The wait is finally over. On June 7, 2023, after remaining silent for over an entire year, the US Food and Drug Administration (“FDA”) Office of Prescription Drug Promotion (“OPDP”) issued its first untitled letter of 2023 to Xeris Pharmaceuticals, Inc. (“Xeris”).[1] The untitled letter involved promotional communications for Recorlev^® (levoketoconazole) tablets for oral use (“Recorlev”) and focused on two of its consumer webpages.[2]

Recorlev is indicated for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s Syndrome for whom surgery is not an option or has not been curative, and further contains a limitation of use regarding fungal infections. OPDP wrote that, for the reasons discussed below, the promotional communications make false or misleading claims and representations about the safety and efficacy of Recorlev. Furthermore, these claims raise public health concerns because the drug has a number of serious and potentially life-threatening risks, including boxed warnings regarding risks of hepatotoxicity and QT prolongation.

False or Misleading Claims about Efficacy

OPDP focused on three key areas of the promotional materials in concluding that the materials created false or misleading claims about efficacy.

OPDP’s first concern was the misrepresentation of the clinical study results in the claim on the “What is Recorlev?” webpage that read:

• The SONICS clinical study supported the efficacy and safety results from LOGICS”
  • “31% of patients had normal cortisol levels after taking Recorlev for 6 months without changing their dose.”
  • “67% of patients who moved on to the second part of the study had normal cortisol levels by the end of the study.”

OPDP determined that this claim overstates the efficacy of Recorlev based upon the CLINICAL STUDIES section of the PI. The SONICS study (Study 2 in the PI) consisted of three phases, including dose titration, maintenance, and extended evaluation, and the primary efficacy endpoint was a measure of uric acid cortisol at the end of the 6-month maintenance phase. According to data from the study, by the end of the titration phase, 67% of patients (i.e., 63 of the original 94 patients that began the titration phase) had normal cortisol levels. Importantly, however, only 77 patients moved from the titration phase to the maintenance phase. So, by the end of the maintenance phase, only 38% (i.e., 29 of the 77 patients that moved from the titration of maintenance phase) of patients had normal cortisol levels, and by the end of extended evaluation phase, only 21% (i.e., 16 of 77) of patients had normal cortisol levels. By selecting the results from the end of the titration phase, which was not the “end of the study,” OPDP found that Xeris had plainly overstated the efficacy of the drug.

OPDP’s second concern was that the page omitted information necessary to interpret results from the SONICS study. Near the end of the section describing the SONICS study, the PI notes that the results should be interpreted with caution, as 51% of patients discontinued treatment prematurely due to adverse reaction, lack of efficacy, or other reasons. This omission creates a misleading impression about the drug’s efficacy because it undermines the reader’s ability to understand and evaluate the study results with the proper context.

OPDP’s third concern was the misleading impression created by the claim on the “What is Recorlev?” webpage, which read:

“Recorlev – More patients (52%) who were on a stable and steady dose of Recorlev had normal cortisol levels.”

ODPD determined that the claim created a misleading impression regarding the efficacy of Recorlev, based upon data from the CLINICAL STUDIES section of the PI. The 52% (i.e., 11 of the 21 patients on Recorlev in the withdrawal phase) claim implies that the results represent the general experience of patients with the drug, when in reality the results presented were based on a small, select subset of patients in the study who demonstrated that they were able to tolerate the drug. The LOGICS study (Study 1 in the PI) consisted of two phases, a dose titration and maintenance dose followed by a randomized withdrawal phase. Seventy-nine patients entered the dose titration and maintenance phase, and only those who achieved a stable therapeutic dose for at least 4 weeks and a normal mean urinary free cortisol at the end of the phase were eligible for the withdrawal phase. Only 39 patients entered the withdrawal phase, as over half of those who entered the titration and maintenance phase discontinued for various reasons (including adverse reactions and lack of efficacy). So, 52% of the withdrawal group receiving Recorlev achieved normal cortisol levels at the end of the withdrawal phase (i.e., 11 of the 21 patients who were randomized to Recorlev from the 39 who entered the withdrawal phase). OPDP concluded that it was misleading to suggest that the results from this so-called “enriched” patient population represent the general experience expected by patients taking the drug.

False or Misleading Risk Presentation

OPDP was also concerned that the promotional communications minimized the serious and significant risks associated with the use of Recorlev. The “Taking Recorlev” webpage includes the following presentation under the header “Monitoring and side effects”:

• “Monitoring”
  • “As with other medicines for Cushing’s, monitoring by your doctor is important so they know how you’re doing
  • Heart and liver tests before and during treatment with Recorlev will help your doctor avoid side effects”
• “Possible side effects”
  • “[s]ide effects can occur with Recorlev, including some that are serious.”

OPDP concluded that this claim understates the serious and significant side effects associated with the use of Recorlev because the communications failed to discuss information regarding Recorlev’s boxed warnings or specific side effects associates with the drug, including those that are potentially fatal. As noted earlier, boxed warnings for the product include hepatotoxicity, which has been associated with fatal outcomes or the need for liver transplantation, and QT prolongation, which has caused life-threatening ventricular dysrhythmias. Furthermore, the presentation suggests that heart and liver tests alone will enable patients to “avoid” side effects. OPDP shows heightened concern over the webpage’s presentation considering that a number of patients in the clinical studies experienced these potentially life-threatening side effects. Specifically, per the WARNINGS AND PRECAUTIONS section of the PI, 13% of patients using Recorlev suffered drug-induced liver injury, and 14.7% of patients experienced a change in baseline QT interval. Additionally, the PI notes that other serious, adverse reactions unrelated to the heart and liver occurred in over 20% of patients treated with the drug.

What Does This Tell Us?

Issuing their last untitled letter in June of 2022, OPDP has given us little insight into their priorities for over a year now, and it was widely pondered among industry whether OPDP would be writing letters at all this year. Unsurprisingly, the much-anticipated first untitled letter of the year involved violations that OPDP felt presented serious public health risks and focused on the familiar themes of false or misleading benefit and risk presentation. OPDP seemed particularly concerned with misleading claims regarding the efficacy of Recorlev, especially the claims that overstated percentages (like saying 67%, instead of 21% of patients who moved onto the second phase of Study 2 had normal cortisol levels). To compound concerns, these claims were used to bolster the results of Study 1, from which Xeris also made misleading claims. And of course, safety minimization—especially when combined with mischaracterization and presented in an overall misleading fashion—will set OPDP’s radar to high alert. OPDP’s focus on the misleading claims of both efficacy and risk suggest a heightened concern for the patient, considering the drug carries with it potentially life-threatening side effects.

Like all three of last year’s untitled letters, the Recorlev letter concerned materials that were submitted under Form2253, which pharmaceutical manufacturers are required to use to submit all promotional materials at the time of first use. Although, one such Untitled Letter in 2022 was prompted, in part, by an alert through the Bad Ad Program, suggesting more eyes than just OPDP’s are watching.[3]

Moving into the back half of 2023, will we get more nuanced enforcement with concepts that surround the consistent with label guidance (see 2022 warning letters for Trulicity®[4], Duobrii[5]—which we covered in our blog post here; and Roszet[6]—which we covered in our blog post here). Or, will OPDP continue to concentrate on low-hanging fruit, singling out the most noticeable violations that present the greatest concern for public health? It certainly remains to be seen, and meantime, industry will be watching closely.

[1] Untitled Letter available here: Untitled Letter Recorlev (fda.gov)

[2] Promotional Material available here: Recorlev Promotional Material (fda.gov)

[3] 2022 Untitled Letter available here: NOV Letter | TRULICITY® (dulaglutide) injection, for subcutaneous use (fda.gov)

[4] Untitled Letter available here: NOV Letter | TRULICITY® (dulaglutide) injection, for subcutaneous use (fda.gov)

[5] Untitled Letter available here: Untitled Letter DUOBRII (fda.gov)

[6] Untitled Letter available here: Untitled Letter Roszet (fda.gov)

Julian Klein contributed to this article.