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New England Journal of Medicine publishes late-stage clinical data for dupilumab in moderate-to-severe asthma1,2

* Results showed dupilumab demonstrated a significant improvement in multiple asthma endpoints in two Phase 3 clinical trials in patients with uncontrolled moderate-to-severe asthma, irrespective of minimum baseline eosinophil levels or other biomarkers of Type 2 inflammation, when compared to placebo1,2

 

GUILDFORD, UK – May 22nd, 2018 –The New England Journal of Medicine (NEJM) today published detailed results from two Phase 3 trials on the use of dupilumab for the treatment of moderate-to-severe asthma. The results showed that dupilumab significantly reduced the risk of severe asthma attacks (exacerbations), improved ability to breathe (lung function), and reduced dependence on oral corticosteroids (OCS) compared to placebo.1,2 The trials, known as QUEST and VENTURE, are part of a pivotal clinical trial programme that evaluated dupilumab in uncontrolled asthma patients.3,4 These data were simultaneously presented at the American Thoracic Society 2018 International Conference.5,6

Dupilumab demonstrated significant improvements in the key primary and secondary endpoints across the overall populations in both QUEST and VENTURE compared to placebo, with the largest benefit experienced in patients with more severe Type 2 inflammatory asthma, as evidenced by elevated blood eosinophils or exhaled nitric oxide levels.1,2 Type 2 asthma can also be characterised by other parameters, including elevated Immunoglobulin E (IgE).7 Dupilumab blocks the IL-4/IL-13 pathway, which is emerging as a central driver of Type 2 allergic inflammation in asthma.8

The use of dupilumab as an add-on maintenance treatment for adults and adolescents with uncontrolled moderate-to-severe asthma is currently under regulatory review in several countries, including the U.S., Japan and in the European Union (EU), and the safety and efficacy for this use have not been evaluated by any regulatory authority.

 

About LIBERTY ASTHMA QUEST

The Phase 3 QUEST trial showed that a broad population of adults and adolescents with moderate-to-severe asthma (no minimum blood eosinophil level requirement or other biomarker requirement at baseline) benefited when dupilumab was added to their standard therapies.1 Dupilumab reduced severe asthma attacks (measured by annualised severe exacerbation rate) and improved lung function (measured by absolute change from baseline to Week 12 in pre-bronchodilator forced expiratory volume in 1 second (FEV1)), compared to placebo in the overall study population (co-primary endpoints).1 Lung function improvements were observed from the first measurement two weeks after receiving the first dose of dupilumab, and improvements were sustained throughout the 52-week trial.1 Patients also reported improved asthma control and quality of life, as measured by the 5-item Asthma Control Questionnaire (ACQ-5) and Asthma Quality of Life Questionnaire (AQLQ).1

About 20 percent of people with asthma continue to have uncontrolled symptoms despite available treatments,” 9,10,11 said Professor Christopher Brightling, NIHR Senior Investigator, University of Leicester. “The exciting results published today in the New England Journal of Medicine showed that dupilumab reduced asthma attacks compared to placebo and therefore might become a new treatment option for moderate-to-severe asthma.”

The QUEST trial enrolled 1,902 patients worldwide including 1,795 adults and 107 adolescents.1 The four study groups included patients treated with 200 mg every other week (loading dose of 400 mg), 300 mg every other week (loading dose of 600 mg), and two separate placebo groups.1 All patients continued on a medium-or high-dose inhaled corticosteroid (ICS) and up to two additional controller medicines throughout the study.1

The NEJM publication provides data on key endpoints, including data in the table below.1

QUEST Data Summary

Placebo-adjusted reduction in annualised rate of severe asthma exacerbations over 52 weeks

 

200 mg Dupilumab (n=631) vs. Placebo (n=317)

300 mg Dupilumab (n=633) vs. Placebo (n=321)

Overall population1

48 percent*

46 percent*

 

200 mg Dupilumab (n=264) vs. Placebo (n=148)

300 mg  Dupilumab (n=277) vs. Placebo (n=142)

Patients with 300 eosinophils/microlitre or greater

66 percent*±

67 percent*

Placebo-adjusted absolute (percent) change in lung function (measured by FEV1) from baseline to week 122

 

200 mg Dupilumab (n=611) vs. Placebo (n=307)

300 mg Dupilumab (n=610) vs. Placebo (n=313)

Overall population1

140 mL*

(9 percent)

130 mL*

(9 percent)

 

200 mg Dupilumab (n=256) vs. Placebo (n=144)

300 mg Dupilumab (n=266) vs. Placebo (n=139)

Patients with 300 eosinophils/microliter or greater

210mL±

(13 percent)

240mL*

(18 percent)

1Co-primary endpoint, *p-value <0.001, ±p-value nominal

2Number of patients with FEV1 measurement at week 12

For the 52-week treatment period, the overall rate of adverse events was similar across treatment groups (81 percent in the combined dupilumab-treated group and 83 percent in the combined placebo-treated group).1 The rate of serious adverse events was 8 percent in the combined dupilumab-treated group and 8 percent in the combined placebo-treated group.1 The most frequent adverse events that occurred more frequently with dupilumab treatment vs. placebo were injection site reactions (17 percent vs. 8 percent, respectively), back pain (4.4 percent vs. 3.6 percent, respectively) and eosinophilia (4 percent vs. 1 percent respectively).1

 

ABOUT LIBERTY ASTHMA VENTURE

The Phase 3 VENTURE trial, also did not require minimum biomarker levels for enrollment.2 The study showed that adults and adolescents with severe, steroid-dependent asthma who were treated with dupilumab, when added to standard therapies, could reduce their use of OCS medications while improving asthma control compared to placebo at 24 weeks.2 With dupilumab, OCS use decreased by 70 percent in the overall population (vs. 42 percent for placebo), and 80 percent for patients with baseline eosinophil levels 300 cells/microlitre or greater (vs. 43 percent for placebo).2 Despite reductions in OCS, patients treated with dupilumab reduced the risk of severe asthma attacks and improved their lung function compared with the placebo group.2

“Many people with severe asthma rely on regular oral corticosteroids to control their symptoms,”12,13,14 added Professor Christopher Brightling. “In the Phase 3 VENTURE trial, the majority of patients treated with dupilumab and standard therapies, when compared to placebo, substantially reduced their use of oral steroids, and nearly half of patients completely stopped using oral steroids, while improving their asthma.”

The 24-week VENTURE study enrolled 210 patients (103 in the dupilumab group and 107 in the placebo group) with severe asthma who regularly used maintenance OCS in the six months prior to enrollment in the study.2 The two study groups were 300 mg dupilumab every other week (loading dose of 600 mg) and placebo.2 All patients continued on a high-dose ICS and up to two additional controller medicines throughout the study.2 The prescribed OCS in the study was prednisone or prednisolone.2

The NEJM publication provides data on key endpoints, including data in the tables below.2,15

VENTURE Data Summary

Reduction in OCS dose at 24 weeks

 

300 mg Dupilumab (n=103)

Placebo (n=107)

Overall population1

70 percent*

42 percent

 

300 mg Dupilumab (n=48)

Placebo (n=41)

Patients with 300 eosinophils/microlitre or greater

80 percent*

43 percent

Proportion of patients with 50 percent or greater reduction in OCS

Overall population

80 percent*

50 percent

Proportion of patients who reduced their OCS dose to less than 5 mg per day

Overall population

69 percent*

33 percent

1Primary Endpoint, *p-value vs. placebo <0.001

VENTURE Data Summary, Continued

Difference between 300 mg Dupilumab (n=103) vs. Placebo (n=107)

(Overall population)

Difference between 300 mg Dupilumab (n=48) vs. Placebo (n=41)

(Patients with 300 eosinophils/ microlitre or greater)

Change in annualised rate of severe asthma exacerbations over 24 weeks

59 percent reduction*

71 percent reduction±

Absolute (percent) change in FEV1 from baseline to 24 weeks

220 mL

improvement*

320 mL

improvement**

*Nominal p-value vs. placebo < 0.001

** Nominal p-value vs. placebo < 0.005

For the 24-week treatment period, the overall rate of adverse events was similar across treatment groups (62 percent in the dupilmab-treated group and 64.5 percent in the placebo-treated group).2 The rate of serious adverse events was 9 percent in the dupilumab-treated group and 6 percent in the placebo-treated group.2 The most frequent adverse events that occurred more frequently with dupilumab treatment vs. placebo were injection site reaction (9 percent vs. 4 percent, respectively), bronchitis (7 percent vs. 6 percent, respectively), sinusitis (7 percent vs. 4 percent, respectively) and eosinophilia (14 percent vs. 1 percent, respectively).2

 

About dupilumab

Dupilumab is a human monoclonal antibody that is designed to specifically inhibit overactive signaling of two key proteins, IL-4 and IL-13,  involved in Type 2 inflammation that causes uncontrolled symptoms in many people with moderate-to-severe asthma.16

Dupilumab Development Programme

Sanofi and Regeneron are studying dupilumab in a broad range of clinical development programmes for diseases driven by Type 2 inflammation. Dupilumab is being jointly developed by Sanofi and Regeneron under a global collaboration agreement.

For more information on dupilumab clinical trials please visit www.clinicaltrials.gov.

About Sanofi

Sanofi is dedicated to supporting people through their health challenges. We are a global biopharmaceutical company focused on human health. We prevent illness with vaccines, provide innovative treatments to fight pain and ease suffering. We stand by the few who suffer from rare diseases and the millions with long-term chronic conditions.

With more than 100,000 people in 100 countries, Sanofi is transforming scientific innovation into healthcare solutions around the globe.

Sanofi, Empowering Life

For more information, please visit  www.sanofi.co.uk


[1] Castro  M, Corren J, Pavord I.D. et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med 2018; DOI: 10.1056/NEJMoa1804092.

[2] Rabe K.F., Nair P.K., Bruselle G.G. et al. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med 2018;DOI: 10.1056/NEJMoa1804093.

[3] Castro M, Corren J, Pavord I.D. et al. Evaluating the Efficacy and Safety of Dupilumab in Uncontrolled Moderate-to-Severe Asthma, LIBERTY ASTHMA QUEST. Clinical Trials. Available at: https://clinicaltrials.gov/ct2/show/NCT02414854?term=quest&cond=asthma&rank=1. (Accessed May 2018).

[4] Rabe K.F., Nair P.K., Bruselle G.G. et al. Evaluation of Dupilumab in Patients with Severe Steroid Dependent Asthma (VENTURE).Clinical Trials. Available at: https://clinicaltrials.gov/ct2/show/NCT02528214?term=venture&cond=asthma&rank=1. (Accessed May 2018).

[5] Castro M, Corren J, Pavord I.D. et al. A Randomized, Controlled Phase 3 Study, LIBERTY ASTHMA QUEST, Evaluating the Efficacy and Safety of Dupilumab in Uncontrolled Moderate-to-Severe Asthma.American Thoracic Society 2018, San Diego, California, 18-23 May 2018.

[6] Rabe K.F., Nair P.K., Bruselle G.G. et al. Dupilumab in Patients with Corticosteroid-Dependent Severe Asthma: Efficacy and Safety Results from the Randomized, Double-Blind, Placebo-Controlled Phase 3 LIBERTY ASTHMA VENTURE Study. American Thoracic Society 2018, San Diego, California, 18-23 May 2018.

[7] Robinson D, Humbert M, Buhl R, et al. Revisiting type 2-high and type 2-low airway inflammation in asthma: current knowledge and therapeutic implications. Clin Exp Allergy 2017;47:161-75.

[8] Gandhi NA, Pirozzi G, Graham NMH. Commonality of the IL-4/IL-13 pathway in atopic diseases. Expert Rev Clin Immunol 2017;13:425-37.

[9] Bateman ED, Boushey HA, Bousquet J, et al.; GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004;170:836-44.

[10] Hermosa JL, Sánchez CB, Rubio MC, Mínguez MM, Walther JL. Factors associated with the control of severe asthma. J Asthma 2010;47:124-30.

[11] Peters SP, Ferguson G, Deniz Y, Reisner C. Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment. Respir Med 2006;100:1139-51.

[12] O’Byrne PM, Pedersen S, Lamm CJ, Tan WC, Busse WW; START Investigators Group. Severe exacerbations and decline in lung function in asthma. Am J Respir Crit Care Med 2009;179:19-24.

[13] Goleva E, Hauk PJ, Boguniewicz J, Martin RJ, Leung DYM. Airway remodeling and lack of bronchodilator response in steroid resistant asthma. J Allergy Clin Immunol 2007;120:1065-72.

[14] Shaw DE, Sousa AR, Fowler SJ, et al. Clinical and inflammatory characteristics of the European U BIOPRED adult severe asthma cohort. Eur Respir J 2015;46:1308-21.

[15] Rabe KF, Nair P, Brusselle G, et al. Supplementary Appendix: Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med. DOI: 10.1056/NEJMoa1804093.

[16] Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016 Jan;15(1):35-50.

Date of preparation: May 2018 - Job bag number:SAGB.RESP.18.05.0729

Updated: May 22, 2018

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