Genentech is "bucking a trend" by charging less for its multiple sclerosis (MS) drug despite at least equal efficacy to others and improved safety, neurologist Michael Racke told BioWorld Today, talking about the approval by the FDA for Ocrevus (ocrelizumab) as the first and only disease-modifying drug for relapsing as well as primary progressive MS, the two forms most prevalent among patients at the time of diagnosis. "If you're sort of on the fence as an insurance company about whether you're going to approve patients going on this drug," cost may swing the decision, he said.

Racke, who specializes in treating patients with MS at the Ohio State University Wexner Medical Center, took part in the trials conducted by Genentech, a unit of Roche AG, with Ocrevus. The CD20-positive B cell-targeting therapy seems certain to make an impact on the MS market in general and on powerhouse Biogen Inc., becoming "fairly soon, a big player," he said. "It's not always easy to compare across clinical trials," he added, but Genentech's drug is "probably the most efficacious." Trials with Ocrevus are investigating biomarkers and how well the drug works in people who have failed other MS medications.

Leerink analyst Geoffrey Porges said that "competition for Biogen's MS franchise was not a key part of our recent downgrade of [the company], but we do expect this approval to have some impact on share and volume trends for Biogen's products, particularly Tysabri (natalizumab)," approved in 2004. Ocrevus, given every six months, had been awarded breakthrough therapy designation, fast track status, and priority review. Ocrevus turned up superior efficacy on three measures when compared to Rebif (interferon beta-1a, EMD Serono Inc.). "Ocrevus has impressive, but not necessarily class-leading efficacy; (Tysabri and Lemtrada [alemtuzumab, from Sanofi SA unit Genzyme Corp.] probably still claim that crown)," Porges wrote in a report. It's the dosing schedule that brings the magic, in his opinion, "but [this] also comes with some risks. There were serious infections during the drug's clinical development, and in the case of such complications, physicians are likely to find it difficult to reverse the drug's effect and restore immunity. MS specialists were shocked by the early adverse events observed with Tysabri, and that drug's history is likely to serve as a cautionary note for any burst of enthusiasm about Ocrevus." He predicted that use of the new therapy will be limited to second-line and third-line patients with relapsing/remitting disease "but [we] do anticipate that the drug will get significant adoption in patients with primary progressive MS. In this setting the drug is more or less the only game in town, and given the dismal prognosis in that disease segment, Ocrevus should be widely adopted in the relatively small primary progressive population," he predicted.

Ocrevus rang the bell in a pair of relapsing MS phase III trials, OPERA I and OPERAII, reducing relapses per year by nearly half, slowing the worsening of disability, and significantly reducing lesions as detected by magnetic resonance imaging (MRI) vs. Rebif over the two-year controlled treatment period. Serious adverse effects and serious infection rates came out about the same.

In a phase III study called ORATORIO testing Ocrevus against primary progressive MS, which is highly disabling, the drug significantly slowed the advance of disability and reduced signs of disease activity in the brain shown by MRI compared to placebo, with a median follow-up of three years. Adverse events, including serious ones, arose in numbers similar across the placebo and drug groups. (See BioWorld Today, July 1, 2015.)

Infusion reactions and upper respiratory tract infections – mostly categorized as mild to moderate – were the commonest side effects with Ocrevus. Full results from all three phase III experiments appeared in January in The New England Journal of Medicine.

Racke called the approval "personally rewarding." His researchers had been "very much involved" in testing Rituxan (rituximab, jointly marketed by Biogen and Genentech) against primary progressive MS, where the anti-CD20 therapy failed. "But if you looked at the patient subsets, it worked in the patients under 51 and who had active disease," he said, a finding that influenced design of Ocrevus experiments. "This whole area of targeting B cells in MS is going to give us a lot of different options," he said.


Ocrevus is priced at $65,000 per year, "broadly in line" with other MS medications after rebates, said Jefferies analyst Jeffrey Holford, who forecast peak sales of $5 billion for Ocrevus, given its strong efficacy and a "relatively mild" toxicity. He wrote in a report that the drug's success "will be important in helping mitigate the anticipated competition from biosimilar threats" to Basel, Switzerland-based Roche's Herceptin (trastuzumab) for breast and gastric cancers as well as Rituxan (rituximab), approved for rheumatoid arthritis and other indications.

Leerink's Porges, though, took a somewhat different view, and suggested that Ocrevus may be "resetting price in the MS market," as the cost represents a 10 percent discount to the current wholesale acquisition cost (WAC) of Tysabri and a 25 percent discount to the WAC of Tecfidera. It is unclear what the size of discounts for Ocrevus will be; Ocrevus is likely to compete most directly with Tysabri and Lemtrada, in the most severe end of the disease spectrum where treatment options are limited and disease outlook is grave." Racke did not altogether agree. "Drugs like Tysabri and Lemtrada are for patients who have more frequent attacks or more evidence of inflammation, perhaps," but Tysabri explicitly didn't work in patients with progressive MS, he said. "Nothing that had been tried previously worked. Everything that's been approved so far is for relapsing MS."

The medicines cited by Porges "are all office administered, and hence subject to the usual mark-ups of such drugs when physician purchased," the analyst noted. "As such, they compete less directly with self-administered and oral medicines for MS, which coincidentally are directed to patients with less severe disease." He estimated the discount on Biogen's Tecfidera (dimethyl fumarate) as high as 40 percent and the net price after rebates of about $55,000 per year. "We believe discounting is substantially more for Tecfidera than it is for Tysabri, and the price of Ocrevus (especially after rebates and discounts) is likely to be in the same range as Tysabri," a prosect that would "put pressure on this part of Biogen's portfolio which provides steady revenue of about $1 billion in the U.S."

Brian Abrahams, who covers Biogen for Jefferies, found Ocrevus' label mostly clean. "Notably, there was no boxed warning around progressive multifocal leukoencephalopathy [PML] (observed with other anti-CD20 antibodies and expected that Ocrevus might have as well) or malignancies (modest imbalances seen in some prior studies)," he said in a report. "However, the label does call out an increased risk of malignancies including breast cancer, something which could have an incremental impact on usage, though similar warnings on other drugs like Enbrel [etanercept, Amgen Inc.] have not materially affected their market potential. Importantly, this does not require additional monitoring. The label mentions possibility of PML with the class but that no cases have yet been seen with Ocrevus, [which is] reasonable in our view."