A lot of development dollars are shed when the FDA withdraws approval or requests that a drug be withdrawn from the market because new potential risks have come to light. And it’s not just the brand company that feels the loss.
When Eisai Co. Ltd. announced last week that it was withdrawing its weight-loss drug Belviq (lorcaserin) due to FDA concerns about cancer risks, the news hit several drug companies that have been developing lorcaserin generics for nearly a decade, said Brandon Boyd, director of market strategy, biopharma & generics at Clarivate Analytics. Those companies have invested millions of dollars in development programs referencing Belviq, as well as in patent litigation.
Aurobindo Pharma Ltd., of Hyderabad, India., Lupin Ltd., of Mumbai, and Zydus Cadila Ltd., of Ahmedabad, India, had each filed an abbreviated new drug application (ANDA) with the FDA for lorcaserin immediate-release tablets; Lupin and Tel Aviv, Israel-based Teva Pharmaceutical Industries Ltd. had filed ANDAs for lorcaserin extended-release generics.
In addition, Boyd noted that three of the generic companies had challenged Belviq and Belviq XR patents under the Hatch-Waxman Paragraph IV certification process. “Individually, these four companies easily spent a million dollars-plus to develop their generic version and file an ANDA; then each Paragraph IV patent challenge cost a few million dollars more in litigation expenses,” Boyd said.
The losses don’t stop there. Citing Newport intelligence, Boyd said 13 manufacturers of active pharmaceutical ingredients (APIs), nearly all of which are in India, were associated with lorcaserin. Besides the one that provided the API for the brand drug, six had been confirmed with commercially available formulations, one was in early stage API development and five had unconfirmed reports of production.
Given the slow market uptake for Belviq, which launched in 2013, and other weight-loss drugs that launched soon after, it may seem surprising that there was that much interest in lorcaserin generics and APIs. Once expected to be a blockbuster, Belviq saw its sales peak in 2015 at $56 million, according to Cortellis. By 2017, sales had dropped to $47 million, rising again last year to $51 million – well below the original expectations.
Part of the problem was a burst of competition and older generics that dominated the market. Belviq was the first of three weight-loss drugs approved within a short time frame. The other drugs, Vivus Inc.’s Qsymia (phentermine/topiramate) and Orexigen Therapeutics Inc.’s Contrave (naltrexone and bupropion), also struggled to meet expectations.
During an earnings call in 2015, Vivus CEO Seth Fischer acknowledged that the overall branded obesity drug market had “developed at a substantially slower rate than expected.” He attributed the lackluster performance to a lack of widespread consumer awareness of the drugs and a resistance among both public and private payers to reimburse for new drugs when much cheaper generics were available of drugs that had been on the market for years.
Generic phentermine, which has been around since the late 1950s for short-term weight loss treatment, was the most widely prescribed obesity therapy in 2015, comprising more than 80% of the total obesity drug prescriptions. Putting numbers to those percentages, Fischer said generic phentermine accounted for about 8.2 million prescriptions that year compared with a combined 1.7 million for all branded obesity drugs.
With that resistance and much lower than expected sales, why would so many generic companies target lorcaserin?
It’s a matter of timing. Lorcaserin would have first caught the attention of generic drug manufacturers when it entered phase III trials in 2006, said Boyd, who worked in pipeline portfolio management, market research and commercial strategy in the generics division of Teva prior to joining Clarivate.
“Generic drug companies routinely monitor innovative products while still in clinical development and will typically select these new branded drugs for generic production before the brand has even received its first approval,” he explained. They often pursue many different generics to spread the risk of a few products failing “across a larger pool of relatively successful products, or a few lucky home runs,” Boyd said.
He noted that only the large, well-established generic and API manufacturers pursued lorcaserin, reflecting the relatively higher commercial risk associated with the drug. “These firms can afford to fail occasionally; smaller firms cannot,” he said. “Ultimately, occasional failure is a basic cost of doing business in the generic drug industry, as it is in the innovative drug industry.”
Stumbles along the way
Developed by Arena Pharmaceuticals Inc., lorcaserin did have some stumbles on its way to approval – stumbles that may have made generic and API developers swallow hard. In 2010, an FDA advisory committee voted 9 to 5 against approval, saying potential risks of tumors, psychiatric effects and heart problems outweighed lorcaserin’s benefits.
While many of the panelists found the drug promising, others said they were “spooked” by preclinical studies showing an increase of mammary and other tumors in rats treated with the drug. The uncertainty of how those results would translate in humans gave the panel some pause, given the potential for the drug to be used by hundreds of thousands of women. The FDA followed the adcom’s advice, issuing a complete response letter a month later.
But Arena’s resubmission of lorcaserin in 2012 once again fed blockbuster expectations. That year, Belviq, and its anticipated approval, was a big part of the buzz at J.P. Morgan. Anticipating a shift in the FDA’s mindset toward obesity treatment, conference goers were looking at 2012 as the “year of obesity.”
A few months later, the FDA gave Belviq its approval, making it the first new obesity drug to be approved in 13 years. That approval, along with the FDA’s green light for Vivus Inc.'s Qsymia, made No. 3 in BioWorld’s Top 10 news stories for 2012. (Eisai acquired all of Arena's rights to develop and market lorcaserin in January 2017.)
With obesity growing into a global health problem, Belviq had blockbuster written all over it by the time it launched in 2013. And the companies already developing lorcaserin generics and APIs likely expected they had a winner in their pipeline. But then the drug entered the real world.