OUTCOME ASSESSMENTS OF PRIMARY ENDPOINTS OF NEW DRUGS APPROVED BY THE FDA (2011-2015)

A. Gnanasakthy; C. DeMuro

doi:10.1016/j.jval.2016.03.1962

New Drugs for the Treatment of Heart Failure

US Cardiology Review ◽

10.15420/usc.2017:17:1 ◽

2017 ◽

Vol 11 (2) ◽

pp. 62 ◽

Cited By ~ 2

Author(s):

Amarinder Bindra ◽

Shelley A Hall ◽

◽

Keyword(s):

Heart Failure ◽

Sinoatrial Node ◽

New Drugs ◽

Common Denominator ◽

Primary Endpoints ◽

Neprilysin Inhibitor ◽

Omecamtiv Mecarbil ◽

Angiotensin Receptor Neprilysin Inhibitor ◽

The Common ◽

Relaxin Receptor

Angiotensin receptor-neprilysin inhibitor, Entresto® (Novartis), a combination of sacubitril and valsartan, and funny channel inhibitor of the sinoatrial node, Corlanor® (Amgen), are two new drugs that have been Food and Drug Association-approved for treatment of symptomatic heart failure patients. Their mechanisms of action differ from each other and from the heart failure drugs available prior to their approval. Reduction in mortality is the hallmark of Entresto, while reduction in hospitalizations was the common denominator of both Entresto and Corlanor. These drugs are generally well tolerated and are widely used by heart failure cardiologists. Another promising agent, omecamtiv mecarbil, a myosin activator, is currently under trials, while RLX030, a relaxin receptor agonist, did not meet primary endpoints in a study.

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A Prospective Phase II Study on Tandem Autografting-Nonmyeloablative Allografting for Newly Diagnosed Myeloma: Final Results of the Gruppo Italiano Trapianto Midollo Osseo.

Blood ◽

10.1182/blood.v110.11.3026.3026 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3026-3026

Author(s):

B. Bruno ◽

M. Rotta ◽

F. Patriarca ◽

D. Mattei ◽

B. Allione ◽

...

Keyword(s):

Phase Ii ◽

Phase Ii Study ◽

Chronic Gvhd ◽

New Drugs ◽

Newly Diagnosed ◽

Disease Response ◽

Post Transplant ◽

Primary Endpoints ◽

Prospective Phase

Abstract The development of nonmyeloablative conditionings has recently reduced the transplant-related mortality (TRM) and extended the eligible age for transplantation up to 65–70 years. From January 2000 to June 2005, 106 newly diagnosed patients younger than 65 years were enrolled in a prospective phase II study at 15 Italian Centers. Fifty-eight were also previously described in a comparison of autografting with allografting based on a genetic randomisation (Bruno et al. N Engl J Med 2007). Here we report on a larger GITMO experience with a longer follow-up. Induction chemotherapy consisted of VAD-based regimens, followed by a cytoreductive autograft with melphalan 200 mg/m2, and by a non-myeloablative 2 Gy TBI-based allograft from an HLA-identical sibling. Graft-vs-host disease (GVHD) prophylaxis included cyclosporin and mycophenolate mofetil. Primary endpoints were overall (OS) and event-free (EFS) survivals. Secondary endpoint was TRM. One-hundred-two (96%) patients, median age 54 (30–65), completed the tandem program whereas 4 withdrew their consent. After a median follow-up of 54 (21–94) months, OS was not reached and median EFS was 35 (31–56) months post-transplant. Incidences of acute grade II-IV GHVD and extensive chronic GVHD were 40% and 50% respectively. Fourteen (13%) patients died from TRM, 14 (13%) from disease progression, 2 from lung cancer (2%) and 1 from lymphoma (1%). Overall response, defined as complete (CR) and partial remission, was 91% (93/102), with 53 patients achieving CR. Overall 39/102 patients relapsed, however only 8/53 of those who reached CR post-transplant. By multivariate-analysis disease response prior to allografting was significantly associated with longer OS (HR 0.27, CI 0.09–0.80, p<0.018) and longer EFS (HR 0.23, CI 0.11–0.49, p<0.001). Interestingly, chronic GVHD was not correlated with either the achievement of post-transplant CR (HR 0.87, CI 0.45–1.65, p<0.66) or its duration (HR 0.79, CI 0.45–1.40, p<0.42). Presence of del(13) was evaluated only in a subset of 39 patients: 13 carried del(13) and 26 did not. OS was not reached in the patients without del(13) and was 52 months in patients with del(13) (p=0.32), however EFS was not reached in the patients without del(13) whereas was 27 months for patients with del(13) (p=0.04). Given the encouraging results, the design of prospective studies that incorporate new drugs to cytoreduce the disease pre-transplant and enhance graft-vs.-myeloma are warranted to lower relapse rates and improve clinical outcomes.

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Phase II study of ipilimumab (IPI) in children and adolescents with unresectable stage III or IV malignant melanoma (MEL).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e21006 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e21006-e21006 ◽

Cited By ~ 1

Author(s):

Alberto S. Pappo ◽

Christophe Bergeron ◽

Lia Gore ◽

Leonard S. Sender ◽

Ira J. Dunkel ◽

...

Keyword(s):

Partial Response ◽

Median Number ◽

New Drugs ◽

Stage Iii ◽

Primary Endpoints ◽

Unresectable Stage ◽

Immune Mediated ◽

Previously Treated ◽

Prior Systemic Therapy ◽

Grade 3

e21006 Background: IPI (anti-CTLA4) is approved for treatment of advanced MEL in adults, and more information on efficacy and safety of IPI in younger patients (pts) is needed. Methods: Pts from study CA184-178 (NCT01696045) age 12 to <18 yrs with previously treated or untreated, unresectable stage III or IV malignant MEL received up to 4 doses of IPI at 3 or 10 mg/kg Q3W. Key exclusion criteria were ocular MEL, active brain metastases, or autoimmune disease. Primary endpoints were 1-yr overall survival (OS) and safety. Results: From April 2013 to June 2016, 12 pts received either IPI 3 mg/kg (n=4) or 10 mg/kg (n=8); 2 did not meet study criteria and were not treated. For the 3 and 10 mg/kg groups, median age was 13 yrs and 15 yrs, 50% and 63% were male, 25% and 13% had elevated baseline lactate dehydrogenase, and 75% and 50% had prior systemic therapy, respectively. Median number of IPI doses received was 4.0 (range: 2–4) for 3 mg/kg and 3.0 (range: 1–4) for 10 mg/kg. At 1 yr, 3/4 pts on 3 mg/kg and 5/8 pts on 10 mg/kg were alive (Table). Two pts on 10 mg/kg had partial response and 1 pt from each group had stable disease (Table). One pt had ongoing partial response >2 yrs without further treatment. Treatment-related grade 1-4 adverse events were reported in 2/4 and 7/8 pts in 3 and 10 mg/kg groups, respectively. There was 1 grade 3-4 immune-mediated adverse reaction with 3 mg/kg (hepatitis) and 5 with 10 mg/kg (hepatitis [2] and pyrexia [2] were most common). The study was stopped early due to slow accrual. Conclusions: At >1 yr of follow-up, IPI demonstrated activity in MEL pts aged 12 to <18 yrs, with a safety profile consistent with that observed in adults. Our trial highlights the difficulties of enrolling children with rare diseases in clinical trials for drugs that are approved in adults, suggesting adolescents should be included earlier in adult trials of promising new drugs. Clinical trial information: NCT01696045. [Table: see text]

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Two isoprenylated flavonoids from Dorstenia psilurus activate AMPK, stimulate glucose uptake, inhibit glucose production and lower glycemia

Biochemical Journal ◽

10.1042/bcj20190326 ◽

2019 ◽

Vol 476 (24) ◽

pp. 3687-3704 ◽

Cited By ~ 2

Author(s):

Aphrodite T. Choumessi ◽

Manuel Johanns ◽

Claire Beaufay ◽

Marie-France Herent ◽

Vincent Stroobant ◽

...

Keyword(s):

Glucose Uptake ◽

Human Cancer ◽

Glucose Production ◽

Liver Mitochondria ◽

New Drugs ◽

Structural Isomer ◽

Rat Liver Mitochondria ◽

Ionization Mass ◽

Ampk Activation ◽

Starting Point

Root extracts of a Cameroon medicinal plant, Dorstenia psilurus, were purified by screening for AMP-activated protein kinase (AMPK) activation in incubated mouse embryo fibroblasts (MEFs). Two isoprenylated flavones that activated AMPK were isolated. Compound 1 was identified as artelasticin by high-resolution electrospray ionization mass spectrometry and 2D-NMR while its structural isomer, compound 2, was isolated for the first time and differed only by the position of one double bond on one isoprenyl substituent. Treatment of MEFs with purified compound 1 or compound 2 led to rapid and robust AMPK activation at low micromolar concentrations and increased the intracellular AMP:ATP ratio. In oxygen consumption experiments on isolated rat liver mitochondria, compound 1 and compound 2 inhibited complex II of the electron transport chain and in freeze–thawed mitochondria succinate dehydrogenase was inhibited. In incubated rat skeletal muscles, both compounds activated AMPK and stimulated glucose uptake. Moreover, these effects were lost in muscles pre-incubated with AMPK inhibitor SBI-0206965, suggesting AMPK dependency. Incubation of mouse hepatocytes with compound 1 or compound 2 led to AMPK activation, but glucose production was decreased in hepatocytes from both wild-type and AMPKβ1−/− mice, suggesting that this effect was not AMPK-dependent. However, when administered intraperitoneally to high-fat diet-induced insulin-resistant mice, compound 1 and compound 2 had blood glucose-lowering effects. In addition, compound 1 and compound 2 reduced the viability of several human cancer cells in culture. The flavonoids we have identified could be a starting point for the development of new drugs to treat type 2 diabetes.

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