Serono SA and Biogen Inc. continued to lob fire at each other in their battle to prove superiority in the multiple sclerosis drug space.
Geneva-based Serono reported at the Consortium of Multiple Sclerosis Centers meeting that its Rebif (interferon beta-1a) was more effective in reducing the frequency of relapses over the course of a 63-week study when compared to Biogen's Avonex (interferon beta-1a). Cambridge, Mass.-based Biogen fired back at the San Diego gathering with long-term findings - eight years of data - showing that its lower-dose drug produced lower levels of neutralizing antibodies.
Serono's data stem from the EVIDENCE trial, a 677-patient study that compared the proportion of relapsing, remitting MS patients who were relapse-free after 24 weeks (primary endpoint) and 48 weeks. About 90 percent of patients continued for an average of 63 weeks and were treated with either high-dose Rebif or low-dose Avonex.
At that point, 56 percent of Rebif patients remained relapse-free vs. 48 percent of Avonex patients (p=0.023). Serono said Rebif patients had a 17 percent relative increase in the risk to remain relapse-free compared to Avonex patients, adding that other measures such as overall relapse rate, time to first relapse and steroid use for relapses were also significantly better in Rebif patients than Avonex patients.
Hillel Panitch, a clinical researcher from the University of Vermont College of Medicine who presented the data, called the findings significant in demonstrating that findings from the original trial remained evident for a longer period.
"Rebif continues to prevent relapses and reduce MRI activity, and it does that more effectively than Avonex," he told BioWorld Today. Data showed that Rebif treatment reduced the number of brain lesions shown in magnetic resonance imaging, although Serono acknowledged that an exact relationship between MRI findings and clinical outcomes for patients remains unknown. But Panitch called the prevention of new lesions found on MRI a major therapeutic objective.
Deborah Brown, Serono's executive vice president of neurology, also pointed to the longer-term corroboration of the original results.
"At 16 months, this study comparing ourselves to Avonex is actually longer than the pivotal study for Avonex, for the patients who finished 15 months," she told BioWorld Today. "I think that resonates with physicians."
But according to Jennifer Chao, an analyst with RBC Capital Markets in New York, the relative benefit of Rebif treatment declined over the 63-week period. She said Rebif's benefit declined from 32 percent at the 24-week mark to 21 percent at 48 weeks and 15 percent at 63 weeks. RBC makes a market in Biogen's securities.
"The current controversy has really centered on whether the use of high-dose interferon potentially leads to long-term benefit with respect to reduction in relapse rate and brain lesions," Chao told BioWorld Today. "The dilemma is this: We don't have long-term data for Rebif, and the potential risk with high-dose interferon is the development of neutralizing antibodies."
The incidence of neutralizing antibodies seen with Rebif is about 24 percent, compared to Avonex's 5 percent incidence.
"The effect of neutralizing antibodies also is unclear, but it's believed by specialists to play a role in causing patients to eventually become nonresponsive to interferon therapy over time," Chao added, noting that such an outcome could compromise patients' use of the three interferon treatments on the market. That leaves only one other treatment alternative - Copaxone (glatiramer acetate, from Teva Pharmaceutical Industries Ltd.).
Chao said the FDA asked the interferon product makers to conduct additional studies focused on the long-term role of neutralizing antibodies in treatment. But Serono's investigator downplayed the concerns.
"The fact is that there is a higher incidence of neutralizing antibodies, but as people will see when I present this study, the occurrence of neutralizing antibodies did not have an impact on the clinical outcome and a minor impact on the MRI outcome," Panitch said. "In fact, patients with neutralizing antibodies who were on Rebif still did better than the patients taking Avonex, who by in large did not develop neutralizing antibodies."
Biogen's long-term data were culled from 224 patients who were treated for about six years, with 86 treated for up to eight years. Results showed that adverse events generally were consistent with prior trials of Avonex, with only 2 percent discontinuing treatment due to adverse events. Last week the FDA approved a prefilled syringe of Avonex for once-weekly dosing.
"Our data shows long-term results, and MS is a long-term disease," Amy Brockelman, manager of public affairs at Biogen, told BioWorld Today. "Rebif's launch is the flattest MS launch in the U.S. to date."
Though Brown said she had not yet seen Biogen's data, she said, "The pivotal control portion of their study was in patients who completed 15 months. Any data that they are looking at from that point forward is uncontrolled, open-label data, and you have to be critical in your assessment of that because there is no control group."
Rebif is marketed in the U.S. in partnership with New York-based Pfizer Inc. Serono reported U.S. sales of $40.3 million as part of its first-quarter financial results, and bullishly projected at least a 30 percent share of the U.S. market by 2006. The company also said it has gained 36 percent of the European market. (See BioWorld Today, April 25, 2003.)
For the quarter, Avonex's sales totaled $189 million, and Biogen continues to expect steady U.S. sales growth. (See BioWorld Today, April 25, 2003.)
"We are seeing trends that U.S. neurologists appear to be more conservative-minded than their European counterparts, and we believe this is the primary reason why Avonex is maintaining a dominant market share in the U.S. in the early stage, relapsing, remitting MS setting," Chao said, adding that most patients are diagnosed initially with early stage MS and develop a loyalty to their first treatment.
She said doctors write Avonex prescriptions about 50 percent of the time for front-line, early stage, remitting MS in the U.S., while Rebif has captured 8 percent to 9 percent of the same market since its April 2002 approval. Copaxone sells to about 28 percent of the U.S. market, while Betaferon/Betaseron (interferon beta-1b, from Berlex Laboratories Inc. and Chiron Corp.) holds about a 19 percent share, Chao added.
Potentially adding to the mix down the road is Antegren (natalizumab), Biogen's late-stage investigational product from a new class of drugs. It remains in two Phase III trials in MS.
"Where are new patients going to go as we get into the new treatment paradigm," Chao asked, "and where are switchers going to go?"