Editor's Note: Since this story's original publication on July 10, Elevar has adjusted its expected refile timeline and the story has been updated to reflect that.
After a meeting with the FDA last week, Elevar Therapeutics and Jiangsu Hengrui Pharma are preparing to refile their PD-1 combination around the end of September or October, the two companies confirmed to Fierce Pharma in an updated estimate.
Previously, during a Tuesday interview with Fierce Pharma, Elevar CEO Saeho Chong, Ph.D., said that the company was aiming for the “October time frame.” But he also tempered expectations by pointing to a plan to incorporate additional clinical data in the resubmissions and the need for the two companies to work together, saying that the partners would definitely file “no later than the end of this year.”
Investors, who were clearly disappointed in that cautious estimate, dragged down the stock price of Elevar’s Korean parent company, HLB.
Elevar’s now accelerated timeline is targeting refilings by around late September or October the latest. The more optimistic estimate is being buttressed by a commitment from Hengrui, which said it will be ready to resubmit by Sept. 20, ahead of a big national holiday in China.
The two companies’ applications for China-approved PD-1 inhibitor camrelizumab and the VEGFR tyrosine kinase inhibitor rivoceranib for combined use in liver cancer were spurned by the FDA in May because of problems identified during a manufacturing inspection for camrelizumab. Hengrui is responsible for filing for camrelizumab and Elevar takes care of the rivoceranib application.
The complete response letters were surprising to the drugmakers, because Hengrui, by that time, had already provided a “very comprehensive, well thought-out” response to the FDA’s citations in a Form 483, Chong told Fierce Pharma during Tuesday’s interview.
For both companies, an FDA approval for the combo would have marked their first commercial innovative products in the U.S.
The Elevar chief was more convinced that the applications fell victim to unfortunate timing after seeing the post action letter (PAL), which “clearly outlined that the FDA was quite happy with all the responses to the observations,” Chong said.
Separate from a Form 483 that’s issued upon completion of an inspection, a PAL laying out inspection deficiencies is typically sent to the manufacturing facility a couple weeks after its related complete response letter is issued. In this case, the PAL took longer and only reached the responsible Hengrui plant one day before the scheduled FDA meeting July 2.
The FDA’s position during the meeting was that Elevar and Hengrui can resubmit the applications right away if the partners feel comfortable that everything has been resolved, according to Chong.
In a statement to Fierce Pharma, a Hengrui Pharma spokesperson said: “Following a productive meeting with the FDA on July 2, we feel confident we have addressed the FDA’s concerns.”
The original inspection was done in December, and Hengrui provided the responses around year-end about five months before the FDA’s target decision date of May 16. Despite what later appeared to be satisfactory responses, Chong speculated that the FDA still rejected the drug combination because the review team wasn’t sure whether a reinspection would be required by the PDUFA deadline. The fact that the factory in question has never produced a commercial product for the U.S. market didn’t infuse confidence, either.
That’s still the question today, because Hengrui needs to close the Form 483 with the FDA’s inspection team as a prerequisite for the drug review team to greenlight the two companies’ therapies. The need for an on-site reinspection will also determine the FDA’s review timeline, which won’t be clear until the FDA accepts the resubmissions, Chong said. A simpler class 1 resubmission comes with a two-month review cycle, whereas a class 2 refiling will trigger a six-month cycle.
Another new element that the companies plan to include in their resubmissions is an additional 14 months’ worth of follow-up of the phase 3 CARES-310 trial. At the final overall survival analysis, the combination of camrelizumab and rivoceranib reduced the risk of death by 36% compared with Bayer’s old standard Nexavar in patients with previously untreated liver cancer, according to data presented at the 2024 American Society of Clinical Oncology annual meeting. Patients on the Elevar/Hengrui regimen lived a median 23.8 months, the longest reported for any treatment from a global phase 3 trial in this disease setting.
Given the updated data, it’s possible that the FDA may consider the resubmission a class 2 item that requires more review time.
Besides manufacturing shortfalls, the FDA also pointed to unfinished clinical trial site inspections because of travel restrictions. During last week’s meeting, the FDA confirmed to the companies that the agency considers the gap a secondary problem and that it can complete the inspections if necessary for the resubmission, according to Chong.
Because of the unexpected setback, Elevar has put commercial launch activities on halt and “made some strategic decision to reorganize” the company, including delaying the hiring of a sales team, Chong said. But some of the early preparations, including market access discussions, have been in place.
“We have prepared very well to do commercial launch at this point, but we are at pause,” Chong said. “We’re pausing some of those activities until some later time, but it’s much easier to start the engine back up.”