D. Schlichting

Baricitinib in Patients with Refractory Rheumatoid Arthritis

BACKGROUND In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs). METHODS In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose. RESULTS Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs. 27%, P<0.001). Differences between the higher-dose baricitinib group and the placebo group were also significant for the HAQ-DI score and the DAS28-CRP but not for an SDAI score of 3.3 or less. Adverse-event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71% and 77%, respectively, vs. 64%), including infections (44% and 40%, vs. 31%). The rates of serious adverse events were 4%, 10%, and 7% in the three groups, respectively. Two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels. CONCLUSIONS In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01721044.).

Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate.

Objectives To investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate. Methods In this phase IIb study, 301 patients were randomised 2:1:1:1:1 to receive once daily doses of placebo or 1, 2, 4 or 8 mg baricitinib for 12 weeks. Patients assigned to 2, 4 and 8 mg baricitinib continued blinded treatment for an additional 12 weeks. Patients assigned to placebo or 1 mg baricitinib were reassigned to 2 mg twice daily or 4 mg once daily baricitinib between weeks 12–24. The primary endpoint was the proportion of patients in the combined 4 and 8 mg groups achieving an American College of Rheumatology 20% (ACR20) response versus placebo at week 12. Results Significantly more patients in the combined baricitinib 4 and 8 mg groups compared with placebo achieved an ACR20 response at week 12 (76% vs 41%, p<0.001). At week 12, significant differences versus placebo were also observed in patients achieving ACR50, ACR70 and remission as measured by Disease Activity Score for 28-joint counts, Clinical Disease Activity Index and Simplified Disease Activity Index. Patients receiving 2, 4, or 8 mg baricitinib maintained or improved in all measures through 24 weeks. Similar proportions of patients experienced at least one adverse event in the placebo and baricitinib groups. Serious infections developed in three patients receiving baricitinib. No cases of tuberculosis, herpes zoster, opportunistic infections or deaths were reported. Dose-dependent decreases in haemoglobin were observed with baricitinib. Conclusions Baricitinib improved the signs and symptoms of RA in methotrexate inadequate responders with active disease. Baricitinib was well tolerated with no unexpected safety findings through week 24. Trial registration number NCT01185353.

Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis

BACKGROUND Baricitinib is an oral, reversible inhibitor of the Janus kinases JAK1 and JAK2 that may have therapeutic value in patients with rheumatoid arthritis. METHODS We conducted a 52‐week, phase 3, double‐blind, placebo‐ and active‐controlled trial in which 1307 patients with active rheumatoid arthritis who were receiving background therapy with methotrexate were randomly assigned to one of three regimens in a 3:3:2 ratio: placebo (switched to baricitinib after 24 weeks), 4 mg of baricitinib once daily, or 40 mg of adalimumab (an anti–tumor necrosis factor α monoclonal antibody) every other week. End‐point measures evaluated after adjustment for multiplicity included 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) (the primary end point), the Disease Activity Score for 28 joints (DAS28), the Health Assessment Questionnaire–Disability Index, and the Simplified Disease Activity Index at week 12, as well as radiographic progression of joint damage as measured by the van der Heijde modification of the total Sharp score (mTSS) (range, 0 to 448, with higher scores indicating greater structural joint damage) at week 24. RESULTS More patients had an ACR20 response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%, P<0.001). All major secondary objectives were met, including inhibition of radiographic progression of joint damage, according to the mTSS at week 24 with baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P<0.001) and an increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P=0.014). Adverse events, including infections, were more frequent through week 24 with baricitinib and adalimumab than with placebo. Cancers were reported in five patients (two who received baricitinib and three who received placebo). Baricitinib was associated with reductions in neutrophil counts and increases in levels of creatinine and low‐density lipoprotein cholesterol. CONCLUSIONS In patients with rheumatoid arthritis who had had an inadequate response to methotrexate, baricitinib was associated with significant clinical improvements as compared with placebo and adalimumab. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358.)

Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study

Background Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor. Methods In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3. Results More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein. Conclusions In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage. Trial registration number NCT01721057; Results.

Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease‐Modifying Antirheumatic Drug Treatment

We undertook this phase III study to evaluate baricitinib, an orally administered JAK‐1/JAK‐2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease‐modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs.

Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study

Objective. To evaluate efficacy and safety, baricitinib [Janus kinase (JAK) 1/JAK2 inhibitor] was compared with placebo in Japanese patients with active rheumatoid arthritis (RA) despite background treatment with methotrexate (MTX). Methods. This was a phase IIB, double-blind, randomized, placebo-controlled study (clinicaltrials.gov: NCT01469013). Patients had moderate to severe active adult-onset RA despite stable treatment with MTX. Patients (n = 145) were randomized in a 2:1:1:1:1 ratio to placebo or 1 mg, 2 mg, 4 mg, or 8 mg oral baricitinib daily for 12 weeks. The primary analysis compared the combined 4/8-mg dose groups with placebo for the American College of Rheumatology (ACR) 20 response rate at 12 weeks. Other outcomes included additional measures of disease activity, physical function, laboratory abnormalities, and adverse events. Results. A significantly higher proportion of patients in the combined 4/8-mg baricitinib group (37/48, 77%) compared with the placebo group (15/49, 31%) had at least an ACR20 response after 12 weeks of treatment (p < 0.001). Significant improvements in disease activity, remission, and physical function were observed as early as Week 2 of treatment with baricitinib, particularly with daily doses of ≥ 4 mg. Only 1 patient receiving baricitinib discontinued because of an adverse event. Adverse event rates with baricitinib doses ≤ 4 mg daily were similar to placebo, but there was a higher incidence of adverse events and laboratory abnormalities in the 8-mg group. Conclusion. In this phase II study, baricitinib was well tolerated and rapidly improved the signs, symptoms, and physical function of Japanese patients with active RA, supporting continued development of baricitinib (clinicaltrials.gov NCT01469013).

Circulating endothelial and endothelial progenitor cells in patients with severe sepsis

Elevated circulating endothelial cell (CEC) and circulating endothelial progenitor cell (CEPC) counts may indicate vascular damage and disease status, but data on these cell populations in patients with severe sepsis are limited. This study compared CEC and CEPC counts in patients with and without severe sepsis following intensive care unit (ICU) admission. Venous blood samples were collected within 24 h, 48-72 h, and 120-144 h. Baseline demographics, 28-day mortality, ICU and hospital days, and Sequential Organ Failure Assessment (SOFA) scores were recorded. Patients with (n=18) and without (n=28) severe sepsis were balanced for mean age (63.7 and 61.3 years, respectively) and gender. There were no differences in 28-day mortality, ICU days, or hospital days. Baseline SOFA scores were higher in the sepsis group. At 48-72 h, patients with severe sepsis had significantly higher median CEC counts (51.5 vs. 28.0 cells/4 ml of blood, P=0.02). CEC values for all ICU patients were significantly (P<0.05) higher than in healthy volunteers. CEPC counts in both cohorts ranged from 0 to >21 colonies/4 ml blood (mean=1.13±2.25; median=0) without significant differences at any time point. This study demonstrates the ability to quantify CECs and CEPCs using consensus methodology. Understanding the relationship between CEC/CEPC counts and outcomes may provide insight into the mechanisms of endothelial cell changes in severe sepsis.

Patient-reported outcomes from a randomised phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON)

Objectives To assess baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis, who had insufficient response or intolerance to ≥1 tumour necrosis factor inhibitors (TNFis) or other biological disease-modifying antirheumatic drugs (bDMARDs). Methods In this double-blind phase III study, patients were randomised to once-daily placebo or baricitinib 2 or 4 mg for 24 weeks. PROs included the Short Form-36, EuroQol 5-D, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patients Global Assessment of Disease Activity (PtGA), patients assessment of pain, duration of morning joint stiffness (MJS) and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis. Treatment comparisons were performed with logistic regression for categorical measures or analysis of covariance for continuous variables. Results 527 patients were randomised (placebo, 176; baricitinib 2 mg, 174; baricitinib 4 mg, 177). Both baricitinib-treated groups showed statistically significant improvements versus placebo in most PROs. Improvements were generally more rapid and of greater magnitude for patients receiving baricitinib 4 mg than 2 mg and were maintained to week 24. At week 24, more baricitinib-treated patients versus placebo-treated patients reported normal physical functioning (HAQ-DI <0.5; p≤0.001), reductions in fatigue (FACIT-F ≥3.56; p≤0.05), improvements in PtGA (p≤0.001) and pain (p≤0.001) and reductions in duration of MJS (p<0.01). Conclusions Baricitinib improved most PROs through 24 weeks compared with placebo in this study of treatment-refractory patients with previously inadequate responses to bDMARDs, including at least one TNFi. PRO results aligned with clinical efficacy data for baricitinib. Trial registration number NCT01721044; Results.

LB0005 12-week results of a phase 2B dose-ranging study of LY3009104 (INCB028050), an oral JAK1/JAK2 inhibitor, in combination with traditional dmards in patients with rheumatoid arthritis

Background LY3009104 (LY) is a novel, oral inhibitor of the JAK1/JAK2 signalling pathway known to be important in the pathobiology of rheumatoid arthritis (RA). Objectives To compare efficacy and safety of LY versus placebo (PBO) in patients (pts) with moderate to severe RA with inadequate response to methotrexate (MTX). Methods In this Phase 2b, 24-week randomized, double-blind, PBO-controlled study, pts with active RA on stable MTX were randomized 2:1:1:1:1 to receive either PBO or 1 of 4 once-daily LY doses (1, 2, 4, or 8 mg) for 12 weeks. The primary endpoint to evaluate the efficacy of LY was assessed by the combined proportion of pts in the 4-mg and 8-mg dose groups who achieved an ACR20 response compared to PBO over 12 weeks. Results Of the 301 pts randomized and treated, 76% of the combined 4- and 8-mg (75% of the 4-mg and 78% of the 8-mg dose) groups achieved ACR20 responses compared with 41% of PBO-treated pts (p ≤.001) by the end of 12 weeks. Similarly, greater proportions of pts achieved disease remission as judged by DAS28-CRP in the 4-mg (37%) and 8-mg (22%) dose groups compared to PBO (4%; Table 1). Onset of efficacy was rapid for ACR20, ACR50, ACR70, and DAS28-CRP, with statistically significant differences seen from Week 2 onwards. A greater percentage of pts achieved the MCID for the HAQ-DI in the 4-mg (60%) and 8-mg (67%) dose groups compared to PBO (41%) at week 12. Most adverse events (AEs) were mild. A similar rate of infections was observed in PBO (12%) and combined LY (14%) groups representing the most common treatment emergent AE. No deaths or opportunistic infections occurred in the active treatment groups. One pt taking PBO was diagnosed with an opportunistic infection of toxocariasis. Serious AEs were reported in 6 pts (2 in PBO; 3 in 2-mg; 1 in 8-mg). Decreases in hemoglobin, small increases in serum creatinine, and increases in LDL and HDL were seen (Table 2). Pt demographics across treatment groups were similar (83% female, mean age 51 years, mean duration of RA 5–7 years, HAQ-DI, 1.02–1.31; DAS28 [ESR], 6.0–6.6). Table 1. Endpoints PBO 1 mg LY 2 mg LY 4 mg LY 8 mg LY 4+8 mg LY (N=98) (N=49) (N=52) (N=52) (N=50) (N=102) % ACR20† 41 57* 54 75** 78** 76** % ACR50† 10 31* 17 35** 40** 37** % ACR70† 2 12* 8 23** 20** 22** DAS28-CRP†§ –1.0 –1.5* –1.4* –2.2** –2.1** N/A % DAS28 <2.6† 4 14* 15* 37** 22** N/A †Non-responder imputation and 1-sided p-value (Fisher’s exact test); §2-sided p-value from LY dose vs PBO (ANCOVA: treatment is a fixed factor and baseline is a covariate [LS mean change, LOCF]); *p<0.05; **p≤0.001 vs. PBO. Table 2. Mean (SD) Change from Baseline; 12 Weeks PBO 4 mg LY 8 mg LY Hemoglobin (g/dL) –0.14 (0.62) –0.15 (0.80) –0.57 (0.92) Neutrophil count (103/mm3) –0.03 (1.52) –0.30 (1.79) –0.68 (2.06) Creatinine (mg/dL) 0.01 (0.08) 0.11 (0.36) 0.09 (0.27) HDL cholesterol (mg/dL) 0.92 (11.57) 7.55 (13.40) 7.25 (13.92) LDL cholesterol (mg/dL) –4.4 (25.06) 9.5 (30.29) 12.0 (23.36) Conclusions Clinical efficacy of LY against PBO was demonstrated in this Phase 2b study of LY in combination with background MTX in pts with moderate to severe RA. LY was well tolerated. No new safety signals were detected when compared to previously conducted studies with LY. Disclosure of Interest E. Keystone Grant/Research support from: Abbott Laboratories, Amgen Inc, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Centocor Inc, F.Hoffman-La Roche Inc, Genzyme Inc, Merck, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, UCB, Consultant for: Abbott Laboratories, AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company, Centocor Inc, F.Hoffman-La Roche Inc, Genentech Inc, Merck, Nycomed, Pfizer Pharmaceuticals, UCB, Speakers Bureau: Abbott Laboratories, Bristol-Myers Squibb Company, F.Hoffman-La Roche Inc, Merck, Pfizer Pharmaceuticals Inc, UCB, Amgen, Janssen Inc., P. Taylor Grant/Research support from: AstraZeneca, Merck, UCB, Celgene, Consultant for: Eli Lilly & Co, Celgene, UCB, Novartis, Merck, NovoNordisk, Abbott, Pfizer, AstraZeneca, Roche, Takeda, M. Genovese Grant/Research support from: Lilly, Pfizer, Rigel, AstraZeneca, Consultant for: Lilly, Pfizer, Rigel, AstraZeneca, Vertex, Biogen-Idec, Astellas, D. Schlichting Shareholder of: Eli Lilly & Co, Employee of: Eli Lilly & Co, S. Beattie Shareholder of: Eli Lilly & Co, Employee of: Eli Lilly & Co, C. Gaich Shareholder of: Eli Lilly & Co, Employee of: Eli Lilly & Co, R. Fidelus Gort Employee of: Incyte Corp., M. Luchi Shareholder of: Incyte Corp., Employee of: Incyte Corp., W. Macias Shareholder of: Eli Lilly & Co, Employee of: Eli Lilly & Co

OP0029 Baricitinib, An Oral Janus Kinase (JAK)1/JAK2 Inhibitor, in Patients with Active Rheumatoid Arthritis (RA) and an Inadequate Response to TNF Inhibitors: Results of the Phase 3 RA-Beacon Study

Background In ph 2 studies, baricitinib (bari) improved disease activity with an acceptable safety profile in patients (pts) with active RA naïve to biologic DMARDs (bDMARDs).1,2 Objectives To report results from a ph 3 study of bari in pts with active RA and an inadequate response or intolerance to ≥1 TNF inhibitor (TNFi). Methods Pts with active RA (TJC & SJC ≥6, hsCRP ≥3mg/L) on conventional DMARDs (cDMARDs) were randomized 1:1:1 to placebo (PBO) or bari (2 or 4 mg) QD for 24 wks. All bDMARDs were discontinued ≥28d prior to treatment. Primary endpoint was ACR20 response at Wk 12 for bari 4 mg vs. PBO. Results Of 527 randomized pts, 57% had received ≥2 bDMARDs and 38% had received ≥1 non-TNFi bDMARD. Fewer pts discontinued treatment prior to Wk 24 on bari 2 or 4 mg vs. PBO (10%, 11%, 18%, respectively). ACR20 response at Wk 12 was higher with bari 4 mg vs. PBO (55% vs. 27%, p≤0.001). Improvements in ACR20, ACR50, ACR70, DAS28, CDAI, SDAI, and HAQ-DI were seen (Table), many as early as Wk 1. Treatment benefit was sustained through Wk 24 for the 4 mg dose. More TEAEs occurred in pts receiving bari 2 or 4 mg compared to PBO (71%, 77%, 64%, respectively) including infections (44%, 40%, 31%, respectively). SAE rates through 24 wks were similar among pts receiving bari 2 or 4 mg or PBO (4%, 10%, and 7%, respectively) including serious infections (2%, 3%, and 3%, respectively). There were no opportunistic infections, TB, or GI perforations. Two non-melanoma skin cancers and 2 major adverse cardiovascular events, including 1 death (stroke), were seen with bari 4 mg. Lab findings were consistent with ph 2 studies. Abnormalities leading to discontinuation were infrequent. Wk 12 Wk 24 PBO 2 mg QD 4 mg QD PBO 2 mg QD 4 mg QD (N=176) (N=174) (N=177) (N=176) (N=174) (N=177) ACR20 27 49*** 55*** 27 45*** 46*** ACR50 8 20** 28*** 13 23* 29*** ACR70 2 13*** 11** 3 13*** 17*** DAS28-hsCRP ≤3.2 9 24*** 32*** 11 20* 33*** DAS28-hsCRP <2.6 4 11** 16*** 6 11 22*** DAS28-ESR ≤3.2 4 13** 12** 7 12 17** DAS28-ESR <2.6 1 6** 6* 3 5 9* CDAI ≤10 11 24** 28*** 15 23 31*** CDAI ≤2.8 2 3 6 3 5 9* SDAI ≤11 9 22*** 28*** 14 22* 31*** SDAI ≤3.3 2 2 5 2 5 9** HAQ-DI MCID ≥0.22 43 59** 67*** 30 50*** 53*** Data are % patients achieving response (NRI);* p≤0.05,** p≤0.01,*** p≤0.001 vs. PBO. Conclusions In pts with active RA on cDMARDs and an inadequate response to bDMARDs, once daily oral bari was associated with rapid and sustained clinical improvements through 24 wks, with an acceptable safety and tolerability profile. The largest benefit was seen with the 4 mg dose. Additional ph 3 studies in bDMARD-naive pts are ongoing. References Keystone et al. Ann Rheum Dis 2015;24:333-340 Tanaka et al. Arthritis Rheum 2013;65(S10):S765 Disclosure of Interest M. Genovese Grant/research support from: Abbvie, Astellas, Eli Lilly & Company, Galapagos, Pfizer, Vertex, Consultant for: Abbvie, Astellas, Eli Lilly & Company, Galapagos, Pfizer, Vertex, J. Kremer Grant/research support from: Abbvie, Amgen, BMS, Genentech, Eli Lilly & Company, Pfizer, UCB, Consultant for: Eli Lilly & Company, Employee of: Corrona, O. Zamani Grant/research support from: Eli Lilly & Company, C. Ludivico Grant/research support from: Eli Lilly & Company, M. Krogulec Grant/research support from: Eli Lilly & Company, L. Xie Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, S. Beattie Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, A. Koch Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, T. Cardillo Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, T. Rooney Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, W. Macias Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, D. Schlichting Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, J. Smolen Grant/research support from: Abbvie, Janssen, MSD, Pfizer, Roche, UCB, Consultant for: Abbvie, Amgen, Astra-Zeneca, Astro, Celgene, Glaxo, Janssen, Eli Lilly & Company, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB