A Phase 2a/b, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Study to Evaluate the Efficacy and Safety of Linustedastat (OG-6219) in Women with Moderate to Severe Endometriosis-Related Pain

Overall, 353 patients (mean age of 35.2 years) were included. No statistically significant differences were reported between linustedastat and placebo for OPP, DYS, NMPP, or dyspareunia scores or in the number of rescue medication tablets used compared to placebo (p> 0.05) at any dose. Serum estrogens levels showed statistically significant differences versus placebo at visit 5 and visit 7; serum progesterone levels showed no differences. Linustedastat was generally well tolerated, with TEAEs of mild to moderate severity. A dose-related trend of methemoglobinemia was observed.

Despite a theoretical rationale, selective inhibition of HSD17β 1 with linustedastat did not show any trends indicative of clinical efficacy in reducing ERP. Linustedastat was safe and well tolerated in pre-menopausal women with moderate to severe ERP. Clinical Trial Registration Information: A Study to Investigate Efficacy and Safety of OG-6219 BID in 3 Dose Levels Compared With Placebo in Participants Aged 18 to 49 With Moderate to Severe Endometriosis-related Pain (ELENA); NCT05560646; https://clinicaltrials.gov/study/NCT05560646.

dysmenorrhea, dyspareunia, endometriotic lesions, estrogen, HSD17β 1, overall pelvic pain

Endometriosis is a chronic, estrogen-dependent gynecological condition characterized by ectopic endometrial-like tissue, commonly presenting with pelvic pain, painful ovulation, pain radiating to the back, dysmenorrhea (DYS), dyspareunia, menorrhagia, and infertility.1,2 It affects up to 10% of women of reproductive age globally.3 Endometriosis-related pain (ERP) imposes a significant impact on patients’ quality of life and contributes to a substantial economic burden.4–8 Diagnosis is often delayed, further complicating timely treatment and increasing the overall burden on patients and healthcare systems.9,10 Current treatment options for ERP include pharmacological, surgical, and complementary therapies.11,12 Treatment remains challenging due to limited long-term efficacy and side effects of pharmacological therapies such as nonsteroidal anti-inflammatory drugs and hormone therapy, as well as high disease recurrence rates following surgical interventions.11,13 Furthermore, delay in diagnosis and treatment often lead to disease progression, resulting in complications such as infertility or chronic pain that may not respond to hormonal therapy or surgery.10,14 Recent efforts in clinical development for bringing new therapies have not yielded conclusive evidence of efficacy.15 Given these conditions, there is a clear need for alternative treatment strategies to address these unmet clinical challenges. Estrogen (estradiol [E2]) is a central driver of endometriosis, promoting the growth and persistence of endometriotic lesions and amplifying the inflammation and pain associated with the disease. Estrogen-driven inflammation is thought to be the central process that shapes the pathology of endometriosis.16,17 Thus, hormonal therapy suppressing estrogen activity remains one of the cornerstones of management of ERP. However, their long-term use is limited by hypoestrogenic side effects.18,19 This underscores the need for early therapeutic strategies that regulate estrogen levels to relieve symptoms, while maintaining sufficient estrogen levels to mitigate potential hypoestrogenic effects. Local biosynthesis of estrogen plays a critical role in the pathophysiology of endometriosis. This process is regulated by the hydroxysteroid-17β-dehydrogenases (HSD17βs) enzymes, a family of oxidoreductase enzymes that regulate specific steroidal hormones activity by interconverting active and inactive forms in the final steps of their biosynthesis.20 In both the endometrium and endometriosis lesions, HSD17βs regulate the balance between the less potent estrone (E1) and the more potent E2 and are essential for the regulation of intra-tissue estrogenic concentrations. This intra-tissue hormone metabolism is known as intracrinology and is considered an important part of the endocrine control at the end organ level.21,22 HSD17β1 catalyzes the conversion of E1 to E2, and HSD17β2 catalyzes the oxidation of E2 into E1. Therefore, the HSD17β1 enzyme is a promising drug target in endometriosis, because of its putative role in E2 biosynthesis in ovaries and peripheral target tissues (e.g, endometriosis implants), making it particularly relevant for early-stage treatment.23,24 Inhibition of HSD17β can regulate the intratissue estrogen concentrations in the endometrium and endometriotic lesions, thereby suppressing estrogen-driven lesion growth without significantly affecting systemic estrogen levels; this may reduce off-target effects compared to other hormonal therapies.19,23 The potency of several inhibitors of HSD17β1 in endometriosis lesions has already been published in various preclinical studies.25–27 However, based on our knowledge, no clinical trial data is available for endometriosis. Linustedastat (also known as OG-6219) a novel HSD17β1 enzyme inhibitor, is being developed for the treatment of moderate to severe ERP. By selectively blocking the conversion of E1 to E2 within lesions, linustedastat aims to reduce local estrogen activity. The objective of this global phase 2a/b study was to determine the efficacy, safety, and tolerability of 3 dose levels of linustedastat (50, 100, and 150 mg twice daily [BID]) in pre-menopausal women aged 18 to 49 years with moderate to severe ERP.

Study Design This was a phase 2a/b, randomized, double-blind, placebo-controlled, four-arm, multicentre, proof‑of‑concept, dose-range study conducted between October 2022 and May 2025 (ClinicalTrials.gov identifier: NCT05560646). The overall study duration was approximately 28 weeks which included an initial screening period of approximately 2–4 weeks to collect safety laboratory assessments; a screening cycle (SC; 1 menstrual cycle); a baseline cycle (BC; single-blind placebo run-in, approximately 4 weeks); a randomized double-blind treatment period comprising three complete menstrual cycles (approximately 12 weeks; treatment cycle [TRC] 1, 2, and, 3); and a safety follow-up cycle (SFC) of 1 menstrual cycle (approximately 4 weeks). After randomization, participants were evaluated monthly, at the mid luteal phase (for visit 5), and at the beginning of the menstrual cycle (early follicular phase) for visits 6, 7 and 8; Supplementary figure 1). The study was approved by the Independent Ethics Committee and was conducted in accordance with the principles of the Declaration of Helsinki, International Council for Harmonization Good Clinical Practice and applicable regulatory requirements. All participants provided written informed consent. Study Patients Eligible patients included pre-menopausal women aged 18 to 49 years who had spontaneous, regular, menstrual cycle with a cycle length between 21 and 32 days at least 1 month before screening visit and had a surgical diagnosis of endometriosis within the last 4 months up to 10 years prior to screening visit. Patients were required to have moderate to severe ERP in recent menstrual cycle(s), based on a validated, disease-specific instrument with a numerical rating scale (NRS) cutoff score of ≥4 (0 to 10 scale, with 0 [no pain] and 10 [extremely severe pain]) and ERP that had not been treated with hormones in the previous 1 to 2 months. Key exclusion criteria included the presence of chronic pelvic or non-pelvic pain not attributable to endometriosis that required chronic analgesic use or other chronic therapy, history of ERP that was refractory to hormonal treatment, history or family history of hereditary abnormal hemoglobin or enzymatic deficiencies that can potentially result in methemoglobinemia, clinically significant abnormalities on electrocardiography (ECG) or QT interval prolongation at the screening visit or the randomization visit. Detailed inclusion/exclusion criteria are provided in Supplementary Box 1. Study Treatment Participants were randomized in a 1:1:1:1 ratio to receive oral linustedastat at one of three dose levels, 50 mg, 100 mg, or 150 mg or placebo, administered BID over the treatment period. Linustedastat and placebo were administered as identical-appearing tablets to ensure blinding. No dose modification was allowed during the study. Randomization and treatment assignment were managed using an Interactive Response Technology system. Naproxen sodium tablets were provided as rescue medication for the management of ERP and the study participants were instructed not to deviate from the investigators’ recommendations on dose. Participants were allowed to take naproxen only for ERP and not for other pain conditions or for prophylactic use. Use of concomitant analgesic medication other than rescue medication was allowed for other acute conditions than ERP. The intake of the rescue medication and any other pain medication were daily captured in the electronic handheld device. Assessments Participants used a disease-specific, patient-reported outcome (PRO) instrument, an electronic device (eDiary) daily through the end-of-study visit to record the worst pelvic pain experienced each day on an 11-point numerical rating scale for capturing DYS, non-menstrual pelvic pain (NMPP), and dyspareunia. This validated PRO instrument has a numerical rating scale that measures pain severity on a 0 (no pain) to 10 (worst pain imaginable).28 The eDiary also captured information on vaginal bleeding patterns (bleeding and non-bleeding days), use of rescue medication, and any use of analgesic pain medications outside of the allowed rescue therapy. Study Endpoints The primary efficacy endpoint was the change in mean overall pelvic pain (OPP) score from the BC to TRC3, assessed using the PRO instrument with the daily NRS. The OPP score was defined as the combination of DYS score (pain over menses days) and NMPP score (pain during non-bleeding days) in a full menstrual cycle. The mean OPP score for each cycle was calculated as the total of pain scores reported during the cycle divided by the number of days during the cycle in which the score was reported. The primary safety endpoint was the proportion of participants who experienced any adverse events (AEs) or treatment-emergent adverse events (TEAEs), or serious adverse events (SAEs) during the study period. Secondary efficacy endpoints included changes from BC to TRC3 in mean DYS, NMPP, and dyspareunia scores, as well as changes in the mean number of rescue medication tablets administered for ERP, and percent of days with rescue medication use. Dyspareunia mean scores were calculated as the total dyspareunia scores reported during the cycle divided by the number of days when participants engaged in any sexual activity that involved full vaginal penetration during the cycle (ie, the number of days during the cycle when a dyspareunia score was reported). For the other secondary endpoints, the mean scores were calculated in the same way as the mean OPP score. Pharmacodynamic (PD) endpoints included the evaluation of serum hormone levels, specifically E1, E2, follicle‑stimulating hormone (FSH), luteinizing hormone (LH), progesterone and androgens. They were assessed overtime (pre-randomization at visit 1 to the end of treatment at visit 7 and versus placebo, at the early follicular phase (visit 6 and 7), and at the mid luteal phase (visit 5). Additional safety endpoints included abnormalities in clinical laboratory assessments, vital signs, and physical examinations; the proportion of participants who prematurely discontinued study treatment due to AEs or SAEs; and the occurrence of adverse events of special interest (AESIs). AESIs were defined as selected AEs (non-serious and serious) that might be potential precursors or prodromes for more serious medical conditions. These AESIs included methemoglobinemia formation and hemolysis. Hemolysis was characterized as an AESI if three of the following out-of-normal range conditions are met: a) low hemoglobin or hematocrit; b) low haptoglobin; c) high reticulocyte count; d) high indirect (unconjugated) bilirubin. Methemoglobinemia was characterized as an AESI if methemoglobin >ULN or when pulse oximetry >2% as measured by a Rad-57 Handheld Pulse CO-Oximeter with Masimo Rainbow.29 Sample Size Calculation A total of 380 participants (95 per group) were randomized to provide 84% power to detect a 1-point difference in mean OPP score between any linustedastat dose group and placebo from BC to TRC3, assuming a common standard deviation (SD) of 2.2. Power calculation was performed based on a 2-sided test with Type I error of 0.05 and assuming a dropout rate of 10%. Statistical Analysis Efficacy analyses were conducted in the modified full analysis set, which included all randomized participants who received at least one dose of study treatment and who completed at least one subsequent eDiary entry (PRO). Safety analyses were conducted among all randomized participants who received at least one dose of study treatment (safety analysis set). Primary and secondary efficacy endpoints were analyzed using a mixed model for repeated measurements. The response vector for the model was the change in daily mean value from the BC to TRC 1, 2, and 3. Model terms included the BC mean, treatment, time (ie, cycle), and treatment-by-time interaction. An unstructured error structure was assumed. Pharmacodynamic endpoints were compared between each linustedastat dose group versus placebo using analysis of covariance on the change from baseline to V5 and V7 separately, with treatment as a fixed factor and the baseline value as a covariate. A multiplicative model was used, i.e., the dependent variable and the covariate were log-transformed before analysis and estimated treatment ratios and 95% CI were obtained by back-transformation.

Patients Of 736 patients screened, 354 patients were randomized and 353 received at least one dose of study treatment (one patient discontinued prior to treatment due to a protocol violation; 50 mg BID [n=88], 100 mg BID [n=88], 150 mg BID [n=89], and placebo [n=88]). Therefore, 353 patients were included in the modified full analysis set and safety analysis set. Overall, 315 patients (89.0%) completed the study. The most common reason for withdrawal was discontinuation due to AEs (n=9), followed by participant withdrawal (n=7), other reasons (prohibited medication use, low or ineligible pain scores, relocation, or non-adherence to visit schedules; n=7), and loss to follow-up (n=5; Figure 1). Demographics and baseline characteristics were generally similar across treatment groups (Table 1). The majority of patients were white (96.9%) and not Hispanic or Latino (95.5 %). The overall mean (SD) age was 35.2 (7.1) years, with 58.6% in the 35 to 49 years age group. The mean (SD) baseline scores for OPP, DYS, NMPP and dyspareunia were 5.8 (1.6), 7 (1.6), 5.5 (1.7) and 5.0 (2.4), respectively. Most patients had moderate OPP score severity (90.7%) and the mean (SD) daily rescue medication use at baseline was 0.6 (0.6) tablets per day on 33.0% (29.1%) days per cycle. | Table 1 Demographics and Baseline Characteristics | Efficacy The mean OPP scores across treatment cycles for linustedastat 50, 100, and 150 mg BID groups and the placebo group are presented in Figure 2A. There were no statistically significant differences in the change in mean OPP score from BC between any of the three doses of linustedastat and placebo during TRC3 (50 mg BID; 100 mg BID; 150 mg BID: 0.34 [95% CI: −0.25 to 0.93], p=0.25; 0.19 [95% CI: −0.40 to 0.77], p=0.53; −0.25 [95% CI: −0.83 to 0.34], p=0.41, respectively; Figure 2B). Similarly, no statistically significant difference in the change in mean OPP score (from BC for TRC 1 and 2, and SC for SFC) was observed between any of the three doses of linustedastat and placebo (Supplementary table 2). Daily mean OPP scores by day relative randomization are illustrated in Figure 2C. There were no statistically significant differences in the change in mean DYS, NMPP, or dyspareunia scores from BC to TRC3 between any of the three doses of linustedastat and placebo (Figure 3A–C, respectively). A similar lack of difference was observed for all of these scores between any of the three linustedastat doses and placebo during TRC1 and 2, and SFC (Supplementary table 1). The change in mean number of rescue medication tablets used from the BC to TRC3 (Figure 3D), and percent of days with rescue medication use (Figure 3E) showed no statistically significant difference between any of the three doses of linustedastat and placebo. Similar results were observed for TRC 1 and 2, and the SFC (Supplementary table 2). Pharmacodynamics (PD) At visit 5 (mid luteal phase), the geometric mean E2 concentration ratios versus baseline for the 100 mg BID (p=0.02) and 150 mg BID (p<0.01) groups were statistically significantly higher compared to placebo, while at visit 7 (early follicular phase), they were statistically significantly higher for all the three linustedastat treatment groups compared to placebo (p<0.01 for all three doses); Supplementary figure 2A. The geometric mean E1 concentration ratio versus baseline in the linustedastat 150 mg BID group was statistically significantly higher compared with the placebo group at visit 5 (p<0.05; Supplementary figure 2B). The geometric mean progesterone concentration ratio versus baseline at the mid luteal phase (visit 5) in all the three linustedastat treatment groups was not statistically significantly different compared with placebo. The geometric mean FSH concentration ratio versus baseline was statistically significantly lower in the linustedastat 100 mg BID group compared with the placebo group at visit 7 (p=0.01; Supplementary figure 2C). There were no statistically significant differences between linustedastat and placebo for geometric mean LH concentration ratios versus baseline at visits 5 and 7. No statistically significant differences were observed between linustedastat and placebo for any of the androgens assessed (testosterone, free testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate). Safety and Tolerability More than half of the participants in each group reported at least one TEAE (Table 2). Most TEAEs reported were mild to moderate in severity. The linustedastat 150 mg BID group reported a higher frequency of TEAEs compared with the other groups, including study drug-related TEAEs (18.0%), TEAEs leading to study drug discontinuation (5.6%), and TEAEs leading to study discontinuation (4.5%; Table 2). The most frequently reported TEAEs (≥3% of the overall population) were headache (19.3%), upper respiratory tract infection (8.8%), and nasopharyngitis (3.4%) with similar incidence across the treatment groups (Supplementary table 3). | Table 2 Treatment-Emergent Adverse Events (Safety Analysis Set) | Only one SAE (abdominal pain) was reported in the study (in the linustedastat 50 mg BID group; considered not related to study treatment; Table 2). The patient received treatment for abdominal pain, and the SAE was reported as resolved. A single suspected unexpected SAE involving increased hepatic enzymes was reported and was considered medically significant. No deaths were reported in the study. AESIs including methemoglobinemia formation and hemolysis were reported in the linustedastat 150 mg BID group (4.5%) and the linustedastat 100 mg BID group (1.1%, Table 2). AESIs were asymptomatic and mild; however, a dose-related trend of methemoglobinemia formation was observed. Overall, 6 (1.7%) patients reported methemoglobinemia. Although no AEs of hemolysis were reported, a dose-related trend of low hemoglobin/hematocrit, low haptoglobin and high reticulocyte count across the treatment groups was observed (Supplementary table 4). No clinically significant findings were observed in laboratory parameters, vital signs, physical examinations, or ECG parameters. Overall, 2.8% of patients reported TEAEs that led to discontinuation of study treatment, most commonly due to methemoglobinemia formation and ECG QT interval prolongation (0.8% each; Supplementary table 5). Most participants had a QT corrected for heart rate by Fridericia’s cube root formula (QTcF) of ≤450 msec. No participants had a QTcF of >480 msec. There were no participants with QTcF change from baseline >60 msec at any visit. No clinically significant hypoestrogenic symptoms associated with the study drug were reported. There were no statistically significant differences between active treatment groups and the placebo group in changes in endometrial thickness from pre- to post-randomization.

Although, several preclinical studies have demonstrated the potency of HSD17β1 inhibitors in reducing estradiol synthesis within endometriotic lesions,25–27 this is the first clinical study evaluating an HSD17β1 inhibitor for the treatment of ERP. In this phase 2, randomized, double-blind clinical trial, linustedastat, the selective inhibitor of HSD17β1 enzyme did not improve moderate-to-severe ERP compared to placebo. There were no statistically significant differences between any of the three doses (50, 100, and 150 mg BID) of linustedastat and placebo for any of the primary or the secondary efficacy endpoints. From the PD perspective, for estrogens and gonadotropins, even though there were some isolated statistically significant differences compared to placebo in the early follicular phase (visit 7), there were no trends and no evidence of dose-related effect. However, there was no difference compared to placebo for the mid luteal phase progesterone surge. In terms of safety, linustedastat was generally well tolerated when administered at doses ranging from 50 mg to 150 mg BID for up to three months. However, a higher incidence of TEAEs was observed in the 150 mg BID treatment group. The underlying hypothesis of the present study was that treatment with linustedastat would result in reduction of local E2 production at the endometriotic lesions and further translate into ERP improvement. The study findings do not support the hypothesis that selective inhibition of HSD17β1 alone has a direct and clinically meaningful impact on ERP. The lack of efficacy observed with linustedastat highlights the challenges of translating enzymatic inhibition into symptomatic relief, particularly given the complex and multifactorial nature of endometriosis which involves hormonal, inflammatory and immunological pathways.30–32 As reported in previous studies, combination therapies targeting HSD17β1 alongside other enzymes such as steroid sulfatase or aromatase or progestins may be necessary to achieve meaningful pain relief in women with endometriosis.25,33 The complex nature of endometriosis hinders the identification of clinically relevant metrics for assessing drug efficacy.30 In line with ongoing clinical trials and current research practices, the present study adopted pain reduction, rather than lesion regression, as the primary efficacy endpoint, reflecting patient-centered outcomes.30 However, linustedastat showed no efficacy compared to placebo in OPP, DYS, NMPP, or dyspareunia scores. Notably, these findings suggest that HSD17β1 inhibition may be insufficient to alleviate ERP due to the presence of multiple compensatory estrogen biosynthesis pathways.33 Linustedastat was generally well tolerated. No significant hypoestrogenic symptoms were reported with Linustedastat, compared to other hormonal therapies.34,35 However, a dose-related occurrence of AESIs, including mild and asymptomatic methemoglobinemia formation, was observed. This observation can be linked to the formation of hydroxylamine, a putative metabolite generated in vivo during the conversion of linustedastat to the primary metabolite, FOR-1011. Hydroxylamine is an endogenous intermediate in cellular metabolism; however, it has been associated with acute hematologic toxicity, including hemolysis and methemoglobin formation, and chronic non-mutagenic carcinogenicity in rodent models.36 No hydroxylamine-related toxicity has been observed in preclinical or Phase 1 studies of linustedastat, and its systemic exposure in vivo has not yet been quantified. Although no AEs of hemolysis were reported, a dose-related trend was noted involving mild and asymptomatic decreases in hemoglobin and hematocrit levels, reduced haptoglobin, and elevated reticulocyte counts. These findings, while clinically mild and asymptomatic, may be associated with the presence of hydroxylamine. Overall findings from this study demonstrated that linustedastat was well tolerated. Linustedastat demonstrated lack of systemic meaningful impact on the reproductive hormones and endometrial growth pattern. Of note, the midluteal progesterone surge was not different compared to placebo in any of the treatment arms and similar lack of difference versus placebo was demonstrated in a phase 1 study in healthy premenopausal women treated for 14 days, over the follicular phase of the menstrual cycle.37 The efficacy results of this phase 2 study do not support the theory that inhibition of HSD17β1 enzyme has a direct impact on pain associated with endometriosis. The lack of efficacy with this tissue-specific hormone inhibitor in reducing moderate to severe ERP further underscores the complexity of the disease pathogenesis and highlights the potential need for combination therapies for comprehensive symptom control. Given the heterogeneity of endometriosis in terms of lesion biology, pain mechanisms, and patient priorities, personalized treatment paradigms are essential for better management. Strengths and Limitations To our knowledge, this is the first time a HSD17β1 inhibitor has been tested in subjects with ERP. The PD data for the reproductive hormones demonstrated a lack of clinically significant systemic impact, further supporting the intracrinology-based mechanism of action. The study has certain limitations that include a lack of geographical and racial diversity, with an overrepresentation of white participants from one country (Poland) and a lack of histological confirmation of the baseline condition, which could have led to the inclusion of participants with other gynecological conditions. However, this reflects routine clinical practice in the diagnosis of endometriosis, where histological confirmation is typically not performed, thereby making this approach feasible for recruitment in a noninvasive study. Another limitation of the study is that the impact of linustedastat on endometriotic lesions was not assessed; this could be linked with the well-demonstrated lack of correlation between the macroscopic stage of the lesions and pain score.

Present study findings do not support the hypothesis that selective inhibition of the HSD17β1 enzyme has a direct therapeutic impact on ERP. Across all evaluated doses of linustedastat (50, 100, and 150 mg BID), there were no statistically significant differences compared to placebo in OPP, DYS, NMPP, or dyspareunia scores. Furthermore, no trends suggestive of clinical efficacy were observed. Despite the lack of efficacy, linustedastat was generally well tolerated over the three-month treatment period, indicating a favorable safety profile, and its PD profile supports the lack of systemic clinically meaningful impact on reproductive hormones. Overall findings underscore the need for broader therapeutic strategies that address the multifactorial nature of ERP. Abbreviations AEs, adverse events; AESIs, adverse events of special interest; BC, baseline cycle; BID, twice daily; DYS, dysmenorrhea; ERP, endometriosis-related pain; FSH, follicle stimulating hormone; HSD17βs, hydroxysteroid-17β dehydrogenases; LH, luteinizing hormone; NMPP, non-menstrual pelvic pain; NRS, numeric rating scale; OPP, overall pelvic pain; PD, pharmacodynamic; PRO, patient reported outcomes; SAEs, serious adverse events; SC, screening cycle; SFC, safety follow-up cycle; TEAEs, treatment emergent adverse events; TRC, treatment cycle. Data Sharing Statement The manuscript provides all necessary data and analyses to support the scientific discussions. To protect the privacy of trial participants and preserve the sponsor’s confidentiality, the authors will not share additional data or information related to the clinical trials mentioned in this manuscript without the sponsor’s permission. Readers interested in obtaining further information are invited to submit a data sharing proposal, detailing the purpose of their request, to the authors via the provided Email addresses following the manuscript’s publication. Data sharing decisions will be reviewed and granted on a case-by-case basis. Ethics Approval and Consent to Participate The study was approved by the Independent Ethics committee and was conducted in accordance with the principles of the Declaration of Helsinki, the International Council for Harmonization Good Clinical Practice and applicable regulatory requirements. The study was reviewed and approved by the WCG Institutional Review Board (approval number: 20224129). All participants provided written informed consent. Acknowledgments Medical writing support was provided by Satya Lavanya Jakki, PhD, and Shalini Vasantha, PhD, of Indegene Limited, Bangalore, India. Author Contributions All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; they took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agreed to be accountable for all aspects of the work. Funding The study was funded by Organon. Disclosure FA, JY, LP, DC, KG and LD are employees of Organon. KW declares no competing interests.

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