Sarfez Pharmaceuticals, Inc.

The Office of Prescription Drug Promotion (OPDP) of the U.S. Food and Drug Administration (FDA) has reviewed the promotional communications, two Soaanz webpages (webpages)1, a healthcare provider pamphlet (pamphlet), and an exhibit booth panel (exhibit panel) for SOAANZ® (torsemide) tablets, for oral use (Soaanz). The pamphlet was made available at the booth where the exhibit panel was displayed at the American College of Cardiology (ACC) Annual Scientific Session & Expo on April 6-8, 2024, and viewed by two OPDP representatives. The webpages, pamphlet, and exhibit panel make false or misleading claims and representations about the efficacy and risks associated with Soaanz. Thus, the webpages, pamphlet, and exhibit panel misbrand Soaanz within the meaning of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and make its distribution violative. 21 U.S.C. 352(a), (n); 321(n); 331(a). See 21 CFR 202.1 (e)(3)(i); (e)(5); (e)(7)(viii). In addition, these materials were not submitted at the time of initial dissemination or publication as required by 21 CFR 314.81(b)(3)(i). These violations are especially concerning from a public health perspective because the promotional communications misrepresent both the efficacy and risk profile of Soaanz, a product with multiple contraindications and warnings and precautions, that is indicated to treat edema associated with heart failure or renal disease in adults. Both heart failure and renal disease are complex, debilitating medical conditions that disproportionately affect vulnerable populations (e.g., elderly patients) and represent significant public health concerns.

Below are the indication and summary of the most serious risks associated with the use of Soaanz.2 According to the INDICATIONS AND USAGE section of the FDA-approved prescribing information (PI)3:

SOAANZ is indicated in adults for the treatment of edema associated with heart failure or renal disease.

Soaanz is contraindicated in patients with known hypersensitivity to Soaanz, in patients who are anuric, and in patients with hepatic coma. The PI for Soaanz contains warnings and precautions regarding hypotension and worsening renal function, electrolyte and metabolic abnormalities, and ototoxicity. Discontinuation of therapy due to adverse reactions occurred in 6% of patients treated with Soaanz.

OPDP notes that our advisory comments dated May 6, 2022, to Sarfez addressed draft promotional communications for Soaanz (b)(4). We are concerned that Sarfez continues to promote Soaanz as more favorable to other loop diuretics, including other torsemide products, when this has not been demonstrated, as well as failing to present the benefits and serious risks of the drug in a truthful and non-misleading manner, despite OPDP’s prior comments.

Prescription drug advertisements and labeling (promotional communications) misbrand a drug if they are false or misleading with respect to efficacy and risks. The determination of whether promotional communications are misleading includes, among other things, not only representations made or suggested in promotional communications, but also failure to reveal facts that are material in light of the representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested in the materials.

The webpages make the following claims and representations regarding Soaanz (emphasisoriginal):

“Slow Drug Release Novel Torsemide Formulation May Help Patients With Bladder Sensitivity” (soaanz.com)

“SOAANZ May Help Patients Who Experience Worsening Bladder Problems With The Use Of Generic Loop Diuretics.” (soaanz.com)

“If you are a heart failure patient experiencing bladder issues from generic loop diuretics, SOAANZ may help.” (soaanz.com)

“Key Benefits Of SOAANZ:”o “SOAANZ does not cause excessive or acute urination but retains diuretic effectiveness.” “Have a look at some key benefits of SOAANZ: . . .• Causes No Excessive Urination• Maintains Natriuresis For Up to 8 hours.” (soaanz.com)

“No excessive urination” (sarfez.com)

“Specially formulated for patients whose bladder symptoms get worse with the use of a loop diuretic; or haveo persistent edemao symptoms of worsening heart failureo problem of excessive urinationo developed hypokalemia” (sarfez.com)

“Benefits of SOAANZ®. . .o May help with incidences of hypokalemiao May reduce excessive urination” (sarfez.com)In addition, the webpages include an embedded video that states (in pertinent part):

“If you have heart failure and are taking a furosemide-class diuretic, but excessive urination is affecting your daily life try SOAANZ”

The pamphlet4 makes additional claims and representations regarding Soaanz. For example, (emphasis original; footnotes omitted):

Page one

“Prevents sudden and excessive urination while maintaining diuretic efficacy.”

“Try SOAANZ®o If patients continue to experience: Refractory edema Signs of worsening HF5 Worsening bladder problems”

“Features of SOAANZ®o Reduces peak urination . . .o Does not cause excessive urination”

Page two

“Maintains natriuretic efficacy”

“Reduces peak urination by 30%”

Page three

“No acute and excessive urination”

“Maintains diuretic efficacy”

“Induces natriuresis for up to 8h”

“SOAANZo May help patients whose bladder problems get worse with the use of a generic loop diuretic.”

Page four

“SOAANZ releases drug slowly and does not cause excessive or abrupt urination”o This headline claim is accompanied by three graphical depictions of drug release and urine excretion for generic torsemide vs. Soaanz. One of the graphical depictions, titled “Lower Acute Diuresis,” include two bar graphs that compare urine volume over specific time points for 20 mg Torsemide vs. 20 mg Soaanz. The graph on the left presents urine volume for hours 0-2 and hours 8-13. The graph on the right presents urine volume for hours 0-23.

The exhibit panel includes the following claims presented in conjunction with the proprietary and established names for Soaanz (emphasis original, footnote omitted):

“NO EXCESSIVE URINATION”

“May benefit heart failure patients who feel sudden need to urinate with use of a loop diuretic”

These claims create a misleading representation of the drug by misrepresenting the “Key benefits of SOAANZ” (emphasis original). Specifically, these claims represent that Soaanz is “specially formulated for patients whose bladder symptoms get worse with the use of a loop diuretic” because, unlike other loop diuretics, it “reduces peak urination,” “does not cause excessive or abrupt urination,” and “does not cause excessive or acute urination butretains diuretic effectiveness” when this has not been demonstrated. The bioavailability study used to support the approval of Soaanz, compared the bioavailability of torsemide between Soaanz and Demadex (torsemide). The study was designed to collect urine from patients using Soaanz and from patients using Demadex over 23 hours at pre-specified time intervals. Study participants were encouraged to empty their bladder at those time points. Such pre-specified urine collection time points do not reflect the frequency or urgency of urination, nor do they support the ability to specify the precise time at which peak diuretic activity takes place. Consequently, the bioavailability study does not provide evidence to suggest that reductions in peak urination from Soaanz compared to torsemide or other loop diuretics results in a clinically meaningful reduction in the frequency or urgency of urination. Moreover, this study does not support the conclusion that Soaanz reduces or does not cause “excessive urination.” OPDP notes that during the 23-hour collection period (i.e., the approximate dosing interval used for both torsemide products (Soaanz and Demadex) in the bioavailability study), the mean urine volume collected was similar between Soaanz and torsemide (4369 mL vs 4552 mL, respectively). Therefore, the bioavailability study does not provide evidence to suggest that there is a clinically meaningful difference in the drugs’ effect on urine production (diuresis).

In addition, the bar graphs on page four of the pamphlet with the title “Lower Acute Diuresis” compare urine volume excretion from 20 mg Soaanz vs. 20 mg Torsemide and suggest that Soaanz will result in decreased acute diuresis as compared to the referenced listed torsemide drug. However, the graph on the left selectively presents more favorable data for Soaanz and mispresents the findings from the bioavailability study used to support approval of Soaanz. Specifically, this graph includes data for earlier time frames in which Soaanz was associated with lower urine volume excretion than torsemide (t=0-2hrs) and select later time frames in which it was slightly higher (t=8-13hrs). However, intermediate time frames in which Soaanz was associated with higher urine volume excretion (t=2-8 hours) are not presented. The omission of this data misleadingly suggests that Soaanz does not cause “excessive urination,” and that urine output volume with Soaanz was only higher than torsemide after eight hours post-dose, when the bioavailability study did not demonstrate this.

Furthermore, claims that Soaanz may help, “if you are a heart failure patient experiencing bladder issues from generic loop diuretics,” or if you are a “patient[] whose bladder problems get worse with the use of a generic loop diuretic,” and that Soaanz is “specially formulated” for patients who have “persistent edema,” “refractory edema,” “symptoms of worsening heart failure,” “signs of worsening HF,” “problem[s] of excessive urination,” or who “developed hypokalemia” misleadingly suggest that Soaanz is superior to generic loop diuretics due to its pharmacologic profile, when this has not been demonstrated. No references are cited to support these claims of superiority, nor are we aware of data to support these claims. The bioavailability study used to support the approval of Soaanz does not provide evidence to support suggestions that there are clinically meaningful differences between Soaanz and torsemide with respect to persistent or refractory edema, signs or symptoms of worsening heart failure, or problems with excessive urination, or hypokalemia. Therefore, the claims suggesting that Soaanz is superior to generic loop diuretics are misleading.

The claims cited from the website and pamphlet above, also misleadingly represent that Soaanz can uniquely help patients with heart failure that are using a loop diuretic by mitigating “bladder issues,” “bladder problems,” “bladder sensitivity,” or “hypokalemia.” However, the bioavailability study was not designed to collect information reflecting patient benefits with respect to bladder issues, bladder problems, or bladder sensitivity. As noted above, urine was collected at pre-specified intervals and participants were encouraged to empty their bladder at those intervals; therefore, the bioavailability study collection timepoints are not reflective of helping these patients by mitigating bladder-related issues, problems, or sensitivity. Moreover, according to the WARNINGS AND PRECAUTIONS, Electrolyte and Metabolic Abnormalities section of the Soaanz PI, “SOAANZ can cause potentially symptomatic hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, and hypochloremic alkalosis. . . .” (underlined emphasis added). These claims which represent that Soaanz provides a benefit for patients by mitigating “bladder issues,” “bladder problems,” “bladder sensitivity,” or “hypokalemia” are also misleading.

Finally, claims that Soaanz, “maintains natriuretic efficacy,” “induces natriuresis for up to 8h,” and “maintains natriuresis for up to 8 hours” misleadingly represent that Soaanz has shown a benefit regarding natriuretic efficacy, when this has not been demonstrated. The study cited6 in support of some of these claims precludes the drawing of conclusions regarding Soaanz and its impact on natriuresis or natriuretic efficacy. For example, this crossover study had a limited sample size of only 10 healthy subjects who received 1 dose of each torsemide formulation. The study does not support conclusions regarding the natriuretic effect of Soaanz in patients with edema associated with heart failure or renal disease. In fact, the study notes (in pertinent part), “Further studies over a more prolonged period in target patient populations will be required to test whether these short-term beneficial effects in healthy subjects translate into enhanced therapeutic efficacy.” Consequently, these claims, which represent that Soaanz has demonstrated a benefit regarding natriuretic efficacy, are misleading.

For all these reasons, the claims cited above create misleading representations and suggestions of the drug by misrepresenting the efficacy and risk profile of Soaanz. FDA is not aware of evidence to support representations and suggestions that pharmacologic differences between Soaanz and other loop-diuretic class drugs, including torsemide, result in clinically meaningful differences in diuresis (including frequency and urgency of urination), electrolyte abnormalities associated with loop diuretics, or natriuresis. If you have data to support these claims, please submit them to FDA for review. We acknowledge that the pamphlet includes the following footnote on page one (in pertinent part), “[SOAANZ] is not studied in patients with bladder problems (or OAB7).” We also acknowledge that the exhibit panel includes the following statement in small font towards the bottom of the panel (emphasis original), “Disclaimer: Inferential claim; SOAANZ is not studied in patients with bladder instability.” However, neither the footnote in the pamphlet nor the statement on the exhibit panel mitigate the misleading representations made or suggested by these promotional communications.

The exhibit panel makes the following statement about the use of Soaanz (footnote omitted):

“May benefit heart failure patients who feel sudden need to urinate with use of a loop diuretic”

This claim omits material information from the full FDA-approved indication for Soaanz and misleadingly represents Soaanz’s effectiveness in heart failure patients. Specifically, the INDICATIONS AND USAGE section of the PI states the following (underlined emphasis added):

SOAANZ is indicated in adults for the treatment of edema associated with heart failure or renal disease.

By failing to disclose this material information from the INDICATIONS AND USAGE section of the PI, the exhibit panel creates a misleading representation about the drug’s FDA-approved indication.

Promotional communications misbrand a drug if they are false or misleading with respect to risk. The determination of whether promotional communications are misleading includes, among other things, not only representations made or suggested in promotional communication, but also failure to reveal facts that are material in light of the representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested in the materials.

The exhibit panel contains claims about the benefits of Soaanz, as discussed above, but fails to include any risk information about the drug. By omitting the risks associated with Soaanz, the exhibit panel fails to provide material information about the consequences that may result from the use of Soaanz and therefore misleadingly represents the drug’s risks.

The webpages and pamphlet include claims such as, “Causes no excessive urination”, “Does not cause excessive urination” and “No excessive urination.” These claims misleadingly minimize the serious risks caused by excessive urination as discussed in the WARNINGS AND PRECAUTIONS, Hypotension and Worsening Renal Function section of the PI for Soaanz. That section states: “Excessive diuresis may cause potentially symptomatic dehydration, blood volume reduction, and hypotension and worsening renal function including acute renal failure particularly in salt-depleted patients or those taking renin-angiotensin aldosterone inhibitors.” (in pertinent part, underlined emphasis added). By stating that Soaanz, “causes no excessive urination” or “does not cause excessive urination,” the promotional communications undermine the serious risks of dehydration, blood volume reduction, hypotension, and worsening renal function associated with Soaanz. FDA is not aware of data to support claims that Soaanz has a different safety profile than other torsemide products. If you have data to support these claims, please submit them to FDA for review.

FDA regulations require any labeling or advertising devised for promotion of the drug product to be submitted at the time of initial dissemination of the labeling and at the time of initial publication of the advertisement for a prescription drug product. Each submission is required to be accompanied by a completed transmittal Form FDA-2253 (Transmittal of Advertisements and Promotional Labeling for Drugs for Human Use) and is required to include a copy of the product’s current professional labeling. A copy of the webpages, pamphlet, and exhibit panel were not submitted to OPDP under cover of Form FDA-2253 at the time of initial dissemination or publication as required by 21 CFR 314.81(b)(3)(i).

For the reasons discussed above, the webpages, pamphlet, and exhibit panel misbrand Soaanz within the meaning of the FD&C Act and make its distribution violative. 21 U.S.C. 352(a), (n); 321(n); 331(a). See 21 CFR 202.1(e)(3)(i); (e)(5); (e)(7)(viii). Furthermore, Sarfez did not comply with 21 CFR 314.81(b)(3)(i).

This letter notifies you of our concerns and provides you with an opportunity to address them. OPDP requests that Sarfez cease any violations of the FD&C Act. Please submit a written response to this letter within 15 working days from the date of receipt, addressing the concerns described in this letter, listing all other promotional communications (with the 2253 submission date) for Soaanz that contain representations such as those described above, and explaining your plan for the timely discontinuation of such communications, or for ceasing distribution of Soaanz.

Failure to adequately address this matter may lead to regulatory action. If you believe that your products are not in violation of the FD&C Act, please include in your submission to us your reasoning and any supporting information for our consideration within 15 working days from the date of receipt of this letter.

Additionally, we request that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective communication(s) about the concerns discussed in this letter. The corrective communication(s) should be disseminated to the audience(s) that received the promotional communications identified in the opening paragraph of this letter. OPDP recommends that corrective communication(s) include a description of the promotional communication(s) identified in this letter, which misbrand Soaanz; include a summary of the concerns described in this letter; and provide information to correct each of these concerns. Corrective communication(s) should be free of promotional claims and presentations. To the extent possible, corrective communication(s) should be distributed using the same media, and generally for the same duration of time and with the same frequency as the promotional communication(s) identified in the opening paragraph of this letter.

The concerns discussed in this letter do not necessarily constitute an exhaustive list of potential violations. It is your responsibility to ensure compliance with each applicable requirement of the FD&C Act and FDA implementing regulations.

Please direct your response to the undersigned at the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Prescription Drug Promotion, 5901-B Ammendale Road, Beltsville, Maryland 20705-1266. A courtesy copy can be sent by facsimile to (301) 847-8444. Please refer to MA 6 in addition to the NDA number in all future correspondence relating to this particular matter. All correspondence should include a subject line that clearly identifies the submission as a Response to Warning Letter. You are encouraged, but not required, to submit your response in eCTD format. All correspondence submitted in response to this letter should be placed under eCTD Heading 1.15.1.6.

Questions related to the submission of your response letter should be emailed to the OPDP Regulatory Project Manager at CDER-OPDP-RPM@fda.hhs.gov.