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 Posted: Wed Mar 27, 2013 6:30 pm Post subject: MS research gears up for new drugs (MedPage Today) |
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From MedPage Today, March 26, 2013:
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MS Research Gears Up for New Drugs
By John Gever, Senior Editor, MedPage Today
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
SAN DIEGO -- A host of upcoming and recently approved multiple sclerosis drugs are on the horizon. Here's a look at four of them, plus a peek at an entirely novel treatment approach.
For physicians interested in the newest MS therapies, last week's meeting of the American Academy of Neurology offered a feast of well-funded research on investigational agents including alemtuzumab (Lemtrada), dimethyl fumarate (BG-12), ocrelizumab, and laquinimod.
Primary analyses of the pivotal studies for the investigational agents had all been reported previously, either in meeting presentations or in detailed announcements from the drugs' manufacturers. Presentations at the meeting therefore focused on longer-term efficacy and safety data.
One novel agent -- a monoclonal antibody against a human protein -- aims at testing a tantalizing MS disease hypothesis.
Herewith is a rundown.
Alemtuzumab
The highlight study of this drug focused on 3-year data on patients who participated in the drug's two open-label pivotal trials.
Alemtuzumab, for which an FDA approval decision is slated for this fall, has been closely watched in the MS field because it is administered in two courses 1 year apart, with additional dosing only if patients show significant clinical worsening.
One of the two phase III studies, CARE-MS I, had enrolled treatment-naive patients and the other, CARE-MS II, involved patients who were failing on other drugs for relapsing-remitting MS. In both studies, the comparator treatment was standard interferon-beta-1a (Rebif).
After completion of the 2-year randomized phases, patients initially receiving alemtuzumab who chose to remain in the extension study were monitored for relapse or new MRI lesion activity, in which case they could receive another course of therapy.
Edward Fox, MD, of Central Texas Neurology Consultants in Round Rock, Texas, told AAN attendees that nearly all patients completing the randomized phases agreed to enter the extension study. Patients in the original interferon arms had not yet completed the first year of post-treatment monitoring, so he reported extension results only for patients initially assigned to alemtuzumab.
Relapse rates in these patients during the first year of the extension -- that is, the second full year after their last alemtuzumab dose -- averaged 0.24 and 0.25 in the CARE-MS I and CARE-MS II alemtuzumab arms, respectively. Corresponding retreatment rates during the extension were 18% and 20%, Fox reported.
Autoimmune reactions have been the most serious adverse effects seen previously with alemtuzumab, and this was confirmed in the extension. Nearly 20% of patients developed autoimmune thyroid abnormalities during the extension, for a cumulative 3-year rate of 30%.
However, Fox told MedPage Today that the condition had been manageable, with patients receiving standard treatments for hyperthyroidism. He said his impression was that patients did not find it a severe burden, and it did not appear to compromise the drug's effectiveness against MS.
More serious conditions including autoimmune thrombocytopenia and nephropathy were much rarer, with cumulative 3-year incidence rates of 1.3% and 0.3%, respectively.
Fox said strict monitoring and patient education with respect to autoimmune effects would be critical to keeping alemtuzumab as a relatively safe treatment.
Dimethyl Fumarate
An oral drug, dimethyl fumarate has drawn attention because of very impressive reductions in relapse rates, MRI activity, and disability progression in its controlled phase III trials in relapsing-remitting MS.
In a platform presentation, Robert Fox, MD, of the Cleveland Clinic, reported on a secondary analysis of the two pivotal studies, dubbed DEFINE and CONFIRM, focusing on the time course of the drug's efficacy effect.
Given twice daily at 240 mg, dimethyl fumarate demonstrated a significant reduction in relapse rate relative to placebo within the first 10 weeks of treatment, Fox said.
Also, new and/or enlarging T2 lesions seen in MRI scans were lower by 72% within 24 weeks compared with placebo. This suppression of MRI disease activity was maintained through week 96 in the pooled data, with a reduction of 82% during treatment weeks 48 to 96.
Gadolinium-enhancing lesions were reduced even more -- by 88% during the first 24 weeks and by 83% from weeks 48 to 96, Fox reported.
The drug's safety and tolerability were addressed separately in a poster presentation by Fox and colleagues, who reported early results from an extension study called ENDORSE, in which participants in the pivotal studies who have chosen continued open-label treatment are being followed for up to 5 years.
In the poster report, nearly 1,600 patients had completed 6 months in the extension, with 1-year data on about 1,100. Some 40% of these had switched to dimethyl fumarate from placebo or open-label glatiramer acetate, which also served as a comparator in the pivotal studies.
Patients who had previously taken dimethyl fumarate in the randomized phases showed few adverse effects during the extension, although that was expected since patients with tolerability problems would have been less likely to continue with the drug.
Among patients who switched to dimethyl fumarate in the extension, a total of 15% discontinued because of adverse effects. Gastrointestinal complaints accounted for the bulk of these, with about one-quarter of discontinuations attributed to flushing or pruritus.
As in the controlled phases, mild elevations in liver enzymes were common, but rates higher than three times the upper limit of normal were seen only in about 6% of patients who switched to dimethyl fumarate. Renal events were seen in about 10% to 12% of all patients in the extension, including those who had taken the drug in the randomized phases.
Separately, dimethyl fumarate's developer, Biogen Idec, said last week that the drug had been endorsed by the European Union's Committee for Medicinal Products for Human Use, paving the way for final European approval. The firm expects the FDA to issue an approval decision within days. Biogen Idec has settled on Tecfidera as its brand name for the drug.
Ocrelizumab
This injectable biologic drug, which targets the same cell-surface protein on B cells as rituximab (Rituxan), was highlighted in a platform presentation by Stephen Hauser, MD, of the University of California San Francisco.
He reported 144-week results from a randomized phase II study in 218 patients with relapsing-remitting MS. The trial began with a 24-week phase in which patients were assigned to one of two ocrelizumab doses, placebo, or interferon-beta. Data from that phase were previously reported.
Patients in the two ocrelizumab arms continued, while those in the comparator groups switched to the lower, 600 mg/24 weeks ocrelizumab dose (the higher dose was 1,000 mg/24 weeks) through week 96. Treatment was then stopped and patients were followed off-drug for 48 more weeks.
Hauser reported that 168 patients of the original 218 remained in the study for the full 144 weeks, with six stopping during the treatment phase for insufficient response and eight because of adverse effects, including one death.
The trial's primary endpoint was the number of gadolinium-enhancing MRI lesions. From baseline mean levels of 1.5 to 4 in the four original treatment arms, these lesion counts were knocked down to near zero by week 12 in the two ocrelizumab arms and all the way to zero by week 48. They remained at zero through week 120 before rebounding to a mean of about 0.3 at the final MRI scan.
Adjusted annualized relapse rates during weeks 96-144 were 0.116 in the original placebo group, 0.082 in the original low-dose ocrelizumab group, 0.352 in the original high-dose group, and 0.076 in the original interferon group.
The lone death in the study involved a patient who developed a systemic inflammatory response syndrome at week 12 and died 2 weeks later.
Other serious adverse events -- a total of 27 during treatment and seven during post-treatment follow-up -- included infections, two cases of seizure, inflammatory episodes in various organs, and two cases of suicidal ideation or attempt.
None of the infections involved opportunistic pathogens, and the overall safety profile was consistent with earlier reports, Hauser said.
Three phase III trials are now under way with results expected late in 2015, he said.
Laquinimod
As in the trials for the other drugs, patients in a phase III trial of laquinimod -- an orally active immune modulator -- were invited to continue in an open-label extension. Results from the first year were reported by Giancarlo Comi, MD, of the University Vita-Salute San Raffaele in Milan, Italy.
In the randomized, placebo-controlled phase of the so-called ALLEGRO study, patients receiving the drug showed a modest but statistically significant 23% reduction in annualized relapse rates and a 36% reduction in disability progression, Comi noted.
In the extension, primary endpoints were safety and disability progression in patients continuing on laquinimod versus those switching to the drug from placebo.
Of the 864 patients completing the 2-year randomized phase (about 80% of the original enrollment), all but 25 agreed to participate in the extension, planned to last for 18 months.
Cumulative 3-year relapse rates were higher for patients in the original placebo group compared with those randomized to laquinimod, Comi reported. But annualized relapse rates in the former placebo patients during the first year of the extension were similar to those seen in the laquinimod group during their second year on therapy (0.23 versus 0.24, respectively).
Rates of disability progression were also similar in the two groups during the extension. In the patients who remained on the drug for the full 3 years, just under 15% had confirmed 6-month disability progression by the end of year three, Comi said.
Adverse events were less frequent in the extension than in the randomized phase, even among those patients switching from placebo. The most common events were headache, back pain, urinary tract infection, diarrhea, cough, abdominal pain, and liver enzyme elevations.
Most such events were mild. During the extension, about 1.5% of patients showed liver enzyme levels more than three times the upper limit of normal.
Five deaths occurred in the study, including two in the extension phase. Two were suicides; the others were an acute coronary event, a train accident, and complications from pneumonia.
Overall, Comi said, the safety profile seen in earlier studies was confirmed in the extension, with many types of events becoming less common over time with continued treatment.
An Entirely Novel Approach
Another drug study reported here could revolutionize thinking about MS altogether if the agent proves to be beneficial in larger trials.
GeNeuro in Geneva, Switzerland, has developed a monoclonal antibody against a human protein apparently expressed from what used to be called "junk DNA" in the human genome.
Addressing attendees at the AAN meeting, the company's CEO, François Curtin, MD, MPhil, MBA, noted that about 8% of the human genome is believed to be "human endogenous retrovirus" (HERV) sequences -- in effect, fossilized remnants of retroviruses that once infected human ancestors.
Most HERV sequences are incapable of expression, but "some elements are active," Curtin said.
One such element produces a protein, he said, that appears to be a viral envelope protein and that has been associated with MS. It has been dubbed MSRV-Env and has been found on the surface of monocytes and microglia known to be active in the disease, as well as within brain lesions visualized in MRI scans.
Curtin said that infections by other current viruses such as Epstein-Barr virus -- which has also been linked with MS -- may trigger expression of MSRV-Env. Lab studies have shown that the protein is capable of triggering cellular events consistent with MS pathology such as cytokine release, inhibition of nerve myelination, and expression of intercellular adhesion molecules at the blood-brain barrier.
His firm has developed a monoclonal antibody targeting this protein, and Curtin reported early results from a phase IIa clinical study.
So far, 10 patients have been dosed with the agent, he said. Single doses at 2 or 6 mg/kg have been administered to five patients each.
In the low-dose group, four showed no change in MRI lesions 4 weeks after dosing compared with baseline, with one patient showing a decrease. One patient with primary progressive MS had a "decrease of inflammation," Curtin said.
Only four patients in the high-dose group had their 4-week MRI scans when Curtin finalized his presentation, with all four showing stable lesions.
A total of 16 adverse events were noted in the 10 patients, ranging from neurological symptoms such as tremor and limb spasticity to bradycardia, tachycardia, and bladder infection.
Patients in the trial are now receiving additional doses and the firm expects to have final 6-month results from the study in September.
Session co-moderator Anthony Reder, MD, of the University of Chicago, commented that numerous viral theories of MS have been suggested but proof has been elusive.
Nevertheless, he said, the effectiveness of interferon-beta as an MS treatment is a hint that something viral is involved in the disease. Interferons are a leading component of antiviral host-defense mechanisms in humans and many other organisms, and are actually thought to predate the dinosaurs.
Thus, Reder suggested, the notion that a fossilized retrovirus could play a role in MS is not far-fetched.
On the other hand, Edward Fox told MedPage Today that he has seen too many novel theories of MS fail in clinical-trial tests to get excited about MSRV-Env at this point.
________________________________________
All the studies were supported by the individual drugs' manufacturers including Genzyme/Sanofi, Biogen Idec, Genentech/Roche, Teva, and GeNeuro.
Edward Fox reported relationships with Bayer, Biogen Idec, EMD Serono, Genzyme, Novartis, Opexa Therapeutics, Teva, Eli Lilly, GlaxoSmithKline, Novartis, Ono Pharmaceutical, Roche Diagnostics, and Sanofi.
Robert Fox reported relationships with Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva.
Hauser reported relationships with BioMarin and Receptos.
Comi reported relationships with Novartis, Teva, Sanofi, Genzyme, Merck Serono, Biogen, Actelion, Almirall, Roche, and Bayer.
Curtin is an employee of GeNeuro.
______________________________
Primary source: American Academy of Neurology
Source reference:
Fox E, et al "Durable efficacy of alemtuzumab in relapsing-remitting multiple sclerosis patients who participated in the CARE-MS studies: Three year follow-up" AAN 2013; Abstract S41.001.
Additional source: American Academy of Neurology
Source reference:
Kappos L, et al "Timecourse of treatment effects of BG-12 (dimethyl fumarate) for relapsing–remitting multiple sclerosis" AAN 2013; Abstract S41.005.
Additional source: American Academy of Neurology
Source reference:
Hauser S, et al "Week 144 results of a phase II, randomized, multicenter trial assessing the safety and efficacy of ocrelizumab in patients with relapsing–remitting multiple sclerosis (RRMS)" AAN 2013; Abstract S31.004.
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