Long-Term Efficacy of Dupilumab in Moderate-to-Severe Asthma Phenotyped by Blood Eosinophils and Exhaled Nitric Oxide

Abstract

Background

Asthma treatment aims to reduce symptom severity and exacerbation risk. Dupilumab, a human monoclonal antibody, blocks the shared receptor for IL-4/IL-13, key drivers of type 2 inflammation. In the Evaluation of Dupilumab in Patients With Persistent Asthma (QUEST) study (NCT02414854), add-on dupilumab every 2 weeks vs placebo was shown to significantly reduce severe asthma exacerbations and improve prebronchodilator (BD) FEV₁ in patients with uncontrolled, moderate-to-severe asthma. Treatment effects were greater in patients with elevated baseline type 2 biomarkers (blood eosinophil count ≥ 150 cells/μL or fractional exhaled nitric oxide ≥ 25 parts per billion).

Research Question

What is dupilumab’s long-term efficacy (up to 3 years) in patients with moderate-to-severe type 2 asthma?

Study Design and Methods

Patients enrolled in QUEST (receiving placebo or dupilumab), who completed 96 weeks of dupilumab treatment in the open-label extension Long-Term Safety Evaluation of Dupilumab in Patients With Asthma (TRAVERSE) study (NCT02134028), were included. This prespecified analysis evaluated long-term efficacy in patient populations identified by baseline type 2 biomarker level. End points were annualized exacerbation rate (AER) and change from baseline in pre-BD FEV₁ (L), asthma control (5-item Asthma Control Questionnaire), and asthma-related quality of life (Asthma Quality of Life Questionnaire).

Results

A total of 663 patients were included. AER was 1.72 to 2.24 at QUEST baseline in dupilumab groups across type 2 populations. AER decreased in populations with elevated type 2 biomarkers to 0.36 to 0.49 during QUEST’s 52-week treatment period, which was sustained over 96 weeks in TRAVERSE. In patients with low type 2 biomarker levels, there was no clinically meaningful AER reduction in QUEST or TRAVERSE, but rates remained below parent study baseline. Similar trends were seen with improvements in pre-BD FEV₁, 5-item Asthma Control Questionnaire, and Asthma Quality of Life Questionnaire; greatest improvements were seen in groups with one or more elevated type 2 biomarker.

Intrepretation

This study suggests that long-term dupilumab treatment results in sustained and clinically meaningful efficacy in patients with moderate-to-severe type 2 asthma characterized by elevated blood eosinophil count and/or fractional exhaled nitric oxide.

Clinical Trial Registration

ClinicalTrials.gov; No.: NCT02134028; URL: www.clinicaltrials.gov

Take-home Points.

Study Question: What is the long-term efficacy (up to 3 years) of dupilumab in patients with moderate-to-severe type 2 asthma?

Results: Our results showed that dupilumab demonstrated greater effects in patients with type 2 biomarkers over 3 years.

Interpretation: This study suggests that long-term dupilumab treatment results in sustained and clinically meaningful reductions in severe asthma exacerbations, and improvements in lung function, asthma control, and asthma-related quality of life in patients with moderate-to-severe type 2 asthma characterized by elevated blood eosinophil count and/or fractional exhaled nitric oxide.

Asthma is a heterogeneous disease characterized by respiratory symptoms, expiratory airflow limitation, and chronic inflammation of the airways.¹ It is the most common chronic disease in children, and has been estimated to affect approximately 262 million people worldwide.^2,3 Although the underlying pathogenesis varies and may be mixed, approximately 50% to 70% of patients have asthma characterized by the presence of type 2 inflammation.4, 5, 6

Current treatment of asthma is aimed at reducing the severity of symptoms and minimizing the risk of exacerbations. In patients with severe eosinophilic or allergic asthma, add-on biologics targeting underlying type 2 inflammation (eg, IL-5, IL-4, IgE, thymic stromal lymphopoietin) should be considered in patients with frequent exacerbations or poor control on high-dose inhaled corticosteroids and long-acting beta agonist combination therapy.¹ In the phase 3 LIBERTY ASTHMA QUEST study (QUEST; NCT02414854), add-on dupilumab 200 mg and 300 mg every 2 weeks vs matched placebo reduced severe asthma exacerbations significantly, improved prebronchodilator (BD) FEV₁, and was generally well tolerated with an acceptable safety profile in patients with uncontrolled, moderate-to-severe asthma.⁷ Long-term efficacy of dupilumab has also been demonstrated in the LIBERTY ASTHMA TRAVERSE open-label extension study (TRAVERSE; NCT02134028), in which the efficacy of dupilumab in reducing exacerbations and improving lung function observed in the phase 2 and 3 parent studies was maintained through 48 and 96 weeks of additional add-on therapy in patients with uncontrolled, moderate-to-severe asthma.⁸

Type 2 biomarkers (blood eosinophil count and fractional exhaled nitric oxide [Feno]) are prognostic biomarkers associated with increased exacerbation frequency.⁸ Previous analysis of data from phase 2 and 3 clinical trials has indicated that blood eosinophil levels and Feno can be used to identify patients with greatest potential response to dupilumab; consistent treatment efficacy was seen in patients with blood eosinophil count ≥ 150 cells/μL or Feno ≥ 25 parts per billion (ppb).^8,9 Based on these findings, we assessed the long-term efficacy of dupilumab in patients from QUEST who enrolled in the TRAVERSE open-label extension study categorized by parent study baseline (PSBL) blood eosinophil count and Feno level.

Study Design and Methods

Study Design and Participants

TRAVERSE was a multicenter open-label extension study that enrolled patients with moderate-to-severe or oral corticosteroid-dependent asthma who had previously taken part in either a phase 2 ( EXPEDITION) or phase 3 (QUEST, VENTURE) dupilumab asthma study (see Wechsler et al⁸ for full details of study design and patient eligibility). The study was conducted in accordance with the Declaration of Helsinki and principles of Good Clinical Practice. Written informed consent was obtained prior to enrollment from all patients (or their parents/legal guardians, as appropriate). The protocol and informed consent forms were approved by ethics committees and institutional review boards for each of the study sites prior to patient enrollment.⁸

This analysis was conducted to evaluate long-term response to dupilumab; the population selected included patients enrolled to TRAVERSE from QUEST who had been exposed to dupilumab for all 96 weeks of the TRAVERSE open-label extension study. All patients were taking medium- to high-dose inhaled corticosteroids together with one or more controlled medications at PSBL; patients requiring oral corticosteroids were excluded from enrollment in QUEST.⁷ During the QUEST study, patients with uncontrolled moderate-to-severe asthma were given dupilumab 200 mg or 300 mg every 2 weeks or matched placebo every 2 weeks for 52 weeks. Patients enrolled directly to TRAVERSE from the end-of-treatment visit in QUEST. All patients enrolled in TRAVERSE were treated with subcutaneous add-on dupilumab 300 mg every 2 weeks for up to 96 weeks, depending on their date of enrollment (see Wechsler et al⁸ for further details). Full details of inclusion and exclusion criteria for the QUEST study have been published previously.⁷

End Points

For the current analysis, patients were categorized into the four following biomarker subgroups based on QUEST baseline blood eosinophil count and Feno level: (1) blood eosinophil count ≥ 150 cells/μL and Feno ≥ 25 ppb; (2) blood eosinophil count ≥ 150 cells/μL and Feno < 25 ppb; (3) blood eosinophil count < 150 cells/μL and Feno ≥ 25 ppb; and (4) blood eosinophil count < 150 cells/μL and Feno < 25 ppb. A blood eosinophil threshold of ≥ 150 cells/μL is a well-established biomarker for type 2 inflammation as per the Global Initiative for Asthma 2022 guidelines.¹ The main analysis was performed for patients enrolled from QUEST who completed 96 weeks of treatment in TRAVERSE (3 years of treatment across QUEST and TRAVERSE), with additional analyses on the entire study population of patients enrolled from QUEST, including those who did not complete 96 weeks of treatment (Supplementary Materials). Annualized severe exacerbation rates during TRAVERSE and change from PSBL in pre-BD FEV₁ over time were performed for both populations. In addition, change from PSBL in asthma control (as measured by 5-item Asthma Control Questionnaire [ACQ-5] scores) and asthma-related quality of life (as measured by Asthma Quality of Life Questionnaire [AQLQ] scores) over time were evaluated for patients who completed 96 weeks of treatment in TRAVERSE. A severe exacerbation was defined as a deterioration of asthma requiring the use of systemic corticosteroids for ≥ 3 days, or hospitalization or emergency department visit because of asthma, requiring systemic corticosteroids.

Statistical Analysis

Patients were classified into dupilumab/dupilumab or placebo/dupilumab groups, depending on which treatment they had received in the QUEST study. All analyses performed were descriptive, with no formal statistical hypotheses tested. End points are presented as mean values for each of the four biomarker subgroups and treatment groups at PSBL, end of the 52-week treatment period in QUEST, and TRAVERSE weeks 48 and 96. Unadjusted annualized exacerbation rate (AER) was calculated as the total number of events occurring during the relevant treatment period divided by the total number of patient-years followed during the same treatment period. All analyses were conducted using SAS software, version 9.4 (SAS Institute) or higher.

Results

In total, 1,530 patients from QUEST enrolled in TRAVERSE. Of these, 663 completed 3 years of treatment across the two studies and were included in this analysis (eosinophil count ≥ 150 cells/μL and Feno ≥ 25 ppb, n = 293; eosinophil count ≥ 150 cells/μL and Feno < 25 ppb, n = 200; eosinophil count < 150 cells/μL and Feno ≥ 25 ppb, n = 54; eosinophil count < 150 cells/μL and Feno < 25 ppb, n = 116). Further details of the patient subgroups included in this analysis are found in e-Figure 1. Data for all patients enrolled from QUEST (ie, including those who did not complete 3 years of treatment) are provided in the Supplementary Materials. When categorized by biomarker subgroup and treatment group (dupilumab/dupilumab and placebo/dupilumab), PSBL characteristics (other than blood eosinophil count and Feno) were broadly similar across groups, with no clear trends associated with biomarker levels in either the group of patients who completed 3 years of treatment (Table 1) or all patients enrolled from QUEST (e-Table 1).

Table 1.

Baseline Demographics and Disease Characteristics for Subgroups of Patients From QUEST Who Enrolled in TRAVERSE Who Completed 3 Years of Treatment Categorized by Baseline Blood Eosinophil Count and Feno Levels

Characteristic	Blood Eosinophil Count ≥ 150 cells/μL and Feno ≥ 25 ppb		Blood Eosinophil Count ≥ 150 cells/μL and Feno < 25 ppb		Blood Eosinophil Count < 150 cells/μL and Feno ≥ 25 ppb		Blood Eosinophil Count < 150 cells/μL and Feno < 25 ppb
	PBO/DPL (n = 107)	DPL/DPL (n = 186)	PBO/DPL (n = 58)	DPL/DPL (n = 142)	PBO/DPL (n = 18)	DPL/DPL (n = 36)	PBO/DPL (n = 36)	DPL/DPL (n = 80)
Age, y	33.6 ± 16.6	28.9 ± 17.5	31.8 ± 18.7	26.7 ± 18.1	29.6 ± 15.0	27.4 ± 17.0	29.2 ± 16.1	26.7 ± 18.9
Pre-BD FEV1, L	1.72 ± 0.55	1.88 ± 0.56	1.79 ± 0.60	1.76 ± 0.59	1.73 ± 0.42	1.76 ± 0.70	1.80 ± 0.59	1.79 ± 0.64
Percent predicted pre-BD FEV1	56.59 ± 12.97	59.62 ± 11.94	58.60 ± 13.46	58.44 ± 12.49	56.17 ± 11.01	56.86 ± 13.47	59.42 ± 13.08	59.66 ± 12.67
FEV1 reversibility, %	28.32 ± 19.23	28.48 ± 18.34	28.53 ± 16.11	25.92 ± 20.67	37.30 ± 23.15	24.79 ± 19.09	25.08 ± 19.52	26.81 ± 23.95
No. of severe asthma exacerbations in past yeara	2.29 ± 2.07	2.24 ± 2.12	2.26 ± 1.95	2.00 ± 1.71	2.44 ± 2.66	1.72 ± 1.03	2.19 ± 2.04	2.11 ± 1.88
ACQ-5 scoreb	2.76 ± 0.79	2.69 ± 0.80	2.78 ± 0.80	2.78 ± 0.80	2.50 ± 0.45	2.64 ± 0.71	2.68 ± 0.73	2.76 ± 0.73
AQLQ(S) global scorec	4.14 ± 1.01	4.28 ± 1.08	4.23 ± 1.01	4.22 ± 1.13	4.40 ± 0.86	4.35 ± 1.11	4.35 ± 1.11	4.22 ± 1.00

Values are reported as mean ± SD. ACQ-5 = 5-item Asthma Control Questionnaire; AQLQ(S) = standardized Asthma Quality of Life Questionnaire; BD = bronchodilator; DPL = dupilumab; Feno = fractional exhaled nitric oxide; PBO = placebo.

^aSevere asthma exacerbation prior to the study is defined as any treatment with one systemic (oral or parenteral) steroid burst or more for worsening asthma or hospitalization or an emergency department/urgent medical care visit for worsening asthma.

^bScores on the ACQ-5 questionnaire range from 0 to 6, with lower scores indicating better asthma control.

^cScores on the AQLQ(S) questionnaire range from 1 to 7, with higher scores indicating better quality of life.

Annualized Exacerbation Rate

In the three populations identified by elevation of either type 2 biomarker (eosinophil count ≥ 150 cells/μL and/or Feno ≥ 25 ppb) who completed 96 weeks of treatment, AER decreased in the dupilumab vs placebo groups by the end of 52 weeks of treatment in QUEST. The low exacerbation rate was sustained throughout TRAVERSE in the dupilumab/dupilumab group (AER in eosinophil count ≥ 150 cells/μL and Feno ≥ 25 ppb group, 0.161; in eosinophil count ≥ 150 cells/μL and Feno < 25 ppb group, 0.319; and in eosinophil count < 150 cells/μL and Feno ≥ 25 ppb group, 0.180), whereas patients who had previously received placebo and initiated dupilumab in TRAVERSE showed a reduction in AER to rates similar to the dupilumab/dupilumab group by end of treatment in TRAVERSE (AER in eosinophil count ≥ 150 cells/μL and Feno ≥ 25 ppb group, 0.241; in eosinophil count ≥ 150 cells/μL and Feno < 25 ppb group, 0.279; and in eosinophil count < 150 cells/μL and Feno ≥ 25 ppb group, 0.120) (Fig 1). The greatest reductions were observed in patients with elevated levels of type 2 biomarkers. Although reductions in AER were observed during QUEST in patients with eosinophil count < 150 cells/μL and Feno < 25 ppb who received dupilumab, these reductions were similar to those observed in the placebo group. Similar trends were seen in analyses of all patients (completers and noncompleters combined) who enrolled from QUEST, with the smallest changes from baseline observed in the group of patients with eosinophil count < 150 cells/μL and Feno < 25 ppb (e-Fig 2).

Figure 1.

Unadjusted AER by biomarker subgroup in patients from QUEST who enrolled in TRAVERSE and completed through to 96 wk. ^aCalculated as the total number of events that occurred during the treatment period divided by the total number of patient-years followed in the treatment period. AER = annualized exacerbation rate; DPL = dupilumab; Feno = fractional exhaled nitric oxide; PBO = placebo; PPB = parts per billion.

FEV₁

In patients who completed 3 years of treatment, at PSBL the mean pre-BD FEV₁ ± SD ranged from 1.72 ± 0.55 to 1.88 ± 0.56 L across the biomarker and treatment groups, respectively. By the end of QUEST, the largest improvements in pre-BD FEV₁ were observed in patients with blood eosinophil count ≥ 150 cells/μL and Feno ≥ 25 ppb at PSBL (improvements of approximately 0.5 L for the dupilumab group) (Fig 2). For patients with blood eosinophil count < 150 cells/μL and Feno < 25 ppb, change in FEV₁ was numerically lower in the dupilumab group than placebo. Across all four biomarker groups, changes observed during QUEST were sustained throughout TRAVERSE in the dupilumab/dupilumab group, with a similar magnitude of changes observed in patients who had previously received placebo. Similar results were seen when all patients enrolled from QUEST were evaluated (e-Fig 3).

Figure 2.

Mean change from PSBL in prebronchodilator FEV₁ by biomarker subgroup in patients from QUEST who enrolled in TRAVERSE and completed 96 wk of treatment. Feno = fractional exhaled nitric oxide; PPB = parts per billion; PSBL = parent study baseline.

Change in ACQ-5 and AQLQ

At PSBL, mean ACQ-5 scores varied from 2.50 to 2.78 across biomarker and treatment groups, respectively. By week 48 of TRAVERSE, mean ACQ-5 scores were reduced across all four biomarker groups (indicative of improved asthma control), with numerically similar degrees of change in placebo/dupilumab and dupilumab/dupilumab recipients. By week 48, change in ACQ-5 ranged from −1.36 to −1.88 in patients with elevated type 2 biomarkers, and from −1.36 to −1.40 in those without elevated biomarkers, resulting in changes from uncontrolled asthma at baseline to near, or just below, the threshold for well-controlled asthma by the end of the studies (Fig 3).

Figure 3.

Change in ACQ-5 score by biomarker subgroup in patients from QUEST who enrolled in TRAVERSE and completed through to 96 wk. ACQ-5 = 5-item Asthma Control Questionnaire; DPL = dupilumab; Feno = fractional exhaled nitric oxide; PBO = placebo; PPB = parts per billion; PSBL = parent study baseline.

Similar trends were observed in AQLQ scores, indicative of improved quality of life. Baseline scores ranged from 4.14 to 4.40 and had decreased to 1.10 to 1.64 by week 48 of TRAVERSE across all four biomarker groups; however, the greatest changes were seen in populations with at least one elevated type 2 biomarker (Fig 4).

Figure 4.

Change in AQLQ score by biomarker subgroup in patients from QUEST who enrolled in TRAVERSE and completed through to 96 weeks. AQLQ = Asthma Quality of Life Questionnaire; DPL = dupilumab; Feno = fractional exhaled nitric oxide; PBO = placebo; PPB = parts per billion; PSBL = parent study baseline.

Improvements were greater with dupilumab vs placebo for both ACQ-5 and AQLQ at week 0 of TRAVERSE, for all type 2 biomarker subgroups.

Discussion

In a previous analysis, we demonstrated that dupilumab led to sustained efficacy and acceptable safety for up to 3 additional years after parent phase 2b/3 studies. Here, we demonstrate that patients identified by the type 2 biomarkers, blood eosinophil count or Feno, show similar sustained efficacy. This analysis further supports the clinical utility of these biomarkers, alone or in combination, to identify patients who could demonstrate a sustained response to dupilumab.

These analyses provide further information to health care practitioners and patients for how to use blood eosinophil count and Feno to predict the response to dupilumab. IL-4 and IL-13 play an important role in airway remodeling, by influencing the contractility of smooth muscle cells, inhibiting eosinophil migration, and contributing to fibrosis and changes in mucus production.¹⁰ By targeting the shared IL-4/IL-13 receptor, dupilumab inhibits IL-4- and IL-13-induced inflammatory responses, thus reducing the release of IgE, proinflammatory cytokines, and nitric oxide.^10,11 In all three populations evaluated in the current analysis that had at least one elevated type 2 biomarker, dupilumab treatment resulted in sustained improvements in AER, lung function, control, and quality of life, with long-term exacerbation rates as low as 0.12 after 3 years of treatment. The greatest efficacy was observed in patients with elevated levels of both blood eosinophils and Feno, who achieved an FEV₁ improvement of around 0.5 L and reduced exacerbation rates in this population from around two per year to one every 3 to 4 years. Patients with elevated levels of either marker also achieved asthma control levels in, or close to, the well-controlled range by the end of the study. A recent post hoc analysis of QUEST showed that higher baseline Feno levels were associated with greater clinical effects in dupilumab vs placebo, independently of eosinophil levels.¹² We observed a similar effect through TRAVERSE, with baseline Feno ≥ 25 ppb appearing to be associated with better long-term reductions in exacerbation rates irrespective of eosinophil levels. However, patient numbers in the eosinophil count < 150 cells/μL and Feno ≥ 25 ppb group are low; therefore, this should be interpreted with caution. In the population with both blood eosinophil count < 150 cells/mL and Feno < 25 ppb, response to dupilumab was not significantly different from response to placebo during the randomized QUEST study. These results support the use of blood eosinophil count or Feno to identify patients who are expected to demonstrate rapid and sustained response to treatment with dupilumab.

These results emphasize the sustained efficacy of dupilumab over time. In all three populations with at least one elevated biomarker, lung function improvements and exacerbation reduction remained remarkably stable. In addition, there was evidence of a cumulative effect of dupilumab over time in patients with both biomarkers elevated because further reductions in exacerbations and improvements in asthma control were seen during the TRAVERSE study. This finding is supported by biomarker data, which show that IgE and blood eosinophil count are still falling during the third year of treatment with dupilumab⁸; however, further studies are needed to establish the magnitude of this effect and its potential mechanism.

There are several limitations to this study. Although the analysis by baseline type 2 inflammatory biomarkers was prespecified, additional subgroups including just those patients that completed 3 full years of exposure were analyzed in a post hoc fashion, and the study was not designed or powered to compare efficacy or show significance across different biomarker subgroups. Additionally, the sample sizes of each biomarker-defined population differed substantially, and relatively few patients were included with eosinophil count < 150 cells/μL and Feno ≥ 25 ppb at baseline. As an open-label extension study, a limitation of the TRAVERSE study in general was the potential bias of enrollment of patients who had seen a positive response to treatment during the parent study, compared with those who had seen less response. However, enrollment from the parent studies to the open-label extension was high, and was balanced between treatment and placebo arms. Finally, this analysis was conducted to better understand how these biomarkers may be used in a predictive or prognostic fashion. Although we recognize the absence of biomarker levels over time as a limitation, these results suggest that even a one-time value can distinguish patient populations with variable outcomes.

Interpretation

This analysis of the TRAVERSE open-label extension study adds to the growing evidence of dupilumab’s sustained efficacy for up to 3 years in patients with asthma and evidence of elevated type 2 biomarkers (blood eosinophil count or Feno), with very low AERs observed by the end of this post hoc analysis. Although responses were observed in patients without elevated type 2 biomarkers, AER was lower and change in FEV₁ greater in populations with either or both biomarkers elevated, further supporting the role of dupilumab in the long-term treatment of patients with moderate-to-severe asthma.

Funding/Support

This research was sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

Financial/Nonfinancial Disclosures

The authors have reported to CHEST Pulmonary the following: M. E. W. has received personal fees from Amgen, AstraZeneca, Avalo Therapeutics, Boehringer Ingelheim, Cerecor, Cohero Health, CytoReason, Eli Lilly, Equillium, Genzyme, GSK, Incyte, Kinaset Therapeutics, Novartis, OM Pharma, Phylaxis, Pulmatrix, RAPT Therapeutics, Regeneron Pharmaceuticals Inc., resTORbio, Roche-Genentech, Sanofi, Sentien Biotechnologies, Sound Biologics, Tetherex Pharmaceuticals, Teva, and Upstream Bio; and grants and personal fees from GSK and Sanofi. I. D. P. has received speaker fees from Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals Inc., Sanofi, and Teva; payments for organizing educational events from AstraZeneca, GSK, Regeneron Pharmaceuticals Inc, Sanofi, and Teva; consultant fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Genentech, GSK, Knopp Biosciences, Merck, Novartis, Regeneron Pharmaceuticals Inc., Sanofi, and Teva; international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, and Teva; a research grant from Chiesi; payments to support FDA approval meetings from GSK; payments for use of the Leicester Cough Questionnaire (of which he is a co-patent holder) in clinical trials from Bayer, Insmed, and Merck; and acted as an expert witness for a patent dispute involving AstraZeneca and Teva. A. P. reports grants, personal fees, nonfinancial support, and other support from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Mundipharma, and Teva; personal fees and nonfinancial support from Menarini, Novartis, and Zambon; and grants from Sanofi (all outside the submitted work). K. R. C. has received grants and personal fees from AstraZeneca, Bellus Health, Boehringer Ingelheim, CSL Behring, Genentech, Grifols, Kamada, Mereo BioPharma, Novartis, Regeneron Pharmaceuticals Inc., Sanofi, and Takeda; and grants from Amgen, Baxter, and GSK. A. A., N. P.-A., J. A. J.-N., P. J. R., E. L., N. A., H. W. S., and M. H. are employees of Sanofi, and may hold stock and/or stock options in the company. Y. D., B. A., and D. J. L. are employees and shareholders of Regeneron Pharmaceuticals Inc. None declared (N. A.).