Long-term safety and tolerability of ambrisentan treatment for pediatric patients with pulmonary arterial hypertension: An open-label extension study.

This open-label, extension study assessed long-term safety, tolerability, and efficacy of ambrisentan in a pediatric population (age 8- < 18 years) with pulmonary arterial hypertension (PAH). Following completion of a 6-month, randomized study, participants entered the long-term extension at individualized ambrisentan dosages (2.5/5/7.5 or 10 mg/day). Safety assessments included adverse events (AEs), AEs of special interest, and serious AEs (SAEs); efficacy outcomes included 6-min walking distance (6MWD) and World Health Organization functional class (WHO FC). Thirty-eight of 41 (93%) randomized study participants entered the extension; 21 (55%) completed (reaching age 18 years). Most participants received concomitant phosphodiesterase-5 inhibitors (n = 25/38, 66%). Median ambrisentan exposure was 3.5 years. Most participants experienced ≥ 1 AE (n = 34/38, 89%), and 21 (55%) experienced SAEs, most commonly worsening PAH (n = 3/38, 8%), acute cardiac failure, pneumonia, or anemia (n = 2/38; 5% each); none considered ambrisentan-related. Seven participants (18%) died, with recorded reasons (MedDRA preferred term): cardiac failure (n = 2), PAH (n = 2), COVID-19 (n = 1), acute right ventricular failure (n = 1), and failure to thrive (n = 1); median time to death: 5.2 years. Anemia and hepatotoxicity AEs were generally mild to moderate and did not require ambrisentan dose adjustment. Assessed at study end in 29 participants (76%), mean 6MWD improved by 17% (standard deviation: 34.3%), and all (29/29, 100%) had improved or unchanged WHO FC.    Conclusion: Long-term weight-based ambrisentan dosing, alone or combined with other PAH therapies in children with PAH aged 8- < 18 years, exhibited tolerability and clinical improvements consistent with prior randomized study results.    Trial registration: NCT01342952, April 27, 2011. What is Known: • The endothelin receptor antagonist, ambrisentan, is indicated for treatment of pulmonary arterial hypertension (PAH). Previous studies have shown similar efficacy and tolerability in pediatric patients as in adults. What is New: • This open-label extension study assessed the long-term use of ambrisentan in pediatric patients (8-<18 years) with PAH, most of whom were also receiving recommended background PAH treatment. • Weight-based dosing of ambrisentan, given alone or in combination with other PAH therapies, was well tolerated with clinical improvements consistent with prior randomized study results.

Positive Predictors for Response to Ambrisentan Combination Therapy in Pulmonary Arterial Hypertension.

The AMBITION study (NCT01178073) provided the first long-term clinical evidence for initial combination therapy with ambrisentan and tadalafil in patients with pulmonary arterial hypertension (PAH). Nevertheless, predictors of treatment response were not assessed.To identify predictors for response to initial combination therapy, we examined data from 302 patients with PAH (World Health Organization Functional Class II or III) who received initial combination therapy from the modified intention-to-treat population of the AMBITION study (n = 605). A responder was defined as not having undergone a clinical failure event. Univariate and multivariate analyses were performed. Multivariate logistic regression with interactive backward selection was used to assess the independent association of potential predictors with response.Treatment responders were younger, more often female, and less likely to have comorbidities or a requirement for oxygen therapy, compared with nonresponders. At multivariate analysis, female sex (odds ratio [OR] 2.67; 95% confidence interval [CI] 1.29, 5.52; P = 0.0081), longer 6-minute walk distance (OR 1.01; 95% CI 1.00, 1.01; P = 0.0039), lower baseline log N-terminal-prohormone of brain natriuretic peptide (OR 0.70; 95% CI 0.52, 0.94; P = 0.0190), and aldosterone antagonist use (OR 2.54; 95% CI 1.03, 6.26; P = 0.0436) independently predicted response to initial combination therapy.Besides demographic factors, the absence of comorbidities and less severe disease state, and the use of aldosterone antagonist therapy identified patients with PAH most likely to respond to initial combination therapy with ambrisentan and tadalafil. Further study to evaluate the role of aldosterone antagonist therapy in PAH is warranted.

A pilot study of Pan-FGFR inhibitor ponatinib in patients with FGFR-altered advanced cholangiocarcinoma.

Background Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations. Methods This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results Twelve patients were enrolled prior to early termination of the trial. Partial responses were observed in 1 from 12 patients. Median PFS was 2.4 months and median OS was 15.7 months. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed. Conclusions Ponatinib as a single agent in FGFR altered BTC is tolerable with limited clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.

Comparative assessment of efficacy and safety of ambrisentan and bosentan in patients with pulmonary arterial hypertension: A meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Two endothelin receptor antagonists, ambrisentan and bosentan, have been demonstrated to be effective individually compared with placebo in the treatment of patients with pulmonary arterial hypertension (PAH). This network meta-analysis compared the efficacy and safety of ambrisentan and bosentan in patients with PAH. METHODS: Clinical trials were identified from the Cochrane Central Register of Controlled Trials (CENTRAL/CCTR), EMBASE and PubMed databases. Weighted mean differences (MD) with 95% confidence intervals (CI) were calculated for continuous outcomes (6-min walk distance [6MWD] and Borg dyspnoea index [BDI]). Hazard ratio (HR) was calculated for binary outcomes, including clinical worsening, discontinuation due to adverse events (AEs) and liver dysfunction. Surface under cumulative ranking curve (SUCRA) was used to rank the treatments in each index. RESULTS: Five clinical trials from four published studies (total patients: n = 920) were included. Ambrisentan and bosentan showed no significant difference in 6MWD (MD: -1.32; 95% CI: -27.87, 25.31, SUCRA score: ambrisentan 0.73, bosentan 0.77), BDI (MD: -0.16; 95% CI: -0.98, 0.65, SUCRA score: ambrisentan 0.83, bosentan 0.66), clinical worsening (HR: 0.99; 95% CI: 0.33, 2.94, SUCRA score: ambrisentan 0.75, bosentan 0.74) and discontinuation due to AEs (HR: 0.84; 95% CI: 0.11, 5.86, SUCRA score: ambrisentan 0.47, bosentan 0.57). However, ambrisentan was significantly better than bosentan with respect to abnormal liver function (HR: 23.18; 95% CI: 2.24, 377.20, SUCRA score: ambrisentan 0.99, bosentan 0.02). WHAT IS NEW AND CONCLUSION: The results of this network meta-analysis suggest that ambrisentan was similar to bosentan in efficacy, while it exhibited better tolerability with respect to abnormal liver function in comparison with bosentan, in patients with PAH.

INSIGHT 2: a phase II study of tepotinib plus osimertinib in MET-amplified NSCLC and first-line osimertinib resistance.

MET amplification (METamp), a mechanism of acquired resistance to EGFR tyrosine kinase inhibitors, occurs in up to 30% of patients with non-small-cell lung cancer (NSCLC) progressing on first-line osimertinib. Combining osimertinib with a MET inhibitor, such as tepotinib, an oral, highly selective, potent MET tyrosine kinase inhibitor, may overcome METamp-driven resistance. INSIGHT 2 (NCT03940703), an international, open-label, multicenter phase II trial, assesses tepotinib plus osimertinib in patients with advanced/metastatic EGFR-mutant NSCLC and acquired resistance to first-line osimertinib and METamp, determined centrally by fluorescence in situ hybridization (gene copy number ≥5 and/or MET/CEP7 ≥2) at time of progression. Patients will receive tepotinib 500 mg (450 mg active moiety) plus osimertinib 80 mg once-a-day. The primary end point is objective response, and secondary end points include duration of response, progression-free survival, overall survival and safety. Trial registration number: NCT03940703 (clinicaltrials.gov).

Osimertinib is used to treat a type of lung cancer that has specific changes (mutations) in a gene called EGFR. Although tumors will usually shrink (respond) during treatment with osimertinib, they can stop responding, or become resistant, to osimertinib. A common cause of resistance is 'MET amplification', which describes when extra copies of a gene called MET are present. Lung cancer that is resistant to osimertinib due to MET amplification could be treated by combining osimertinib with a treatment that blocks MET, such as tepotinib. INSIGHT 2 is an ongoing study that is designed to learn about the effects and safety of tepotinib combined with osimertinib, in patients with lung cancer that has stopped responding to osimertinib because of MET amplification. A plain language version of this article is available and is published alongside the paper online: www.futuremedicine.com/doi/suppl/10.2217/fon-2021-1406.

Effects of food on the pharmacokinetics of ensartinib in healthy Chinese subjects.

Ensartinib is a promising, aminopyridazine-based small molecule that potently inhibits anaplastic lymphoma kinase. This random, two-period, crossover study evaluated the effects of food on the pharmacokinetics of ensartinib after a single dose (225 mg) in healthy Chinese subjects. The pharmacokinetic parameters of ensartinib were calculated using non-compartmental analysis. Twenty-four healthy Chinese subjects age 20-44 years were included in this study. The area under the concentration-time curve of ensartinib was ~25% lower after the intake of a high-fat, high-calorie meal before dosing, whereas the maximum plasma concentration was decreased by ~37%, illustrating the statistically significant effect of food on ensartinib pharmacokinetics. In addition, food intake prolonged the absorption phase of ensartinib (median time to maximum plasma concentration, from 4.5 to 6 hours). Population pharmacokinetic (PopPK) analysis was conducted using NONMEM, and the influences of food, age, sex, body weight and body mass index were studied via covariate analysis. In this analysis, ensartinib plasma concentrations were best described by a one-compartment model with Weibull absorption. The final model included food and age as covariates on apparent distribution and apparent clearance. Based on the final PopPK model, food was identified as a significant covariate for apparent clearance, apparent volume of distribution and absorption rate constant, consistent with the results of non-compartmental pharmacokinetic analysis.

TG68, a Novel Thyroid Hormone Receptor-ß Agonist for the Treatment of NAFLD.

Activation of thyroid hormone receptor ß (THRß) has shown beneficial effects on metabolic alterations, including non-alcoholic fatty liver disease (NAFLD). Here, we investigated the effect of TG68, a novel THRß agonist, on fatty liver accumulation and liver injury in mice fed a high-fat diet (HFD). C57BL/6 mice fed HFD for 17 or 18 weeks, a time when all mice developed massive steatohepatitis, were then given TG68 at a dose of 9.35 or 2.8 mg/kg for 2 or 3 weeks, respectively. As a reference compound, the same treatment was adopted using equimolar doses of MGL-3196, a selective THRß agonist currently in clinical phase III. The results showed that treatment with TG68 led to a reduction in liver weight, hepatic steatosis, serum transaminases, and circulating triglycerides. qRT-PCR analyses demonstrated activation of THRß, as confirmed by increased mRNA levels of Deiodinase-1 and Malic enzyme-1, and changes in lipid metabolism, as revealed by increased expression of Acyl-CoA Oxidase-1 and Carnitine palmitoyltransferase-1. The present results showed that this novel THRß agonist exerts an anti-steatogenic effect coupled with amelioration of liver injury in the absence of extra-hepatic side effects, suggesting that TG68 may represent a useful tool for the treatment of NAFLD.

Pharmacologic control of homeostatic and antigen-driven proliferation to target HIV-1 persistence.

The presence of latent human immunodeficiency virus 1 (HIV-1) in quiescent memory CD4 + T cells represents a major barrier to viral eradication. Proliferation of memory CD4 + T cells is the primary mechanism that leads to persistence of the latent reservoir, despite effective antiretroviral therapy (ART). Memory CD4 + T cells are long-lived and can proliferate through two mechanisms: homeostatic proliferation via γc-cytokine stimulation or antigen-driven proliferation. Therefore, therapeutic modalities that perturb homeostatic and antigen-driven proliferation, combined with ART, represent promising strategies to reduce the latent reservoir. In this study, we investigated a library of FDA-approved oncology drugs to determine their ability to inhibit homeostatic and/or antigen-driven proliferation. We confirmed potential hits by evaluating their effects on proliferation in memory CD4 + T cells from people living with HIV-1 on ART (PLWH) and interrogated downstream signaling of γc-cytokine stimulation. We found that dasatinib and ponatinib, tyrosine kinase inhibitors, and trametinib, a MEK inhibitor, reduced both homeostatic and antigen-driven proliferationby >65%, with a reduction in viability <45%, ex vivo. In memory CD4 + T cells from PLWH, only dasatinib restricted both homeostatic and antigen-driven proliferation and prevented spontaneous rebound, consistent with promoting a smaller reservoir size. We show that dasatinib restricts IL-7 induced proliferation through STAT5 phosphorylation inhibition. Our results establish that the anti-cancer agent dasatinib is an exciting candidate to be used as an anti-proliferative drug in a clinical trial, since it efficiently blocks proliferation and iswell tolerated in patients with chronic myeloid leukemia (CML).

Capmatinib successfully overcomes tepotinib-induced intolerable peripheral edema.

In May 2020 and February 2021, capmatinib and tepotinib, respectively were approved by the Food and Drug Administration (FDA) for the treatment of metastatic non-small cell lung carcinoma harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations. Herein, we present a case of intolerable peripheral edema caused by tepotinib, in which MET inhibitor could be continued by switching to capmatinib. Peripheral edema has been identified as one of the most common adverse events in capmatinib and tepotinib; however, there is no unified management for this adverse event. This is the first report that two MET inhibitors have different effects on the development of peripheral edema, and that the MET inhibitors can be continued by switching these drugs.

Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial.

In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.

Lateral hypothalamus involvement in control of stress response by bed nucleus of the stria terminalis endocannabinoid neurotransmission in male rats.

The endocannabinoid neurotransmission acting via local CB1 receptor in the bed nucleus of the stria terminalis (BNST) has been implicated in behavioral and physiological responses to emotional stress. However, the neural network related to this control is poorly understood. In this sense, the lateral hypothalamus (LH) is involved in stress responses, and BNST GABAergic neurons densely innervate this hypothalamic nucleus. However, a role of BNST projections to the LH in physiological responses to stress is unknown. Therefore, using male rats, we investigated the role of LH GABAergic neurotransmission in the regulation of cardiovascular responses to stress by CB1 receptors within the BNST. We observed that microinjection of the selective CB1 receptor antagonist AM251 into the BNST decreased the number of Fos-immunoreactive cells within the LH of rats submitted to acute restraint stress. Treatment of the BNST with AM251 also enhanced restraint-evoked tachycardia. Nevertheless, arterial pressure increase and sympathetically-mediated cutaneous vasoconstriction to restraint was not affected by CB1 receptor antagonism within the BNST. The effect of AM251 in the BNST on restraint-evoked tachycardia was abolished in animals pretreated with the selective GABAA receptor antagonist SR95531 in the LH. These results indicate that regulation of cardiovascular responses to stress by CB1 receptors in the BNST is mediated by GABAergic neurotransmission in the LH. Present data also provide evidence of the BNST endocannabinoid neurotransmission as a mechanism involved in LH neuronal activation during stressful events.

Serial evaluation of the pharmacokinetics of ponatinib in patients with CML and Ph + ALL.

Although tyrosine kinase inhibitors (TKIs) play a crucial role in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), intolerance and resistance to TKIs have been serious problems. Due to a lack of research, the importance of the pharmacokinetics (PK) of TKIs is currently unclear. We examined the PK of the third-generation TKI ponatinib to monitor side effects and efficacy during treatments for one patient with CML-chronic phase (CP-CML) and two who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), one for CML-blastic crisis (BC-CML) and one for Ph + ALL. The patient with CP-CML was intolerant to multiple TKIs (dasatinib, nilotinib, imatinib, and bosutinib) and thus was switched to ponatinib (15 mg/day). The patients who received allo-HSCT for BC-CML and Ph + ALL received ponatinib (15 mg/day) as maintenance therapy. Notably, serial evaluation of the PK of ponatinib showed that the median trough values (ng/ml) were 17.2 (12.2-34.5), 33.1 (21.2-40.3) and 27.7 (13.6-29.9) in patients 1, 2, and 3, respectively. These values were around the target concentration (23 ng/ml). All patients are maintaining complete remission without side effects. In conclusion, serial evaluation of PK of ponatinib may yield meaningful information about its safety and efficacy.

A deep learning approach to identify gene targets of a therapeutic for human splicing disorders.

Pre-mRNA splicing is a key controller of human gene expression. Disturbances in splicing due to mutation lead to dysregulated protein expression and contribute to a substantial fraction of human disease. Several classes of splicing modulator compounds (SMCs) have been recently identified and establish that pre-mRNA splicing represents a target for therapy. We describe herein the identification of BPN-15477, a SMC that restores correct splicing of ELP1 exon 20. Using transcriptome sequencing from treated fibroblast cells and a machine learning approach, we identify BPN-15477 responsive sequence signatures. We then leverage this model to discover 155 human disease genes harboring ClinVar mutations predicted to alter pre-mRNA splicing as targets for BPN-15477. Splicing assays confirm successful correction of splicing defects caused by mutations in CFTR, LIPA, MLH1 and MAPT. Subsequent validations in two disease-relevant cellular models demonstrate that BPN-15477 increases functional protein, confirming the clinical potential of our predictions.

Randomised Phase 1b/2 trial of tepotinib vs sorafenib in Asian patients with advanced hepatocellular carcinoma with MET overexpression.

BACKGROUND: This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression. METHODS: In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP). RESULTS: In Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26-0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib. CONCLUSIONS: Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression. TRIAL REGISTRATION: ClinicalTrials.gov NCT01988493.

Multiple retrospective analysis of survival and evaluation of cardiac death predictors in a population of dogs affected by degenerative mitral valve disease in ACVIM class C treated with different therapeutic protocols.

Clinical records of dogs with spontaneous degenerative mitral valve disease (DMVD) with clinical signs related to congestive heart failure (CHF) recruited during routine clinical practice between 2001 and 2018 at the Cardiology Unit of the Veterinary Teaching Hospital (University of Milan) were included in this retrospective cohort study. Baseline echocardiographic data were evaluated. Median survival time (MST) was calculated. Data on therapeutic treatment, ISACHC (International Small Animal Cardiac Health Council) or ACVIM (American College of Veterinary Internal Medicine) classes were reviewed based on the inclusion period and type of endpoint (i.e. cardiac death or death for other causes). A univocal classification was needed, and the patients classified in ISACHC classes II, IIIa and IIIb, visited before 2009, were reallocated to ACVIM class C. The main goal of this data review was to retrospectively evaluate 259 clinical records of subjects belonging to ACVIM C class examined between 2001 to 2018 and 202 dogs examined between 2010 to 2018. In this way, in the second group, the bias of the reclassification was avoided. The MST (median survival time) of these subjects was 531 d (2001-2018) and 335.5 d (2010-2018), respectively. Univariate survival regression analysis for subjects included from 2010 to 2018 showed as significantly related to cardiac death (CD): left atrium to aorta ratio (LA/Ao) (HR 2.754, p=0.000), E wave (HR 2.961, p=0.000), E/A ratio (HR 1.372, p=0.000), end-diastolic (HR 1.007, p=0.000) (EDVI) and end-systolic (HR 1.012, p=0.026) (ESVI) volume indexes, allometric diastolic (HR 4.018, p=0.000) (LVIDdN) and systolic (HR 2.674, p=0.049) (LVIDsN) left ventricular internal diameters, age (HR 1.006, p=0.009) and pulmonary hypertension severity (HR=1.309, p=0.012) (PH). Multivariate analysis, adjusted for age, showed that the only variable that determined a statistically significant difference in MST was PH severity (HR 1.334, p=0.033). The type of therapeutic treatment within this class was not significant for the MST of the subjects.

Effects of Resmetirom on Noninvasive Endpoints in a 36-Week Phase 2 Active Treatment Extension Study in Patients With NASH.

Resmetirom (MGL-3196), a selective thyroid hormone receptor-ß agonist, was evaluated in a 36-week paired liver biopsy study (NCT02912260) in adults with biopsy-confirmed nonalcoholic steatohepatitis (NASH). The primary endpoint was relative liver fat reduction as assessed by MRI-proton density fat fraction (MRI-PDFF), and secondary endpoints included histopathology. Subsequently, a 36-week active treatment open-label extension (OLE) study was conducted in 31 consenting patients (including 14 former placebo patients) with persistently mild to markedly elevated liver enzymes at the end of the main study. In patients treated with resmetirom (80 or 100 mg orally per day), MRI-PDFF reduction at OLE week 36 was -11.1% (1.5%) mean reduction (standard error [SE]; P < 0.0001) and -52.3% (4.4%) mean relative reduction, P < 0.0001. Low-density lipoprotein (LDL) cholesterol (-26.1% [4.5%], P < 0.0001), apolipoprotein B (-23.8% [3.0%], P < 0.0001), and triglycerides (-19.6% [5.4%], P = 0.0012; -46.1 [14.5] mg/dL, P = 0.0031) were reduced from baseline. Markers of fibrosis were reduced, including liver stiffness assessed by transient elastography (-2.1 [0.8] mean kilopascals [SE], P = 0.015) and N-terminal type III collagen pro-peptide (PRO-C3) (-9.8 [2.3] ng/mL, P = 0.0004 (baseline ≥ 10 ng/mL). In the main and OLE studies, PRO-C3/C3M (matrix metalloproteinase-degraded C3), a marker of net fibrosis formation, was reduced in resmetirom-treated patients (-0.76 [-1.27, -0.24], P = 0.0044 and -0.68, P < 0.0001, respectively). Resmetirom was well tolerated, with few, nonserious adverse events. Conclusion: The results of this 36-week OLE study support the efficacy and safety of resmetirom at daily doses of 80 mg and 100 mg, used in the ongoing phase 3 NASH study, MAESTRO-NASH (NCT03900429). The OLE study demonstrates a potential for noninvasive assessments to monitor the response to resmetirom from an individual patient with NASH.

Efficacy and safety of ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: a case series from a single institute.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is an aggressive leukemia that occurs in 20-40% of adult patients. Ph + ALL is caused by the Philadelphia chromosome (Ph), which consists of a t(9;22)(q34;q11) reciprocal translocation leading to the formation of a BCR-ABL1 fusion gene. The disease is treated with targeted therapy comprising ABL1 tyrosine kinase inhibitors (TKIs). Ponatinib is a third generation TKI that demonstrates higher binding affinity for ABL1 than first/second generation TKIs. Although intensive combined immunotherapy with ponatinib greatly improves the prognosis of Ph + ALL, the safety and efficacy profiles of ponatinib in Japanese patients are unclear. This retrospective study investigated five cases of Ph + ALL at a single institute to evaluate safety and efficacy profiles. Three patients achieved a deep molecular response (DMR) following combined intensive treatment with ponatinib as induction chemotherapy. Four patients received consolidative allogenic stem cell transplantation (allo-SCT) during their first complete response. Three of the four experienced early relapse within 100 days; they subsequently received ponatinib, and one of the three achieved a DMR. No patient experienced severe cardiovascular events. This case series suggests that ponatinib at a concentration of least 30 mg exhibits anti-leukemia effects in Japanese patients with Ph + ALL.

Translational pharmacokinetic-pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose.

Tepotinib is a highly selective and potent MET inhibitor in development for the treatment of patients with solid tumors. Given the favorable tolerability and safety profiles up to the maximum tested dose in the first-in-human (FIH) trial, an efficacy-driven translational modeling approach was proposed to establish the recommended phase II dose (RP2D). To study the in vivo pharmacokinetics (PKs)/target inhibition/tumor growth inhibition relationship, a subcutaneous KP-4 pancreatic cell-line xenograft model in mice with sensitivity to MET pathway inhibition was selected as a surrogate tumor model. Further clinical PK and target inhibition data (derived from predose and postdose paired tumor biopsies) from a FIH study were integrated with the longitudinal PKs and target inhibition profiles from the mouse xenograft study to establish a translational PK/pharmacodynamic (PD) model. Preclinical data showed that tumor regression with tepotinib treatment in KP-4 xenograft tumors corresponded to 95% target inhibition. We therefore concluded that a PD criterion of sustained, near-to-complete (>95%) phospho-MET inhibition in tumors should be targeted for tepotinib to be effective. Simulations of dose-dependent target inhibition profiles in human tumors that exceeded the PD threshold in more than 90% of patients established an RP2D of tepotinib 500 mg once daily. This translational mathematical modeling approach supports an efficacy-driven rationale for tepotinib phase II dose selection of 500 mg once daily. Tepotinib at this dose has obtained regulatory approval for the treatment of patients with non-small cell lung cancer harboring MET exon 14 skipping.

Phase 1b/2 trial of tepotinib in sorafenib pretreated advanced hepatocellular carcinoma with MET overexpression.

BACKGROUND: This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenib pretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression. METHODS: Eligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b ('3 + 3' design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2). RESULTS: In Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5-74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P < 0.0001). Median time to progression was 4 months. In Phase 2, 28.6% of patients had treatment-related Grade ≥3 adverse events, including peripheral oedema and lipase increase (both 6.1%). CONCLUSIONS: Tepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit-risk balance in sorafenib pretreated aHCC with MET overexpression. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02115373.