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Vosoritide, an analog of C-type natriuretic peptide, has been developed for the treatment of children with achondroplasia. The pharmacokinetics of vosoritide and relationships between plasma exposure and efficacy, biomarkers, and safety endpoints were evaluated in a phase II, open-label, dose-escalation study (N = 35 patients aged 5–14 years who received daily subcutaneous injections for 24 months) and a phase III, double-blind, placebo-controlled study (N = 60 patients aged 5–18 years randomized to receive daily subcutaneous injections for 52 weeks). Pharmacokinetic parameters for both studies were obtained from non-compartmental analysis. Potential correlations between vosoritide exposure and changes in annualized growth velocity, collagen type X marker (CXM; a biomarker of endochondral ossification), cyclic guanosine monophosphate (cGMP; a biomarker of pharmacological activity), heart rate, and systolic and diastolic blood pressures were then evaluated. The exposure–response relationships for changes in both annualized growth velocity and the CXM biomarker saturated at 15 μg/kg, while systemic pharmacological activity, as measured by urinary cGMP, was near maximal or saturated at exposures obtained at the highest dose studied (i.e. 30 μg/kg). This suggested that the additional bioactivity was likely in tissues not related to endochondral bone formation. In the phase III study, following subcutaneous administration at the recommended dose of 15 μg/kg to patients with achondroplasia aged 5–18 years, vosoritide was rapidly absorbed with a median time to maximal plasma concentration (Cmax) of 15 minutes, and cleared with a mean half-life of 27.9 minutes after 52 weeks of treatment. Vosoritide exposure (Cmax and area under the concentration-time curve [AUC]) was consistent across visits. No evidence of accumulation with once-daily dosing was observed. Total anti-vosoritide antibody (TAb) responses were detected in the serum of 25 of 60 (42%) treated patients in the phase III study, with no apparent impact of TAb development noted on annualized growth velocity or vosoritide exposure. Across the exposure range obtained with 15 µg/kg in the phase III study, no meaningful correlations between vosoritide plasma exposure and changes in annualized growth velocity or CXM, or changes from predose heart rate, and systolic or diastolic blood pressures were observed. The results support the recommended dose of vosoritide 15 µg/kg for once-daily subcutaneous administration in patients with achondroplasia aged ≥ 5 years whose epiphyses are not closed. NCT02055157, NCT03197766, and NCT01603095.

Vosoritide is a drug developed for the treatment of achondroplasia and has demonstrated increases in the growth velocity of children with this condition. Achondroplasia is a skeletal dysplasia (a condition affecting children’s bones and joints meaning they do not grow in the typical way) and is also referred to as dwarfism. There are currently no approved treatments for achondroplasia, except for growth hormone in Japan. When a new drug is being developed, it is essential to conduct clinical studies after many other steps to assess how well the drug works and whether it has any side effects. These studies of new drugs are carried out before the drug is approved to treat, improve, or reduce physical problems of certain conditions. This summary reports the results from two clinical studies looking at vosoritide as a potential treatment for children with achondroplasia. Study A compared different doses of vosoritide to find out which is the safest and shows the best results with the fewest side effects. Study B looked at how well vosoritide works compared with a nonactive medicine (known as a placebo) and the side effects. In these studies, vosoritide increased bone growth velocity in children with achondroplasia. Children receiving the drug every day generally only had mild side effects. Serious health conplications were generally medical events seen in children with achondroplasia even if they do not take vosoritide. No children stopped taking vosoritide during the studies due to safety reasons. How well vosoritide works and the side effects in children over a longer period of time are still being studied. ClinicalTrials.gov NCT numbers: NCT02055157 and NCT03197766 .

Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification.In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 μg per kilogram of body weight (8 patients in cohort 1), 7.5 μg per kilogram (8 patients in cohort 2), 15.0 μg per kilogram (10 patients in cohort 3), or 30.0 μg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 μg per kilogram and then to 15.0 μg per kilogram, and in cohort 2, the dose was increased to 15.0 μg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months.During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 μg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 μg per kilogram for up to 42 months.In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).

BACKGROUNDAdvanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis.METHODSWe conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia. The primary outcome was the best overall response.RESULTSThe overall response rate was 60% (95% confidence interval [CI], 49 to 70); 45% of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy. The median best percentage changes in bone marrow mast-cell burden and serum tryptase level were -59% and -58%, respectively. The median overall survival was 28.7 months, and the median progression-free survival was 14.1 months. Among the 16 patients with mast-cell leukemia, the median overall survival was 9.4 months (95% CI, 7.5 to not estimated). Dose reduction owing to toxic effects occurred in 56% of the patients; re-escalation to the starting dose was feasible in 32% of those patients. The most frequent adverse events were low-grade nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of the patients, respectively, mostly in those with preexisting cytopenias.CONCLUSIONSIn this open-label study, midostaurin showed efficacy in patients with advanced systemic mastocytosis, including the highly fatal variant mast-cell leukemia.

Non-alcoholic fatty liver disease (NAFLD) is associated with features of the metabolic syndrome (MetS) and may be an expression of the syndrome within the liver. Using screening data from the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study (n = 42 149), we examined whether alanine aminotransferase (ALT), a biomarker for NAFLD, clustered with features of MetS and whether the clusters differed across global geographic regions.

This phase 1b trial investigated several doses and schedules of midostaurin in combination with daunorubicin and cytarabine induction and high-dose cytarabine post-remission therapy in newly diagnosed patients with acute myeloid leukemia (AML). The discontinuation rate on the 50-mg twice-daily dose schedule was lower than 100 mg twice daily, and no grade 3/4 nausea or vomiting was seen. The complete remission rate for the midostaurin 50-mg twice-daily dose schedule was 80% (FMS-like tyrosine kinase 3 receptor (FLT3)-wild-type: 20 of 27 (74%), FLT3-mutant: 12 of 13 (92%)). Overall survival (OS) probabilities of patients with FLT3-mutant AML at 1 and 2 years (0.85 and 0.62, respectively) were similar to the FLT3-wild-type population (0.78 and 0.52, respectively). Midostaurin in combination with standard chemotherapy demonstrated high complete response and OS rates in newly diagnosed younger adults with AML, and was generally well tolerated at 50 mg twice daily for 14 days. A phase III prospective trial is ongoing (CALGB 10603, NCT00651261).

Purpose Midostaurin (PKC412) is a multitargeted tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 receptor (FLT3), c-KIT, and other receptors. Midostaurin is active in patients with acute myeloid leukemia and systemic mastocytosis. Although no substantive risk for cardiac abnormalities has been observed with midostaurin in clinical studies thus far, some TKIs have been shown to affect cardiac repolarization. Here we evaluated midostaurin’s effect on cardiac repolarization. Methods This phase I study evaluated the effect of midostaurin (75 mg twice daily for 2 days; 75 mg once on day 3) on the heart rate–corrected QT (QTc) interval in a parallel design with active (moxifloxacin) and placebo control arms in healthy volunteers. Results The maximum mean QTc change from baseline corrected using Fridericia’s correction (QTcF) for midostaurin compared with placebo was 0.7 ms at 24 h post dose on day 3. The highest upper bound of the 1-sided 95% CI was 4.7 ms, which excluded 10 ms, demonstrating a lack of QTcF prolongation effect. Assay sensitivity was demonstrated by modeling the moxifloxacin plasma concentration versus QTcF change from baseline, which showed a clear positive increase in QTcF with increasing moxifloxacin plasma concentrations, as expected based on previous studies. In the 4-day evaluation period, a minority of participants (34.6%) experienced an adverse event; 97.0% were grade 1. No grade 3 or 4 adverse events were reported. Conclusion Midostaurin demonstrated a good safety profile in healthy volunteers, with no prolonged cardiac repolarization or other changes on the electrocardiogram. Electronic supplementary material The online version of this article (doi:10.1007/s00280-012-1825-y) contains supplementary material, which is available to authorized users.

BACKGROUND: Because composite end points augment event rates, they are often thought to increase statistical power. This may not be true if the intervention has a lesser effect on some components of the composite. Consequently, treatment effect size may depend on the choice of composite. METHODS: To explore this issue, we performed a meta-analysis to determine the effect of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on individual cardiovascular (CV) outcomes. We then applied these treatment effects to 2 different composite CV outcomes generated using blinded data from the ongoing Nateglinide and Valsartan in Impaired Glucose Tolerance (IGT) Outcomes Research (NAVIGATOR) trial and analyzed them on a time-to-first-event basis. The composites were CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure and an "extended" composite that included hospitalization for angina and coronary revascularization. RESULTS: The odds reductions due to angiotensin-converting enzyme/angiotensin receptor blocker treatment estimated from the meta-analysis were as follows: CV death: 13%, P < .0001; nonfatal myocardial infarction: 16%, P < .00001; nonfatal stroke: 14%, P = .006; heart failure: 28%, P < .00001; hospitalization for angina: 7%, P = .02; and revascularization: 5%, P = .17. For the CV composites, the projected odds reduction was larger (17.8%, 95% CI 0.452-1.189) for the narrower composite compared with the extended CV composite (11.7%, 95% CI 0.623-1.136); that is, use of the extended composite reduced power to detect a difference between treatment groups. CONCLUSIONS: Although the use of CV composites augments event rates, it may not increase statistical power. Inclusion of events little influenced by an intervention may reduce the precision of the composite end point and mask treatment effects.

Abstract 4362 Midostaurin (PKC412) is a multi-targeted tyrosine kinase inhibitor (TKI) of several receptors, including wild-type and mutant variants of KIT and the FMS-like tyrosine kinase 3 (FLT3) receptor, and has known roles in hematopoiesis and leukemia. Midostaurin has demonstrated activity in acute myeloid leukemia (AML) and myelodysplastic syndrome in phase 1 and 2 trials, and is currently under investigation in a randomized phase 3 AML study at 50mg twice daily (bid) in combination with chemotherapy and a phase 2 monotherapy study of aggressive systemic mastocytosis (ASM) at 100mg bid. Despite the absence of specific midostaurin-related cardiac toxicity issues, we conducted a dedicated phase 1 study to directly investigate the effect of midostaurin on QTc interval. Healthy subjects were randomized to 3 treatment arms: placebo; midostaurin administered orally at 75mg bid on days 1 and 2 and once daily (od) on day 3; or an active control arm of moxifloxacin administered orally at 400mg od on day 3. The primary variable was QTcF interval on day 3 corrected for baseline and placebo in the midostaurin and moxifloxacin treatment arms. Drug exposure levels at each time point were confirmed for moxifloxacin, midostaurin, and its two metabolites – CGP62221 and CGP52421. Of 192 subjects enrolled, 166 completed the study. 24 of 80 subjects discontinued in the midostaurin arm: 19 (23%) due to adverse events (AEs), 17 of which encompassed expected gastrointestinal events. No patients were discontinued for AEs in the other 2 treatment groups. Discontinued patients were not included in the ECG analysis. In time-matched analysis of QTcF interval change, the maximum mean change in the midostaurin arm corrected for baseline and placebo was 0.72ms with a 90% confidence interval (CI) upper bound of 4.71ms, which excluded 10ms. At each nominal time point, the mean change from baseline placebo-corrected for midostaurin was 30ms or >480ms change from baseline for QTcF or QTcI. For QTcB the only occurrences of change were in the 30–60ms category: 1 (1.3%) of the subjects on midostaurin met this non-specific outlier criterion; 7 (15.9%) on moxifloxacin; and 1 (1.5%) on placebo. 1 new U-wave abnormality was noted in the moxifloxacin group. The peak plasma concentration of midostaurin achieved in the present study (mean 2273ng/mL) covered the peak and trough plasma exposure observed at 50mg bid (2220ng/mL and 1005ng/mL, respectively) in AML patients. The peak level achieved for midostaurin was also above the steady-state trough level of 1060ng/mL, but below the peak concentration of 3500ng/mL, for the 100mg bid dose. Midostaurin was safe and generally well tolerated: 97% of the AEs noted in subjects while on study drug (n=61; 40%) were reported as grade 1. No grade 3/4 AEs were reported. While some TKIs exert pharmacologic effects on QTc interval, this carefully conducted trial demonstrates that midostaurin at 75mg bid has no effect on heart rate, AV conduction, or cardiac depolarization. The midostaurin exposure achieved in this study exceeds the peak and trough levels for the 50mg bid dose regimen under investigation in the AML phase 3 trial. The midostaurin exposure achieved also exceeds the steady state trough level, but not the peak level, of the 100mg bid dose regimen under investigation in the phase 2 ASM trial. Further, the effects of the long-acting metabolite CGP52421 cannot be fully addressed by this short study. Due to the lack of QT prolongation observed in this trial, we recommend reduced but continued ECG monitoring and omission of QT-related exclusion criteria in future midostaurin clinical trials. Disclosures: del Corral: Novartis Pharmaceuticals Corporation: Employment. Dutreix:Novartis Pharmaceuticals Corporation: Employment. Huntsman Labed:Novartis Pharmaceuticals Corporation: Employment. Rai:Novartis Pharmaceuticals Corporation: Employment. Grosch:Novartis Pharmaceuticals Corporation: Employment. Morganroth:eResearchTechnology Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Wang:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership.

Abstract 634 FLT3, a transmembrane receptor tyrosine kinase constitutively activated via mutation in blasts of patients (pts) with AML, is an important therapeutic target. Blasts from approximately 25% of pts have a length or internal tandem duplication (ITD) mutation in the juxtamembrane region or tyrosine kinase domain (TKD1) of FLT3, which is associated with reduced disease-free survival and overall survival (OS), particularly in pts with normal cytogenetics. Blasts from 5–10% of pts have a point mutation (typically D835Y) in the tyrosine kinase domain (TKD); the effect of this mutation on prognosis is uncertain. Midostaurin (PKC412) is a multi-targeted kinase inhibitor with demonstrated clinical activity in FLT3-mutant (FLT3–mut) and FLT3-wild-type (FLT3–wt) AML (peripheral blood blast reduction in 70% and 30% of pts, respectively) but rarely produces complete remissions). Preclinical studies demonstrated synergy between FLT3 inhibitors and chemotherapy. We conducted a Phase 1b trial to investigate the feasibility of administering daunorubicin (60 mg/m2 IV, days 1–3) and cytarabine (100 mg/m2 IVCI, days 1–7) induction and high-dose cytarabine post-remission therapy (3 gm/m2 over 3h every 12h, days 1, 3, and 5 for 3 cycles) plus oral midostaurin at 100 mg or 50 mg each twice daily on days 8–21 (sequentially) or days 1–7, 15–21 (concomitantly) with all chemo cycles in newly diagnosed pts under age 61 with de novo AML. Whereas 100 mg of midostaurin plus induction chemotherapy was poorly tolerated due to nausea and vomiting, the 40 pts who received 50 mg of midostaurin orally twice daily ( 20 each on the sequential and concomitant schedules; 27 FLT3–wt; 13 FLT3–mut [9 with an ITD]), tolerated the combination well. Median midostaurin exposure was 133 days (range 21–975) for the FLT3–mut pts and 90 days (range 7–1016) for FLT3–wt pts. Maintenance therapy with midostaurin was allowed with investigator discretion and was received by 5 pts (3 FLT3–mut, 2 FLT–wt). The median ages for the FLT3–wt and FLT3–mut pts were 50 years (range 25–60) and 46 years (range 20–65), respectively. 77% of the FLT3–mut pts displayed normal, 15% adverse and 8% other intermediate cytogenetics compared with 18.5%, 26%, and 26%, respectively, for FLT3-wt (also 18.5% favorable; 11% unknown). Complete response occurred in 32/40 (80%) of all pts (20/27 [74%] of FLT3–wt patients, 12/13 [92%] of FLT3–mut pts). Patients were censored at the last date they were known to be alive with a median post treatment follow-up for FLT3-mut pts of 1059 days and 1086 days for FLT3-wt. Even accounting for their differing cytogenetics and ages, the OS of the FLT3–mut subgroup was expected to be inferior to that of the FLT3–wt subgroup. However, we report that the 1 and 2 year OS for the pts with FLT3–mut AML was 85% and 62%, respectively, and was comparable to that of the FLT3–wt subgroup (81% and 59%, respectively). Although based on small numbers and not stratified for type of FLT3 mutation (TKD, ITD, ITD length, location, or allelic ratio), these long-term results suggest that combination therapy with a FLT3 inhibitor and chemotherapy might be effective enough to obviate the perceived need for allogeneic stem cell transplantation for FLT3–mut AML pts in first complete remission. Moreover, these data support the rationale for the ongoing international phase 3 study of induction, post-remission intensification, and maintenance with midostaurin (50 mg po bid) or placebo. Disclosures: Stone: Novartis: Research Funding, ad hoc consultancy; Cephalon: ad hoc consultancy. Off Label Use: midostaurin with chemothereapy for AML. Paquette:Novartis: Honoraria, Research Funding, Speakers Bureau. Schiller:Novartis: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Genzyme: Research Funding; Vion: Research Funding; Centocor: Research Funding; Eli Lilly: Research Funding; Celgene: Research Funding. Schiffer:Novartis: Consultancy, Research Funding; Genzyme: Consultancy. Ehninger:Novartis: Honoraria, Research Funding. Cortes:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Wyeth: Research Funding. Kantarjian:Novartis: Research Funding. DeAngelo:Bristol-Myers Squibb: Speakers Bureau; Celgene: Speakers Bureau; Enzon: Speakers Bureau; Novartis: Speakers Bureau. Huntsman-Labed:Novartis: Employment, Equity Ownership. Dutreix:Novartis: Employment, Equity Ownership. Rai:Novartis: Employment, Equity Ownership. Giles:Novartis: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Vion: Research Funding.