Benlysta's Broad Label Prepares The Way For A New Blockbuster

The broad labeling that FDA approved for Benlysta (belimumab), the breakthrough lupus drug Human Genome Sciences Inc. shares with GlaxoSmithKline PLC, could position the biologic for widespread reimbursement. [See Deal] That the first-in-class inhibitor was approved is far from surprising, based on the huge unmet need and lack of options for lupus patients. HGS and GSK bolstered their case with a pair of successful Phase III studies, a reasonable safety record, and an advisory committee endorsement. Still, in an era where positive regulatory news is less frequent, the product's generous labeling was a pleasant bonus.

Analysts had feared that labeling would carry explicit subpopulation restrictions based on issues raised during the Arthritis Advisory Committee's November 2010 review of the drug's biologics license application. Reviewers questioned inconclusive clinical trial results for African American patients; moreover, patients with either severe, active CNS or kidney disease were excluded from the pivotal BLISS program, leading to concerns that FDA might limit the drug's use in these specific patient groups, which are not small in number. As it turns out, no specific contraindications for these patient populations are included in the label, with cautionary language highlighting reviewers' concerns. Instead, Benlysta's indication is for treatment of adult patients with active, auto-antibody-positive, systemic lupus erythematosus who are receiving standard therapy, which includes corticosteroids, anti-malarials, immunosuppressives and nonsteroidal anti-inflammatory drugs.

"Our label fairly describes the patient population from our trials," HGS Chief Commercial Officer Barry Labinger said on a call to discuss the approval. It's "exactly what we were looking for. It includes our real-world spectrum of patients with active disease, and it's not specific to any particular manifestations." For now, Benlysta's target market is the 200,000 or so US patients with moderate to severe disease. That estimate could be conservative. FDA puts the SLE population at around 300,000, minimum.

A decision by US regulators was just the first step in a worldwide launch of the product. Human Genome's partner GSK submitted a Marketing Authorization Application to the European Medicines Agency in June 2010, and the partners anticipate a decision in the second half of the year. Applications also are pending in Canada, Australia, Switzerland, Russia, Brazil and the Philippines.

As the companies wait for ex-US approval of Benlysta, the medicine's launch is already in full swing. A Benlysta sales force of 150 "account managers" is set to begin calling on rheumatology accounts, both in hospitals and in the community, Labinger said. Nearly 90% of them have experience with biologics in rheumatology, and the majority have had success with those products in the same territory they will be covering for Human Genome, he said. Labinger predicted rheumatologists could start prescribing the medicine in early April, revealing Benlysta would cost $443 for a 120-mg vial and $1,477 for a 400-mg vial. Extrapolating from the average weight of US and Canadian patients in the Phase III program, the price comes out to about $35,000 a year per patient, Labinger said.

But that cost could be higher. It assumes the vials are used efficiently, with 13 infusions per year at the average patient weight, JP Morgan analyst Cory Kasimov commented in a March 10 research note. And that may or may not be the case. Analysts from International Strategy and Investment Group calculate the average patient will require a 730-mg dose, which translates to just over six 120-mg vials of drug. Thus, depending on the patient, physicians may have to buy additional vials to adequately dose the medicine. Furthermore, because the therapy includes a loading dose, the price in year one is likely to be closer to $38,000 or $40,000.

The consensus all along has been that if it won approval, Benlysta would be a blockbuster. ISI projects Benlysta sales of around $73 million for eight months in 2011, with sales adding up to $350 million in 2012 and over $2 billion by 2015 – an estimate shared by others. In a March 10 note applauding the opportunity afforded by the broad labeling, Barclays Capital analysts predicted "rapid adoption by commercial payors" and put peak US sales at $2.7 billion.

HGS's deal with GSK is a complex sharing arrangement. The biotech books sales in the US, as well as all the gross profit, with a line item going back to GSK with its share, Chief Financial Officer David Southwell explained. In Europe the scheme will be exactly the opposite. "It's truly a 50-50 effort, and we share the profits," he said.

HGS was expensing the inventory build through the R&D line through late last year, when it switched to capitalizing it, so there is no cost-of-goods impact on the income statement right now, he said. Once HGS runs through the inventory, the drug will be expensed as it is sold.

Launch plans include physician, patient and payor education; patient assistance and co-pay programs; and reimbursement services and support. Southwell outlined the strategy, including the plan to sell the infused biologic as a "buy and bill" product, during a March 2 analyst meeting in New York. Labinger estimates about two-thirds of lupus patients are under commercial insurance, and the rest are evenly split between Medicare and Medicaid. This likely provides near-term advantages to Human Genome since commercial payors are likely to begin covering Benlysta right away as a medical benefit, though there may be what he calls a "learning curve." The company anticipates that insurers will impose prior authorization requirements as they do for other biologics, however, and that patients will be required to have tried some initial therapies before advancing to Benlysta. The goal is to ensure that requirements for prior therapies allow access for patients with disease activity despite treatment with low-dose steroids and Plaquenil (hydroxychloroquine), the only alternatives available with a reasonable safety profile, Labinger said. If patients are on those therapies and still having problems, Benlysta should be made available to them, he argued.

In addition, HGS has the data in hand to support Benlysta use in patients with CNS and renal disease who are not in an acute flare. (They were part of the Phase III program.) Labinger estimated that only about 5 to 10% of patients at any one time are in a severe phase, where they are on aggressive IV cyclophosphamide, a chemotherapeutic. At that point, he said, "we'll wait for them to calm down a little bit and then try to get them on board."

Part of HGS' Phase IV commitment is to conduct a "robust" study of Benlysta in African American patients and patients of African American descent. "We need to get the firm answer" on efficacy, Labinger said. In the meantime, he said he expects physicians will make case-by-case decisions. "I'm very optimistic that Benlysta will get fully fair consideration for African American patients." There's no limitation of use in the label, there's no contraindication in the label. It's just information, so I'd be very surprised if any payor decided on the basis of that information to restrict access to this drug to that important population," Labinger asserted.

African Americans are an important population for Benlysta. Labinger estimated the percentage of SLE patients who are African American at 20 to 30%. And, while on the whole SLE affects more women than men, three times as many African America women as Caucasian women are stricken by the disease. Analysts believe FDA's decision to reference inconclusive data on African Americans in the label's clinical data section sends an important message to payors and physicians. It's different from "asserting a claim that it does not work" in these patients, says ThinkEquity analyst Brian Skorney, who is confident the labeling will not interfere with patient use or reimbursement. Leerink Swann analyst Seamus Fernandez shares that sentiment. In a March 9 note to investors, Fernandez emphasized the mixed efficacy evidence will have no impact on use in the African American population. The Barclays analysts, however, say they "do expect exclusion of patients based on race," despite the fact that labeling highlights the limitations in the data.

Benlysta had mixed results in its attempt to show a steroid sparing effect, a major secondary endpoint and a goal FDA sets for lupus therapies in its guidance on drug development for the disease. Although study results trended positive, they were never a bullseye, and HGS resorted to a pooled analysis in its application. Again the generous labeling may offer enough of a backdoor claim to be used in sales pitches. The Clinical Trials section notes, with accompanying data, that "the proportion of patients able to reduce their average prednisone dose by at least 25% … was not consistently significantly different" relative to placebo. Thus, the sponsors could play up that sometimes there was benefit over placebo, but it wasn't always statistically significant. In its release on the approval, FDA even states that "results suggested, but did not definitively establish, that some patients reduced their steroid doses."

Asked during the call whether a claim could be made, Labinger said he wasn't sure how HGS would be able to "characterize some of those data in promotions," adding that the company is in the process of finalizing marketing materials and getting advisory comments from FDA. According to JP Morgan's Kasimov, the fact that steroid sparing is mentioned in the label at all is good news. The mention "could offer some flexibility for the sales reps when detailing physicians, in our view."

– Shirley Haley