Less than two years after Merrimack Pharmaceuticals Inc. won approval of Onivyde (irinotecan liposome injection) for second-line pancreatic cancer, pundits are weighing Paris-based Erytech Pharma SA's odds with eryaspase (Graspa), which has landed solid phase IIb results in the same indication: a 43 percent reduction in death risk.

It's not strictly a matter of facing off in the marketplace, Erytech CEO Gil Beyen told BioWorld Today, noting that, given Graspa's mechanism of action, "there is no reason why [Graspa] could not be combinable with Onivyde." Graspa consists of asparaginase – an enzyme already approved under various trade names for cancer in the EU – that is encapsulated in red blood cells for delivery.

Shares of Erytech (EPA:ERYP) closed Monday at €25 (US$27.18), up €10.70, or 75 percent. Officials slated a conference call for Tuesday to discuss the results with investors.

The 140-patient study in France met its co-primary endpoints, yielding significant improvement in progression-free survival (PFS) and overall survival (OS) in patients given the Graspa-plus-chemotherapy regimen vs. chemo alone. Specifically, Graspa was added to the standard of care (gemcitabine or FOLFOX) and compared to the standard of care alone in a 2-to-1 randomization. Beyen said a "positive surprise," among others, is that Graspa worked well regardless of the patients' expression of asparagine synthetase (ASNS). "The original hypothesis, based on early preclinical work that people had done, would be that you would expect a stronger result in ASNS-negative patients, but it happens to be very similar," he said. "Both groups benefit, and in the entire population we have very strong total results. My base hypothesis is that yes, there are differences you can see on the level of the enzyme, but the quantity of ASNS, even when high, may not be sufficient to cope with the massive dose of asparaginase" that comes with Graspa.

Chief Medical Officer Iman El-Hariry noted that ASNS turned out to have more of a prognostic than therapeutic effect. "This is almost counter-intuitive, based on what we expected from the battery of data not only in leukemia but also – not much but still, data – that were published in pancreatic cancer. Really, what we'll have to do now is dig deep down" in the outcomes to understand the role of the ASNS marker, she said.

The primary goal of the study was to evaluate the effect of eryaspase on PFS or OS in patients with low ASNS, about 70 percent of the study population, with a prespecified hazard ratio below 0.85 for either PFS or OS. This endpoint was met, showing a HR of 0.73 for PFS and 0.62 for OS. In the entire patient population, the study achieved a HR of 0.57 for OS (95 percent CI; 0.38, 0.85) (p=0.034) with a median OS of 26.1 weeks (95 percent CI; 21.0, 28.9) for the Graspa arm vs. 19 weeks (95 percent CI; 12.3, 21.7) for the standard of care arm. Similar results were observed for PFS. The treatment was generally well tolerated. Complete results will be presented at an upcoming medical conference, and will be submitted for publication, the company said.

El-Hariry acknowledged that the study is proof of concept but it's randomized. "You don't have many trials of that size in second-line pancreatic cancer," she said. "You don't have many trials with an excellent, really great survival outcome," and the results are worth taking to regulators in the U.S. and Europe. "We'll have to see what the feedback is," she said. "It's not unreasonable to go and ask the question." With pancreatic cancer generally, "the problem is, we are only starting to identify the different pathways [involved]. The biology of the disease is becoming much more well established."

ANALYST SEES 'BEST-CASE SCENARIO'

In 2015, two days earlier than expected, the FDA approved Cambridge, Mass.-based Merrimack's Onivyde for use in combo with fluorouracil and leucovorin, for patients with advanced pancreatic cancer previously treated with gemcitabine.

The drug bore a black-box warning concerning risks of fatal or severe complications from neutropenia, or low white blood cell count, and diarrhea that can occur in some patients. At the start of this year, in a potential $1 billion-plus deal, financially squeezed Merrimack sold Onivyde and its generic version of Doxil (liposomal doxorubicin hydrochloride for injection, Janssen Products LP) candidate to Ipsen SA, of Paris. (See BioWorld Today, Oct. 23, 2015, and Jan. 10, 2017.)

Jefferies analyst Peter Welford said that, "given a significant survival benefit in a well-controlled trial vs. standard of care, we envisage Erytech to initiate regulatory discussions to potentially file Graspa for second-line pancreatic cancer, representing a 'best-case' scenario." Onivyde, he reminded investors, was approved for the indication in both the U.S. and Europe based on the phase III NAPOLI-1 study with average OS 26.9 vs. 18.2 weeks (HR=0.75; p=0.039), "perhaps a similar benefit to Graspa at best, albeit in a larger 417-patient trial," he wrote in a report. In relapsed/refractory acute lymphoblastic leukemia (ALL) or those hypersensitive to current asparaginase therapies, "management still targets refiling Graspa with the EMA in the summer for potential approval by about the end of 2018. We assume further ALL trials could commence after FDA feedback by year-end, likely at EU sites initially, for potential U.S. launch in about the second half of 2020," he estimated.

El-Hariry explained that "we ended up withdrawing our [EU] dossier at the end of last year because we needed to [gather] additional data based on what was expected by the agency."

CEO Beyen, asked whether ex-U.S. partner Recordati Group, of Milan, Italy, would commercialize Graspa in pancreatic cancer in its territories, said this is yet to be seen. Through its Orphan Europe arm, Recordati has rights in ALL and acute myeloid leukemia, but "we have very eagerly held onto our rights outside Europe and in all other indications, except for Israel, where we have Teva [Pharmaceuticals Industries Ltd., of Petah Tikva, Israel]. Basically, the strategy is to keep options open. U.S. investors typically want us to hold onto our U.S. rights, for sure. A separate negotiation [would be] necessary" for Recordati to assume pancreatic-cancer rights. "It's good to play a bit hard to get," he said.

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