Not so fast for some accelerated approvals

The US conditional approval pathway has enjoyed years of expansion, but now the FDA is trying to put the toothpaste back into the tube.

Make no mistake, the FDA is getting tough on accelerated approvals. Companies with oncology drugs greenlit under this pathway are getting short shrift if they fail to make the grade – just ask GSK, which recently had to pull Blenrep from the market just two weeks after flunking a confirmatory trial.

But the agency is casting its net further, recently closing off the accelerated pathway to new projects that do not already have a confirmatory trial under way. ADC Therapeutics and MEI Pharma are the latest to feel the pain, and Evaluate Vantage identifies others that need to watch out, including Iovance, Arvinas and Adaptimmune.

If too many AAs have been given away in the past, and if too many remain unconfirmed, the FDA is tackling both ends of this problem. Drugs are being pulled from the market, as several makers of PD-(L)1 MAbs found last year, and new aspirants face a higher hurdle.

Cami down the khazi

The situation was made clear last month when ADC halted investment into its anti-CD25 project camidanlumab tesirine, which had succeeded in an uncontrolled phase 2 trial in Hodgkin’s lymphoma. ADC wanted this to serve as the basis for an AA next year, but the FDA said no.

According to ADC, for the FDA to consider this pathway, “a randomised confirmatory phase 3 study must be well under way and ideally fully enrolled at the time of any BLA filing”. No such study is under way for cami, and since it would take at least two years for one to be fully enrolled ADC’s AA plan has effectively been abandoned.

This week MEI Pharma discontinued efforts to develop zandelisib outside Japan, deciding to wind down the phase 3 Coastal study of this PI3K inhibitor. This came after the FDA had “discouraged” the company from filing on the basis of phase 2 data, and after an April adcom voted against any further accelerated approvals of PI3K inhibitors based on uncontrolled trials.

If Mirati investors winced at this development you can hardly blame them: the company’s adagrasib is probably the most prominent oncology project currently awaiting AA, due by December 14. But a confirmatory phase 3 study, Krystal-12, is enrolling; though its precise recruitment status is unclear it certainly meets the criterion of being well under way.

Likewise Abbvie, which filed epcoritamab on the basis of the phase 1/2 Epcore NHL-1 study, and pointed out that phase 3 monotherapy and combo trials were already ongoing.

The situation is less clear for Iovance, which has endured a litany of delays with its TIL project lifileucel, the last of which saw a BLA put back from 2022 to the first quarter of next year. A confirmatory phase 3 Keytruda combo study is to begin in late 2022, and is “expected to be well under way”, Iovance says, by the time a potential approval comes in late 2023.

Adaptimmune plans to complete a rolling BLA for afami-cel in synovial sarcoma and myxoid/round cell liposarcoma next year, based on the phase 2 Spearhead-1 trial. A confirmatory study has not begun, however. And Arvinas investors hope that the AR degrader bavdegalutamide can be filed once the phase 1/2 Ardent study in prostate cancer yields 100 patients’ worth of data, but here too there is no sign of a phase 3 trial.

US accelerated approvals (AAs): 10 projects to watch*
Project Mechanism Company Study possibly backing AA Comment/confirmatory ph3 trial
Adagrasib Kras G12C inhibitor Mirati Krystal-1, NSCLC 14 Dec 2022 Pdufa; Krystal-12 enrolling
Epcoritamab Anti-CD20 T-cell engager Abbvie/Genmab Epcore NHL-1, non-Hodgkin's lymphoma 21 May 2023 PdufaEpcore DLBCL-1 enrolling
Lifileucel TIL therapy Iovance Biotherapeutics Ph2 C-144-01, melanoma BLA filing delayed to Q1 2023; ph3 Keytruda combo trial to start late 2022
Afami-cel Anti-Mage-A4 eTCR Adaptimmune Spearhead-1, sarcoma BLA filing planned Q4 2022; no confirmatory trial evident
Granite-001 mRNA neoantigen therapy Gritstone Bio Ph2/3 study in colorectal cancer; preliminary ph2 data due Q4 2023
Obe-cel Anti-CD19 Car-T therapy Autolus Therapeutics Felix, adult ALL Reportedly positive interim analysis Dec 2022; no confirmatory trial evident
Zipalertinib (CLN-081) EGFR exon 20 inhibitor Otsuka (bought back from Cullinan) Pivotal ph2 NSCLC study started in Q4 2022 (no entry) No confirmatory trial evident
Bavdegalutamide (ARV-110) Protac AR degrader Arvinas Ardent, mCRPC No confirmatory trial evident
STRO-002 Anti-FRα ADC Sutro Registrational ph2 plan to be decided by end 2022 No confirmatory trial evident
Tuspetinib (HM43239) Kinase inhibitor Aptose Biosciences Ph2 studies planned if expansion cohorts (starting Q4 2022) are supportive No confirmatory trial evident
Note: *projects identified as proceeding along an expedited pathway, through breakthrough therapy designation and/or with fast-track status, or whose makers have identified the possibility of an AA pathway. Source: Evaluate Pharma & company communication.

There are several companies that like Arvinas are still some way off filing, but which are on an expedited path and so need to start thinking now about getting a confirmatory study in place – not to mention determining whether self-funding such a trial makes economic sense in the current market.

These include Sutro with STRO-002, Otsuka with zipalertinib, Aptose with tuspetinib and Autolus with obe-cel. Most of those assets are in mid-stage trials that could, if positive, back an AA filing – and the phase 2 part of obe-cel’s Felix trial yielded apparently positive data yesterday. But none is in phase 3.

Sutro’s plight is magnified by the recent AA of Immunogen’s Elahere (like STRO-002 this is a FRα-targeting ADC), and Sutro has previously insisted that the AA pathway was a possibility for STRO-002. It now says it is in talks with the FDA over study design, and pledges to formulate a registrational plan by the end of this year.

However, Sutro faces more immediate problems than the need to get phase 3 up and running; Immunogen hopes to generate topline data from its confirmatory Mirasol trial in early 2023, and if this results in Elahere gaining full approval the AA avenue for a similarly acting project will be closed off.

The FDA had come under criticism for becoming too lenient with granting AAs and expanding the pathway’s scope, and in oncology its review of PD-(L)1 MAb approvals sent a clear message. Roche’s Tecentriq was one of several that had its wings clipped as a result, the drug being withdrawn in second-line urothelial carcinoma and having its first-line label narrowed.

Last month Tecentriq’s urothelial carcinoma indication was pulled entirely. The narrowed front-line indication was highly confusing, and the drug’s fate was sealed when final readout from Imvigor-130, the last potentially confirmatory trial that had already raised serious doubts, drew a blank.

And there are ample signs of the FDA’s retrenchment across the board: 2022’s AA tally shows a marked decline on previous years.

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