The FDA’s Office of Prescription Drug Promotion (OPDP) sent a June 7 Untitled Letter to Xeris Pharmaceuticals Inc. alleging that the company made false or misleading claims and representations about the safety and efficacy of Recorlev (levoketoconazole) tablets on several consumer webpages submitted to the agency for review.

“These violations are especially concerning from a public health perspective,” OPDP said, “because the promotional communications create a misleading impression regarding the safety and effectiveness of Recorlev, a drug with a number of serious and potentially life-threatening risks, including boxed warnings regarding the risks of hepatotoxicity and QT prolongation.”

This is the first Untitled Letter that OPDP has issued since June 2, 2022. In total, OPDP issued three Untitled Letters and one Warning Letter in 2022.

In the Xeris letter, OPDP alleged that one claim — “67% of patients who moved on to the second part of the study had normal cortisol levels by the end of the study” — misleadingly overstated the efficacy of Recorlev. OPDP noted that according to the clinical studies section of the FDA-approved prescribing information (PI), the study in question “consisted of three phases (dose titration, maintenance, and extended evaluation). Out of the 94 patients who enrolled in the study and entered the dose titration phase, 77 patients ‘moved on to the second part of the study’ (i.e., maintenance phase). At the end of the maintenance phase, only 29 of those 77 (38 percent) patients had normal cortisol levels. By the end of the extended evaluation phase, the number of patients with normal cortisol levels decreased to 16 of those 77 (21 percent) patients.”

OPDP acknowledged in the letter that according to the PI, 67 percent of patients in the study had normal cortisol levels at the end of the titration phase. However, the office said, “the titration phase was not the ‘end of the study.’ In addition, regardless of whether the end of the maintenance phase or extended evaluation phase is considered the ‘end of the study,’ both phases failed to attain the results claimed on the webpage, with 38 percent and 21 percent of patients reaching normal cortisol levels, respectively, rather than 67 percent. Therefore, suggesting that 67 percent of patients who ‘moved on to the second part of the study’ had normal cortisol levels by the end of the study significantly overstates the efficacy of the product.”

OPDP Alleges Material Omitted That Is Necessary to Interpret Study Results

OPDP further alleged that the webpage presentation omitted material information necessary to interpret any results from the study. “Specifically,” the office said, “the clinical studies section of the PI states, ‘[b]ecause 51 percent of patients discontinued treatment prematurely due to adverse reaction, lack of efficacy, or other reasons, these results should be interpreted with caution.’ The omission of this material information from the webpage undermines the ability of the reader to understand and evaluate the study results presented and thereby creates a misleading impression about the drug’s efficacy.”

OPDP also cited another claim: “Recorlev — More patients (52 percent) who were on a stable and steady dose of Recorlev had normal cortisol levels.” “This claim creates a misleading impression regarding the efficacy of Recorlev,” the office said, “because it implies that the results represent the general experience of patients with the drug. On the contrary, the results presented are based on a small, select subset of patients enrolled in the study who had already demonstrated that they were able to tolerate and respond to the drug.”

Quoting from the clinical studies section of the PI, OPQP reported in the Untitled Letter that the study consisted of two phases, a dose titration and maintenance phase followed by a randomized withdrawal phase. “Seventy-nine patients entered the dose titration and maintenance phase,” the office said. “Patients who achieved a stable therapeutic dose for at least four weeks and achieved a normal mean urinary free cortisol (i.e., ‘normal cortisol levels’) at the end of the dose titration and maintenance phase were eligible for the withdrawal phase. Only 39 patients with ‘normal cortisol levels’ entered the withdrawal phase.”

“Over half of the patients who entered the titration and maintenance phase of the study discontinued for various reasons, including experiencing adverse reactions and lack of efficacy,” OPQO added. “Of the 39 patients that continued to the withdrawal phase of the study, 21 were randomized to Recorlev, and 18 to placebo. It is only out of those 21 patients in the Recorlev group (from the 79 that underwent dose titration) that 52 percent (11/21) achieved ‘normal cortisol levels’ at the end of the withdrawal phase.”

“It is misleading to suggest that the results from this enriched patient population represent the general experience expected in patients who take Recorlev,” OPDP alleged.

OPDP Alleges Serious and Significant Risks Minimized

OPDP also contended that the company’s webpage “minimizes the serious and significant risks associated with the use of Recorlev by acknowledging that ‘[s]ide effects can occur with Recorlev, including some that are serious,’ without discussing information regarding Recorlev’s boxed warnings or specific side effects associated with the drug, including those that are potentially fatal. Additionally, this presentation suggests that heart and liver tests alone will enable patients to ‘avoid’ side effects altogether.”

“The webpage’s presentation is especially concerning given that a number of patients taking Recorlev in clinical studies experienced these potentially life-threatening side effects,” OPDP said. “For example, the warnings and precautions section of the PI states that 13 percent of patients using Recorlev experienced drug-induced liver injury, and 14.7 percent of patients experienced a change-from-baseline QTcF >60 msec. The PI also notes that Recorlev is associated with multiple other serious and potentially life-threatening risks unrelated to heart or liver problems, as well as numerous common adverse reactions, many of which occurred in more than 20 percent of patients treated with the drug.”

OPDP acknowledged in the Untitled Letter that risk information for Recorlev is presented separately in the indication and important safety information” section of the webpage. “However,” OPDP said, “this does not mitigate the misleading impression created by the ‘Monitoring and side effects’ presentation because the boxed warnings are relegated to the middle of this consolidated risk section, after the contraindications and indication and use statement, and without any significant signal to alert the viewer to them.”

“The overall effect of this webpage’s presentation of risk information undermines the communication of the significant and potentially fatal risks associated with Recorlev and thereby misleadingly minimizes the risks associated with the use of Recorlev,” OPDP said.

OPDP requested that the company respond within 15 working days by addressing the office’s concerns, listing all promotional communications (with the submission date of the Form FDA 2253) for Recorlev that contained representations similar to those cited in the Untitled Letter and explaining any plan for discontinuing the use of the communications, or for ceasing distribution of the drug.

Editor’s Note: FDA Warning and Untitled Letters as well as HHS Office for Human Research Protections (OHRP) Determination Letters are available in Thompson Information Services’ FDA Enforcement Letter Database, which is available to subscribers of Thompson's FDA Compliance Expert.