Anish Mehta

The Cathepsin K Inhibitor Odanacatib Suppresses Bone Resorption in Women With Breast Cancer and Established Bone Metastases: Results of a 4-Week, Double-Blind, Randomized, Controlled Trial

BACKGROUNDnMetastatic bone disease (MBD) is a frequent complication in patients with breast cancer and is associated with significant morbidity. This study assessed the pharmacokinetics, efficacy, and safety of odanacatib, a selective Cat K inhibitor, in reducing markers of bone resorption in women with breast cancer and MBD.nnnPATIENTS AND METHODSnWomen with breast cancer and MBD were randomized 2:1 (double-blind) to oral odanacatib 5 mg daily for 4 weeks or intravenous (I.V.) zoledronic acid (ZA) 4 mg given once at study initiation. Plasma samples were collected for pharmacokinetic analysis. Bone resorption was assessed by measuring urinary N-telopeptide of type I collagen corrected for creatinine (uNTx; primary objective, pmol BCE/µmol creatinine). Adverse events (AEs) were monitored throughout the 4-week study and up to 14 days after last dose.nnnRESULTSnA total of 43 patients (mean age, 60 years) received odanacatib (n = 29) or ZA (n = 14); 40 patients completed 4 weeks of treatment. The mean percent change in uNTx values at week 4 was -77% (95% CI, -82 to -71; odanacatib) and -73% (95% CI, -80 to -62; ZA). Mean (standard deviation) plasma concentration of odanacatib was 511.7 (202.9) nM; the range was 63.7-844.8 nM. The most common AEs were nausea, vomiting, headache, and bone pain, which were generally not attributed to study drug.nnnCONCLUSIONnOdanacatib suppressed uNTx similarly to ZA after 4 weeks of treatment in women with breast cancer and MBD. Odanacatib was generally safe and well tolerated. These results suggest that Cat K inhibition is a potentially important, novel therapeutic approach for treating MBD.

Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials

BACKGROUNDnTildrakizumab is a high-affinity, humanised, IgG1 κ antibody targeting interleukin 23 p19 that represents an evolving treatment strategy in chronic plaque psoriasis. Previous research suggested clinical improvement with inhibition of interleukin 23 p19. We did two phase 3 trials to investigate whether tildrakizumab is superior to placebo and etanercept in the treatment of chronic plaque psoriasis.nnnMETHODSnWe did two three-part, parallel group, double-blind, randomised controlled studies, reSURFACE 1 (at 118 sites in Australia, Canada, Japan, the UK, and the USA) and reSURFACE 2 (at 132 sites in Europe, Israel, and the USA). Participants aged 18 years or older with moderate-to-severe chronic plaque psoriasis (body surface area involvement ≥10%, Physicians Global Assessment [PGA] score ≥3, and Psoriasis Area and Severity Index [PASI] score ≥12) were randomised (via interactive voice and web response system) to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo in reSURFACE 1 (2:2:1), or to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg (2:2:1:2). Randomisation was done by region and stratified for bodyweight (≤90 kg or >90 kg) and previous exposure to biologics therapy for psoriasis. Investigators, participants, and study personnel were blinded to group allocation and remained blinded until completion of the studies. Assigned medication was identical in appearance and packaging. Tildrakizumab was administered subcutaneously at weeks 0 and 4 during part 1 and at week 16 during part 2 (weeks 12 and 16 for participants re-randomised from placebo to tildrakizumab; etanercept was given twice weekly in part 1 of reSURFACE 2 and once weekly during part 2). The co-primary endpoints were the proportion of patients achieving PASI 75 and PGA response (score of 0 or 1 with ≥2 grade score reduction from baseline) at week 12. Safety was assessed in the all-participants-as-treated population, and efficacy in the full-analysis set. These trials are registered with ClinicalTrials.gov, numbers NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2). These studies are completed, but extension studies are ongoing.nnnFINDINGSnreSURFACE 1 ran from Dec 10, 2012, to Oct 28, 2015. reSURFACE 2 ran from Feb 12, 2013, to Sept 28, 2015. In reSURFACE 1, 772 patients were randomly assigned, 308 to tildrakizumab 200 mg, 309 to tildrakizumab 100 mg, and 155 to placebo. At week 12, 192 patients (62%) in the 200 mg group and 197 patients (64%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). 182 patients (59%) in the 200 mg group and 179 patients (58%) in the 100 mg group achieved PGA responses, compared with 11 patients (7%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). In reSURFACE 2, 1090 patients were randomly assigned, 314 to tildrakizumab 200 mg, 307 to tildrakizumab 100 mg, 156 to placebo, and 313 to etanercept. At week 12, 206 patients (66%) in the 200 mg group, and 188 patients (61%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group and 151 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p<0·0001 for 200 mg vs etanercept and p=0·0010 for 100 mg vs etanercept). 186 patients (59%) in the 200 mg group, and 168 patients (59%) [corrected] in the 100 mg group achieved a PGA response, compared with 7 patients (4%) in the placebo group and 149 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p=0·0031 for 200 mg vs etanercept and p=0·0663 for 100 mg vs etanercept). Serious adverse events were similar and low in all groups in both trials. One patient died in reSURFACE 2, in the tildrakizumab 100 mg group; the patient had alcoholic cardiomyopathy and steatohepatitis, and adjudication was unable to determine the cause of death.nnnINTERPRETATIONnIn two phase 3 trials, tildrakizumab 200 mg and 100 mg were efficacious compared with placebo and etanercept and were well tolerated in the treatment of patients with moderate-to-severe chronic plaque psoriasis.nnnFUNDINGnMerck & Co.

Effect of montelukast for treatment of asthma in cigarette smokers

OBJECTIVEnMany asthmatic patients are unable to quit cigarettes; therefore information is needed on treatment options for smokers. This study evaluates 10 mg/d montelukast and 250xa0μg of fluticasone propionate twice daily, each compared with placebo, in patients with self-reported active smoking (unable to quit) and asthma.nnnMETHODSnPatients (ages 18-55 years, with asthma [≥1 year], FEV1 of 60% to 90% of predicted value, airway reversibility [≥12%], and self-reported active smoking [≥0.5 to ≤2 packs per day]) were randomized (after a 3-week, single-blind, placebo, run-in period) to 1 of 3 parallel, 6-month, double-blind treatment arms. The primary efficacy end point was the percentage of days with asthma control during treatment. Adverse experiences (AEs) were also evaluated.nnnRESULTSnThere were 347, 336, and 336 patients randomized to montelukast, fluticasone, and placebo, respectively. The mean percentage of days with asthma control over 6 months of treatment was 45% (montelukast, Pxa0<xa0.05 vs placebo), 49% (fluticasone, Pxa0<xa0.001 vs placebo), and 39% (placebo); the difference between montelukast and fluticasone was not significant (Pxa0=xa0.14). Patients with a smoking history of ≤11 pack years (the median value) tended to show more benefit with fluticasone, whereas those with a smoking history of >11 pack years tended to show more benefit with montelukast. AEs occurred in similar proportions among treatment groups.nnnCONCLUSIONSnIn a population of asthmatic patients actively smoking cigarettes, both 10 mg/d montelukast and 250 μg of fluticasone propionate twice daily significantly increased the mean percentage of days with asthma control compared with placebo.

MK-0448, a specific Kv1.5 inhibitor: safety, pharmacokinetics, and pharmacodynamic electrophysiology in experimental animal models and humans.

Background— We evaluated the viability of IKur as a target for maintenance of sinus rhythm in patients with a history of atrial fibrillation through the testing of MK-0448, a novel IKur inhibitor. Methods and Results— In vitro MK-0448 studies demonstrated strong inhibition of IKur with minimal off-target activity. In vivo MK-0448 studies in normal anesthetized dogs demonstrated significant prolongation of the atrial refractory period compared with vehicle controls without affecting the ventricular refractory period. In studies of a conscious dog heart failure model, sustained atrial fibrillation was terminated with bolus intravenous MK-0448 doses of 0.03 and 0.1 mg/kg. These data led to a 2-part first-in-human study: Part I evaluated safety and pharmacokinetics, and part II was an invasive electrophysiological study in healthy subjects. MK-0448 was well-tolerated with mild adverse experiences, most commonly irritation at the injection site. During the electrophysiological study, ascending doses of MK-0448 were administered, but no increases in atrial or ventricular refractoriness were detected, despite achieving plasma concentrations in excess of 2 &mgr;mol/L. Follow-up studies in normal anesthetized dogs designed to assess the influence of autonomic tone demonstrated that prolongation of atrial refractoriness with MK-0448 was markedly attenuated in the presence of vagal nerve simulation, suggesting that the effects of IKur blockade on atrial repolarization may be negated by enhanced parasympathetic neural tone. Conclusions— The contribution of IKur to human atrial electrophysiology is less prominent than in preclinical models and therefore is likely to be of limited therapeutic value for the prevention of atrial fibrillation.Background— We evaluated the viability of IKur as a target for maintenance of sinus rhythm in patients with a history of atrial fibrillation through the testing of MK-0448, a novel IKur inhibitor.nnMethods and Results— In vitro MK-0448 studies demonstrated strong inhibition of IKur with minimal off-target activity. In vivo MK-0448 studies in normal anesthetized dogs demonstrated significant prolongation of the atrial refractory period compared with vehicle controls without affecting the ventricular refractory period. In studies of a conscious dog heart failure model, sustained atrial fibrillation was terminated with bolus intravenous MK-0448 doses of 0.03 and 0.1 mg/kg. These data led to a 2-part first-in-human study: Part I evaluated safety and pharmacokinetics, and part II was an invasive electrophysiological study in healthy subjects. MK-0448 was well-tolerated with mild adverse experiences, most commonly irritation at the injection site. During the electrophysiological study, ascending doses of MK-0448 were administered, but no increases in atrial or ventricular refractoriness were detected, despite achieving plasma concentrations in excess of 2 μmol/L. Follow-up studies in normal anesthetized dogs designed to assess the influence of autonomic tone demonstrated that prolongation of atrial refractoriness with MK-0448 was markedly attenuated in the presence of vagal nerve simulation, suggesting that the effects of IKur blockade on atrial repolarization may be negated by enhanced parasympathetic neural tone.nnConclusions— The contribution of IKur to human atrial electrophysiology is less prominent than in preclinical models and therefore is likely to be of limited therapeutic value for the prevention of atrial fibrillation.

Evaluation of the dose range of etoricoxib in an acute pain setting using the postoperative dental pain model.

ObjectiveThis study was conducted to evaluate the dose range of etoricoxib in acute pain using the postoperative dental pain model further. MethodsThis double-blind, randomized controlled study evaluated etoricoxib (90 and 120 mg), ibuprofen (600 mg), and acetaminophen (600 mg/codeine) (60 mg, (A/C)) in patients aged ≥18 years with moderate or severe pain after surgical extraction of ≥2 third molars (≥1 impacted). The patients reported pain intensity and pain relief over 24 hours. The primary efficacy endpoint was total pain relief over 6 hours (TOPAR6). Adverse events were evaluated throughout the study. ResultsThere were 588 patients randomized to placebo (n=46), etoricoxib (90 mg (n=191)), etoricoxib (120 mg (n=97)), ibuprofen (2400 mg (n=192)), and A/C (n=62). The overall analgesic effect (TOPAR6) of etoricoxib (90, 120 mg) was significantly greater than that of placebo (P⩽0.001), and not inferior to that of ibuprofen; no discernible difference was observed between etoricoxib 90 and 120 mg. Both etoricoxib doses were superior to A/C (P⩽0.001). Etoricoxib (90 and 120 mg) and ibuprofen (2400 mg) were generally well tolerated and had a similar incidence of adverse events (AEs). A/C was associated with significantly more AEs that led to discontinuation (ie, nausea and vomiting). ConclusionsEtoricoxib (90 and 120 mg) showed similar efficacy in the postoperative dental pain model, which was noninferior to ibuprofen and superior to A/C. A higher number of tooth extractions or a higher mean impaction score may have led to a greater separation in efficacy between the 2 etoricoxib doses.

Add-on montelukast in inadequately controlled asthma patients in a 6-month open-label study: The MONtelukast In Chronic Asthma (MONICA) study

Bronchial asthma often remains uncontrolled despite treatment with inhaled corticosteroids (ICS), long-acting beta(2)-agonists (LABA) or both, necessitating additional treatment. Patients >or=18 years (n=1681) with mild-to-moderate asthma received oral montelukast 10mg added to ICS or ICS+LABAs, and were followed for 6 months in a prospective, open-label observational study. The primary endpoint was change in Asthma Control Test (ACT) score. Secondary endpoints included mini-Asthma Quality-of-Life Questionnaire (mini-AQLQ) and FEV(1)/PEF. Mean ACT scores improved from 14.6+/-4.6 (baseline) to 19.4+/-4.4 (month 6; p<0.0001). Using ACT score categories, the percentage of patients with uncontrolled (57.5%) or poorly controlled (25.0%) asthma at baseline decreased at month 6 (17.6 and 21.7%, respectively); the percentage of patients with well controlled (13.9%) or completely controlled (1.2%) asthma at baseline increased at month 6 (47.5 and 11.4%, respectively). The mini-AQLQ score (mean+/-SD) improved from 4.0+/-1.1 to 5.3+/-1.1 (p<0.0001); FEV(1) increased from 2.46+/-0.89 to 2.60+/-0.92L (p<0.0001). Treatment with montelukast was generally well tolerated. In patients insufficiently controlled with ICS or ICS+LABAs, daily add-on montelukast improved both asthma control and asthma-related quality of life. Clinicaltrials.gov registry number NCT00802789.

Evaluation of the safety, pharmacokinetics and treatment effects of an ανβ3 integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer and bone metastases

Aim:u2003 This study aimed to evaluate the safety, pharmacokinetics and treatment effects of an ανβ3 integrin inhibitor on bone turnover and disease activity in men with hormone‐refractory prostate cancer (HRPC) and bone metastases.

Odanacatib, a selective cathepsin K inhibitor, demonstrates comparable pharmacodynamics and pharmacokinetics in older men and postmenopausal women.

BACKGROUNDnOdanacatib is a cathepsin K inhibitor in development for the treatment of osteoporosis. Evaluation of therapies to ensure that treatment effects are relevant regardless of sex is clinically important.nnnMETHODSnIn this double-blind, randomized controlled trial, older men (aged 50-75 years) and postmenopausal women (aged 45-75 years) were given odanacatib 50 mg once weekly or placebo for 4 weeks. Pharmacodynamic (PD) evaluation measured weighted average inhibition (WAI) of urine amino-terminal cross-linked telopeptide of type I collagen/creatinine (uNTx/Cr) after odanacatib administration. Pharmacokinetic (PK) parameter data were collected, and an analysis of sex as a factor in the PK/PD relationship was conducted. Adverse events were monitored. The hypotheses were that WAI of uNTx/Cr would be >40% (including >40% for the lower limit of the 90% confidence intervals [CIs]) for older men and postmenopausal women, that there would be no important differences in area under the curve from 0 to 168 hours (AUC0-168 h) between men and women, and that odanacatib would be safe and well tolerated.nnnRESULTSnA total of 44 subjects (32 men and 12 women) were randomized. The least squares mean WAI (uNTx/Cr) at week 4 was 42.8% (90% CI, 35.5%-49.3%) for men and 42.7% (90% CI, 30.3%-52.9%) for women; mean values were >40%, but lower bounds were <40% as prespecified in the primary hypothesis. The differences among men and women in PD parameters were not meaningful (0.1; 90% CI, -14.7 to 14.9). PK parameters for both groups were comparable (geometric mean ratio of AUC0-168 h, 0.90; 90% CI, 0.75-1.07). A PK/PD analysis found that the EC50 and maximum fractional inhibition were similar in male and female subjects. There were no notable or serious adverse events in this study.nnnCONCLUSIONSnAlthough the primary hypothesis was not met, there were no clinically meaningful differences in PD, PK, or PK/PD parameters between older men and postmenopausal women, supporting further research on odanacatib (50 mg once weekly) as a treatment for male osteoporosis. Odanacatib was generally well tolerated.

Evaluation of safety, pharmacokinetics, and efficacy of vorinostat, a histone deacetylase inhibitor, in the treatment of gastrointestinal (GI) cancer in a phase I clinical trial

BackgroundControl of epigenetic changes using histone deacetylase inhibitors (HDACi) is thought to be a promising target in therapy of gastrointestinal (GI) cancer. In this study, we evaluated the safety, pharmacokinetics, and efficacy of two dosing regimens of vorinostat, an oral HDACi, in patients with GI tumors.MethodsPatients received either vorinostat 300xa0mg bid for 3 consecutive days followed by 4 rest days per cycle (nxa0=xa010) or vorinostat 400xa0mg qd for 21 consecutive days per cycle (nxa0=xa06). Pharmacokinetic parameters were assessed for the first treatment cycle. Efficacy was determined through evaluation of tumors and assessment of treatment response.ResultsThe median treatment duration of 300xa0mg bid was 52.0xa0days and of 400xa0mg qd was 51.5xa0days. The most common drug-related adverse events were anorexia, nausea, fatigue, and hyperglycemia. Two patients taking 400xa0mg qd had dose-limiting toxicities (DLTs) of thrombocytopenia. No patients taking 300xa0mg bid experienced DLT. Five patients taking 300xa0mg bid and 2 patients taking 400xa0mg qd maintained stable disease for >8xa0weeks, with the maximum duration of 245xa0days. Mean drug exposure (±SD) was generally higher with 400xa0mg qd (area under the curve [AUC0–∞] of 7.75xa0±xa02.79xa0μMxa0h on Day 1 post-dose) compared with 300xa0mg bid (AUC0–∞ of 3.94xa0±xa01.56xa0μMxa0h on Day 1 post-dose).ConclusionsVorinostat 300xa0mg bid for 3 consecutive days followed by 4xa0days of rest was better tolerated in patients with GI cancer than a higher once daily dose. Additionally, there were patients in both groups who achieved stable disease, most maintaining it for longer than 8xa0weeks, suggesting vorinostat as a possible active agent in the treatment of GI cancer.

Perioperative use of etoricoxib reduces pain and opioid side-effects after total abdominal hysterectomy: a double-blind, randomized, placebo-controlled phase III study.

Abstract Objective: To evaluate the effects of two different doses of etoricoxib delivered perioperatively compared with placebo and standard pain management on pain at rest, pain with mobilization, and use of additional morphine/opioids postoperatively. Research design and methods: In this double-blind, placebo-controlled, randomized clinical trial, we evaluated postoperative pain following total abdominal hysterectomy over 5 days in patients receiving placebo or etoricoxib administered 90u2009min prior to surgery and continuing postoperatively. Patients were randomly assigned to receive either placebo (nu2009=u2009144), etoricoxibu200990u2009mg/day (nu2009=u2009142), or etoricoxib 120u2009mg/day (nu2009=u2009144). Average Pain Intensity at Rest over days 1–3 (0- to 10-point numerical rating scale [NRS]) was the primary efficacy endpoint. Secondary endpoints included Average Pain Intensity upon Sitting, Standing, and Walking over days 1–3 (0- to 10-point NRS) as well as Average Total Daily Dose of Morphine over days 1–3. Clinical trial registration: This trial is registered on www.clinicaltrials.gov (NCT00788710). Results: The least squares (LS) means (95% CI) for the primary endpoint were 3.26 (2.96, 3.55); 2.46 (2.16, 2.76); and 2.40 (2.11, 2.69) for placebo, etoricoxib 90u2009mg, and etoricoxib 120u2009mg, respectively, significantly different for both etoricoxib doses versus placebo (pu2009<u20090.001). Patients on etoricoxib 90u2009mg and 120u2009mg required ∼30% less morphine per day than those on placebo (pu2009<u20090.001), which led to more rapid bowel recovery in the active treatment groups by ∼10 hours vs. placebo. A greater proportion of patients on etoricoxib (10–30% greater than placebo) achieved mild levels of pain with movement, defined as pain ≤3/10. Limitations: A key limitation for this study was that movement-evoked pain measurements were not designated as primary endpoints. Conclusion: In patients undergoing total abdominal hysterectomy, etoricoxib 90u2009mg and 120u2009mg dosed preoperatively and then continued postoperatively significantly reduces both resting and movement-related pain, as well as reduced opioid (morphine) consumption that led to more rapid bowel recovery.