Acetylcysteine

The FDA asserts that it released the complete response letters in a bid to “modernize and increase transparency.” When the FDA unexpectedly uploaded around 200 drug rejection letters this week, the regulator provided an in-depth view into the high-stakes discussions that decide whether a medicine will ever make it to market.  The FDA said it released the complete response letters (CRLs) on Thursday morning as part of an effort to “modernize and increase transparency” at the agency. We’ve typically had to rely on the companies themselves to communicate the FDA's rejection rationale in the immediate aftermath of the decisions—assuming they chose to go into any detail at all—so the FDA's document drop offered an opportunity to cross-reference agency records and public communications from pharmas.In addition, the haul of documents offers insight into not only the rationale the FDA employs during its reviews, but also the language the agency uses to communicate these decisions.If you don’t have a spare weekend to read through hundreds of pages of letters, then have no fear; The Fierce Biotech and Fierce Pharma teams have trawled through the documents ourselves and selected some of the examples that we found most enlightening. One caveat to note: Most drugmakers are reasonably transparent when hit with a CRL, and given that the products involved in the initial batch of published responses are all now approved, the FDA’s previous comments don’t reflect the current status of the drugs in question, analysts at Evercore ISI noted in a webinar Friday.“Good companies have no incentive to be tricksy,” given that the information will eventually come out if their drug passes muster at the FDA, Evercore’s Jonathan Miller said on the call.Still, while several companies' press releases “didn’t fully capture” what was disclosed in their respective FDA response letters, “those are absolutely the exception,” he stressed, adding that “the majority of CRLs are well reported.” Response letters are typically tucked into drug approval packages, so most of the information published by the FDA was previously accessible, albeit cumbersome to access. Consolidating the letters certainly makes it easier for the public to glean the FDA’s rationale, though releasing rejection notices for unapproved drugs would represent a greater step toward full transparency.A ‘concerning reduction’ in growth Pfizer’s rare disease strategy suffered an unexpected setback in 2022 when the FDA rejected Ngenla (somatrogon), a potential treatment for pediatric growth hormone deficiency. The CRL came as a surprise—given the drug had already been approved in Japan, Australia and Canada—and Pfizer’s announcement offered no insight into the agency’s decision. But the FDA’s letter now reveals that one of the key reasons for the agency’s decision was a single individual in a phase 3 open-label trial who developed a “concerning reduction” in annualized height velocity (AHV)—in other words, their growth had slowed.  “There are insufficient follow-up data to determine whether the reduction in AHV in this patient was caused by immunogenicity, and we consider attenuation of effectiveness due to immunogenicity to be a potential risk at this time,” the FDA explained in its letter.  The agency requested that Pfizer “provide reassurance that the anti-drug antibody formation caused by [somatrogon] is not expected to have an impact on long-term growth achieved with [somatrogon] and does not interfere with other recombinant human growth hormone formulations.” The FDA was presumably reassured by the data Pfizer included as part of its resubmission, as the pharma eventually secured approval of Ngenla the following year. In poor taste Sometimes, the reason for a drug’s rejection can leave a bad taste in the mouth—literally. When considering a request from Galephar Pharmaceutical to approve Legubeti as an oral solution for acetaminophen overdose, the FDA noted that Legubeti’s long-approved ingredient, N-acetylcysteine, “has an unpleasant odor that may affect the tolerability of oral ingestion.”“Because timely administration of acetylcysteine is essential to mitigate toxicity from acetaminophen overdose, uncertainty remains as to whether ingestion of the full Legubeti dose can be administered, either due to inadequate palatability or inadequate tolerability,” the FDA said in its May 2023 letter. Bad taste or not, Legubeti was later approved by the FDA in 2024.  Cardiovascular risk When Amgen and UCB’s application for Evenity (romosozumab) as a treatment for postmenopausal women with osteoporosis was knocked back by the FDA in 2017, it was no secret that one of the factors at play was an increase in cardiovascular risks identified in two studies. However, when Amgen described the feedback received in the CRL, the pharma was less clear-cut, only referring to the agency’s request to submit more efficacy and safety data from its various phase 3 studies. In fact, the CRL itself confirms that the FDA did indeed home in specifically on the cardiovascular risks when explaining the rational for the rejection, pointing explicitly to preliminary findings from the phase 3 Arch study, which it said showed “a higher incidence of cardiovascular serious adverse events with romosozumab compared to alendronate in women with postmenopausal osteoporosis.” A “similar signal” was seen in the Bridge study, the FDA also noted in the letter.  “These findings raise concerns that romosozumab may increase cardiovascular risk,” the FDA added. “Although [the Frame phase 3 study] did not appear to have a cardiovascular safety signal, these disparate findings across studies require detailed review once the completed final analyses have been submitted.” Evenity was eventually approved in 2019 with a boxed warning for the risk of stroke, heart attack, and cardiovascular death. ‘Weak and contradictory' evidence Sometimes it’s not what you say, but how you say it. That’s certainly one reason why the FDA’s letter to Orphazyme is interesting. When the Danish biopharma’s application for Miplyffa (arimoclomol) in the rare lysosomal storage disorder Niemann-Pick disease type C was rejected in 2021, Orphazyme was open about the fact that “additional qualitative and quantitative evidence” had been requested in a number of areas, including the validity and interpretation of its primary endpoint, along with additional data to support a benefit-risk assessment.  In its letter, we can now see that the FDA was even blunter in its own language. The agency branded the company’s submitted evidence for Miplyffa’s effectiveness as “weak and contradictory” a total of three times in the same letter and stressed that it had already identified various concerns with the primary endpoint measurement “at several time points during your [investigational new drug] development.”  The letter went on to list the various times the FDA had tried to hammer home its concerns, before noting that—“despite our advice”—the requested data had not been included in the final drug application. Orphazyme's CRL was "one of the ones where it got a little bit spicy," said Evercore's Miller, who noted that the rejection potentially offers "the first example here where I would say there's some suspect decision-making at the company." The FDA document can’t have been easy reading at Orphazyme’s Copenhagen HQ, and the company was eventually acquired in full by KemPharm. Luckily, Miplyffa’s story didn’t end there and KemPharm, which rebranded as Zevra Therapeutics, went on to see the med become the first approved treatment for Niemann-Pick disease type C. Third-party data concerns In other instances, the CRLs highlighted shortfalls by contract development and manufacturing organizations (CDMOs), which often go unnamed in FDA and company communications.  When Checkpoint Therapeutics received a rejection for its oncology asset cosibelimab in late 2023, the company attributed the FDA’s decision to issues uncovered during an inspection of a  “third-party contract manufacturing organization.”  That manufacturer, as the company’s CRL shows, was Samsung Biologics. Samsung Bio offered remediation solutions after the FDA uncovered problems during an inspection of one of its production facilities in Incheon, South Korea, but the FDA stated in its complete response letter to Checkpoint that “not all deficiencies have been satisfactorily resolved.”  Samsung Bio's response to the inspection findings didn’t sit right with the FDA, which asserted in the CRL that it had “identified concerns regarding the reliability of data generated at Samsung Biologics."“The concerns impact data that support drug substance and drug product manufacturing process validation and process characterization,” the FDA said in its rejection notice. “Therefore, the adequacy of the proposed cosibelimab manufacturing process and overall control strategy cannot be determined at this time to support the licensure of cosibelimab.”  Checkpoint’s PD-L1 inhibitor, cosibelimab, ultimately secured FDA approval last December as a new treatment option for certain types of cutaneous squamous cell carcinoma.