Where is a biosimilar when you need one?

A few weeks ago, I reported on an advisory committee of the Food and Drug Administration overwhelmingly recommending that the agency approve a biosimilar form of infliximab. If the FDA follows this recommendation, and every indication was that it would, it would become the second biosimilar drug approved for U.S. marketing, and a top agency official recently noted during Congressional testimony that the FDA biosimilar program had 59 additional agents working their way through the agency’s development program. A 2014 report cited more than 700 biosimilars under development worldwide.

But when analysts and journalists list the top reference drugs for biosimilars in the pipeline, one reference biologic agent conspicuously absent is alteplase, the thrombolytic also known as tissue plasminogen activator (TPA), which is approved for lysing clots that cause MIs and acute ischemic strokes.

Alteplase, marketed under the brand name Activase, is the only thrombolytic drug with U.S. approval for treating acute ischemic stroke. Although results from several studies published in 2015 rapidly boosted endovascular thrombectomy to physically remove clots causing acute ischemic strokes, this new intervention has by no means relegated intravenous alteplase to the sidelines. Experts I spoke with in February at the International Stroke Conference unanimously endorsed treatment with alteplase as the unshaken keystone of acute ischemic stroke treatment (for appropriate patients), even in the thrombectomy era. Thrombolysis is seen as a complement to thrombectomy rather than a treatment eclipsed by thrombectomy.

Although alteplase treatment remains central it’s also become increasingly expensive. According to a report at the Stroke Conference by Dr. Dawn Kleindorfer, a neurologist and co–medical director of the comprehensive stroke center at the University of Cincinnati, the price paid by Medicare for alteplase given to acute ischemic stroke patients more than doubled during 2005-2014. Upward pricing became especially dramatic starting in 2010, she noted, with a price tag of about $6,400/100 mg vial (enough for roughly one dose) by mid-2014. The cost for alteplase jumped from 27% of the amount hospitals got reimbursed by Medicare for treating a patient with acute ischemic stroke in 2006 to 53% of the reimbursement in 2013, Dr. Kleindorfer reported.

“I think this might impact the ability of hospitals to provide health care because the [alteplase] cost is so high and now more than half the reimbursement,” she warned. Despite its high price, alteplase “remains cost effective,” she noted, and use of the drug in recent years has increased, not dropped.

Dr. Kleindorfer was at a complete loss to explain why alteplase’s price has risen so much since 2010, and she noted that the drug received FDA approval in 1996 and is now off patent for the acute ischemic stroke indication (as well as the acute MI indication). Despite that, no biosimilar has appeared or seems to be under announced development, nor has any other thrombolytic drug received FDA approval for the stroke indication.

In fact, the history of thrombolytics for acute ischemic stroke is notably checkered. For example, an alternative thrombolytic, desmoteplase, showed early signs of promise for treating acute ischemic stroke, but the Danish drug company Lundbeck halted development of desmoteplase in late 2014 after the drug failed to achieve target primary endpoints in pivotal trials. Another thrombolytic, reteplase (Retavase), has had FDA approval for treating acute MI since 1996 but has never received approval for acute ischemic stroke. A spokesperson for Chiesi, the company that currently markets Retavase, declined to comment on why an indication for stroke was never pursued. A third thrombolytic similar to alteplase, tenecteplase, showed promise for treating acute ischemic stroke in a relatively recent phase II study, where it actually showed superiority to alteplase in a head-to-head comparison, but tenecteplase is owned and marketed by Genentech as TNKase (for acute MI only), the same company that also markets alteplase and so has little incentive to develop tenecteplase as an alternative stroke treatment.

“Even a doubling of the price [for TPA, alteplase] doesn’t change whether the drug is cost effective, but this effectively reduces hospital reimbursements that support acute stroke programs,” commented Dr. S. Claiborne Johnston in an interview. “This will ultimately impact the enthusiasm for and use of TPA,” predicted Dr. Johnston, dean of the Dell Medical School of the University of Texas in Austin and a researcher who has analyzed the economics of thrombolytic drugs for acute ischemic stroke.

“The lack of competition [to alteplase for treating acute ischemic stroke] is an example of how our current biopharma marketplace is dysfunctional,” Dr. Johnston told me. “Trials of new agents are difficult, expensive, and protracted, and there is some question whether any agent that works better [than alteplase] at lysing a clot would also produce a higher hemorrhage risk. We really need a biosimilar, but the path to develop this is not as easy as for [generic] drugs.” Although the higher price alteplase now commands might make development of a biosimilar even more attractive, Dr. Johnston said he was unaware of any company that so far is venturing down that path.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

Seeking an alteplase alternative for stroke