Eagle Hopes To Build On Bendamustine Success With Injectable Reformulations

With concentrated, lower-volume injectables, the specialty firm is finding larger patient bases for the cancer drug bendamustine and the muscle relaxant dantrolene.

Having succeeded with a more rapid infusion formulation of Teva Pharmaceutical Industries Ltd. cancer drug Treanda (bendamustine), specialty firm Eagle Pharmaceuticals Inc. has proof-of-principle for its business model of reformulating injectable products to broaden their reach.

The firm's next step will be to build up its Ryanodex product by adding an indication for exertional heat stroke and, down the road, for acute treatment of drug overdoses.

In an interview, Eagle CEO Scott Tarriff explained that his company's strategy is to find and address gaps in the way existing drugs are delivered. Bendeka, its formulation of bendamustine, is both easier to use and can be infused much more quickly than Teva's existing Treanda product. Eagle is partnered with Teva on the reformulation, which was approved for chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma this past December. (Also see "Eagle flies on Teva bendamustine deal; FDA OK pending " - Scrip, 18 Feb, 2015.)

During its quarterly earnings call May 9, Teva reported that it already has converted 71% of the user base for Treanda over to Bendeka. Tarriff noted that Treanda has been a $750m product, and with his company in line for 20% royalties on Teva sales of Bendeka, this could be a significant earner for his firm. Bendeka sales totaled $38m during the first quarter of 2016, its first full quarter on the market, and April sales were trending toward $45m, Tarriff pointed out on Eagle's first quarter earnings call, also held on May 9.

Ryanodex is an injectable formulation of the generic dantrolene, a skeletal muscle relaxant approved to treat malignant hyperthermia. (Also see "Eagle takes sporadic flight on US Ryanodex nod " - Scrip, 24 Jul, 2014.) While that initial indication brings Eagle about $2m a quarter in sales, Tarriff sees much more earnings potential for the drug in exertional heat stroke and later in treating Ecstasy and methamphetamine overdoses.

"Eagle exists primarily to find gaps in the way drugs are delivered," Tarriff said. "We do that by speaking to the stakeholders – the physician, the patient, the pharmacist, the nurse and the payers. We concentrate on hospital products and thus far we've been primarily if not exclusively in injectables. We're finding places where injectables just could be improved, where they are inefficient."

Bendeka is a good illustration. Teva's Treanda, on the market for roughly six years, is infused in solution of 500 mL of sodium chloride, an administration that takes between 30 and 60 minutes to complete. Eagle's reformulation is a higher concentration that can be infused in about 10 minutes, in about 50 mL of sodium chloride.

The impetus for reformulating bendamustine was clinicians' complaints about the "chair time" needed to dose Treanda, a burden both for medical practices and patients, Tarriff said.

"We started shipping product to customers on Jan. 28," he said. "The advantages of our drug are just tremendous. If you think about the chair time, it's great. We're reducing the volume load," which is important for the CLL and NHL settings because the patients tend to be elderly. "There's quite a bit of renal suppression or renal failure with these patients, and we've eliminated 90% of the sodium chloride."

Getting Insights From Hospital Pharmacists

The key factor for Eagle, Tarriff explained, is idea generation. Eagle has some in-house technology that enables it to reformulate some of the drugs it works with, but it also will go external to obtain technology it needs to make a product idea into reality. For example, Eagle partnered with Elan Corp. PLC, whose drug delivery business was acquired in 2011 by Alkermes PLC, for the nanotechnology know-how and application it needed to turn dantrolene into a lower-volume, easier-to-use product that may now be useful in acute disease settings.

Eagle, which went public with a $53.7m initial public offering in 2014, does not have a formal medical advisory board, but does call upon a group of hospital pharmacists for insight, Tarriff said. "We've gone that route because they're the people are actually administering the drugs," he explained. "We also speak to a large number of community oncologists, because we're most interested in how drugs are delivered, on the patient side of things rather than the indication side. That's where our advisory board is."

Dantrolene has been in use for roughly 40 years, but it is a very cumbersome drug. The standard dosage is 720 mL, spread across a dozen 60 mL vials, which needs to be reconstituted quickly and then infused into patients often facing a potentially terminal health crisis. With Alkermes' nanotech application, Eagle was able to reformulate dantrolene into the branded Ryanodex, a single-vial 5 mL injectable. "You can imagine how that's changing the paradigm for these malignant hyperthermia patients," Tarriff said.

Currently, exertional heat stroke does not have an approved drug therapy. It is the second-leading cause of non-combat death for the US military and also a primary cause of student athlete deaths globally, Tarriff pointed out. Meanwhile, literature suggests there are about 125,000 hospitalizations annually related to Ecstasy/MDMA overdoses, he said.

In addition to a 34-patient clinical trial conducted last year in Saudi Arabia, Eagle has conducted a number of preclinical models of Ryanodex and is preparing for a meeting with FDA in July that may lead to the initiation of pivotal trials in exertional heat stroke. The drug has been granted orphan disease status and fast-track status by FDA.

"[Saudi Arabia was] the only place where we were able to find enough patients in a controlled setting to be able to run that clinical trial," Tarriff said. "The data looked great, it showed pretty significant improvement in neurological impairment and in a subset of our primary endpoint, which is non-intubated patients, we have a statistical improvement by using our drug over standard of care."

If Eagle is able to take Ryanodex into a pivotal study this year for exertional heat stroke, Tarriff thinks it could reach market by 2017. But if FDA requires additional data or another study before pivotal trials, the timeline could be pushed back to a 2018 approval. The process should move quickly because Eagle uses the 505(b)(2) pathway, relying on data previously accepted for already-approved agents. Ryanodex was initially approved in 2014 using the animal rule, Tarriff said, under which animal data can be used to provide limited safety and efficacy data.

"These are [patients] who could wind up with core body temperature of 106-110°, which means the temperature of their brain is three-quarters of a degree or a degree higher than that, and the neurological impairment associated with it doesn't always reverse," or could have organ damage that requires replacement, Tarriff said. "You could have never have used the drug practically speaking with the old formulation – if it's used correctly, it will probably be administered by a first responder in a military situation or on the football or soccer field."

For the overdose indications, Eagle has entered a clinical development agreement with the National Institutes of Health and hopes to file an IND later this year. A pivotal program could be completed very quickly, Tarriff added, perhaps even in a weekend.

"Once you get the patients, the studies are easy," he said. "You could do a methamphetamine study over the course of a weekend. Not knowing exactly what FDA wants, but from what we believe, [those] would be appropriate trials. With 125,000 hospitalizations a year, if we did our trial over New Year's Eve, we could probably run our entire clinical trial."

Eagle is in contention with FDA over another issue, however, as the agency in March denied a request for seven years of orphan exclusivity for Bendeka. FDA ruled orphan exclusivity did not apply because Bendeka had not demonstrated clinical superiority to Treanda, a decision Eagle is contesting.

The point could be moot, however, as Teva announced June 10 that it had gotten a favorable ruling in US District Court for the District of Delaware in a patent-infringement proceeding the Israeli firm took against five generic companies seeking to bring generic bendamustine to market before patent expiry in 2026.

This article has also been published in Pink Sheet Daily . Scrip brings selected complementary coverage from our sister publications to our subscribers.