作者: Esteban de la Rosa, Rafael José ; Liu, Shiguang ; Iqbal, Sajida ; Hariri, Ali ; Shen, Yuqian ; Kowthalam, Madhurima Uppara ; Gross, Oliver ; Maski, Manish ; Gale, Daniel P ; Lin, Julie ; Zhang, Qi ; Appel, Gerald ; Wang, Fang ; Sayer, John A ; Ding, Jie ; Hall, Matthew

Key Points

Lademirsen, an anti–microRNA-21 therapy, was generally well-tolerated in adults with Alport syndrome at risk of rapid disease progression.

There were no significant differences between lademirsen-treated and placebo-treated participants in eGFR at any timepoint.

The proportions of participants with prespecified reductions in eGFR at weeks 24 and 48 were not significantly different for lademirsen versus placebo.

BackgroundPreclinical models of disease have suggested that targeting microRNA-21 (miRNA-21) may slow the decline in kidney function in individuals with Alport syndrome (AS). The objective of this study was to investigate the effects of the anti–miRNA-21 oligonucleotide, lademirsen, on rate of eGFR decline in adults with AS at risk of rapid disease progression.MethodsThis study was a phase 2 trial of lademirsen, with a randomized, double-blind, placebo-controlled period followed by an open-label period. Adults with AS, eGFR >35 to <90 ml/min per 1.73 m2, and evidence of rapidly progressive kidney dysfunction were randomized 2:1 to lademirsen 110 mg subcutaneously once weekly or placebo for 48 weeks. After a planned interim analysis (after 24 of 43 randomized participants completed the week 48 study visit or discontinued before week 48), the trial was terminated for futility.ResultsForty-three adults with AS (26 men, 17 women) participated (mean age 34 years), and 28 (lademirsen: n=19; placebo: n=9) completed 48 weeks of double-blind treatment. All participants in both groups developed treatment-emergent adverse events, mainly respiratory tract infections, headache, dizziness, metabolic/electrolyte disturbances, and anemia. Treatment was discontinued in three lademirsen-treated participants in the double-blind period and one participant in the open-label period, owing to treatment-emergent adverse events. The least squares mean eGFR slope (95% confidence interval) over 48 weeks in the lademirsen and placebo groups was −5 (−8.7 to −1.1) and −5 (−10.2 to 0.8) ml/min per 1.73 m2 per year, respectively. No significant differences between groups were identified in eGFR at any timepoint or in proportion of participants with prespecified reductions in eGFR at week 24 or 48.ConclusionsWhile anti–miRNA-21 therapy with lademirsen was generally well-tolerated with an acceptable safety profile, no meaningful improvement in rate of kidney function decline in adults with AS at risk of rapidly progressive disease was observed.Clinical Trial registration number: NCT02855268.

2022-09-01·British Journal of Cancer

Repositioning canakinumab for non-small cell lung cancer—important lessons for drug repurposing in oncology

Review

作者: Prasad, Vinay ; Lythgoe, Mark P

AbstractCanakinumab is an anti-interleukin-1β monoclonal antibody approved for use in a range of immune-related disorders. During the clinical investigation (CANTOS trial) for prevention of cardiovascular complications, therapy was linked to a reduction in both the occurrence and mortality of lung cancer. This unexpected observation fuelled the rapid initiation of four large clinical trials to evaluate potential anticancer efficacy (in combination with chemotherapy and/or immunotherapy), before fully validating these observations in a dedicated study. The first two trials (CANOPY-1 and 2) have now been reported and have both have failed to meet their primary efficacy endpoints. In this article, we explore the scientific and clinical rationale behind the development of canakinumab in oncology, the repurposing approach utilised and implications this may have for the wider drug repurposing field in the development of new cancer medicines.

2021-07-20·JAMA1区 · 医学

Effect of Canakinumab vs Placebo on Survival Without Invasive Mechanical Ventilation in Patients Hospitalized With Severe COVID-19

1区 · 医学

Article

作者: Gordeev, Ivan ; Black, Mellisa ; Rali, Parth ; Tahir, Hasan ; Overton, Turner ; Behne, Ann ; Jacobson, Jeffrey M. ; Patel, Maulin ; Martynenko, Tatiana I. ; Agafina, Alina S. ; Whelan, Sarah ; Patel, Nimesh ; Marawan, Amr ; Brown, James ; Vecchiè, Alessandra ; Kemp, Heather ; Sedhai, Yub Raj ; Ibe, Ikenna ; Lachmann, Helen J. ; Hardin, Mary ; Shirinian, Mihran ; Randeva, Harpal ; Deutsch, Henley ; Hsue, Priscilla Y ; Greer, Joan ; Turner, Juanita ; Frankel, Robert ; Sharma, Kavita ; Chen, Yu ; Taiwo, Babafemi ; Spence, Kathryn ; Di Marco, Fabiano ; McKee, Kim ; Van Tassell, Benjamin ; Arduino, Roberto ; Harmon, Mary ; Mamary, Albert J. ; Dorey-Stein, Zachariah ; Duke, Christina ; Bogdanov, Roman ; Ho, Ai-Chen ; Marchetti, Nathaniel ; Meng, Jamie ; Sehgal, Sameep ; Gupta, Rohit ; Gónzalez-García, Andrés ; Fernandez-Romero, Gustavo ; Fung, Monica ; Trufanov, Konstantin V. ; Malyshev, Yury ; Tan-Augenstein, Gwendolyn ; Sagar, Manish ; Abbate, Antonio ; Codella, Stephen ; Dominguez-Castillo, Eduardo ; Zheng, Matthew ; Mochalova, Anastasia S. ; Fomina, Daria ; Jaffe, Fredric ; Bonaventura, Aldo ; Pak, Mary ; Chiandussi, Damian A. ; Montpetit, Alison ; Ladd, Amy ; Mills, Nicole ; Thomas, Georgia ; Earl Clary, Rick ; Payne, William ; Shenoy, Kartik ; Kuritzkes, Daniel R. ; Vega-Sanchez, Maria Elena ; Wohlford, George ; Sculthorpe, Robin ; Ruiz-Seco, Pilar ; Neogi, Tuhina ; Priday, Anna ; Chua, Joel V. ; Papi, Alberto ; Salerno, Daniel ; Sears, Melissa ; Faguer, Stanislas ; Sims, Earl Kenneth ; Satti, Aditi ; Gangemi, Andrew ; Stepanenko, Tatiana ; Malhotra, Vinay ; Kissin, Eugene ; Noviello, Stephanie ; Savic, Sinisa ; Solanich-Moreno, Xavier ; Mokha, Janpreet ; Privalov, Dmitry V. ; Krachman, Samuel ; Chowdhury, Junad ; Lioznov, Dmitry A. ; Stewart, Jeffrey ; Christian, Manan ; O’Brien, Joyce ; Shani, Jacob ; Trojanowski, Marcin ; Pablos-Alvarez, José Luis ; Caricchio, Roberto ; Desai, Parag ; Lachiewicz, Anne ; Tackett, Hilary ; Verga, Steven ; Criner, Gerard J. ; Estrada, Vicente ; Mihalick, Virginia ; Patel, Vishal ; Bujan, Segundo ; Markley, Roshanak ; Li, Yuhan ; Mbualungu, James ; Morone, Natalia ; Owen, Catherine ; Brady, Jason

ImportanceEffective treatments for patients with severe COVID-19 are needed.ObjectiveTo evaluate the efficacy of canakinumab, an anti-interleukin-1β antibody, in patients hospitalized with severe COVID-19.Design, Setting, and ParticipantsThis randomized, double-blind, placebo-controlled phase 3 trial was conducted at 39 hospitals in Europe and the United States. A total of 454 hospitalized patients with COVID-19 pneumonia, hypoxia (not requiring invasive mechanical ventilation [IMV]), and systemic hyperinflammation defined by increased blood concentrations of C-reactive protein or ferritin were enrolled between April 30 and August 17, 2020, with the last assessment of the primary end point on September 22, 2020.InterventionPatients were randomly assigned 1:1 to receive a single intravenous infusion of canakinumab (450 mg for body weight of 40-<60 kg, 600 mg for 60-80 kg, and 750 mg for >80 kg; n = 227) or placebo (n = 227).Main Outcomes and MeasuresThe primary outcome was survival without IMV from day 3 to day 29. Secondary outcomes were COVID-19-related mortality, measurements of biomarkers of systemic hyperinflammation, and safety evaluations.ResultsAmong 454 patients who were randomized (median age, 59 years; 187 women [41.2%]), 417 (91.9%) completed day 29 of the trial. Between days 3 and 29, 198 of 223 patients (88.8%) survived without requiring IMV in the canakinumab group and 191 of 223 (85.7%) in the placebo group, with a rate difference of 3.1% (95% CI, -3.1% to 9.3%) and an odds ratio of 1.39 (95% CI, 0.76 to 2.54; P = .29). COVID-19-related mortality occurred in 11 of 223 patients (4.9%) in the canakinumab group vs 16 of 222 (7.2%) in the placebo group, with a rate difference of -2.3% (95% CI, -6.7% to 2.2%) and an odds ratio of 0.67 (95% CI, 0.30 to 1.50). Serious adverse events were observed in 36 of 225 patients (16%) treated with canakinumab vs 46 of 223 (20.6%) who received placebo.Conclusions and RelevanceAmong patients hospitalized with severe COVID-19, treatment with canakinumab, compared with placebo, did not significantly increase the likelihood of survival without IMV at day 29.Trial RegistrationClinicalTrials.gov Identifier: NCT04362813.

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