Key Takeaways
- The US FDA issued 16 complete response letters for novel agents in 2024, but one of the impacted applications already has been approved and four more have been resubmitted.
- By the end of 2024, the FDA approved 11 of the 21 novel agents that received CRLs in 2023.
- CRLs roughly are split between clinical and quality topics, but substantial clinical concerns require the longest and most extensive efforts to continue development.
The US Food and Drug Administration maintained a high rate of complete response letter actions for novel agent applications in 2024, but recent history suggests that many of the 16 CRL recipients will return for approval in 2025.
CRLs are never welcome, but many products are resubmitted and approved within a relatively short time. Indeed, Astellas addressed inspection deficiencies at a third-party manufacturer cited in a January 2024 CRL quickly enough that its gastrointestinal oncologic Vyloy (zolbetuximab-clzb) received approval in October.
By the end of 2024, the FDA had cleared 11 of the 21 novel agents known to have received CRLs in 2023, the Pink Sheet’s US FDA Performance Tracker Complete Response Letters tracker shows.
Another two candidates from the 2023 CRL cohort are eyeing 2025 approvals. Aldeyra’s dry eye drug reproxalap has a 2 April goal date and an expanded AbbVie option agreement. Outlook Therapeutics intends to refile Lytenava (bevacizumab gamma) for wet age-related macular degeneration in the first quarter of 2025.
Over the last year, the agency also issued 16 CRLs to novel agents. When combined with the FDA’s 61 novel approvals, the CRL rate for 2024 was 21%. At least two of every 10 agency decisions on novel agents resulted in a CRL for the fourth straight year.
The declining percentage of first-cycle approvals in the annual novel cohorts reflects the slow and steady rise in CRLs. Only 77% of the 2024 novel agents made it to approval on a single cycle, the lowest rate in a decade.
But CRLs of the past can become the second-, third- and even fourth-cycle approvals of the present.
In 2024, almost a quarter of the novel approvals required more than one review cycle. The median review time for the 14 multicycle approvals was 26.7 months from original submission to approval, much higher than the 8.6-month median for first-cycle approvals, but not absurdly high.
Back Already
As 2025 starts, the resubmitted applications of four 2024 CRL recipients are under FDA review.
Elevar/Hengrui Pharma’s camrelizumab and Elevar’s rivoceranib, a novel/novel combination for hepatocellular carcinoma, are on track for FDA action by 20 March after resubmitting with responses to the agency’s manufacturing and bioresearch monitoring concerns.
Abeona’s cell therapy prademagene zamikeracel has a 29 April second cycle goal date for recessive dystrophic epidermolysis bullosa. The resubmission addresses the FDA’s requests for additional chemistry, manufacturing and controls information on methods validation and inspection observations.
Regeneron announced the resubmission of its bispecific antibody linvoseltamab BLA for multiple myeloma on 13 January at the JP Morgan conference. The third-party fill/finish manufacturer cited in the CRL currently is in compliance, the company said. Linvoseltamab likely has user fee goal date in July or earlier.
Regeneron struck out with new bispecific antibodies in 2024, also receiving CRLs for BLAs for the accelerated approval of odronextamab in two hematologic cancer settings, follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). The FDA determined the confirmatory Phase III trial program was not sufficiently underway.
Regeneron said the BLA in FL is advancing with “enrollment underway for a confirmatory study to support resubmission of the BLA for FL to the FDA in the first quarter of 2025.”
Odronextamab was approved in the European Union as Ordspono for both FL and DLBCL.
Rocket Pharmaceuticals has consistently emphasized the “limited additional CMC information” requested in the CRL for the LAD-I gene therapy Kresladi. The company “continues to work with senior leaders and reviewers” at the FDA. Rocket predicts FDA approval of Kresladi in 2025.
Merck listed the HER3-DXd antibody-drug conjugate patritumab deruxtecan as a potential 2025 approval in lung cancer at the JP Morgan conference. Merck is partnered with Daiichi Sankyo on the ADC, which received a CRL citing inspection findings at a third-party manufacturing site.
Patritumab deruxtecan uses the same Daiichi Sankyo antibody-drug conjugate technology, DXd ADC, as two Daiichi Sankyo/AstraZeneca breast cancer therapies: the blockbuster Enhertu (trastuzumab deruxtecan) and the first novel approval of 2025, Datroway (datopotamab deruxtecan-dlnk).
Clinical Vs Quality Concerns
During the recent rise in CRL rates, the letters have been roughly balanced between focusing on clinical concerns about the adequacy of the evidence of safety and efficacy and quality deficiencies in the manufacturing process. CRLs can include many types of concerns, but one category typically dominates.
In 2023, nine novel agent CRLs were related to quality issues and 10 to clinical development, while one cited a labeling problem. The reasons for one CRL were not disclosed by the sponsor.
Quality topics were more popular in 2024, reported in nine CRLs, compared with clinical issues, seen in seven. One-third of the quality CRLs involved a third-party manufacturer.
Quality deficiencies can be easier to resolve than clinical problems, especially when the FDA calls for a new clinical trial to be conducted.
In 2023, seven of the novel agent CRLs called for a new clinical trial and at least three others required significant new clinical trial data.
Two of those seven products were approved in 2024. Mesoblast’s mesenchymal stem cell therapy Ryoncil (remestemcel-L-rknd) was approved after its third review cycle and the company re-negotiated the new evidence required with the FDA. The 2023 CRL for Eli Lilly’s Alzheimer’s disease therapy Kisunla (donanemab-azbt) deemed the data insufficient for accelerated approval, so the company resubmitted with data from the study intended to be the confirmatory trial and received full approval.
Across the 14 multicycle approvals in 2024, five overcame CRLs calling for substantial new clinical data.
A 2021 FDA CRL questioning the scale used to measure disease progression in the single Phase II/III trial in the Miplyffa NDA was too much for sponsor Orphazyme, which was subsequently acquired in a fire sale by Kempharm. The new sponsor, now renamed Zevra, resubmitted with information on the scale, natural history comparisons, real-world data from early access programs in the US and EU, and four-year data from an open-label extension of the Phase II/III trial.
As recommended by a 2021 CRL, Iterum conducted a new trial of the antibiotic Orlynvah (sulopenem etzadroxil and probenecid) for uncomplicated urinary tract infections using a different comparator. The resubmitted NDA with the new trial earned FDA approval, but only for the narrow indication of women with limited or no oral treatment options.
Akebia Therapeutics engaged the FDA’s formal dispute resolution process after Vafseo (vadadustat) received a CRL in 2022 that cited safety concerns outweighing benefit in the dialysis-dependent and non-dialysis portions of the chronic kidney disease population. The Office of New Drugs denied Akebia’s request, but agreed an indication only for dialysis-dependent CKD patients would not require additional clinical data. Akebia resubmitted and was approved for the limited claim.
Hanging On
Five of the CRLs issued to novel agents in 2024 called for a new clinical trial. Two of the products seek psychiatric indications, Minerva’s roluperidone for negative symptoms of schizophrenia and Lykos’ midomafetamine (MDMA)-assisted therapy for post-traumatic stress disorder, while two others, Zealand’s glepglutide for short bowel syndrome Vanda’s tradipitant for gastroparesis, come from gastroenterology.
Novo Nordisk sought a broad label for its basal insulin icodec in type 1 and type 2 diabetics, but the FDA found the type 1 diabetes evidence lacking.
Only Zealand’s glepaglutide program is moving forward smoothly. The company expects a Type A meeting with the FDA in the first quarter, but already is planning to initiate a second Phase III trial, known as EASE-5, in the second half of the year. The study is intended to provide confirmatory evidence for US resubmission and support regulatory submissions outside the US and European Union.
Vanda quickly engaged with the agency after receiving a CRL for tradipitant, resulting in the 16 January publication of the FDA’s proposal to refuse to approve the NDA and a notice of opportunity for a hearing (NOOH) before the FDA Commissioner.
Lykos has been attending to its corporate survival after receiving a CRL for the first psychedelic NDA. The midomafetamine CRL followed a negative advisory committee meeting that highlighted explosive clinical trial conduct allegations. After significant executive and board turnover, the company on 14 January said it was committed to working towards “an aligned go-forward financing strategy.”
In the aftermath of the CRL, Lykos explored formal dispute resolution. After an October 2024 meeting, however, the company said it had agreed with the agency on “a path forward, including an additional Phase III trial, and a potential independent third-party review of prior Phase III clinical data.”
Minerva’s roluperidone NDA received a 2022 refuse-to-file letter, which was appealed. The FDA granted the appeal and filed the NDA six months later, but the review resulted in an extensive CRL that called for an additional study and called into question the submitted trial’s statistical significance, the adequacy of the safety database, and evidence that an observed effect on negative symptoms corresponds to clinically meaningful change.
“We have continued to have interactions with the FDA with the goal of addressing the questions raised in the CRL,” Minerva’s third quarter 2024 SEC filing states.
Minerva is at risk of delisting from NASDAQ, with a 31 March deadline to demonstrate compliance.
CRLs sometimes provoke financial and existential crises for small sponsors. F2G Ltd. took more than a year after a 2023 CRL for the antifungal olorofim to organize a $100m funding round. The cash will enable continued development to respond to the FDA’s request for more data.
Atara Biotherapeutics is in precarious financial shape after receiving the first novel agent CRL of 2025 for its off-the-shelf T-cell therapy Ebvallo (tabelecleucel). Ebvallo was approved by the European Medicines Agency in December 2022, but the FDA was concerned by inspection findings at a third-party manufacturing facility.
Atara partnered with Pierre Fabre to develop the product.
Split The Difference
Only part of the broad type 1 and type 2 diabetes population included in Novo Nordisk’s basal insulin icodec indication appears to have concerned the FDA’s clinical reviewers. The agency convened an advisory committee review of the type 1 diabetes claim, which concluded that hypoglycemia risk outweighed a limited benefit.
The insulin icodec CRL also cited manufacturing issues, which may have prevented a split decision, where only part of the requested indication is approved.
In 2023, the FDA returned split decisions on GlaxoSmithKline’s Jesduvroq (daprodustat) and Biogen/Sage’s Zurzuvae (zuranolone). Jesduvroq was approved for anemia of CKD in dialysis-dependent patients, but not for non-dialysis dependent CKD, while Zurzuvae was approved for postpartum depression, but received a CRL for major depression.
