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Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial.
Aronne, LJ, Sattar, N, Horn, DB, Bays, HE, Wharton, S, Lin, WY, Ahmad, NN, Zhang, S, Liao, R, Bunck, MC, et al
JAMA. 2024;(1):38-48
Abstract
IMPORTANCE The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. OBJECTIVE To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction. DESIGN, SETTING, AND PARTICIPANTS This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. INTERVENTIONS Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. MAIN OUTCOMES AND MEASURES The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. RESULTS Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. CONCLUSIONS AND RELEVANCE In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04660643.
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Efficacy and safety of iruplinalkib (WX-0593) in ALK-positive crizotinib-resistant advanced non-small cell lung cancer patients: a single-arm, multicenter phase II study (INTELLECT).
Shi, Y, Chen, J, Zhang, H, Zhang, Z, Zhang, Y, Wang, Z, Zhang, S, Zhao, J, Liu, C, Wang, X, et al
BMC medicine. 2023;(1):72
Abstract
BACKGROUND Iruplinalkib (WX-0593) is an anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor. Here we reported the single-arm, phase II study (INTELLECT) results of the efficacy and safety of iruplinalkib for ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC) patients. METHODS ALK-positive crizotinib-resistant advanced NSCLC patients aged ≥18 years, with Eastern Cooperative Oncology Group performance status of 0-2 were eligible. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg orally once daily. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR). RESULTS From August 7, 2019, to October 30, 2020, 146 patients were included. As of the data cut-off date on November 30, 2021, the median follow-up time was 18.2 months (95% confidence interval [CI] 16.8-18.8). IRC-assessed ORR and disease control rate (DCR) were 69.9% (95% CI 61.7-77.2%) and 96.6% (95% CI 92.2-98.9%), respectively. Investigator-assessed ORR and DCR were 63.0% (95% CI 54.6-70.8%) and 94.5% (95% CI 89.5-97.6%), respectively. Investigator-assessed median duration of response and progression-free survival (the same as median time to progression) were 13.2 months (95% CI 10.4-17.7) and 14.5 months (95% CI 11.7-20.0), respectively. Corresponding IRC-assessed results were 14.4 months (95% CI 13.1-not evaluable [NE]), 19.8 months (95% CI 14.5-NE), and NE (95% CI 14.5-NE), respectively. Investigator-assessed intracranial ORRs were 46% (41/90, 95% CI 35-56%) in patients with central nervous system metastases and 64% (27/42, 95% CI 48-78%) in patients with measurable intracranial lesions. Overall survival data were immature. Treatment-related adverse events (TRAEs) occurred in 136/146 (93.2%) patients. The most common TRAEs were aspartate aminotransferase increased (63 [43.2%]), alanine aminotransferase increased (54 [37.0%]), and blood creatine phosphokinase increased (51 [34.9%]). Dose interruption, reduction, and discontinuation due to TRAEs occurred in 21 (14.4%), 16 (11.0%), and four (2.7%) patients, respectively. CONCLUSIONS In this study, iruplinalkib (WX-0593) demonstrated favorable efficacy and manageable safety profiles in patients with ALK-positive crizotinib-resistant advanced NSCLC. Iruplinalkib could be a new treatment option for this patient population. TRIAL REGISTRATION Center for Drug Evaluation of National Medical Products Administration of China: CTR20190789, registered on April 28, 2019; ClinicalTrials.gov: NCT04641754, registered on November 24, 2020.
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Icosapent ethyl therapy for very high triglyceride levels: a 12-week, multi-center, placebo-controlled, randomized, double-blinded, phase III clinical trial in China.
Wang, Z, Zhang, X, Qu, Y, Zhang, S, Chen, Y, Chen, X, Qi, X, Liu, P, Liu, S, Jiang, S, et al
Lipids in health and disease. 2023;(1):71
Abstract
OBJECTIVES Eicosapentaenoic acid in its ethyl ester form is the single active component of icosapent ethyl (IPE). This study was a phase III, multi-center trial assessing the safety and efficiency of IPE for treating very high triglyceride (TG) in a Chinese cohort. METHODS Patients having TG levels (5.6-22.6 mmol/L) were enrolled and randomly assigned to receive a treatment of oral intake of 4 g or 2 g/day of IPE, or placebo. Before and after 12 weeks of treatment, TG levels were assessed and the median was calculated to determine the change between the baseline and week 12. In addition to examining TG levels, the impact of such treatments on other lipid changes was also investigated. The official Drug Clinical Trial Information Management Platform has registered this study (CTR20170362). RESULTS Random assignments were performed on 373 patients (mean age 48.9 years; 75.1% male). IPE (4 g/day) lowered TG levels by an average of 28.4% from baseline and by an average of 19.9% after correction for placebo (95% CI: 29.8%-10.0%, P < 0.001). In addition, plasma concentration of non-high-density lipoprotein cholesterol (non-HDL-C), very low-density lipoprotein (VLDL) cholesterol, and VLDL-TG remarkedly reduced after IPE (4 g/day) treatment by a median of 14.6%, 27.9%, and 25.2%, respectively compared with participants in placebo group. Compared to the placebo, neither 4 nor 2 g of IPE daily elevated LDL-C levels with statistical significance. IPE was well tolerated by all the treatment groups. CONCLUSIONS IPE at 4 g/day dramatically lowered other atherogenic lipids without a noticeable increase in LDL-C, thereby decreasing TG levels in an exceptionally high-TG Chinese population.
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Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial.
Wadden, TA, Chao, AM, Machineni, S, Kushner, R, Ard, J, Srivastava, G, Halpern, B, Zhang, S, Chen, J, Bunck, MC, et al
Nature medicine. 2023;(11):2909-2918
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Abstract
The effects of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, on weight reduction after successful intensive lifestyle intervention are unknown. This double-blind, placebo-controlled trial randomized (1:1) adults with body mass index ≥30 or ≥27 kg/m2 and at least one obesity-related complication (excluding diabetes), who achieved ≥5.0% weight reduction after a 12-week intensive lifestyle intervention, to tirzepatide maximum tolerated dose (10 or 15 mg) or placebo once weekly for 72 weeks (n = 579). The treatment regimen estimand assessed effects regardless of treatment adherence in the intention-to-treat population. The coprimary endpoint of additional mean per cent weight change from randomization to week 72 was met with changes of -18.4% (standard error (s.e.) 0.7) with tirzepatide and 2.5% (s.e. 1.0) with placebo (estimated treatment difference -20.8 percentage points (95% confidence interval (CI) -23.2%, -18.5%; P < 0.001). The coprimary endpoint of the percentage of participants achieving additional weight reduction ≥5% was met with 87.5% (s.e. 2.2) with tirzepatide and 16.5% (s.e. 3.0) with placebo achieving this threshold (odds ratio 34.6%; 95% CI 19.2%, 62.6%; P < 0.001). The most common adverse events with tirzepatide were gastrointestinal, with most being mild to moderate in severity. Tirzepatide provided substantial additional reduction in body weight in participants who had achieved ≥5.0% weight reduction with intensive lifestyle intervention. ClinicalTrials.gov registration: NCT04657016 .
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Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.
Garvey, WT, Frias, JP, Jastreboff, AM, le Roux, CW, Sattar, N, Aizenberg, D, Mao, H, Zhang, S, Ahmad, NN, Bunck, MC, et al
Lancet (London, England). 2023;(10402):613-626
Abstract
BACKGROUND Weight reduction is essential for improving health outcomes in people with obesity and type 2 diabetes. We assessed the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, versus placebo, for weight management in people living with obesity and type 2 diabetes. METHODS This phase 3, double-blind, randomised, placebo-controlled trial was conducted in seven countries. Adults (aged ≥18 years) with a body-mass index (BMI) of 27 kg/m2 or higher and glycated haemoglobin (HbA1c) of 7-10% (53-86 mmol/mol) were randomly assigned (1:1:1), using a computer-generated random sequence via a validated interactive web-response system, to receive either once-weekly, subcutaneous tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. All participants, investigators, and the sponsor were masked to treatment assignment. Coprimary endpoints were the percent change in bodyweight from baseline and bodyweight reduction of 5% or higher. The treatment-regimen estimand assessed effects regardless of treatment discontinuation or initiation of antihyperglycaemic rescue therapy. Efficacy and safety endpoints were analysed with data from all randomly assigned participants (intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT04657003. FINDINGS Between March 29, 2021, and April 10, 2023, of 1514 adults assessed for eligibility, 938 (mean age 54·2 years [SD 10·6], 476 [51%] were female, 710 [76%] were White, and 561 [60%] were Hispanic or Latino) were randomly assigned and received at least one dose of tirzepatide 10 mg (n=312), tirzepatide 15 mg (n=311), or placebo (n=315). Baseline mean bodyweight was 100·7 kg (SD 21·1), BMI 36·1 kg/m2 (SD 6·6), and HbA1c 8·02% (SD 0·89; 64·1 mmol/mol [SD 9·7]). Least-squares mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was -12·8% (SE 0·6) and -14·7% (0·5), respectively, and -3·2% (0·5) with placebo, resulting in estimated treatment differences versus placebo of -9·6% percentage points (95% CI -11·1 to -8·1) with tirzepatide 10 mg and -11·6% percentage points (-13·0 to -10·1) with tirzepatide 15 mg (all p<0·0001). More participants treated with tirzepatide versus placebo met bodyweight reduction thresholds of 5% or higher (79-83% vs 32%). The most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhoea, and vomiting and were mostly mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Serious adverse events were reported by 68 (7%) participants overall and two deaths occurred in the tirzepatide 10 mg group, but deaths were not considered to be related to the study treatment by the investigator. INTERPRETATION In this 72-week trial in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg provided substantial and clinically meaningful reduction in bodyweight, with a safety profile that was similar to other incretin-based therapies for weight management. FUNDING Eli Lilly and Company.
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A Phase 1 Trial to Evaluate the Relationship Between Fluoride Intake and Urinary Fluoride Excretion in Healthy Participants.
Gillespie, G, Jackson Rudd, D, Zhang, S, Schaeffer, A, Tomek, C, Larson, P, Stoch, SA, Iwamoto, M
Journal of clinical pharmacology. 2022;(2):190-198
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Abstract
Chronic overexposure to fluoride can have deleterious effects in the musculoskeletal system. Some fluorine-containing therapeutics, such as voriconazole, release fluoride through metabolism. Therefore, drug-related fluoride exposure should be assessed for novel therapeutics suspected of releasing fluoride through metabolism. Two trials were conducted to identify the optimal method of assessing drug-related fluoride exposure. In trial 1, designed to assess reproducibility of fluoride pharmacokinetics in urine and plasma, 14 participants were administered a fluoride-restricted diet and once-daily doses of sodium fluoride (2.2 mg [1 mg of fluoride] on days 1 and 2; and 13.2 mg of sodium fluoride [6 mg of fluoride] on days 3 and 4). In trial 2, designed to confirm the selected method for fluoride detection, 12 participants were administered a fluoride-restricted diet and randomized to receive voriconazole (400 mg twice, 12 hours apart, on day 1 [131 mg/d of fluoride maximum], then 3 doses of 200 mg every 12 hours [65.3 mg/d of fluoride maximum]) or placebo. Plasma fluoride concentrations and urinary fluoride excretion were assessed in each trial. Assessment of plasma fluoride concentrations in trial 1 was limited by 301 of 854 samples (35.2%) below the lower limit of quantitation. Urine fluoride excretion was readily measured and demonstrated a decrease from baseline during the fluoride-restricted diet phase, as well as dose-proportional increases with fluoride administration. In trial 2, increases in urine fluoride were successfully observed in participants administered voriconazole. In conclusion, fluoride exposure was optimally assessed by urinary fluoride excretion in conjunction with strict dietary fluoride restrictions, as measurements were consistent and reproducible.
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Population pharmacokinetics of mobocertinib in healthy volunteers and patients with non-small cell lung cancer.
Gupta, N, Pierrillas, PB, Hanley, MJ, Zhang, S, Diderichsen, PM
CPT: pharmacometrics & systems pharmacology. 2022;(6):731-744
Abstract
Mobocertinib is an oral tyrosine kinase inhibitor approved for treatment of patients with locally advanced or metastatic non-small cell lung cancer (mNSCLC) with epidermal growth factor receptor gene (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. This population pharmacokinetic (PK) analysis describes the PK of mobocertinib and its active metabolites, AP32960, and AP32914, using data from two phase I studies in healthy volunteers (n = 110) and two phase I/II studies in patients with mNSCLC (n = 317), including the pivotal phase I/II study. The plasma PK of mobocertinib, AP32960, and AP32914 were well-characterized by a joint semimechanistic model that included two compartments for mobocertinib with absorption via three transit compartments, two compartments for AP32960, and one compartment for AP32914. The observed time-dependency in PK was described by an enzyme compartment with drug and metabolite concentration-dependent stimulation of enzyme production, resulting in the enzyme increasing the apparent clearance of mobocertinib, AP32960, and AP32914. Effects of healthy volunteer status (vs. patients with mNSCLC) on apparent oral clearance of all three moieties and on apparent central volume of distribution for mobocertinib were included as structural covariates in the final model. No clinically meaningful differences in mobocertinib PK were observed based on age (18-86 years), race, sex, body weight (37.3-132 kg), mild-to-moderate renal impairment (estimated glomerular filtration rate 30-89 ml/min/1.73 m2 by modification of diet in renal disease equation), or mild-to-moderate hepatic impairment, suggesting that no dose adjustment is required based on these covariates in patients with mNSCLC.
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Innate immune remodeling by short-term intensive fasting.
Qian, J, Fang, Y, Yuan, N, Gao, X, Lv, Y, Zhao, C, Zhang, S, Li, Q, Li, L, Xu, L, et al
Aging cell. 2021;(11):e13507
Abstract
Previous studies have shown that long-term light or moderate fasting such as intermittent fasting can improve health and prolong lifespan. However, in humans short-term intensive fasting, a complete water-only fasting has little been studied. Here, we used multi-omics tools to evaluate the impact of short-term intensive fasting on immune function by comparison of the CD45+ leukocytes from the fasting subjects before and after 72-h fasting. Transcriptomic and proteomic profiling of CD45+ leukocytes revealed extensive expression changes, marked by higher gene upregulation than downregulation after fasting. Functional enrichment of differentially expressed genes and proteins exposed several pathways critical to metabolic and immune cell functions. Specifically, short-term intensive fasting enhanced autophagy levels through upregulation of key members involved in the upstream signals and within the autophagy machinery, whereas apoptosis was reduced by down-turning of apoptotic gene expression, thereby increasing the leukocyte viability. When focusing on specific leukocyte populations, peripheral neutrophils are noticeably increased by short-term intensive fasting. Finally, proteomic analysis of leukocytes showed that short-term intensive fasting not only increased neutrophil degranulation, but also increased cytokine secretion. Our results suggest that short-term intensive fasting boost immune function, in particular innate immune function, at least in part by remodeling leukocytes expression profile.
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Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients.
Davar, D, Dzutsev, AK, McCulloch, JA, Rodrigues, RR, Chauvin, JM, Morrison, RM, Deblasio, RN, Menna, C, Ding, Q, Pagliano, O, et al
Science (New York, N.Y.). 2021;(6529):595-602
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Abstract
Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma.
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Deep learning features from diffusion tensor imaging improve glioma stratification and identify risk groups with distinct molecular pathway activities.
Yan, J, Zhao, Y, Chen, Y, Wang, W, Duan, W, Wang, L, Zhang, S, Ding, T, Liu, L, Sun, Q, et al
EBioMedicine. 2021;:103583
Abstract
BACKGROUND To develop and validate a deep learning signature (DLS) from diffusion tensor imaging (DTI) for predicting overall survival in patients with infiltrative gliomas, and to investigate the biological pathways underlying the developed DLS. METHODS The DLS was developed based on a deep learning cohort (n = 688). The key pathways underlying the DLS were identified on a radiogenomics cohort with paired DTI and RNA-seq data (n=78), where the prognostic value of the pathway genes was validated in public databases (TCGA, n = 663; CGGA, n = 657). FINDINGS The DLS was associated with survival (log-rank P < 0.001) and was an independent predictor (P < 0.001). Incorporating the DLS into existing risk system resulted in a deep learning nomogram predicting survival better than either the DLS or the clinicomolecular nomogram alone, with a better calibration and classification accuracy (net reclassification improvement 0.646, P < 0.001). Five kinds of pathways (synaptic transmission, calcium signaling, glutamate secretion, axon guidance, and glioma pathways) were significantly correlated with the DLS. Average expression value of pathway genes showed prognostic significance in our radiogenomics cohort and TCGA/CGGA cohorts (log-rank P < 0.05). INTERPRETATION DTI-derived DLS can improve glioma stratification by identifying risk groups with dysregulated biological pathways that contributed to survival outcomes. Therapies inhibiting neuron-to-brain tumor synaptic communication may be more effective in high-risk glioma defined by DTI-derived DLS. FUNDING A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.