BEYOND and PRECISE Results Suggest Equivalence for Multiple Sclerosis Treatments
April 17, 2008 (Chicago, Illinois) — Final results of the largest multiple sclerosis (MS) trial to date suggest that, in terms of clinical effects, treatment with both 250- and 500-µg doses of interferon beta-1b (Betaferon/Betaseron, Bayer Healthcare Pharmaceuticals) as well as glatiramer acetate (Copaxone, Teva Pharmaceutical Industries) were essentially equivalent in the risk of relapse in patients with relapsing-remitting MS.
Although there was some indication of reduced T2-lesion volume and number with interferon beta-1b, the researchers note, the long-term significance of this difference is unclear.
In a separate presentation, researchers reported full results of a randomized trial of glatiramer acetate vs placebo to prevent conversion to clinically definite MS in patients with clinically isolated syndromes (CIS). They report that fewer patients converted to clinically definite MS with treatment and those who did took longer to do so.
The full results of these studies, the Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose (BEYOND) and PRECISE trials, were presented here at the American Academy of Neurology 60th Annual Meeting. Top-line results from the studies, both company-sponsored trials, were previously announced by the companies in October and December of 2007, respectively.
The BEYOND trial compared the efficacy of 2 doses of interferon beta-1b, 250 and 500 µg, given subcutaneously every other day, with glatiramer acetate in patients with relapsing-remitting MS. This trial was funded by Bayer Schering Pharma AG, Berlin, Germany.
"The hypothesis was that the double dose of Betaseron would be more efficacious than the single dose, 500 µg better than 250 µg, in terms of efficacy, with comparable safety and tolerability," Paul O'Connor, MD, from the University of Toronto and St. Michael's Hospital, in Ontario, told Medscape Neurology & Neurosurgery. The 250-µg dose is currently approved in this indication.
A secondary hypothesis was to compare interferon beta-1b in these 2 doses with glatiramer acetate in terms of efficacy, safety, and tolerability, he said.
Patients eligible for the trial were relapsing-remitting MS patients with Expanded Disability Status Scale (EDSS) scores of 5.0 or less and 1 or more relapses in the year prior to study entry; all were treatment naive. A total of 2244 patients were randomized in a 2:2:1 ratio to the 500-µg dose (n=899), to the 250-µg dose (n=899), or to glatiramer acetate in a dose of 20 mg daily (n=448), also given subcutaneously for > 104 weeks. The average time of follow-up in the trial was about 2.3 years, Dr. O'Connor noted. Patients were evaluated clinically every 3 months and received a magnetic resonance imaging (MRI) scan every 12 months.
The primary end point was relapse risk. Results for this end point, he said, "showed that the performance of all 3 drugs was the same in terms of recurrent relapses, whether you did an intent-to-treat analysis or a per-protocol analysis."
The annualized relapse rate (ARR), a supportive end point, fell by almost 80% compared with the year prior to study entry, but without any intergroup differences, the authors note.
Other secondary end points, including time to confirmed disability and progression or change in "black-hole" volume on MRI, again showed no differences between groups, Dr. O'Connor added.
Some MRI end points did show differences favoring the interferon beta-1b treatment, he noted. The cumulative number of T2 lesions up to the last scan was greater with glatiramer acetate than with either the 500-µg dose (P = .001) or the 250-µg dose (P = .017) of interferon beta-1b. The relative increase in T2-lesion volume was also larger in patients on glatiramer acetate than in the 500-µg (P = .001) or the 250-µg groups (P < .001).
However, the authors write, the longer-term significance of these changes, "if any," is "unclear."
Dropout rates were highest in the high-dose interferon beta-1b group, at 19%; lowest with the lower dose, at 13%; and intermediate, at 17%, with glatiramer acetate. Adverse events were similar to the known profiles of these drugs — notably, flulike symptoms were more common with interferon beta-1b, and injection-site reactions including pain and pruritus were more common with glatiramer acetate.
Beyond the minor MRI differences and slightly different profile of adverse events, Dr. O'Connor noted, "the major message is really the similarity in behavior on efficacy measures of the 2 drugs.
"What this does is that it allows the patient and the doctor to decide more on the basis of items such as how often do you want to get injected or what matters more to you, a flulike symptom vs some soreness where you were injected?" he concluded. "In other words, you can choose on the basis of adverse events as differentiating features."
In a separate presentation here, Giancarlo Comi, MD, from Vita-Salute San Raffaele University, in Milan, Italy, presented final results of the PRECISE trial, which examined the efficacy of early treatment with glatiramer acetate vs placebo in delaying the progression to clinically definite MS among patients with clinically isolated syndromes, a first event suggestive of MS. The study was supported by Teva Pharmaceutical Industries.
The trial, a randomized, controlled, multicenter study, randomized 481 patients with a first clinical event and at least 2 T2-weighted brain lesions at least 6 mm in size on MRI to receive 20 mg/day of glatiramer acetate given subcutaneously or placebo.
The primary end point was time to clinically definite MS based on a second clinical attack. A preplanned interim analysis was performed on data accumulated from approximately 80% of the 3-year study exposure. At that point, the data safety monitoring board, chaired by Dr. O'Connor, who presented the BEYOND results, recommended that the double-blind phase of the trial be stopped for efficacy of treatment with glatiramer acetate, and all patients moved onto active treatment.
Results of this interim analysis showed that treatment reduced the risk of developing clinically definite MS by 45% vs placebo: the 25th percentile time to clinically definite MS was prolonged by 115%, to 722 days with treatment from 336 days for placebo.
PRECISE Primary End Point
|End Point||Hazard Ratio||95% CI||P|
|Time to clinically definite MS||0.55||0.40 – 0.77||.0005|
The proportion of patients who converted to clinically definite MS was reduced from 43% of the placebo group to 25% in the treatment group (P < .0001). MRI activity, including the number of enhancing lesions and the number of new T2 lesions, was significantly lower in the glatiramer-acetate group, he added.
"So there are 2 advantages to treatment," Dr. Comi told Medscape Neurology & Neurosurgery. "About half of the patients didn't have a second attack, and those who had the attack had it about 1 year later compared with the others in a 2-year study. So it's a tremendous effect."
The drug was well tolerated, with adverse effects similar to those already known for this drug, with a 16% withdrawal rate at the interim analysis.
The Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) study, whose 3-year results were reported last year at this meeting and subsequently published (Kappos L et al. Lancet. 2007;370:389-397), showed a benefit from early treatment with interferon beta-1b in this same patient population, Dr. Comi noted. "Now we have a second drug with the same effect in this very early phase."
The patients will continue to be followed per the original protocol out to 5 years, he added. "It will be very interesting to see whether this very early beneficial effect will also lead to advantages in the mid and long term, and this 5-year extension will tell us something about that."
A Choice for Treatment
"There are 2 messages for me" from the combined results of these and the previously published BENEFIT trials, Dr. Comi, who was also a member of the steering committee for the BEYOND trial, told Medscape Neurology & Neurosurgery.
"One is that interferon beta and glatiramer acetate are both doing a very good job," he said. "Of course, some people do better with one, some with the other, and now if you fail with one, you can just try the other, and vice versa."
In addition, both agents have now been shown effective from the beginning of the disease, after first signs, to the end of the relapsing-remitting phase, he noted.
Asked for comment on the PRECISE findings, Mark Keegan, MD, from the Mayo Clinic in Rochester, MN, called the result "important, as it shows that glatiramer acetate has a effect in reducing the likelihood of a second attack that is similar to the beta interferons, and it could be recommended in select patients with this presentation."
Similarly, results from the BEYOND study, showing no benefit of implementing a higher dose of interferon beta-1b over the traditional dose of 250 µg. "It also did not show any significant difference in attacks or progression between either dose of interferon beta-1b and glatiramer acetate," Dr. Keegan noted. "The important features are that those patients currently on the traditional dose of interferon beta-1b or glatiramer acetate should not need to alter treatments if they are doing well on their current therapy."
Dr. O'Connor has received compensation for activities with Biogen Idec, Cognosci, Serono, Teva, Berlex Labs, Genentech, Genzyme, Novartis, Roche and Sanofi-Aventis as a consultant. Disclosures for coauthors on the BEYOND trial appear in the abstract. Dr. Comi reports he has received personal compensation for activities with Teva Pharmaceutical Industries, Merck Serono, Bayer-Schering as a consultant and member of the scientific advisory board; Novartis as a consultant; and Sanofi-Aventis and Biogen-Dompé as a consultant and speaker. Disclosures for coauthors on the PRECISE study appear in the abstract. Dr. Keegan reports no conflict of interest.
American Academy of Neurology 60th Annual Meeting: Abstracts LBS.003, LBS.004. Presented April 16, 2008.
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