Worth the Trouble?
“The entry barrier for biosimilars, in many cases, will be the money companies can afford to spend on clinical trials,” observes Paul Wotton, Ph.D., president and CEO of Antares Pharma, which specializes in biosuperiors based on enhanced delivery. “Faced with the prospect of long development times for a biosimilar, and uncertain revenues, companies may decide that a biobetter would be more worth their while.”
Another doubter is Bassil Dahiyat, Ph.D., CEO of Xencor, who describes biosimilars as a “low-risk, low-reward strategy,” while biosuperiors are “higher risk, higher reward.”
While clinical risk for biosimilars is lower than for biosuperiors and new biological entities, it is not zero. Add to that manufacturing start-up costs, human testing requirements, uncertain reimbursement, competition, no pharmacy-level substitution, the burden of demonstrating similarity, and the almost assured need to employ a BLA-like sales and marketing force.
“A good case could be made to stay out of the biosimilars business altogether,” he explains, “particularly for complex molecules like antibodies.”
Most approved biosimilars are hormones and cytokines. Last autumn, EMEA released guidance on generic monoclonal antibodies, several years after issuing rules for somatropin, G-CSF, erythropoietin, alpha interferon, and insulin. Fourteen drugs have been approved under these guidelines. United States approvals amounted to four hormones: HGH
(Omnitrope®/Sandoz), calcitonin (Fortical nasal spray/Upsher-Smith), hyaluronidase (Hylenex/Baxter), and glucagon (GlucaGen pen delivery system/Novo Nordisk). All have a long history of safe use and were approved under the 505(b)(2) designation usually associated with generic small molecule drugs.
Teva, known for its small molecule knockoffs, has been selling its version of Amgen’s Neupogen (filgrastim) in Europe since 2008. The eponymously named product, TevaGrastim, was approved under abbreviated BLA-like tracks but U.S. approval, which has been delayed for about 18 months, is expected under a full-blown BLA.
Interestingly, the downside to Amgen is limited since it has already moved on to a biobetter. U.S. sales from Neupogen total $900 million, while revenue from Neulasta, a PEGylated version, exceeds $2.5 billion.
“The tumor necrosis factor market is one big biobetter,” notes Sonny Gal, Ph.D., senior analyst at Bernstein Wealth Management. These include the antibody TNF blockers Enbrel, Humira, and Remecaid.
The Sweet Spot
“The clinical path will be somewhat shorter for biosimilars than for new biologicals or biobetters,” Dr. Dahiyat observes, “but if any safety signals arise, you’re toast. The margin of success is very narrow.”
Or, as Widener University economist Joseph Fuhr, Ph.D., puts it, “If just one of these biosimilars turns out bad, if people are injured, it will kill the entire market for years.”
The sweet spot for biosimilars will be drugs that are perfectly equivalent but cost less. Even then, prescribers may need convincing, and regulators will not cut anyone any slack.
Dr. Dahiyat cites the case of MedImmune’s Synagis antibody for preventing respiratory syncytial virus in children. The company sought approval of a second-generation drug through a full BLA, but FDA rejected the drug based on a nonsignificant rise in mild infusion reactions. The lesson is clear for manufacturers of any follow-on biologic: Safety signals will not be tolerated.