Monoclonal

Dupilumab (Dupixent) appears to reduce exacerbations and improve FEV1 in patients with COPD with elevated blood eosinophil counts. James W. Mold, MD, MPH

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Background: Dupilumab, a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation, has shown efficacy and safety in a phase 3 trial involving patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation and an elevated risk of exacerbation. Whether the findings would be confirmed in a second phase 3 trial was unclear.

Methods: In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of 300 cells per microliter or higher to receive subcutaneous dupilumab (300 mg) or placebo every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Key secondary end points, analyzed in a hierarchical manner to adjust for multiplicity, included the changes from baseline in the prebronchodilator forced expiratory volume in 1 second (FEV1) at weeks 12 and 52 and in the St. George's Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better quality of life) total score at week 52.

Results: A total of 935 patients underwent randomization: 470 were assigned to the dupilumab group and 465 to the placebo group. As prespecified, the primary analysis was performed after a positive interim analysis and included all available data for the 935 participants, 721 of whom were included in the analysis at week 52. The annualized rate of moderate or severe exacerbations was 0.86 (95% confidence interval [CI], 0.70 to 1.06) with dupilumab and 1.30 (95% CI, 1.05 to 1.60) with placebo; the rate ratio as compared with placebo was 0.66 (95% CI, 0.54 to 0.82; P<0.001). The prebronchodilator FEV1 increased from baseline to week 12 with dupilumab (least-squares mean change, 139 ml [95% CI, 105 to 173]) as compared with placebo (least-squares mean change, 57 ml [95% CI, 23 to 91]), with a significant least-squares mean difference at week 12 of 82 ml (P<0.001) and at week 52 of 62 ml (P = 0.02). No significant between-group difference was observed in the change in SGRQ scores from baseline to 52 weeks. The incidence of adverse events was similar in the two groups and consistent with the established profile of dupilumab.

Conclusions: In patients with COPD and type 2 inflammation as indicated by elevated blood eosinophil counts, dupilumab was associated with fewer exacerbations and better lung function than placebo.

Author/s:

Surya P Bhatt, Klaus F Rabe, Nicola A Hanania, Claus F Vogelmeier, Mona Bafadhel, Stephanie A Christenson

Migraine — Treatment and Preventive Therapies

Aubrey Delammermore — Thu, 13 Oct 2022 05:00:00 +0000

Date Added:

October 13, 2022

Journal/Publication:

New England Journal of Medicine

Publisher:

Massachusetts Medical Society

Publication Date:

October 13, 2022

Issue:

e35

Volume:

387

URL:

Migraine — Treatment and Preventive Therapies

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Video

DOI (1):

10.1056/NEJMp2212749

Keywords

migraine treatment

preventative therapies

injectable monoclonal antibodies

patient care

treatment

MeSH

Patient-Centered Care

An 11 minute video review of our current understanding of migraine and an update on newer therapies. James W. Mold, MD, MPH

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In this instructional video, Drs. Cynthia Armand and Elizabeth Loder discuss the clinical presentation and pathophysiology of migraine and treatment options for patients.

This video provides essential and useful information for any clinician caring for patients with this common condition. Newer acute and preventive therapies — including triptans, gepants, ditans, and injectable monoclonal antibodies — are discussed, as are the importance of a patient-centered approach and the need to tackle challenges of access to these newer agents.

Author/s:

Armand, C.E., Loder, E., Ropper, A. H.

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19

Devin Evans — Thu, 14 Jan 2021 06:00:00 +0000

Date Added:

January 14, 2021

Journal/Publication:

The New England Journal of Medicine

Publication Date:

December 17, 2020

URL:

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1056/NEJMoa2035002

Keywords

PMID (1):

33332778

MeSH

A review of what is currently known about the monoclonal antibody cocktail for outpatient treatment of COVID-19. James W. Mold, MD, MPH

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Background: Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads.

Methods: In this ongoing, double-blind, phase 1-3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive or serum antibody-negative). Key end points included the time-weighted average change from baseline in viral load from day 1 through day 7 and the percentage of patients with at least one Covid-19-related medically attended visit through day 29. Safety was assessed in all patients.

Results: Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was -0.56 log10 copies per milliliter (95% confidence interval [CI], -1.02 to -0.11) among patients who were serum antibody-negative at baseline and -0.41 log10 copies per milliliter (95% CI, -0.71 to -0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody-negative at baseline, the corresponding percentages were 15% and 6% (difference, -9 percentage points; 95% CI, -29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group.

Conclusions: In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group.

Author/s:

Weinreich, David M., Sivapalasingam, Sumathi, Norton, THomas,, Ali, Shazia, Gao, Haitao, Bhore, Rafia, Musser, Bret J., Soo, Yuhwen, Rofail, Diana, Im, Joseph, Perry, Christina, Pan, Cynthia, Hosain, Romana, Mahmood, Adnan, Davis, John D., Turner, Kenneth C., Hooper, Andrea T., Hamilton, Jennifer D., Baum, Alina, Kyratsous, Christos A., Kim, Yunji, Cook, Amanda, Kampman, Wendy, Kohli, Anita, Sachdeva. Yessica, Graber, Ximena, Kowal, Bari, DiCioccio, Thomas, Stahl, Neil, Lipsich, Leah, Braunstein, Ned, Herman, Gary, Yancopoulos, George D.

Benralizumab for the Prevention of COPD Exacerbations

John Bayhi — Thu, 12 Sep 2019 13:39:58 +0000

Date Added:

September 12, 2019

Journal/Publication:

The New England Journal of Medicine

Publisher:

Massachusetts Medical Society

Publication Date:

September 12, 2019

Issue:

Volume:

381

Pages:

1023-1034

URL:

Benralizumab for the Prevention of COPD Exacerbations

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1056/NEJMoa1905248

Keywords

benralizumab

chronic obstructive pulmonary disease

copd

PMID (1):

31112385

MeSH

benralizumab

eosinophils

pulmonary disease, chronic obstructive

interleukin-5 Receptor alpha subunit

Antibodies

Monoclonal

Humanized

Benralizumab (Fasenra) apparently does not reduce COPD exacerbations so probably no reason to try to remember its name. James W. Mold, MD, MPH

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BACKGROUND:

The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known.

METHODS:

In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) who had frequent exacerbations despite receiving guideline-based inhaled treatment. Patients were randomly assigned to receive benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) every 8 weeks (every 4 weeks for the first three doses) or placebo. The primary end point was the treatment effect of benralizumab, measured as the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56 in patients with baseline blood eosinophil counts of 220 per cubic millimeter or greater. Safety was also assessed.

RESULTS:

In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo.

CONCLUSIONS:

Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).

Author/s:

Criner GJ, Celli, BR, Brightling CE, Agusti, A, Papi, A, Singh, D, Sin, DD, Vogelmeier, CD, Sciurba, FC, Bafadhel, M, Backer, V, Kato, M, Ramirez-Venegas, A, Wei, YF, Bjermer, L, Shih, VH, Jison, M, O'Quinn, S, Makulova, N, Newbold, P, Goldman, M, Martin, UJ