Paul Scholl
Boehringer Ingelheim
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Medicine | 2003
Jerry A. Winkelstein; Mary C. Marino; Hans D. Ochs; Ramsey Fuleihan; Paul Scholl; Raif S. Geha; E. Richard Stiehm; Mary Ellen Conley
The X-linked hyper-IgM (XHIGM) syndrome is an uncommon primary immunodeficiency disease caused by mutations in the gene for CD40 ligand and characterized by normal or elevated serum IgM, reduced levels of IgG and IgA, and defective T-cell function. Because of its rarity, it has been difficult for any single investigator or institution to develop a comprehensive clinical picture of this disorder. Accordingly, a national registry was developed in the United States to provide demographic, genetic, immunologic, and clinical information on a relatively large number of patients with the XHIGM syndrome.A total of 79 patients from 60 unrelated families were registered between January 1997 and July 2002. The estimated minimal incidence was approximately 1/1,030,000 live births. All of the patients had significant IgG deficiency and most had IgA deficiency, but only one-half had elevated IgM levels. Most patients presented initially with a history of an increased susceptibility to infection including Pneumocystis carinii pneumonia. The average age of diagnosis was significantly earlier in patients born into a family with a previously affected individual. However, only one-third of the patients born into a family with a previously affected individual were diagnosed exclusively because of the presence of the positive family history before any clinical symptoms developed. Over half the patients developed symptoms of immunodeficiency and were diagnosed by 1 year of age, and over 90% by 4 years of age.The most prominent clinical infections were pneumonia (81% of patients), upper respiratory infections (49%) including sinusitis (43%) and recurrent otitis (43%), recurrent/protracted diarrhea (34%), central nervous system infections (14%), sepsis (13%), cellulitis (13%), hepatitis (9%), and osteomyelitis (1%). In addition to infections caused by encapsulated bacteria, opportunistic infections were relatively common and were caused by P. carinii, members of the herpes virus family (including cytomegalovirus), Cryptosporidium, Cryptococcus, Candida, Histoplasma, and Bartonella. Sclerosing cholangitis occurred in 5 patients and in 4 of these was associated with Cryptosporidium infection.Eight patients had died at the time of their entry into the Registry; 2 of pneumonia (1 P. carinii and 1 cytomegalovirus), 2 of encephalitis (1 ECHO virus and 1 cytomegalovirus), 2 of malignancy (both hepatocellular carcinoma), 1 of sclerosing cholangitis caused by Cryptosporidium, and 1 of hemolytic uremic syndrome.
The Journal of Allergy and Clinical Immunology | 2015
James G. Krueger; Laura K. Ferris; Alan Menter; Frank Wagner; Alexander White; Sudha Visvanathan; Bojan Lalovic; Stella Aslanyan; Elaine E.L. Wang; David B. Hall; Alan Solinger; Steven John Padula; Paul Scholl
BACKGROUND IL-23 is associated with plaque psoriasis susceptibility and pathogenesis. BI 655066 is a fully human IgG1 mAb specific for the IL-23 p19 subunit. OBJECTIVE This first-in-human proof-of-concept study evaluated the clinical and biological effects of BI 655066 in patients with moderate-to-severe plaque psoriasis. METHODS We performed a single-rising-dose, multicenter, randomized, double-blind, placebo-controlled, within-dose cohort phase I trial. Patients received 0.01, 0.05, 0.25, 1, 3, or 5 mg/kg BI 655066 intravenously, 0.25 or 1 mg/kg BI 655066 subcutaneously, or matched placebo. The primary objective was safety evaluation. RESULTS Thirty-nine patients received single-dose BI 655066 intravenously (n = 18) or subcutaneously (n = 13) or placebo (n = 8). Adverse events were reported with similar frequency in the BI 655066 and placebo groups. Four serious adverse events (not considered treatment related) were reported among BI 655066-treated patients. BI 655066 was associated with clinical improvement from week 2 and maintained for up to 66 weeks after treatment. At week 12, 75%, 90%, and 100% decreases in the Psoriasis Area and Severity Index were achieved by 87%, 58%, and 16% of BI 655066-treated patients (any dose), respectively, versus none receiving placebo. BI 655066 treatment resulted in reduced expression of lesional skin genes associated with IL-23/IL-17 signaling pathways and normalization of psoriatic lesion gene expression profiles to a profile approaching that of nonlesional skin. Significant correlation between treatment-associated molecular changes and psoriasis area and severity index improvement was observed (r = 0.73, P = 2 × 10(-6)). CONCLUSIONS BI 655066 was well tolerated and associated with rapid, substantial, and durable clinical improvement in patients with moderate-to-severe psoriasis, supporting a central role for IL-23 in psoriasis pathogenesis.
Immunology Today | 1994
Paul Scholl; Raif S. Geha
The cognate interaction between T cells and antigen-presenting cells (APCs), mediated by major histocompatibility complex (MHC) class II molecules, results in the delivery of activation signals to the APC. These signals contribute to the expression of co-stimulatory activity by APCs and have important consequences for cell effector function. MHC class II molecules also serve as receptors for B-cell stimulation by microbial superantigens. In this review, Paul Scholl and Raif Geha discuss recent advances in our understanding of mechanisms of MHC class II signaling and analyse their role in human B-cell activation.
The New England Journal of Medicine | 2017
Kim Papp; Andrew Blauvelt; Michael Bukhalo; Melinda Gooderham; James G. Krueger; Jean-Philippe Lacour; Alan Menter; Sandra Philipp; Howard Sofen; Stephen K. Tyring; Beate R. Berner; Sudha Visvanathan; Chandrasena Pamulapati; Nathan Bennett; Mary Flack; Paul Scholl; Steven John Padula
BACKGROUND Interleukin‐23 is thought to be critical to the pathogenesis of psoriasis. We compared risankizumab (BI 655066), a humanized IgG1 monoclonal antibody that inhibits interleukin‐23 by specifically targeting the p19 subunit and thus prevents interleukin‐23 signaling, and ustekinumab, an interleukin‐12 and interleukin‐23 inhibitor, in patients with moderate‐to‐severe plaque psoriasis. METHODS We randomly assigned a total of 166 patients to receive subcutaneous injections of risankizumab (a single 18‐mg dose at week 0 or 90‐mg or 180‐mg doses at weeks 0, 4, and 16) or ustekinumab (45 or 90 mg, according to body weight, at weeks 0, 4, and 16). The primary end point was a 90% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12. RESULTS At week 12, the percentage of patients with a 90% or greater reduction in the PASI score was 77% (64 of 83 patients) for risankizumab (90‐mg and 180‐mg groups, pooled), as compared with 40% (16 of 40 patients) for ustekinumab (P<0.001); the percentage of patients with a 100% reduction in the PASI score was 45% in the pooled 90‐mg and 180‐mg risankizumab groups, as compared with 18% in the ustekinumab group. Efficacy was generally maintained up to 20 weeks after the final dose of 90 or 180 mg of risankizumab. In the 18‐mg and 90‐mg risankizumab groups and the ustekinumab group, 5 patients (12%), 6 patients (15%), and 3 patients (8%), respectively, had serious adverse events, including two basal‐cell carcinomas and one major cardiovascular adverse event; there were no serious adverse events in the 180‐mg risankizumab group. CONCLUSIONS In this phase 2 trial, selective blockade of interleukin‐23 with risankizumab was associated with clinical responses superior to those associated with ustekinumab. This trial was not large enough or of long enough duration to draw conclusions about safety. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT02054481).
The Lancet | 2017
Brian G. Feagan; William J. Sandborn; Geert R. D'Haens; Julián Panés; Arthur Kaser; Marc Ferrante; Edouard Louis; Denis Franchimont; Olivier Dewit; Ursula Seidler; Kyung-Jo Kim; Markus F. Neurath; Stefan Schreiber; Paul Scholl; Chandrasena Pamulapati; Bojan Lalovic; Sudha Visvanathan; Steven John Padula; Ivona Herichova; Adina Soaita; David B. Hall; W. Böcher
BACKGROUND The interleukin-23 pathway is implicated genetically and biologically in the pathogenesis of Crohns disease. We aimed to assess the efficacy and safety of risankizumab (BI 655066, Boehringer Ingelheim, Ingelheim, Germany), a humanised monoclonal antibody targeting the p19 subunit of interleukin-23, in patients with moderately-to-severely active Crohns disease. METHODS In this randomised, double-blind, placebo-controlled phase 2 study, we enrolled patients at 36 referral sites in North America, Europe, and southeast Asia. Eligible patients were aged 18-75 years, with a diagnosis of Crohns disease for at least 3 months, assessed as moderate-to-severe Crohns disease at screening, defined as a Crohns Disease Activity Index (CDAI) of 220-450, with mucosal ulcers in the ileum or colon, or both, and a Crohns Disease Endoscopic Index of Severity (CDEIS) of at least 7 (≥4 for patients with isolated ileitis) on ileocolonoscopy scored by a masked central reader. Patients were randomised 1:1:1 using an interactive response system to a double-blind investigational product, and stratified by previous exposure to TNF antagonists (yes vs no). Patients received intravenous 200 mg risankizumab, 600 mg risankizumab, or placebo, at weeks 0, 4, and 8. The primary outcome was clinical remission (CDAI <150) at week 12 (intention-to-treat population). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02031276. FINDINGS Between March, 2014, and September, 2015, 213 patients were screened, and 121 patients randomised. At baseline, 113 patients (93%) had been previously treated with at least one tumour necrosis factor (TNF) antagonist (which had failed in 96 [79%]). At week 12, 25 (31%) of 82 risankizumab patients (pooled 41 patients in 200 mg and 41 patients in 600 mg arms) had clinical remission versus six (15%) of 39 placebo patients (difference vs placebo 15·0%, 95% CI 0·1 to 30·1; p=0·0489). Ten (24%) of 41 patients who received 200 mg risankizumab had clinical remission (9·0%, -8·3 to 26·2; p=0·31) and 15 (37%) of 41 who received the 600 mg dose (20·9%, 2·6 to 39·2; p=0·0252). 95 (79%) patients had adverse events (32 in the placebo group, 32 randomised to 200 mg risankizumab, 31 randomised to 600 mg risankizumab); 18 had severe adverse events (nine, six, three); 12 discontinued (six, five, one); 24 had serious adverse events (12, nine, three). The most common adverse event was nausea and most common serious adverse event was worsening of underlying Crohns disease. No deaths occurred. INTERPRETATION In this short-term study, risankizumab was more effective than placebo for inducing clinical remission in patients with active Crohns disease. Therefore, selective blockade of interleukin-23 via inhibition of p19 might be a viable therapeutic approach in Crohns disease. FUNDING Boehringer Ingelheim.
Current Topics in Microbiology and Immunology | 1991
Talal A. Chatila; Paul Scholl; François Spertini; Narayanaswamy Ramesh; Nikolaus S. Trede; Ramsay Fuleihan; Raif S. Geha
Toxic shock syndrome (TSS) is a severe multisystem disorder characterized by high fever, hypotension, generalized erythroderma, desquamation of the skin, and dysfunction of multiple organ systems (Chesney 1989; Davis et al. 1980; Todd et al. 1978). TSS is consistently associated with infection by toxigenic strains of Staphylococcus aureus, most commonly in the setting of tampon use during menses or following surgery or trauma. Exotoxins secreted by staphylococcal isolates from patients with TSS, most notably toxic shock syndrome toxin-1 (TSST-1), but also the structurally related staphylococcal enterotoxins, play a key role in the pathophysiology of this disease. It has been recently appreciated that the toxicity of TSST-1 stems from its ability to initiate uncontrolled activation of large numbers of immune cells by virtue of its capacity to bind MHC class II (la) molecules (Scholl et al. 1989a; Uchiyama et al. 1989a). Once bound to la molecules, TSST-1 can transmit activation signals to la+ immune cells including monocytes, B lymphocytes, activated T lymphocytes, and activated natural killer cells. At the same time, la-bound TSST-1 acts as a superantigen that interacts with and activates human T lymphocytes whose T cell receptor β chains bear a particular variable (V) gene sequence, Vβ2 (Choi et al. 1989). In this review, we will focus on the characteristics of the interaction between TSST-1 and la molecules and on the functional consequences of superantigen formation, including Vβ-restricted activation of T lymphocytes and superantigen-mediated cognate T/B cell interaction. We will also examine evidence for the induction by TSST-1 of transmembrane signals via la molecules that regulate intercellular adhesion interactions mediated by lymphocyte function-associated molecule 1 (LFA-1; CD11 a/CD18), T and B lymphocyte activation, and monokine gene transcription. Finally, we will discuss the relevance of the interaction of TSST-1 with la molecules to the pathophysiology of TSS.
Annals of the Rheumatic Diseases | 2018
Dominique Baeten; Mikkel Østergaard; James Cheng-Chung Wei; Joachim Sieper; Pentti Järvinen; Lai-Shan Tam; Carlo Salvarani; Tae-Hwan Kim; Alan Solinger; Yakov Datsenko; Chandrasena Pamulapati; Sudha Visvanathan; David B. Hall; Stella Aslanyan; Paul Scholl; Steven John Padula
Objectives To evaluate the efficacy and safety of risankizumab, a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), in patients with active ankylosing spondylitis (AS). Methods A total of 159 patients with biological-naïve AS, with active disease (Bath Ankylosing Spondylitis Disease Activity Index score of ≥4), were randomised (1:1:1:1) to risankizumab (18 mg single dose, 90 mg or 180 mg at day 1 and weeks 8, 16 and 24) or placebo over a 24-week blinded period. The primary outcome was a 40% improvement in Assessment in Spondylo Arthritis International Society (ASAS40) at week 12. Safety was assessed in patients who received at least one dose of study drug. Results At week 12, ASAS40 response rates were 25.5%, 20.5% and 15.0% in the 18 mg, 90 mg and 180 mg risankizumab groups, respectively, compared with 17.5% in the placebo group. The estimated difference in proportion between the 180 mg risankizumab and placebo groups (primary endpoint) was –2.5% (95% CI –21.8 to 17.0; p=0.42). Rates of adverse events were similar in all treatment groups. Conclusions Treatment with risankizumab did not meet the study primary endpoint and showed no evidence of clinically meaningful improvements compared with placebo in patients with active AS, suggesting that IL-23 may not be a relevant driver of disease pathogenesis and symptoms in AS. Trial registration number NCT02047110; Pre-results.
Basic & Clinical Pharmacology & Toxicology | 2011
Fenglei Huang; Paul Scholl; David B. Huang; Thomas R. MacGregor; Mitchell E. Taub; Richard Vinisko; Mark Castles; Patrick A. Robinson
The objective of this study was to evaluate the pharmacokinetic interaction of ritonavir-boosted BILR 355 (BILR 355/r) with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). This was an open-label, prospective study. For Group A, 26 healthy subjects were given FTC/TDF (200/300 mg) once daily (QD) for 7 days and then co-administered with BILR 355/r (150/100 mg) twice daily (bid) for an additional 7 days. Pharmacokinetics assessments were performed at days 7 and 14. For Group B, eight subjects were given BILR 355/r (150/100 mg) bid for 7 days. The pharmacokinetic data from Group B were also pooled with Group B subjects from other similar studies performed in parallel to this study. After co-administration with BILR 355/r, the geometric mean ratio (GMR, %) and 90% confidence interval (CI, %) of combined versus alone treatment for FTC AUC(0-24,ss) , C(max,ss) and C(0-12,ss) were 160 (154-166), 128 (121-136) and 223 (206-241), respectively; and for tenofovir AUC(0-24,ss) , C(max,ss) and C(24,ss) were 126 (121-132), 131 (117-146) and 132 (124-140), respectively. Co-administration with FTC/TDF resulted in an 18% increase in AUC(0-12,ss) , 14% increase in C(max,ss) and 19% increase in C(12,ss) for BILR 355. BILR 355 was well tolerated in this study. There was no evidence of increased risk of TFV or FTC toxicity upon co-administration of FTC/TDF with BILR 355/r.
The Journal of Clinical Pharmacology | 2011
Fenglei Huang; Paul Scholl; David B. Huang; Thomas R. MacGregor; Richard Vinisko; Mark Castles; Frank Berger; Patrick A. Robinson
The objective of this investigation was to evaluate the pharmacokinetic interaction of lopinavir/ritonavir (LPV/r) with BILR 355. In group A, 26 healthy participants were administered LPV/r (400mg/100mg) twice daily for 14 days, followed by coadministration of BILR 355, 150 mg twice daily for an additional 7 days. Pharmacokinetic assessments were performed on days 14 and 21. In group B, 8 healthy participants were given BILR 355/ritonavir (BILR 355/r, 150mg/100mg) twice daily for 7 days. The pharmacokinetic data from group B (BILR 355/r‐alone group) were also pooled with group B subjects from 3 similar phase I drug‐drug interaction trials performed in parallel to this study. Coadministration with LPV/r resulted in a 51% decrease in steady‐state area under plasma concentration‐time curve from 0 to 12 hours (AUC0–12, ss) and steady‐state maximum measured plasma concentration over a dosing interval (Cmax, ss) and a 50% decrease in steady‐state plasma concentration 12 hours post last dosing (C12, ss) for BILR 355. Exposure to LPV was not changed after coadministration. BILR 355/r was well tolerated in this study. There was no evidence of increased risk of lopinavir or ritonavir toxicity upon coadministration with BILR 355.
Journal of Experimental Medicine | 1994
Allan V. T. Wang; Paul Scholl; Raif S. Geha