Full article reprinted from "The Pink Sheet" October 12, 2009
Human Genome Sciences' Phase III breakthrough with the biologic Benlysta in lupus has renewed hope in new drugs for a difficult-to-treat disease. The question now, though, is how big can the market grow for this elusive condition, given the high unmet need? Read on...
Full article reprinted from "The Pink Sheet" October 12, 2009
Human Genome Sciences' Phase III breakthrough with the biologic Benlysta in lupus has renewed hope in new drugs for a difficult-to-treat disease. The question now, though, is how big can the market grow for this elusive condition, given the high unmet need?
At a time when me-too drugs have fallen out of fashion, the chronic autoimmune disease stands out as a market deserving of attention, with no new drugs approved since sock hops were in vogue.
Up until recently, pharma research was littered with late-stage failures in systemic lupus erythematosus, the most common type of the disease, accounting for about 70 percent of cases. But now, at least one drug is thought to have a good chance of shaking up the market: Benlysta (belimumab, formerly Lymphostat-B), a monoclonal antibody that works against B-lymphocyte stimulator (BylS). HGS has formed 50/50 development and commercialization joint venture for the drug with GlaxoSmithKline.
HGS' recent success in a large Phase III SLE trial is being called a breakthrough, even though benefit over placebo ranged from only 8 percent to 14-percent, depending on the dose. And findings still need to be confirmed in a second study, with results due in November (1 'The Pink Sheet' DAILY, July 20, 2009).
Among other factors contributing to the success was a longer study period, very large study size of more than 800 patients, and new endpoints (2 Pharmaceutical Approvals Monthly, Sept. 1, 2009).
In another boost for the space, soon after HGS' announcement, UCB and Immunomedics released positive Phase IIb results with their anti-CD22 antibody epratuzumab in a trial that bore a few similarities to the Benlysta study in terms of design and patient population.
The ability to actually show efficacy of a lupus drug in clinical trials has generated interest in the market. Prevalence figures are in dispute, but in the U.S., lupus in all its forms is thought to afflict as many as 1.5 million women, commonly in their child-bearing years. Treatment is geared toward reducing inflammation and suppressing the immune system.
The last FDA drug approval came half a century ago, in November 1958, when the anti-malarial quinacrine (Bayer's Atabrine ) was cleared. Previously, the agency had approved three drugs: the corticosteroid meticorten (Schering's Prednisone ) and Sanofi's anti-malarials chloroquine ( Aralen ) and hydroxychloroquine ( Plaquenil ).
Hence, the standard of care has evolved to include off-label treatment with drugs used to tackle other diseases, notably rheumatoid arthritis and cancer.
Depending on the severity of illness, the treatment regimen might include chemotherapy agent cyclophosphamide (Baxter's Cytoxan and generics) and biologics like Genentech/Roche's anti-CD20 antibody Rituxan and the immunosuppressant CellCept (mycophenolate mofetil). However, it's tricky to get reimbursement for expensive off-label drugs and, consequently, biologics are reserved for deathly ill patients who have failed all other therapies.
Benlysta May Cost $20K A Year
During a Sept. 25 talk at a UBS conference, HGS chief executive H. Thomas Watkins reaffirmed plans for a BLA filing in the U.S. in the first half of 2010 and to hit the market by the end of that year. He also indicated that Benlysta would be priced somewhere between the cost for rheumatoid arthritis drugs-- $15,000 to $20,000 per patient per year-- and multiple sclerosis treatments, which run from $20,000 to $30,000.
"Though we have not concluded what the strategy will be, I think a good estimate to use is something in $20,000 range, perhaps even higher, because we recognize that we are entering market without a lot of competition and with a first-in-class treatment that offers huge value," he said.
The lupus market has no parallels in the biopharma industry, due to the heterogenous nature of the disease, lack of data on prevalence and limited treatment options. In its mildest forms, it may cause pain and fever that can be treated with aspirin and in its most severe manifestations, it affects the central nervous system and commonly causes kidney disease, a condition known as lupus nephritis.
Epidemiological information is lacking, although available data suggest an SLE patient population of at least 500,000 in the U.S. Recognizing that this figure is probably too low, the Lupus Foundation of America has commissioned surveys, which have repeatedly shown that there are about 1.5 million diagnosed lupus cases in the U.S. However, they relied on patient self-reports and assumed a broader definition of the disease than is currently accepted (diagnosis criteria is currently under review). Survey data need to be validated in more rigorous epidemiological analyses.
"I am a complete lupus expert and I don't know how many lupus patients there are in the United States, and by the way, neither does anybody else," said Joan Merrill, the foundation's medical director.
With effects on multiple organ systems, lupus commonly causes rashes, arthritis, kidney disease and low platelet counts, but patients may get vastly different combinations of these conditions.
"It's like a Chinese menu. If you lined up 100 patients, you might not get anybody alike," said Merrill, a professor of medicine at the University of Oklahoma Health Sciences Center and chair of clinical pharmacology research at the Oklahoma Medical Research Foundation.
Lupus patients are typically treated by rheumatologists but will also see a range of other specialists including dermatologists, nephrologists and neurologists.
Gauging Future Lupus Market Growth
According to HGS, about 325,000 patients in the U.S. are treated by rheumatologists for SLE, and of these 33 percent are mild, 45 percent are moderate and 22 percent are severe cases.
Writing in an Aug. 4 investor note, ThinkEquity analyst Jason Kolbert noted that at least two-thirds of these patients are candidates for treatment with a biologic therapy. Using the company's price estimates, Benlysta could reap sales of from $1.5 billion in 2011 to almost $2.3 billion in 2014 when U.S. and European markets combined, according to ThinkEquity's forecasts. Of these totals, U.S. sales account for $745 million in 2011 and $1.1 billion in 2014.
Analyst projections for HGS' take of worldwide sales in the future have varied dramatically from a low of $431 million to a high of $1.6 billion, according to the research firm EvaluatePharma. More information is needed on the terms of the GSK deal to get an accurate picture and some analysts are predicting best-case scenarios while others are waiting to see more data, the firm explained.
Taking a conservative approach, Biopharma research firm Decision Resources estimates that from 2008 to 2018, the total SLE market (including U.S., Europe and Japan) for all drugs will grow dramatically, but at lower rates - from $420 million to slightly less than $2 billion. Of these totals, the U.S. market will take the lion's share, growing from $344.6 million in 2008 to $1.6 billion in 2018.
Currently off-label use of two branded agents -CellCept and Rituxan - accounted for about 75 percent of 2008 sales, the firm estimates.
Rituxan, which is approved for rheumatoid arthritis and cancer, spectacularly failed in SLE trials. But doctors continue to use the drug for their more serious cases for a number of reasons. Results from the failed trials have been difficult to interpret and are viewed by experts as inconclusive, Merrill points out. Anecdotal reports and uncontrolled study results indicate efficacy for some patients, and few other options are available.
Rituxan, meanwhile, will lose its patent status in 2013 in Europe and 2015 in the U.S. Its follow-on, second generation anti-CD20 candidate, ocrelizumab, is now in development for lupus nephritis, which affects at least one-third of patients.
Generating drugs to successfully attack lupus is tricky. The disease may affect five organ systems at the same time, making it difficult to develop treatments and measure their efficacy. But the common kidney condition is one area where it is possible to get quantitative data, according to Timothy Behrens, senior director of immunology diagnostics and biomarkers at Genenetch.
Furthermore, looking back at all the uncontrolled case reports in the literature, there were definitely certain subtypes of patients that seemed to be more responsive to Rituxan, for example, Rituxan patients who were also taking Cytoxan. Current research with ocrelizumab will assess whether there is a synergistic effect between Cytoxan and ocrelizumab, Behrens said.
Of about a dozen drugs in development, including five in late-stages, Benlysta looks to be the most promising at the moment, in the view of Decision Resources and other analysts. The drug is closest to reaching the market, has a very good safety profile and there is a strong need for a drug in the moderate illness segment, explained the firm's analyst, Dancella Fernandes.
Benlysta is expected to launch in 2011 in the U.S., followed by ocrelizumab and epratuzumab in 2013.
While HGS clearly had a major breakthrough in trial design, there's still some uncertainty about whether the second pivotal trial will be positive and if the results will show better efficacy than the 8 percent to 14 percent achieved in the first study. Based on the outcomes from the first study, it's difficult to predict the reception from payers, particularly for patients with less severe forms of the disease, Fernandes said.
According to Lupus Foundation membership surveys, about 96 percent of lupus patients have some form of insurance.
One in four is insured by Medicare and/or Medicaid. Lupus can be very disabling but patients may not be impaired enough to get Medicaid assistance or else they may not qualify financially. Two of three respondents reported a complete or partial loss of their income because they are no longer able to work full-time due to complications of lupus. Many who do not have their own insurance are covered through their spouses and those who have none often pay out-of-pocket.
Depending on the reimbursement prospects, new biological drugs will likely be added on to current treatments and will not directly compete with Rituxan, which is now only being used for severe refractory SLE for all manifestations, including involvement of the central nervous system and kidneys. Trials of both Benlysta and epratuzumab excluded patients with active CNS lupus and severe kidney disease.
Rituxan will continue to be used in the most severe patients, but newer drugs like Benlysta could still find a role in treating the moderate symptoms in patients with more severe disease, Merrill said. Strong four-year follow-up safety data from a Phase II study of Benlysta were presented in June at the 2009 Congress of the European League Against Rheumatism and are likely to encourage broader use, she added. Research also strongly suggests that the drug significantly lessens reliance on steroids.
"This is a drug that at least for four years out is very well-tolerated," she said.
The lupus market is expected to see its greatest growth from 2008 to 2013, as Rituxan is increasingly used off-label and with the launch of the premium-priced biologics. Growth will then slow for the subsequent five years, in light of fewer new launches and generic erosion. Furthermore, biosimilars of rituximab are expected to become available starting in 2013.
In 2018, Rituxan and the three new biologics will account for more than 80 percent of SLE sales, according to Decision Resources. The research firm is predicting rituximab will emerge as the 2018 market leader, driven by its use in the area of highest unmet need: severe manifestations refractory to current treatments.
- Emily Hayes
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