Long-term safety, tolerability and antiviral activity of rilpivirine in antiretroviral-naïve adolescents living with HIV-1, aged 12 to less than 18 years: Week 240 findings of a phase 2, open-label study, PAINT

Introduction: This Phase-2 study investigated long-term safety and efficacy of rilpivirine (RPV)+two investigator-selected nucleos(t)ide reverse-transcriptase inhibitors (NRTIs), in HIV-1-infected antiviral therapy-naïve adolescents. Methods: Participants (≥12to <18 years) were treated with RPV 25mg qd+2 NRTIs who entered treatment extension period for up to 240 weeks with visits every 3 months. Long-term safety (analysis of adverse events [AEs], laboratory results), efficacy (virologic-response and outcome for patients with viral load <50 and <400 by time to loss of virologic-response (TLOVR) and FDA Snapshot methods, and CD4+ cell count), and adherence (by pill-count) for up to 240 weeks are presented. Results: 24 of 36 entered treatment extension period and 21 completed week 240. At week 240, viral load <50 copies/mL was achieved by 14/32 (43.8%) participants; virologic-response by TLOVR was higher in participants with baseline viral load≤100,000 copies/mL (48.0%) versus viral load >100,000 copies/mL (28.6%). By FDA Snapshot, viral load < 50 copies/mL at week 240 was 53.1% (17/32) in participants with baseline viral load ≤100,000 copies/mL. Higher response was observed in participants with adherence >95% and baseline viral load ≤100,000 copies/mL. Through week 240, 16/32 participants (50.0%) experienced virologic-failure, including seven who developed treatment-emergent RPV resistance-associated mutations (RAMs; frequently E138K); all 7 had ≥1 treatment-emergent NRTI RAM. No serious AEs after week 48, no discontinuations due to AEs between week 48 and week 240 and no new safety signals were observed. RPV did not affect pubertal development/adolescent growth. Conclusions: At the 5-year follow-up, efficacy was low in adolescents, particularly those with poor adherence and/or high baseline viral load >100,000 copies/mL. To limit the risk of virologic failure, Edurant is restricted to patients with a baseline VL ≤100,000 copies/mL in most countries. In addition, adequate treatment adherence to RPV treatment is imperative for long-term viral suppression and should be emphasized in the management of adolescents living with HIV. RPV exhibited favorable long-term safety profile for adolescents living with HIV-1 with adequate adherence. Clinical Trial Number: NCT00799864

Long-Term Efficacy and Safety of the Oral Pyruvate Kinase Activator Mitapivat in Adults with Non-Transfusion-Dependent Alpha- or Beta-Thalassemia

Background: The thalassemias are a group of red blood cell (RBC) disorders in which ineffective erythropoiesis and hemolysis occur due to imbalanced production and precipitation of globin chains. Thalassemic RBCs have insufficient levels of ATP to meet increased energy demands associated with globin chain imbalance, protein degradation, and cellular oxidative stress responses. Mitapivat (AG-348) is a first-in-class, small-molecule, oral activator of RBC pyruvate kinase (PKR), a key enzyme regulating ATP production via glycolysis. In a phase 2, open-label trial of mitapivat in adults with α- or β-non-transfusion-dependent (NTD) thalassemia (NCT03692052), 80.0% (16/20) of patients (pts) met the primary endpoint of a hemoglobin (Hb) response (increase ≥ 1.0 g/dL from baseline at 1 or more assessments between Wks 4-12, inclusive). Improvements in markers of hemolysis and erythropoiesis were also observed in pts and mitapivat was generally well tolerated. Methods: Pts aged ≥ 18 (yrs) with a known medical history of α- or β-thalassemia, Hb concentration of ≤ 10.0 g/dL, and ≤ 5 RBC units transfused in prior 24 wks and none in 8 wks prior to study drug were eligible for the study. All pts started mitapivat at 50 mg twice daily (BID), escalating to 100 mg BID based on individual safety and Hb assessments. After completion of the 24-wk core period, pts were continued on mitapivat treatment in the extension period if they had achieved a Hb response, or a delayed Hb response (Hb increase of ≥ 1.0 g/dL at ≥ 1 assessment after Wk 12), with no ongoing grade ≥ 3 treatment-emergent adverse events (AE) related to study drug. Eligible pts continued mitapivat at the dose received at their Wk 24 visit. Study visits are conducted every 12 wks and will continue for up to 10 yrs. The extension period of the study is ongoing, here we report data up to Wk 72 visit (data cutoff March 27, 2021). Results: Of the 19 pts who completed the core period, 17 entered the extension period. During the extension period, 16 pts received 100 mg BID mitapivat and 1 received 50 mg BID. As of the cutoff date, 1 pt had discontinued (patient decision). Median (range, in wks) duration of mitapivat treatment for pts who entered the extension period was 70.9; (54.7, 105.6), with 8 of 17 pts receiving 72 wks or more of treatment as of the cutoff date for this analysis. The Median age of pts who entered the extension period was 44 yrs (range 29, 67). Mean baseline (standard deviation [SD]) Hb, total bilirubin and lactate dehydrogenase (LDH) was 8.1 (1.2) g/dL, 40.1 (26.2) μmol/L and 272.4 (121.7) U/L, respectively. Median baseline erythropoietin (EPO) was 70.5 (range 15, 11191) IU/L. Improvements in Hb concentration achieved in the core period were sustained in the extension study (n = 8 at Wk 72; Figure 1). Mean Hb (SD) increase from baseline to Wk 60 (which includes 4 pts with α- and 9 with β-thalassemia) and Wk 72 (which includes 8 pts with β-thalassemia) were 1.5 (0.4) g/dL and 1.7 (0.5) g/dL, respectively. Improvements in markers of hemolysis and ineffective erythropoiesis observed in the core period were maintained in the extension period up to Wk 72 (mean [SD] bilirubin and LDH, -15.8 [16.6] μmol/L and -63.6 [216.0] U/L, respectively; median [range] EPO, -33.0 [-72.0, -16.0] IU/L). The safety profile was consistent with that observed during the core period. AEs occurring in ≥ 15% of pts during the extension period were headache (5/17) and back pain (3/17), none of which were grade ≥ 3. No notable trends for changes in bone mineral density were observed (Figure 2). There were no treatment-related serious AEs during the extension period. Conclusions: In pts with either α- or β-thalassemia, a favorable efficacy-safety profile was observed with long-term treatment with mitapivat. Results show sustained improvements in Hb, hemolysis and ineffective erythropoiesis - despite the globin genotypic heterogeneity of the cohort - and no new safety findings. Mitapivat, through its unique mechanism of action, may represent a novel therapeutic approach for this condition. Two phase 3 trials of mitapivat in α- and β-thalassemia, one in pts who are NTD and one in pts who are transfusion-dependent, will be initiated in 2021. Figure 1 Figure 1. Disclosures Kuo: Bluebird Bio: Consultancy; Alexion: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Apellis: Consultancy; Pfizer: Consultancy, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy. Layton: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cerus: Membership on an entity's Board of Directors or advisory committees. Lal: Chiesi: Consultancy; Agios Pharmaceuticals: Consultancy; bluebird bio, Inc.: Research Funding; La Jolla Pharmaceutical Company: Research Funding; Terumo Corporations: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Insight Magnetics: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Al-Samkari: Dova/Sobi: Consultancy, Research Funding; Moderna: Consultancy; Argenx: Consultancy; Rigel: Consultancy; Amgen: Research Funding; Novartis: Consultancy; Agios: Consultancy, Research Funding. Bhatia: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Kosinski: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Tong: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Lynch: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Uhlig: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Vichinsky: Agios Pharmaceuticals: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Efficacy, Safety, and Durability of Long-Acting Cabotegravir and Rilpivirine in Adults With HIV-1 Infection: ~5-Year Results From the LATTE-2 Study

Background In the LATTE-2 phase IIb study, long-acting (LA) injectable cabotegravir + rilpivirine dosed every 8 weeks (Q8W) or 4 weeks (Q4W) demonstrated comparable efficacy with daily oral antiretroviral therapy (ART) through 96 weeks in ART-naive adults with HIV-1. Here we report efficacy, tolerability, and safety of cabotegravir + rilpivirine LA over ~5 years. Methods After 20 weeks of oral cabotegravir + abacavir/lamivudine, participants were randomized to cabotegravir + rilpivirine LA Q8W or Q4W or continue oral ART through the 96-week maintenance period. In the extension period through Week 256, participants continued their current LA regimen (randomized Q8W/Q4W groups) or switched from oral ART to Q8W or Q4W LA therapy (extension-switch groups). Endpoints assessed included proportion of participants with HIV-1 RNA &lt;50 copies/mL (Snapshot algorithm) and adverse events (AEs). Results At Week 256, 186 (81%) of 230 participants in randomized Q8W/Q4W groups and 41 (93%) of 44 participants in extension-switch groups had HIV-1 RNA &lt;50 copies/mL. No protocol-defined virologic failures occurred after Week 48. Injection-site reactions infrequently resulted in discontinuation (4 [2%] and 1 [2%] participants in randomized Q8W/Q4W and extension-switch groups, respectively). Three participants in randomized Q8W/Q4W groups experienced drug-related serious AEs, including 1 fatal serious AE (Q4W group); none occurred in extension-switch groups. Of 25 participants with AEs leading to withdrawal, 20 were in the randomized Q4W group; no AE leading to withdrawal occurred in &gt;1 participant. Conclusions Cabotegravir + rilpivirine LA exhibited long-term efficacy and tolerability, demonstrating its durability as maintenance therapy for HIV-1 infection (ClinicalTrials.gov, NCT02120352).

Long-term efficacy and safety of sapropterin in patients who initiated sapropterin at < 4 years of age with phenylketonuria: results of the 3-year extension of the SPARK open-label, multicentre, randomised phase IIIb trial

Background During the initial 26-week SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) study, addition of sapropterin dihydrochloride (Kuvan®; a synthetic formulation of the natural cofactor for phenylalanine hydroxylase, tetrahydrobiopterin; BH4), to a phenylalanine (Phe)-restricted diet, led to a significant improvement in Phe tolerance versus a Phe-restricted diet alone in patients aged 0–4 years with BH4-responsive phenylketonuria (PKU) or mild hyperphenylalaninaemia (HPA). Based on these results, the approved indication for sapropterin in Europe was expanded to include patients < 4 years of age. Herein, we present results of the SPARK extension study (NCT01376908), evaluating the long-term safety, dietary Phe tolerance, blood Phe concentrations and neurodevelopmental outcomes in patients < 4 years of age at randomisation, over an additional 36 months of treatment with sapropterin. Results All 51 patients who completed the 26-week SPARK study period entered the extension period. Patients who were previously treated with a Phe-restricted diet only (‘sapropterin extension’ group; n = 26), were initiated on sapropterin at 10 mg/kg/day, which could be increased up to 20 mg/kg/day. Patients previously treated with sapropterin plus Phe-restricted diet, remained on this regimen in the extension period (‘sapropterin continuous’ group; n = 25). Dietary Phe tolerance increased significantly at the end of the study versus baseline (week 0), by 38.7 mg/kg/day in the ‘sapropterin continuous’ group (95% CI 28.9, 48.6; p < 0.0001). In the ‘sapropterin extension’ group, a less pronounced effect was observed, with significant differences versus baseline (week 27) only observed between months 9 and 21; dietary Phe tolerance at the end of study increased by 5.5 mg/kg/day versus baseline (95% CI − 2.8, 13.8; p = 0.1929). Patients in both groups had normal neuromotor development and growth parameters. Conclusions Long-term treatment with sapropterin plus a Phe-restricted diet in patients who initiated sapropterin at < 4 years of age with BH4-responsive PKU or mild HPA maintained improvements in dietary Phe tolerance over 3.5 years. These results continue to support the favourable risk/benefit profile for sapropterin in paediatric patients (< 4 years of age) with BH4-responsive PKU. Frequent monitoring of blood Phe levels and careful titration of dietary Phe intake to ensure adequate levels of protein intake is necessary to optimise the benefits of sapropterin treatment. Trial registration ClinicalTrials.gov, NCT01376908. Registered 17 June 2011, https://clinicaltrials.gov/ct2/show/NCT01376908.

Transcriptome Analysis of Flower Development and Mining of Genes Related to Flowering Time in Tomato (Solanum lycopersicum)

Flowering is a morphogenetic process in which angiosperms shift from vegetative growth to reproductive growth. Flowering time has a strong influence on fruit growth, which is closely related to productivity. Therefore, research on crop flowering time is particularly important. To better understand the flowering period of the tomato, we performed transcriptome sequencing of early flower buds and flowers during the extension period in the later-flowering “Moneymaker” material and the earlier-flowering “20965” homozygous inbred line, and we analyzed the obtained data. At least 43.92 million clean reads were obtained from 12 datasets, and the similarity with the tomato internal reference genome was 92.86–94.57%. Based on gene expression and background annotations, 49 candidate genes related to flowering time and flower development were initially screened, among which the greatest number belong to the photoperiod pathway. According to the expression pattern of candidate genes, the cause of early flowering of “20965” is predicted. The modes of action of the differentially expressed genes were classified, and the results show that they are closely related to hormone regulation and participated in a variety of life activities in crops. The candidate genes we screened and the analysis of their expression patterns provide a basis for future functional verification, helping to explore the molecular mechanism of tomato flowering time more comprehensively.

O-132 Sustained efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: SPIRIT 52-week data

Study question To assess the long-term (52-week) efficacy and safety of relugolix combination therapy (Relugolix-CT) in the treatment of endometriosis-associated pain. Summary answer Relugolix-CT demonstrated a sustained improvement of endometriosis-associated pain and maintenance of bone mineral density (BMD) over the extension treatment period. It was well tolerated. What is known already Endometriosis is a chronic condition characterized by symptoms of menstrual and non-menstrual pain, and dyspareunia, which have a substantial impact on women’s lives. SPIRIT 1 and 2 were Phase 3, randomized, double-blind, placebo-controlled studies of once-daily Relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) in premenopausal women (age 18–50 years) with surgically diagnosed endometriosis and moderate-to-severe dysmenorrhea and non-menstrual pelvic pain (NMPP) at baseline. These trials demonstrated a significant improvement of dysmenorrhea, NMPP and dyspareunia in women treated with Relugolix-CT, with a minimal decline in BMD vs placebo over 24 weeks. Study design, size, duration Women who completed the 24-week pivotal studies (SPIRIT 1 and 2 trials) were eligible to enroll in an open-label, single-arm, long-term safety and efficacy extension study for an additional 80 weeks. All women received once-daily oral Relugolix-CT. Analyses were done based on original randomization in pivotal studies: Relugolix-CT, delayed Relugolix-CT (relugolix 40 mg alone for 12 weeks, then Relugolix-CT for 12 weeks), or placebo. Here, 52-week efficacy and safety outcomes are presented. Participants/materials, setting, methods The primary endpoints were the proportion of dysmenorrhea and NMPP responders at Week 52, based on daily Numerical Rating Scale (NRS) scores (0=no pain, 10=worst pain imaginable). A responder was a woman who achieved a predefined, clinically meaningful reduction from baseline in NRS score with no increase in analgesic use. Secondary efficacy endpoints included change in Endometriosis Health Profile-30 (EHP-30) pain domain scores, and analgesic/opioid use. Safety endpoints included adverse events (AEs) and BMD evaluation. Main results and the role of chance Of 1261 randomized patients, 1044 completed the primary studies; 802 enrolled in the long-term extension and 681 completed 52 weeks of treatment. Baseline demographics and clinical characteristics of the extension population were consistent with those of the original randomized population. Sustained improvement of endometriosis-associated pain was demonstrated with Relugolix-CT through 52 weeks, the proportion of responders for dysmenorrhea was 84.8% and 73.3% for NMPP. NRS least squares (LS) mean scores for dysmenorrhea and NMPP decreased from 7.4 (severe) and 6.0 (moderate) at SPIRIT study baseline to 1.3 (mild) and 2.2 (mild) at Week 52, equating to 82.8% and 62.9% reduction in dysmenorrhea and NMPP, respectively. Mean NRS for dyspareunia decreased from 5.9 (moderate) to 2.4 (mild), demonstrating 60.1% reduction with Relugolix-CT. Daily functioning measured by the EHP-30 pain domain score was improved (–38.1 point) and the majority of women (85.6%) were opioid-free at Week 52. There was no disproportionate increase in the incidence of AEs in the Relugolix-CT group with no new safety signals identified through the 52 weeks. BMD was preserved over the extension period with overall LS mean change from baseline to Week 52 of –0.83% (95% CI: –1.34, –0.32) for lumbar spine in the Relugolix-CT group. Limitations, reasons for caution The study was conducted as an open-label study without a control group over the 28 weeks of the extension period. Wider implications of the findings Relugolix-CT demonstrated a sustained improvement of dysmenorrhea, NMPP, and dyspareunia, and reduced pain-related functional limitations and the need for opioids over 52 weeks in women with moderate-to-severe endometriosis-associated pain. Relugolix-CT was generally well tolerated and associated with minimal BMD loss after treatment initiation followed by BMD maintenance over 52 weeks. Trial registration number NCT03654274

Evaluation of Residual Life of Existing Offshore Platforms in Western Offshore, India

Western offshore oil field in India has nearly 300 offshore platforms for oil and gas exploration, of which almost 50% of platforms have outlived their life. Life extension of these platforms has become essential for further production activities. In many cases, design level analyses combined with ultimate strength assessment, life extension has been granted. However, risk-based assessment based on the probability of failure based on available reserve strength linked to additional life extension could be a logical method. The Reserve Strength Ratio (RSR) is defined as a ratio of reserve capacity of the jacket structure and the design level environmental loads (1 year or 5year or 10 year or 100-year return period). The encounter probability of these design storms for the life extension period has been established probability for the extension period has been used as a threshold to determining the required RSR using the probability of collapse. For the present study, four typical aged wellhead platforms with different water depths are selected, and RSR is evaluated by carrying out push over analysis. The Monte Carlo Simulation method is used to generate the statistical values of RSR. The probability of failure is then calculated by First Order Reliability Method (FORM) using MATLAB for different RSR values. Reassessment criteria for the existing offshore platforms have been described from the reliability analysis results based on probability failure and encounter probability.

ODENZA: A French prospective, randomized, open-label, multicenter, cross-over phase II trial of preference between darolutamide and enzalutamide in men with asymptomatic or mildly symptomatic metastatic castrate-resistant prostate cancer (CRPC).

5046 Background: Darolutamide (Daro) and enzamutamide (Enza) are both next generation androgen receptor inhibitors with demonstrated activity in men with CRPC. Although both agents are associated with survival improvement, their toxicity profiles are different. To help decipher whether this may impact on patient preference, we designed the ODENZA trial. Methods: ODENZA is a prospective, randomized, open-label, multicenter, cross-over, phase II trial of preference between Daro and Enza in men with asymptomatic or mildly symptomatic metastatic CRPC. Patients were randomized 1/1 to receive Daro 1200 mg/d for 12 weeks followed by Enza 160 mg/d for 12 weeks (Daro-Enza arm) or the reverse sequence (Enza-Daro arm). In both arms, the second treatment was given in absence of evidence of cancer progression at week 12. The primary endpoint was patient preference between the two drugs, as assessed by a questionnaire at week 24. The Prescott's test was used to determine treatment preference in patients fullfilling pre planned criteria (exposure to both treatments, no progression at week 12, and completion of the preference questionnaire). A p-value greater than 0.05 indicates that there is no difference in preference between treatments. Stratification factors were performance status and prior taxane for mCSPC. After week 24, patients went on to an extension period during which they received the chosen treatment until progression or toxicity. The main secondary objectives included reasons for preference, response at week 12, cognitive assessment, and toxicity. Results: Overall 249 pts were randomized, median age 72y (68; 79), ECOG PS 0 (56%), prior taxanes (22%). Two hundred pts fulfilled the pre-planned criteria for evaluation of the preference primary endpoint : 97 (48.5% [41.3;55.7]), 80 (40.0% [33.0;47.0]), and 23 (11.5% [6.8;16.2]) chose Daro, Enza, and had no preference, respectively (unilateral p-value of 0.92). After preference assessment, 186 patients entered the extension period: 103 (55.4%) and 83 (44.6%) received Daro and Enza respectively. The most common factors influencing patient preference all numerically favored Daro over Enza, without significant differences were: less fatigue (44% vs 29%), ease of taking the medication (37% vs 31%), better quality of life (36% vs 28%), ability to be more active (26% vs 15%), ability to concentrate (22% vs 15%) and less falls (6% vs 3%). A PSA50 response was achieved in 76.2% and 83.9% at week 12 with Daro and Enza respectively (p = 0.13). Fatigue was the most frequently reported all grade adverse event at week 12, in 21% and 36% with Daro and Enza, respectively. Conclusions: More patients with early mCRPC preferred Daro over Enza, although the difference did not reach significance, with fatigue as the key influencing factor. Clinical trial information: NCT03314324.

337 A Multicenter Open-label Pilot Study Evaluating Next-Dose Transition From Zolpidem to Lemborexant: Analysis of Female Subgroup

Introduction Dosing paradigms for transitioning patients to lemborexant (LEM) from zolpidem (ZOL: immediate [IR] or extended-release [ER]) were examined in E2006-A001-312 (Study 312; NCT04009577), an open-label pilot study. Given insomnia prevalence in women, post hoc analyses in female subjects were conducted. Methods Study 312 included: 3-week Screening Period (subjects continued ZOL); 2-week Titration Period (TITR); 12-week Extension Period (EXT); 4-week Follow-up. Adults with insomnia taking ZOL-IR or ZOL-ER intermittently (3–4 nights/week) or frequently (≥5 nights/week) were enrolled. Subjects with intermittent, or one week each of intermittent and frequent ZOL use, were assigned to Cohort-1 and started TITR with LEM 5mg (LEM5). Frequent ZOL users (Cohort-2) were randomized 1:1 to LEM5 (Cohort-2A) or LEM 10mg (LEM10; Cohort-2B). Subjects who transitioned to LEM could opt into EXT. Subjects could change LEM dose during TITR (only once) and during EXT. The primary endpoint was the proportion of subjects who transitioned to LEM at end of TITR. Treatment-emergent adverse events (TEAEs) were assessed by dose at time of TEAE. Results Overall, 35 subjects were female and 29/35 (82.9%) transitioned to LEM. In Cohort-1, 7 subjects began TITR; all transitioned to LEM (5 subjects ended TITR on LEM5; 2 ended on LEM10). In Cohort-2A, 14 subjects began TITR with LEM5; 12/14 (85.7%) transitioned (6 subjects each ended TITR on LEM5 or LEM10). In Cohort-2B, 14 subjects began TITR with LEM10; 10/14 (71.4%) transitioned to LEM (3 subjects ended TITR on LEM5 and 7 on LEM10). All 29 transitioned subjects opted into EXT, and 27/29 (93.1%) completed the study. Based on modal dose (most frequent dose taken during TITR and EXT combined) groups, median time to first dose change during EXT was 14.5 and 17.0 days for LEM5 and LEM10, respectively. Overall, most TEAEs were mild/moderate in severity. Across TITR and EXT, more TEAEs occurred with LEM10 than with LEM5; the most common TEAEs were somnolence (n=3) and abnormal dreams (n=3). Conclusion Most female subjects successfully transitioned from intermittent or frequent ZOL-IR/ZOL-ER use to LEM and completed the study. LEM was generally well tolerated. The safety profile was consistent with that observed in Phase 3 studies. Support (if any) Eisai Inc.