In what could represent a watershed moment in the FDA’s cancer drug practice, GSK pulled an accelerated approval for multiple myeloma drug Blenrep at the request of the FDA just 15 days after unveiling a confirmatory trial failure. The move reflected a broader makeover happening at the FDA’s oncology department, a GSK executive and an analyst said.
An emphasis on accelerated approval guidelines as part of an “evolving regulatory environment in the U.S.” was the key driver behind GSK’s decision to pull Blenrep “in an expeditious fashion,” Hesham Abdullah, GSK’s global head of oncology development, said in a recent interview with Fierce Pharma.
“Big Pharma is doing the right thing,” SVB Securities analyst Daina Graybosch, Ph.D., said in a separate interview. “This is it. We had an agreement. Let’s follow it. The only way to keep the accelerated approval pathway open is if everybody doesn’t fight it.”
But the changes will be tough for biotech, especially small ones, Graybosch said.
The “agreement” Graybosch referred to was the stipulation that a drug approved under the accelerated approval pathway using a surrogate endpoint should later provide more advanced clinical data to confirm its benefit. But until recently, the FDA hadn’t been actively enforcing the mandate, allowing some cancer drug indications to stay for years without any confirmatory evidence.
Overall alignment from Big Pharma
Using GSK’s Blenrep move as an example, Graybosch said that large biopharma companies have an “overall alignment” with the FDA, that “they’re not going to fight these things to make it more difficult for the FDA,” especially when the confirmatory evidence was pretty clear like in Blenrep’s case.
Blenrep wasn’t the first accelerated approval withdrawal amid the FDA’s renewed scrutiny, but it was one of the fastest and most surprising because the drug has a couple combination data sets that could read out soon next year. PD-1/L1 inhibitors have also pulled multiple indications, most recently a Tecentriq use in certain bladder cancer settings.
In a statement when the Tecentriq withdrawal was made in November, Roche Chief Medical Officer Levi Garraway, M.D., Ph.D., said the Swiss pharma understands “the need to uphold the principles” of the accelerated approval pathway.
The FDA isn’t just tightening the leash on getting failed drugs off the market, Graybosch noted, but it’s also raising the bar on the evidence that can enable an accelerated approval in the first place.
The FDA’s oncology chief Richard Pazdur, M.D., recently made clear that his department wants to get a drug’s confirmatory trial at least underway before granting an accelerated approval and to have that trial design discussion early on. For some indications with little or no unmet medical need, that requirement may mean that the designated trial must be well underway, while other rare diseases may enjoy some “regulatory flexibility,” Pazdur said.
Because the FDA just made its requirement clear, Graybosch foresaw a “massive delay” in the number of cancer drug approvals as companies try to shift gears, review their balance sheets and adjust their regulatory timelines.
ADC Therapeutics’ antibody-drug conjugate camidanlumab tesirine saw its path to an accelerated approval in pretreated Hodgkin lymphoma closed after the FDA required a confirmatory study that’s “well underway and ideally fully enrolled,” the company said in November.
By comparison, ImmunoGen recently won an accelerated approval for its ADC Elahere, or mirvetuximab soravtansine, in ovarian cancer as its confirmatory phase 3 is slated to read out next year.
To Graybosch, the FDA’s not waiting until the phase 3 readout suggests the agency is willing to reward companies that follow the rules, that an accelerated approval—instead of a late full approval—is possible even if the confirmatory data are supposed to come out soon.
The FDA’s harsh stance on accelerated approval is particularly good for Big Pharma, Graybosch said.
Young biotechs, especially those caught in the middle of the policy shift, will struggle, Graybosch said. This means small players will either have to fold their programs—or the entire company—or find a Big Pharma partner to fund a large phase 3 before getting any approval. Either way, Big Pharma wins. Besides, Big Pharma companies simply have so many businesses that they won’t risk falling on the wrong side of the agency, whereas a small firm solely dependent on a drug might fight the FDA hard.
Pazdur has also noted that Big Pharma firms have less trouble following through with confirmatory trial commitments compared with small biotechs. When asked about whether the higher bar for accelerated approval will muffle innovation, Pazdur said that truly innovative drug programs will survive.
Shock, dismay, anger, acceptance
Accelerated approval could be just one element contributing to a drawn-out cancer drug development timeline. The agency is also increasingly focused on long-term patient outcomes and drug dose optimization, GSK’s Abdullah and SVB’s Graybosch noted.
GSK recently pulled a late-line ovarian cancer indication for Zejula and restricted a second-line use to a patient subgroup. The two back-to-back setbacks came as part of a PARP inhibitor classwide re-assessment after phase 3 trials suggested a potential detriment to patients’ life expectance despite earlier signals of tumor control.
What’s more, the FDA recently clamped down on PI3K inhibitors for blood cancer after noticing alarming overall survival outcomes from multiple clinical trials. In its review, the FDA criticized those drugs’ developers for not having properly examined dosing levels to balance efficacy and safety. Data suggest that although those drugs could initially keep tumors in check, their toxicities could outweigh their anti-tumor effects over the long term.
On the new drug approval front. The FDA has asked Roche to provide longer-term data for its Polivy application in first-line diffuse large B-cell lymphoma and for T-cell engager Lunsumio (mosunetuzumab) in follicular lymphoma. In both cases, European regulators have cleared the drugs, while FDA decisions remain forthcoming. Additionally, the FDA granted accelerated approvals to Amgen’s and Mirati Therapeutics’ respective KRAS inhibitor in lung cancer but asked both to run additional postmarketing studies to evaluate a lower dose.
“We’ll have to identify how to best navigate,” GSK's Abdullah said, “somewhat balanced between trying to get these drugs to patients as quickly as possible but also making sure for those drugs where therapeutic indices are relatively small or narrow, that we best manage that dose exploration in the most appropriate way.”
The FDA stepped up its regulatory efforts on proper dose selection under Project Optimus, which was launched in 2021. In an October note to clients, Graybosch and colleagues said the window for postmarketing dose optimization—like what the KRAS inhibitors got—is closing, and that companies need to identify optimized doses during phase 2 studies.
“We believe that Project Optimus could make future drug development in oncology require more detailed evidence of dose optimization in areas with less unmet need, likely prolonging time to approval, and applying to nearly all oncology drugs under review.”
In that SVB October note, an oncology expert who had previously worked on Project Optimus said the initiative sent drug developers into “shock, dismay, to anger and then acceptance.” Once again, the FDA’s latest emphasis on dose optimization and long-term survival data is giving small firms a hard time.
Following the crackdown on PI3K inhibitors, MEI Pharma and Kyowa Kirin folded zandelisib outside of Japan as MEI cut 30% of its workforce. Secura Bio, which relies on Copiktra as its single commercial product, has fought the FDA over the PI3K drug’s use in chronic lymphocytic leukemia. But an FDA internal review and a negative vote from an external advisory committee didn’t bode well.
While GSK and a partnership between AstraZeneca and Merck are operating as usual after chopping off their PARP indications, Clovis Oncology has thrown in the towel. The Colorado biotech filed for bankruptcy following a narrowed label for its PARP inhibitor Rubraca and an FDA request for longer-term overall survival data for a proposed first-line maintenance ovarian cancer indication.
“I think what it means is that we have to have better ways to tease out good ideas,” Graybosch said. “And investors, everybody’s going to have to realize each of those good ideas is going to take more investment before we get to a reasonable signal and to launch. So, everybody’s models are going to have to shift.”