetate injection, Teva Pharmaceutical) in experimental autoimmune encephalomyelitis (EAE) models. The findings, reported by Teva and presented at ECTRIMS/ACTRIMS, will be published in the Journal of Autoimmunity.

For their study, researchers compared mice treated with glatiramer acetate injection against non-treated mice in relapsing-remitting and chronic multiple sclerosis disease models. Researchers observed both remyelination indicative of repair and a drastic reduction of demyelination and axonal loss in mice treated with glatiramer acetate injection.

A second preclinical study demonstrated that a signaling pathway for glatiramer acetate injection deactivated macrophages that induce inflammation and autoimmune response.

In the study evaluating potential neuroprotective effects of glatiramer acetate injection, the in situ pathological manifestations of two different EAE models, the relapsing-remitting PLP-induced and the chronic MOG-induced diseases were analyzed and compared, utilizing both transmission electron microscopy (TEM) and immunohistochemistry. Of note, researchers noted differences in types of degeneration experienced by mice with the different EAE models. Those with chronic disease demonstrated degeneration of axons, while those with relapsing-remitting disease demonstrated demyelination, points out lead author Rina Aharoni, Senior Staff Scientist, Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel. These findings in mice support speculation regarding two distinct disease processes in human chronic MS compared to replapsing remitting MS.

The effect of glatiramer acetate injection on myelin damage/repair and on motor neuron loss/preservation was studied in both models. Quantitative TEM analysis of the relative remyelination extent compared to demyelination provides the first evidence of significant augmentation of remyelination after treatment with glatiramer acetate injection, explains Dr. Aharoni. Loss of motor neuron was also reduced in mice treated with glatiramer acetate, in comparison to that of EAE untreated mice. These effects were obtained even when glatiramer acetate treatment was applied in a therapeutic schedule, after the appearance of clinical symptoms.

Another significant finding, according to Dr. Aharaoni, is that mice who received treatment after a first “episode” of symptoms had a seven-fold higher rate or remyelination relative to controls, while those treated after a second episode had only a three-fold higher rate of remyelination relative to controls. These findings support the importance of initiating MS therapy as early in the disease course as possible.

Ocrelizumab Reduces MS Disease Activity

A Phase II study of ocrelizumab showed a significant reduction in disease activity in patients with relapsing-remitting multiple sclerosis. The reduction, measured by the total number of active brain lesions and relapses previously reported for 24 weeks, was maintained through 96 weeks, the study's endpoint.

Presented at ECTRIMS/ACTRIMS, results from the trial showed that during the 24-96 week treatment period no patient who received a dose of 600mg ocrelizumab developed a new or enlarging brain lesion as measured by MRI. The annualized relapse rate (ARR), the rate of clinical attacks or flare-ups per patient-year, was less than 0.2 attacks per patient per year across the 96-week period. The data also showed that, of the patients who completed the study, two-thirds of the patients in the 600mg group were free of any disease activity (as measured by MRI, relapses or neurological progression) over the 96-week treatment period.

The safety profile over the 96 weeks of the study, developer Roche reports, was consistent with that demonstrated in the earlier 24-week data. No opportunistic infections were reported, and the rate of infections (and serious infections) did not increase over the treatment period. Serious infection rates were similar for ocrelizumab 600mg (1.97 events/100 patient/years) and ocrelizumab 1000 mg (1.93 events/100 patient/years) and did not increase with time on ocrelizumab treatment.

The ocrelizumab Phase III clinical program (Orchestra), consists of two studies in patients with relapsing-remitting multiple sclerosis (Opera I and II) and one study in patients with primary progressive multiple sclerosis (Oratorio). The program has started enrolling patients.

Alemtuzumab Phase III Promising

New data from the CARE-MS I trial presented at ECTRIMS/ACTRIMS show that 78 percent of patients treated with alemtuzumab remained relapse-free for two years, providing statistically significant improvement over interferon beta-1a (78 percent vs 59 percent at two years, p<0.0001) and meeting this secondary endpoint. CARE-MS 1 is the first of two randomized, Phase III clinical trials comparing the investigational drug alemtuzumab (Lemtrada, Genzyme) to high dose subcutaneous interferon beta-1a (Rebif) in patients with relapsingremitting multiple sclerosis.

As has been previously reported, treatment with alemtuzumab resulted in a 55 percent reduction in relapse rate compared to interferon beta-1a over two years of study (p<0.0001), satisfying this co-primary endpoint and meeting the predefined protocol criteria for declaring the study a success, according to a release from Genzyme. “At the two-year time point, very few alemtuzumab patients (eight percent) experienced a sustained increase, or worsening, in disability as measured by the Expanded Disability Status Scale (EDSS) (vs 11 percent of patients in the interferon beta-1a group).” However, the difference between groups for this co-primary endpoint was not statistically significant (p=0.22) and there was no difference in the mean EDSS score between groups.

The CARE-MS I trial compared treatment with alemtuzumab (12mg/day by IV administration for five-days, with a second three-day IV administration one year later), to treatment with subcutaneous interferon beta-1a (44 mcg administered by injection three times per week) in 581 patients with relapsing-remitting MS who had received no previous treatment to suppress MS, except for steroids.

Genzyme is developing alemtuzumab for relapsing MS in collaboration with Bayer HealthCare.

Survey Highlights Walking Difficulties in MS

A majority of patients with MS report trouble with walking or balance, and many say problems began before they received their diagnosis. Results of a Harris Interactive survey (co-sponsored by the National MS Society and Acorda Therapeutics), presented at ECTRIMS/ACTRIMS and reported by Acorda Therapeutics, show:

  • People with MS who have trouble walking report that they fall three times every six months on average.
  • 16% have been told by a doctor to use an assistive walking device but have opted not to do so.
  • 40% of people with walking difficulty "rarely or never" discuss the problem with their doctor.
  • 78% of women and 62% of men report that trouble walking "makes getting around dangerous."
  • 61% of people with MS report that MS has interfered with their ability to work, causing them to lose personal income.
  • 32% say that MS makes them feel isolated.

FDA Reviewing Teriflunomide

FDA agreed to evaluate Aubagio (teriflunomide), Sanofi's drug candidate for the treatment of relapsing forms of multiple sclerosis. Sanofi relayed the message when it presented data on the drug at the ECTRIMS/ACTRIMS meeting. Earlier results from the TEMSO Phase III trials showed that teriflunomide significantly reduced the risk of annual relapses, the primary endpoint, by 31 percent for 7mg and 14mg doses.

New post-hoc analyses showed that teriflunomidetreated patients' annualized rate of relapses leading to hospitalization was significantly reduced by 36 percent with 7mg and by 59 percent with 14mg compared with placebo. The risk of hospitalization per relapse was also significantly reduced by 43 percent for the 14mg dose and numerically reduced by six percent for the 7mg dose. These analyses also showed teriflunomide significantly reduced the annualized rate of emergency medical facility visits (a visit to a medical facility/hospital for emergency care not resulting in an admission) by 42 percent for the 14mg dose and numerically reduced by 31 percent for the 7mg dose vs. placebo.

Sanofi said it expects to submit the drug for EU approval during the first quarter and would provide competition to Novartis' pill Gilenya.

Positive Early PEG-interferon

AZ01, a clinical stage, PEGylated form of human interferon beta-1b for the treatment of relapsingremitting multiple sclerosis, showed positive initial results from its multiple ascending dose (MAD) Phase Ib trial, according to Allozyne. The company say the results demonstrate AZ01's potential for monthly dosing.

The MAD study was conducted as a doubleblind, placebo controlled study and designed to establish the safety, tolerability, pharmacokinetic and pharmacodynamic profile of AZ01 in normal healthy volunteers. Patients on different doses of AZ01 were examined at either 14- or 28-day dosing intervals. Data from the MAD study indicate that AZ01 has a comparable half-life after each administration and the half-life is two to three times longer than other PEGylated interferon beta therapeutics known currently to be in clinical development. In addition to establishing a pharmacokinetic profile, neopterin levels were measured as a pharmacodynamic biomarker for interferon activity. The data indicate a neopterin response that is greater in duration than the PK response thereby suggesting a prolonged biological effect of interferon beta. Overall AZ01 has been well tolerated and subjects dosed experienced typical symptoms associated with interferon beta treatment, most resolving within 24 hours.

The company believes a monthly treatment may increase patient compliance, possibly leading to greater efficacy, as well as decrease of flu like symptoms and injection site reactions compared to existing interferon beta therapies.

Biogen Presents Data on New, Existing Therapies

Efficacy and safety data from a Phase III trial of dimethyl fumarate (BG12, Biogen) showed a low rate of relapses—27 percent for fumarate BID and 26 percent fumarate TID—versus placebo (46 percent). Efficacy was supported by low rates of new gadolinium-enhancing lesions or new or newly enlarging lesions. Annualized relapse rates were 0.384 for placebo, 0.172 for fumarate BID, and 0.189 for fumarate TID.

For greatest clinical benefit, patients to be treated with natalizumab (Tysabri) should initiate therapy early in the disaes course, data show. Key data from multiple posters indicated reduced annualized relapse rates (ARR) associated with anatlziumab, particularly in those treated early in the course of their disease. Data also indicated a long-term benefit for patients who had achieved freedom from disease activity early in their treatment course. Natalizumab-treated patients experienced improved incontinence-related quality of life (QOL).

MS Atrium Launches on Web

MS Atrium (MSAtrium.com), an unbranded physician and patient resource sponsored by Genzyme, has launched. The site is designed to be truly interactive and will be constantly updated for healthcare providers and also patients. There's an MS Alerts App available, an area for educational presentations, and opportunities for interaction among members of the MS community.

OnabotulinumtoxinA Reduces Headache Impact

Treating chronic migraine with onabotulinumtoxinA is associated with significant and clinically meaningful reductions in headache impact and improvements in HRQoL, a study published in the Oct. 11 issue of Neurology finds. The findings were pooled from the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program (PREEMPT 1 and 2) included a 24-week, double-blind phase (two 12-week cycles) followed by a 32-week, open-label phase (three cycles).

A total of 1,384 subjects were included in the pooled analyses (688 received onabotulinumtoxinA; 696 received placebo). Baseline mean total Headache Impact Test-6 and Migraine-Specific Quality of Life Questionnaire v2.1 scores were comparable between groups; 93.1 percent were severely impacted based on HIT-6 scores ≥60. At 24 weeks, in comparison with placebo, onabotulinumtoxinA treatment significantly reduced HIT-6 scores and the proportion of patients with HIT-6 scores in the severe range at all timepoints including week 24 (p < 0.001). OnabotulinumtoxinA treatment significantly improved all domains of the MSQ v2.1 at 24 weeks (p < 0.001).

Phase II/III Trial of Davunetide Set

Allon Therapeutics has successfully achieved the enrollment objective of 300 patients in the Phase II/III clinical trial evaluating the company's lead neuroprotective drug candidate davunetide as a potential treatment for progressive supranuclear palsy.

The trial is being conducted under a Special Protocol Assessment (SPA) with the FDA, which ensures that the agreed clinical trial design meets the FDA's expectations for a pivotal study. Allon has obtained Orphan Drug and Fast Track Status in the US and Orphan Status in the EU. This pivotal trial is based upon statistically significant efficacy demonstrated in patients with amnestic mild cognitive impairment and cognitive impairment associated with schizophrenia. For more details, the clinicaltrials. gov identifying number is NCT01110720.

Positive Xeomin Data Presented, Cost Cut

Five studies on Xeomin (incobotulinumtoxinA), a botulinum neurotoxin type A preparation free from accessory proteins, were presented at the 72nd Annual Assembly of the American Academy of Physical Medicine and Rehabilitation. Highlights include:

"Sustained efficacy of incobotulinumtoxinA […] in cervical dystonia demonstrated by investigator and patient-rated outcomes." The poster assessed the long-term efficacy and tolerability of Xeomin in cervical dystonia in a setting similar to clinical practice. The prospective, multicenter, open-label single-arm Phase IV study found that Xeomin showed sustained efficacy and was well tolerated in the treatment of cervical dystonia for up to 121 weeks. [Poster 130; Dressler, et al.]

"Significant and sustained efficacy of incobotulinumtoxinA […] in upper limb spasticity." This poster included two studies. The first consisted of a randomized, double-blind, placebo-controlled main period and an open-label extension period and evaluated patients with upper limb (UL) post-stroke spasticity. The second was a randomized study of two dilutions of incobotulinumtoxinA that assessed patients with UL spasticity of various etiologies. Study results showed that incobotulinumtoxinA was well tolerated and demonstrated significant, sustained efficacy in UL spasticity. [Poster 138; Kanovsky, et al.]

Also recently presented were findings from a Phase III trial that demonstrate that incobotulinumtoxinA led to clinically relevant reductions in the severity of symptoms, such as excessive blinking and eyelid spasms, among patients with blepharospasm who were previously treated with onabotulinumtoxinA. These findings, as well as data confirming a favorable adverse event profile in single- and repeat-treatment trials, were presented at the 115th Annual Meeting of the American Association of Ophthalmology (AAO). [Posters 0440, 0441]

Merz Pharmaceuticals also announced they have lowered the price of Xeomin by nearly 20 percent. The 100-unit vial size now has a list price of $425 while the 50-unit vial size goes for $212.50.

CNS Disorder Market Expected to Grow

A new report from MarketResearch.com says the Central Nervous System disorders therapeutics market will grow to $59 billion in 2017, up from $53.1 billion in 2010 and $36.8 billion in 2002.

The market is expected to witness fluctuations as a result of patent expiries followed by generic erosion and it will experience slow growth at a Compound Annual Growth Rate* of 1.4% between 2010 and 2017, reaching $58.6 billion, the report says. The analysis attributes growth in the CNS market to rising worldwide geriatric populatios, increased life expectancy, and the anticipated launch of novel molecules. The authors believe the market for Alzheimer's disease and multiple sclerosis will witness a significant growth, as the result of introduction of new chemical entities, several of which show disease modifying characteristic and novel mechanisms of action in current studies.

The report covers the overall global CNS disorder therapeutics market for the eleven indications including: Alzheimer's disease, multiple sclerosis, Parkinson's disease, diabetic neuropathy, major depressive disorder (MDD), bipolar disorder, schizophrenia insomnia, epilepsy, attention deficit hyperactivity disorder (ADHD), and migraine in the leading geographies of the world: the US, the UK, Germany, France, Italy, Spain, and Japan.

* This is the year-over-year growth rate of an investment over a specified period of time. The compound annual growth rate is computed by taking the nth root of the total percentage growth rate, where n is the number of years in the period being considered.

Gilenya Reimbursement Rejected

The oral disease-modifying MS therapy Gilenya (fingolimod, Novartis) is not recommended for NHS reimbursement for certain patients with multiple sclerosis despite Novartis offering a discount, according to a ruling by The National Institute for Health and Clinical Excellence (NICE) in the UK. Previously this year, the agency provisionally rejected the treatment for use in patients with highly active relapsing-remitting MS. The agency's appraisal committee suggested that Gilenya would not be a cost-effective option when "compared with treatments currently offered to people with highly active [relapsing-remitting] MS, such as beta interferons." A final guidance is expected in April.

Epilepsy Surgery Called A Good Option

Neurosurgical treatment is “appealing” for selected people with refractory focal epilepsy, according to a study published in the Oct. 15 issue of The Lancet.

The study reports the long-term outcome of surgery for epilepsy in 615 adults (497 anterior temporal resections, 40 temporal lesionectomies, 40 extratemporal lesionectomies, 20 extratemporal resections, 11 hemispherectomies, and seven palliative procedures [corpus callosotomy, subpial transection]). The prospective annual follow-up for a median was eight years (range one—19). Researchers used Kaplan-Meier survival analysis to estimate time to first seizure, and investigated patterns of seizure outcome.

Researchers used survival methods to estimate that 52 percent (95% CI 48—56) of patients remained seizure free (apart from simple partial seizures [SPS]) at five years after surgery, and 47 percent (42—51) at 10 years. Patients who had extratemporal resections were more likely to have seizure recurrence than were those who had anterior temporal resections. Those who had lesionectomies saw no difference from anterior lobe resection. Those with SPS in the first two years after temporal lobe surgery had a greater chance of subsequent seizures with impaired awareness than did those with no SPS.

Relapse was less likely the longer a person was seizure free and, conversely, remission was less likely the longer seizures continued, the authors write. In 18 (19 percent) of 93 people, late remission was associated with introduction of a previously untried antiepileptic drug. A total of 104 of 365 (28 percent) seizure-free individuals had discontinued drugs at latest follow-up.

Guided Ultrasound Promising for Essential Tremor

Preliminary results of a pilot clinical trial indicate that MR-guided focused ultrasound could safely and effectively control essential tremor (ET). The first 10 patients treated in the study showed a 78 percent improvement in contralateral tremor scores in the hand, as assessed with the Clinical Rating Scale for Tremor (CRST). Functional activities scores improved by 92 percent, as measured in the ‘Disability' subsection of the CRST. Outcomes and complications were comparable to other procedures for tremor, including stereotactic thalamotomy and deep brain stimulation.

Findings were presented by W. Jeffrey Elias, MD at the Congress of Neurological Surgeons this fall. The study uses an investigational technology (ExAblate Neuro, InSightec, Ltd.), which employs MRI to guide and monitor the delivery of focused ultrasound to tremor-causing nerve cells in the thalamus. The single-arm, non-randomized, Phase I study began in February 2011 and is expected to treat 15 patients before concluding. All patients are being followed for three months.

Lazanda Now in Pharmacies

Lazanda (fentanyl, Archimedes Pharma) nasal spray is now available by prescription in US pharmacies. Lazanda is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. FDA approved Lazanda, the first fentanyl nasal spray in the US, in June. It is available through a REMS program intended to minimize the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors.