key: cord-0318389-p8z1oeep
authors: Mukae, H.; Yotsuyanagi, H.; Ohmagari, N.; Doi, Y.; Imamura, T.; Sonoyama, T.; Fukuhara, T.; Ichihashi, G.; Sanaki, T.; Baba, K.; Takeda, Y.; Tsuge, Y.; Uehara, T.
title: A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-like Protease Inhibitor, in Japanese Patients With Mild-to-Moderate COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a Part
date: 2022-05-17
journal: nan
DOI: 10.1101/2022.05.17.22275027
sha: 0e0440e76782acf4f5dced49b38c7d3c0e7b8491
doc_id: 318389
cord_uid: p8z1oeep

For the treatment of coronavirus disease 2019 (COVID-19), antiviral agents that can achieve rapid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduction are warranted. This double-blind, phase 2a part of a phase 2/3 study assessed the efficacy and safety of ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in Japanese patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection. Sixty-nine patients enrolled from 56 sites were randomized (1:1:1) to orally receive 5-day ensitrelvir fumaric acid (375 mg on day 1 followed by 125 mg daily or 750 mg on day 1 followed by 250 mg daily) or placebo and followed up until day 28. The primary outcome was change from baseline in SARS-CoV-2 viral titer. A total of 16, 14, and 17 patients in the ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo groups, respectively, were included in the intention-to-treat population (mean age: 38.8, 40.4, and 38.0 years, respectively). On day 4, the change from baseline in SARS-CoV-2 viral titer (log10 50% tissue culture infectious dose/mL) in patients with positive viral titer and viral RNA at baseline was greater with ensitrelvir 125 mg (mean [standard deviation], -2.42 [1.42]; P = 0.0712) and 250 mg (-2.81 [1.21]; P = 0.0083) versus placebo (-1.54 [0.74]), and ensitrelvir treatment reduced SARS-CoV-2 RNA by -1.4 to -1.5 log10 copies/mL versus placebo. All adverse events were mild to moderate. Ensitrelvir treatment demonstrated rapid SARS-CoV-2 clearance and was well tolerated in patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection (Japan Registry of Clinical Trials identifier: jRCT2031210350).

Takeki Uehara 25 Drug Development and Regulatory Science Division, Shionogi & Co., Ltd. 26 Address: 8F, Nissay Yodoyabashi East, 3-3-13 Imabashi, Chuo-ku, Osaka 541-0042, Japan 27 Email: takeki.uehara@shionogi.co.jp 28

Telephone: +81-6-6209-6907 29 30 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted May 17, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 INTRODUCTION 53

The coronavirus disease 2019 outbreak, caused by infection with severe acute 54 respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly spread worldwide and poses a 55 significant public health burden. As of April 11, 2022, nearly 500 million confirmed cases of 56 COVID-19 and more than 6 million deaths associated with COVID-19 have been reported to the 57 World Health Organization (https://covid19.who.int/). Although at least one-third of 58 SARS-CoV-2 infections are asymptomatic (1), the risk of severe COVID-19 is high in 59 approximately one-fifth of infected individuals, particularly in those with underlying health 60 conditions (2). Shedding of infectious SARS-CoV-2 may persist for approximately 10 days in 61 asymptomatic individuals or patients with mild-to-moderate COVID-19 and up to 4 weeks in 62 those with severe disease after symptom onset (3) (4) (5) . A high viral titer or long persistence of 63 infectious SARS-CoV-2 affects not only the disease severity of infected patients but may also 64 facilitate its spread to their close contacts. Moreover, although vaccination is the cornerstone for 65 controlling COVID-19, it is occasionally associated with post-vaccination breakthrough 66 infections (6). Therefore, from a public health point of view, rapid SARS-CoV-2 reduction in 67 infected patients, in addition to vaccination, is essential for disease control. 68

Several novel treatment options have demonstrated efficacy in reducing the risk of 69 hospitalization, death, or disease progression in patients with COVID-19 at risk of severe 70 disease. These include molnupiravir, a small-molecule ribonucleoside prodrug of 71 N-hydroxycytidine (7); nirmatrelvir, a SARS-CoV-2 3C-like (3CL) protease inhibitor, in 72 combination with ritonavir as a pharmacokinetic booster (8); the SARS-CoV-2 neutralizing 73 monoclonal antibody sotrovimab (9); and the neutralizing antibody cocktail 74 casirivimab/imdevimab (10). In addition, remdesivir has demonstrated efficacy in patients 75 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted May 17, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 hospitalized with COVID-19, with an acceptable safety profile (11). Additional oral antiviral 76 agents that can achieve rapid SARS-CoV-2 reduction as home-based treatment are required for 77 patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection. 78

Ensitrelvir fumaric acid (S-217622; hereafter, ensitrelvir) is a novel oral SARS-CoV-2 79 3CL protease inhibitor that was discovered through joint research by Hokkaido University and 80

Shionogi & Co., Ltd. (12) and is currently developed by Shionogi & Co., Ltd. for the treatment 81 of COVID-19. As the SARS-CoV-2 3CL protease is essential for processing viral complex 82 proteins needed for viral replication (13), its inhibition by ensitrelvir is expected to prevent viral 83 replication. Indeed, ensitrelvir has shown antiviral efficacy in both in vitro and in vivo animal 84 studies (12, 14) . Moreover, its safety, tolerability, and pharmacokinetic profile as single and 85 multiple oral doses have been assessed in a phase 1 study (R. Shimizu, et al., unpublished data) . 86

Currently, a multicenter, randomized, double-blind, placebo-controlled, phase 2/3 study is 87 underway to assess the efficacy, safety, and pharmacokinetics of 5-day oral administration of 88 ensitrelvir (Japan Registry of Clinical Trials identifier: jRCT2031210350). Herein, we report the 89 results of the phase 2a part of this phase 2/3 study that assessed the antiviral efficacy and safety 90 of ensitrelvir in patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 91 infection. 92

This phase 2a part was conducted from September 28, 2021, to January 1, 2022, at 56 sites 96 across Japan (Table S1 ). Of the 70 patients who provided informed consent and were screened, 1 97 was excluded prior to randomization due to protocol deviation. Among the 69 patients 98 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted May 17, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 observed on day 6 in the ensitrelvir 125 mg (P = 0.0108) and 250 mg (P = 0.0041) groups and 145 day 9 in the ensitrelvir 125 mg group (P = 0.0323) (Fig. 2D) . The mean total score of the predefined 12 symptoms in patients with mild-to-moderate COVID-162 19 showed a decreasing trend with time after treatment initiation in all groups (Fig. 4A) . 163

Generally, the mean change from baseline in the total score of the 12 COVID-19 symptoms was 164 numerically greater in the ensitrelvir 125 mg and 250 mg groups versus the placebo group (Fig.  165 4B). A decreasing trend from baseline to 120 hours after dose in the 14 COVID-19 symptom 166 scores was observed. In particular, the scores for respiratory symptoms (stuffy or runny nose, 167 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted May 17, 2022. ; https://doi.org/10.1101/2022.05.17.22275027 doi: medRxiv preprint sore throat, and cough) and feverish symptoms showed a decreasing trend in patients treated with 168 ensitrelvir (Fig. S2) . 169

After treatment initiation, 2 of 14 patients in the placebo group recorded (Table S2) . 174

Treatment-emergent adverse events (TEAEs) were reported in 11 (52.4%), 16 (69.6%), and 9 176 (37.5%) patients in the ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo groups, respectively, 177 all of which were mild to moderate in severity. The most common TEAE observed across groups 178 was a decrease in high density lipoprotein (HDL; 3 [14.3%], 12 [52.2%], and 2 [8.3%] patients 179 in the ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo groups, respectively) ( Table 2) . 180

Transient decrease and increase in HDL and blood triglyceride levels, respectively, were 181 observed in the ensitrelvir groups following treatment initiation but were resolved without 182 additional treatment (Fig. S3) . Additionally, an increase in total bilirubin and iron levels was 183 observed in patients receiving ensitrelvir (Fig. S4 ). Total bilirubin increase observed in 2 patients 184 in the ensitrelvir 250 mg group (Table 2 ) and iron increase observed in 1 patient in the ensitrelvir 185 250 mg group were reported as TEAEs. These changes were asymptomatic and transient, and 186 resolved without additional treatment. No obvious changes compared with placebo were 187 observed in haptoglobin, reticulocytes, and low-density lipoprotein in the ensitrelvir groups, and 188 no laboratory or clinical signs of hemolysis were observed. No serious TEAEs, deaths, or TEAEs 189 leading to treatment discontinuation were reported (Table 2) . 190 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted May 17, 2022. ; https://doi.org/10.1101/2022.05.17.22275027 doi: medRxiv preprint Treatment-related AEs were reported in 5 (23.8%) and 10 (43.5%) patients in the 191 ensitrelvir 125 mg and 250 mg groups, respectively. A decrease in HDL and increase in blood 192 triglycerides were observed to be the most common (≥5% in either group) treatment-related AEs 193 (Table 2 ). All treatment-related AEs resolved without sequelae, except for mild 194 hyperbilirubinemia (total bilirubin level just above the normal range) that lasted until the last 195 visit (day 28) in 1 patient in the 250 mg group. 196 197 DISCUSSION 198 This is the first clinical study to assess the antiviral efficacy and safety of a novel oral 199 SARS-CoV-2 3CL protease inhibitor, ensitrelvir, in patients with mild-to-moderate or asymptomatic SARS-CoV-2 infection. This study used infectious viral titer as the primary 201 endpoint to assess the antiviral efficacy of anti-SARS-CoV-2 agents. A majority of the enrolled 202 patients had been vaccinated, which reflects the real-world scenario. Our results demonstrated 203 promising antiviral efficacy of 5-day oral administration of ensitrelvir in rapid viral titer and viral 204 RNA reduction in this patient population. Patients with mild-to-moderate COVID-19 who were 205 treated with ensitrelvir showed a trend of symptom relief. Treatment with ensitrelvir was 206 generally well tolerated. 207

As patients with COVID-19 may shed infectious viruses for up to 4 weeks depending on 208 the disease severity (3-5), rapid viral clearance is crucial for disease treatment. In the current 209 phase 2a part, reduction in viral titer and viral RNA was observed after ensitrelvir treatment; this 210 efficacy is comparable with or greater than the findings from clinical trials for other anti-SARS-211

CoV-2 infection agents (7, 8, 15 ). Moreover, viral RNA reduction with ensitrelvir was 212 substantial, with a difference from placebo on day 4 reported at -1.4 to -1.5 log 10 copies/mL. The 213 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted May 17, 2022. ; https://doi.org/10.1101/2022.05.17.22275027 doi: medRxiv preprint difference from placebo in viral RNA reduction reported in previous randomized clinical trials 214 on day 5 was -0.547 log 10 copies/mL (least-squares mean) for molnupiravir 800 mg (15) and -215 0.868 log 10 copies/mL (adjusted mean) for nirmatrelvir plus ritonavir (8). In addition, previous 216 randomized clinical trials of anti-SARS-CoV-2 agents were conducted in unvaccinated patients 217 (7, 8, 15) , whereas most patients in our study had been vaccinated. These results indicate the 218 efficacy of ensitrelvir in the rapid clearance of SARS-CoV-2. From the efficacy of ensitrelvir in 219 rapid viral titer and viral RNA reduction, favorable clinical outcomes, such as earlier symptom 220 relief or prevention of severe COVID-19, are expected. 221

Transient decrease in HDL and increase in triglycerides was observed as TEAEs in the 222 current phase 2a part, which was consistent with the findings derived from the previous phase 1 223 study of ensitrelvir (R. Shimizu, et al., unpublished data) . In addition, transient and 224 asymptomatic increase in total bilirubin and iron levels, which was not associated with signs of 225 hepatic or hematologic abnormalities, was observed following ensitrelvir treatment. However, 226 the exact mechanism of these laboratory value changes is yet to be elucidated and further 227 investigation is warranted. 228

This study has some limitations. First, the small sample size and high vaccination rate 229 limit concrete conclusions to be drawn from analyses of the clinical outcomes, such as COVID-230 19 symptoms including respiratory symptoms and disease exacerbation. Second, most of the 231 enrolled patients were infected with the SARS-CoV-2 Delta variant. Our in vitro study results 232 suggested that ensitrelvir has antiviral activity against the Omicron variant, which is the most 233 predominant SARS-CoV-2 variant at the time of publication (12). Thus, the clinical efficacy of 234 ensitrelvir against the Omicron variant or future variants of concern needs to be assessed in the 235 subsequent part of this study. In addition, statistical analyses in subgroups, such as minor 236 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Table S1 . All patients or their legally acceptable representatives provided written 257 informed consent. 258 All rights reserved. No reuse allowed without permission.

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Patients (aged 12 to <70 years; body weight ≥ 40 kg for those aged <20 years to avoid increased 260 drug exposure) who tested positive for SARS-CoV-2 within 120 hours prior to randomization 261 were eligible for study enrollment. Results of SARS-CoV-2 antigen tests or nucleic acid 262 detection testing, including RT-PCR, were used to determine positive SARS-CoV-2 infection. 263

Patients with mild-to-moderate COVID-19 should have had at least 1 moderate or severe 264 symptom among the 12 COVID-19 symptoms (stuffy or runny nose, sore throat, shortness of 265 breath, cough, low energy or tiredness, muscle or body aches, headache, chills or shivering, 266 feeling hot or feverish, nausea, vomiting, or diarrhea; Table S3 ), based on the United States Food 267 and Drug Administration guidance for assessing COVID-19-related symptoms 268 (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/assessing-covid-269

worsening of at least 1 moderate or severe COVID-19 symptom. Patients without the 12 271 COVID-19 symptoms listed above, anosmia, or dysgeusia within 2 weeks prior to randomization 272 were classified as those with asymptomatic SARS-CoV-2 infection. 273

Key exclusion criteria were an awake oxygen saturation of ≤ 93% (room air); need for 274 oxygen administration; worsening of COVID-19 within 48 hours from randomization strongly 275 suspected by the investigator; suspected active and systemic infections requiring treatment 276 (except for COVID-19); current or chronic history of moderate or severe liver disease, known 277 hepatic or biliary abnormalities (except for Gilbert syndrome or asymptomatic gallstones), or 278 kidney disease; recent blood donation (≥400 mL within 12 weeks or ≥ 200 mL within 4 weeks 279 prior to enrollment); use of drugs for COVID-19 within 7 days; and use of strong CYP3A 280 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted May 17, 2022. ; https://doi.org/10.1101/2022.05.17.22275027 doi: medRxiv preprint inhibitors or inducers or St John's wort products within 14 days prior to randomization. 281 Pregnant, possibly pregnant, or breastfeeding women were also excluded. 282

Randomization of patients was performed using an interactive response technology system. For 284 patients with mild-to-moderate COVID-19, the time from the onset of COVID-19 to 285 randomization (<72 hours/≥72 hours) and the presence or absence of COVID-19 vaccination 286 were used as stratification factors. For those with asymptomatic SARS-CoV-2 infection, the 287 presence or absence of COVID-19 vaccination was used as a stratification factor. 288

All patients and study staff were blinded to treatment until the completion of the 28-day 289 follow-up period and database lock, except for designated persons at the sponsor and contract 290 research organization in charge of statistical analyses. Measurements of SARS-CoV-2 viral titer 291 and viral RNA level prior to database lock were allowed in an anonymized manner to avoid 292 unexpected unblinding. Emergency unblinding per the investigator's request was allowed only in 293 the event of AEs to determine an appropriate therapy for the patient. 294

Patients received allocated study drugs orally (ensitrelvir fumaric acid 125 mg, 250 mg, or 296 placebo tablets), which were indistinguishable in appearance, labeling, and packaging. 297

Use of drugs for the treatment of COVID-19; antiviral, antibacterial, or antifungal drugs 298 (except for external use); antipyretic analgesics other than acetaminophen; antitussives and 299 expectorants; combination cold remedy; and CYP3A substrates was prohibited from study 300 initiation to day 28 or study discontinuation. Strong CYP3A inhibitors or inducers, strong P-301 glycoprotein or breast cancer resistance protein inhibitors, and other transporter substrates were 302 prohibited from study initiation to 10 days after the last administration of the study drug or study 303 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted May 17, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 discontinuation. Treatment was discontinued in the event of exacerbation of COVID-19, serious 304 or intolerable AEs, pregnancy, or liver function abnormalities. 305

The primary outcome was a change from baseline (day 1, before drug administration) in SARS-307

CoV-2 viral titer on days 2, 4, 6, 9, 14, and 21 (or study discontinuation). Secondary outcomes 308 included SARS-CoV-2 viral RNA level, proportion of patients with a positive viral titer, and 309 time to viral clearance (first negative SARS-CoV-2 viral titer). SARS-CoV-2 viral titer 310 measurement and RT-PCR using nasopharyngeal swabs were performed at Shionogi 311 TechnoAdvance Research (Osaka, Japan) and LSI Medience (Tokyo, Japan), respectively. 312

Clinical outcomes included the total score of the 12 COVID-19 symptoms, proportion 313 of patients with anosmia, and those with dysgeusia following treatment in patients with mild-to-314 moderate COVID-19. Patients assessed their COVID-19 symptoms on a questionnaire (Table  315 S3) and recorded the scores in a diary twice daily (morning and evening) until day 9 and once 316 daily (evening) from days 10 to 21. Additionally, disease exacerbations were assessed as a post 317 hoc analysis in patients with mild-to-moderate COVID-19. Patients' conditions (exacerbation) 318

were assessed by the investigator using an 8-point ordinal scale (0 = Asymptomatic to 7 = Death, 319 ≥ 3 corresponds to hospitalization or worse symptoms; Table S4 ) on day 1 (before drug 320 administration) and days 2, 4, 6, 9, 14, 21, and 28 (or study discontinuation) . 321

Safety was assessed through TEAEs coded using Medical Dictionary for Regulatory 322 Activities version 24.0. Laboratory tests, vital sign measurements, and electrocardiography were 323 additionally performed. All safety data were evaluated by an independent data and safety 324 monitoring board. Pregnancy tests were performed on day 1 (before drug administration), day 325 28, and at the investigator's discretion for women of childbearing potential. 326 All rights reserved. No reuse allowed without permission.

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To compare change from baseline in SARS-CoV-2 viral titer between each treatment group and 329 the placebo group, 11 patients per group with COVID-19 were required to provide 82.3% power, 330 assuming a difference of 2.5 log, a common SD of 2.2 log, and a 2-sided significance level of 331 10%. Based on the phase 2a study of molnupiravir, which reported an infectious SARS-CoV-2 332 rate of 44% at baseline (15), it was assumed that 50% of patients enrolled in this phase 2a part 333 would have positive RT-PCR results and detectable viral titer at baseline. Thus, the sample size 334 was set to 23 patients per group (69 in total). 335

All randomized patients who tested positive with RT-PCR at baseline were included in 336 the ITT population. All randomized patients who tested positive with RT-PCR and had 337 detectable SARS-CoV-2 viral titer at baseline were included in the mITT population. All 338 randomized patients who received at least 1 dose of the study drug were included in the safety 339 analysis set. 340

A positive SARS-CoV-2 viral titer was defined as ≥ 0.8 log 10 TCID 50 /mL. SARS-CoV-2 341 viral titer and SARS-CoV-2 viral RNA level were compared between each of the ensitrelvir 342 groups and placebo using the van Elteren test. Median time to viral clearance was compared 343 between each of the ensitrelvir groups and placebo using a stratified log-rank test. The 344

proportion of patients with positive SARS-CoV-2 viral titer was compared between each of the 345 ensitrelvir groups and placebo using the Mantel-Haenszel test. All statistical tests were 346 performed with stratification by study cohort (mild to moderate or asymptomatic) and at a 2-347 sided significance level of 0.05. 348

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The copyright holder for this preprint this version posted May 17, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 involved in the collection, management, analysis, and interpretation of data. Institutional authors 371 reviewed and approved the protocol and collected and interpreted the data. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted May 17, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 Data are presented as mean ± SD. *P < 0.05 versus placebo. The gray, dotted, horizontal lines in panels (A) and (C) indicate the lower limit of detection of viral titer (0.8 log 10 TCID 50 /mL) and lower limit of quantification of viral RNA (3.40 log 10 copies/mL), respectively.

ITT, intention-to-treat; mITT, modified ITT; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SD, standard deviation; TCID 50 , 50% tissue culture infectious dose. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Total score of 12 COVID-19 symptoms, mean (SD) b 10.2 (5.7) 8.8 (4.3) 7.3 (3.6) a At the time of this research, hospitalization was recommended for all patients with COVID-19 in Japan irrespective of disease severity or 3 presence of risk factors. Patients were thus eligible for enrollment in all treatment settings (inpatient, outpatient, recuperation at home, or 4 recuperation at designated hotels). 5 b In mild-to-moderate patients in the mITT population (n=13, n=12, and n=14 for the ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo groups, 6 respectively). 7 COVID-19, coronavirus disease 2019; ITT, intention-to-treat; mITT, modified ITT; SD, standard deviation. 8 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Blood triglycerides increased 0 (0.0) 2 (8.7) 0 (0.0) AE, adverse event; TEAE, treatment-emergent AE 10 All rights reserved. No reuse allowed without permission.

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No prespecified statistical hypothesis was set because this phase 2a part was conducted 349 in an exploratory manner. No imputation was performed for missing data, and multiplicity was 350 not considered. All analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary participated in and approved the design and conduct of the study, wrote the protocol, and were 370 All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 17, 2022. ; https://doi.org/10.1101/2022.05.17.22275027 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 17, 2022. ; https://doi.org/10.1101/2022.05.17.22275027 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 17, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022