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Papers by Daniel Alvarez

Additional file 1: Figure S1 Serum drug concentration–time profile for ADA-positive patients in t... more Additional file 1: Figure S1 Serum drug concentration–time profile for ADA-positive patients in the biosimilar, week 26 switch, and week 52 switch treatment groups, by neutralizing antibody status during TP3 A NAb positive, B NAb negative.

British Journal of Clinical Pharmacology, 2020

AimsSingle‐dose pharmacokinetic (PK) studies in healthy subjects have been the design of choice f... more AimsSingle‐dose pharmacokinetic (PK) studies in healthy subjects have been the design of choice for bioequivalence determination for decades. This preference has been recently extended to PK similarity studies of proposed biosimilars. However, PK similarity studies can be complicated by the effect of immunogenicity response on drug disposition. The impact is exacerbated when there is an imbalance in host‐specific immunological characteristics of subjects between the test and reference groups. Such complications remain poorly understood. The purpose of this communication is to show that the impact of immunogenicity response on PK similarity determination can be critical, using adalimumab as an example.MethodsData for adalimumab concentrations and immunogenicity response over 10 weeks were obtained from 133 healthy subjects receiving a 40 mg dose of Humira® in a PK similarity study. Also, a population PK model with a mechanistic construct for delineating the interplay between adalimum...

RMD Open

ObjectivesThis exploratory analysis investigated the potential use of the multibiomarker disease ... more ObjectivesThis exploratory analysis investigated the potential use of the multibiomarker disease activity (MBDA) score to support biosimilarity assessments using data from two randomised controlled trials (RCTs) of biosimilar infliximab (IFX-qbtx) and biosimilar adalimumab (ADL-afzb) versus EU-sourced infliximab (Remicade; IFX-EU) and adalimumab (Humira; ADL-EU) reference products, respectively, both conducted in adult patients with active rheumatoid arthritis.MethodsIn one study, patients (N=650) were randomised 1:1 to IFX-qbtx or IFX-EU (3 mg/kg intravenous at weeks 0, 2 and 6, then every 8 weeks). In the other, patients (N=597) were randomised 1:1 to ADL-afzb or ADL-EU (40 mg subcutaneous every other week). All treatments were given with MTX. Mean values of MBDA scores were calculated at baseline (BL), based on the concentrations of 12 serum proteins using the Vectra disease activity algorithm, and at timepoints throughout treatment period 1 (TP1) of the IFX (weeks 6, 14, 30) and...

Background/objective REFLECTIONS B538–02 is a randomized, double-blind comparative study of the a... more Background/objective REFLECTIONS B538–02 is a randomized, double-blind comparative study of the adalimumab (ADL) biosimilar PF-06410293, (ADL-PF), and reference ADL sourced from the European Union (ADL-EU) in patients with active RA. Therapeutic equivalence was demonstrated based on ACR20 responses at week 12 (primary endpoint). We report long-term safety, immunogenicity, and efficacy of ADL-PF in patients who continued ADL-PF treatment throughout 78 weeks or who switched from ADL-EU to ADL-PF at week 26 or week 52. Methods Eligible patients (2010 ACR/EULAR RA diagnosis criteria for ≥ 4 months; inadequate response to MTX, ≤ 2 doses non-ADL biologic), stratified by geographic regions were initially randomized (1:1) in treatment period 1 (TP1) to ADL-PF or ADL-EU (40 mg subcutaneously, biweekly), both with MTX (10–25 mg/week). At week 26 (start of TP2), patients receiving ADL-EU were re-randomized to remain on ADL-EU or transition to ADL-PF for 26 weeks. At week 52 (start of TP3), all...

Additional file 2: Table S1. Hypersensitivity TEAEs (PT) on or after the date of subject first AD... more Additional file 2: Table S1. Hypersensitivity TEAEs (PT) on or after the date of subject first ADA-positive test (safety population; TP3).

Science Translational Medicine, 2019

TNF concentrations stabilize in patients with rheumatoid arthritis during long-term adalimumab th... more TNF concentrations stabilize in patients with rheumatoid arthritis during long-term adalimumab therapy and are associated with antidrug antibodies.

Biologics : targets & therapy, 2017

To make informed decisions about the safety, efficacy, and clinical utility of a biosimilar, heal... more To make informed decisions about the safety, efficacy, and clinical utility of a biosimilar, health care providers should understand the types and be able to analyze data generated from a biosimilar development program. This article reviews the biosimilar guidelines, the biosimilar development process to provide education and context about biosimilarity, and uses examples from infliximab biosimilars to review the terminology and potential types of analyses that may be used to compare potential biosimilars to the originator biologic. A biosimilar is a biologic product that is highly similar to an approved (originator) biologic, notwithstanding minor differences in clinically inactive components, and with no clinically meaningful differences in terms of the safety, purity, and potency of the product. Due to their complex nature and production in living systems, it is not possible to exactly duplicate the approved originator biologic. To ensure biosimilars provide consistent, safe, and...

Journal of the American Academy of Dermatology, 2014

General practitioners/dermatologists may be aware of musculoskeletal symptoms in patients with ps... more General practitioners/dermatologists may be aware of musculoskeletal symptoms in patients with psoriasis but may have difficulty accurately detecting psoriatic arthritis (PsA). We sought to evaluate 3 PsA screening questionnaires-the Psoriasis and Arthritis Screening Questionnaire (PASQ), Psoriasis Epidemiology Screening Tool (PEST), and Toronto Psoriatic Arthritis Screen (ToPAS)-based on rheumatologist assessment in patients with psoriasis. Consecutive unselected patients with psoriasis, initially evaluated by dermatologists for plaque psoriasis, were randomized to receive 1 of 3 questionnaires. Patients were subsequently evaluated by rheumatologists to establish/exclude clinical PsA diagnosis. Using clinical PsA diagnosis as the standard for comparison, questionnaire accuracy was assessed by calculating sensitivity/specificity and positive/negative predictive values. Of 949 patients with psoriasis evaluated by rheumatologists, 285 (30%) received a clinical diagnosis of PsA (95% co...

Journal of the American Academy of Dermatology, 2013

Background: Prompt identification and treatment of psoriatic arthritis (PsA) in patients with pso... more Background: Prompt identification and treatment of psoriatic arthritis (PsA) in patients with psoriasis is critical to reducing the risk of joint damage, disability, and comorbidities. Objective: We sought to estimate PsA prevalence in patients with plaque psoriasis in 34 dermatology centers in 7 European and North American countries. Methods: Consecutive patients were evaluated by dermatologists for plaque psoriasis and subsequently by rheumatologists for PsA. PsA prevalence was estimated primarily based on rheumatologists' assessment of medical history, physical examination, and laboratory tests. Results: Of 949 patients evaluated, 285 (30%) had PsA (95% confidence interval 27-33) based on rheumatologists' assessment. PsA diagnosis changed in 1.2% of patients when diagnostic laboratory tests were added to medical history and physical examination. Of 285 patients given the diagnosis of PsA, 117 (41%) had not been previously given the diagnosis. Limitations: Bias may have been introduced by lack of standardized diagnostic criteria and unbalanced recruitment based on country populations. Conclusions: In this study, almost a third of patients with psoriasis seen in dermatology centers had PsA as determined by rheumatologists. More than a third of patients with PsA had not been previously given the diagnosis. Clinical evaluation alone is often sufficient basis for PsA diagnosis, but laboratory test results may be helpful in some patients.

Annals of the Rheumatic Diseases, 2020

Background: Glucocorticoids (GCs) are still widely prescribed in rheumatoid arthritis (RA). Despi... more Background: Glucocorticoids (GCs) are still widely prescribed in rheumatoid arthritis (RA). Despite their disease-modifying properties, they are associated with significant adverse effects. The international guidelines recommend the lowest effective dose and the lowest duration of GCs. Previous studies have shown that biologic disease modifying anti-rheumatic drugs (bDMARDs) can have a GC-sparing effect in RA. Objectives: The aim of the study was to assess the impact of the bDMARDs on glucocorticoids use in rheumatoid arthritis Tunisian patients, in real life practice. Methods: RA patients (according to the American College of Rheumatology criteria) who started their first bDMARDs (Tumour necrosis factor(TNF)α inhibitors, Tocilizumab and Rituximab) between January 2016 and august 2019, were recruited from the BINAR« Biologic National Registry», a prospective national Tunisian biologic registry. Oral prednisone intakewascompared at inclusion (M0), at 3 months (M3)and at 6 months(M6) after bDMARDs initiation. Results: 175 patients were included (149 females / 26 males). The mean age was 54.1 years ± 12.6 and the mean disease duration was 6.7 years ± 3.5. The TNFαinhibitors, the Tocilizumab and the Rituximab were prescribed, respectively, in 79.4%, 17.7% and 8.6%. The mean DAS28 index activity was 4.9 ± 1.5 at M0, 4.5 ±1.5 at M3 and 4.2 ± 1.1 at M6 (p=0.78). At inclusion, 150 patients (85.7%) were taking oral prednisone and the mean dose was 8.2 ± 5.4 mg/day. Overall, a significant decrease of oral prednisone use was observed at M3 (78%) and M6 (67.6%). The mean daily dose of oral prednisone was 8.9 ± 4.3mg at M3 (p>0.05) and 8.1 ± 2.7 mg at M6 (P>0.05). At M3 and M6, 4% and 2% of patients (p>0.05) had lowered prednisone doses, respectively. Prednisone discontinuation was observed in 17.7% at M3 and 18.1% at M6. Increased prednisone doses were noted in 2.7% at M3 and 2.6% at M6. The bDMARDs use wasn't associated with oral prednisone decrease at M3 (TNFi p=0.51; Tocilizumab p=0.54; Rituximab p=0, 77) and at M6 (TNFi p=0.61; Tocilizumab p=0.39; Rituximab p=0,64). Conclusion: This study showed a small glucocorticoids sparing-effect of bDMARDs at 3 months and 6 months in rheumatoid arthritis patients with a decrease of oral prednisone use of 18.1% at 6 months. References: [1] Fortunet c, Pers YP, Lambert J et al. Tocilizumab induces corticosteroid sparing in rheumatoid arthritis patients in clinical practice. Rheumatology 2015;54:672_677

Background: Similarity in efficacy, safety, and immunogenicity (IMG) of PF-06410293 (ADL-PF), an ... more Background: Similarity in efficacy, safety, and immunogenicity (IMG) of PF-06410293 (ADL-PF), an adalimumab (ADL) biosimilar, and reference ADL sourced from the European Union (ADL-EU), by subcutaneous (SC) injection using a prefilled syringe (PFS), have been demonstrated in a randomised controlled trial in patients with rheumatoid arthritis (RA) (NCT02480153). Objectives: To determine if the pharmacokinetics (PK), safety and tolerability of ADL-PF were similar following a single SC dose by prefilled pen (PFP) or PFS in healthy subjects (NCT02572245). Methods: In this phase 1, 2-arm study, healthy subjects, aged 18–55 years, were randomised (1:1) to receive ADL-PF (40 mg, SC) in the lower abdomen or upper anterior thigh by PFS or PFP. Primary endpoints were maximum observed serum concentration (Cmax) and area under the serum concentration–time profile from time 0–2 weeks after dosing (AUC0-2wk). Safety, including injection-site reactions (ISRs), and secondary PK endpoints, were also...

Clinical Pharmacology in Drug Development, 2021

This open-label, single-dose, randomized, parallel-group, 2-arm phase 1 bioequivalence (BE) study... more This open-label, single-dose, randomized, parallel-group, 2-arm phase 1 bioequivalence (BE) study assessed the pharmacokinetics (PK), safety, and tolerability of PF-06410293 (ADL-PF), an adalimumab (ADL) biosimilar, following administration by prefilled pen (PFP) or prefilled syringe (PFS). A total of 164 healthy adult subjects were randomized (1:1) to receive ADL-PF (40 mg subcutaneously) in the lower abdomen or upper anterior thigh by PFS or PFP; 163 subjects were included in the primary PK analysis. The concentration-time profiles of the ADL-PF PFS and PFP treatment arms were similar. The 90% confidence intervals for the test/reference ratios of the primary end points (area under the serum concentration-time profile from time 0 to 2 weeks after dosing and maximum observed serum concentration) fell within the 80.00%-125.00% prespecified margin for BE. Comparable numbers of subjects experienced adverse events (AEs) between treatment groups, and injection-site pain was similar at all times and for the 2 injection-site locations. This study demonstrated the BE of ADL-PF following subcutaneous administration using either a PFS or PFP device. ADL-PF by PFS or PFP injection was well tolerated, with the distribution of AEs, including injection-site reactions, being similar between treatment arms.

RMD Open, 2021

ObjectiveTo investigate the efficacy, safety, immunogenicity and pharmacokinetics of biosimilar a... more ObjectiveTo investigate the efficacy, safety, immunogenicity and pharmacokinetics of biosimilar adalimumab (ADL) PF-06410293 (ADL-PF; adalimumab-afzb) versus EU-sourced reference ADL (ADL-EU) in patients with active rheumatoid arthritis (RA) on longer-term treatment and after being switched from ADL-EU to ADL-PF.MethodsIn this multinational, double-blind study, patients with active RA were initially randomised to ADL-PF or ADL-EU for 26 weeks (treatment period (TP) 1). At the start of TP2 (weeks 26–52), patients in the ADL-EU arm were blindly re-randomised 1:1 to remain on ADL-EU (ADL-EU/ADL-EU; n=135) or switched to ADL-PF (ADL-EU/ADL-PF; n=134); patients receiving ADL-PF continued blinded treatment (ADL-PF/ADL-PF; n=283).ResultsThe American College of Rheumatology 20% improvement (ACR20) response rates were comparable between treatment groups at all visits during TP2. At week 52, ACR20 response rates were 82.7% (ADL-PF/ADL-PF), 79.3% (ADL-EU/ADL-EU) and 84.3% (ADL-EU/ADL-PF). Othe...

Drugs, 2021

Over time, clinicians have become increasingly comfortable embracing the prescription of biosimil... more Over time, clinicians have become increasingly comfortable embracing the prescription of biosimilars-highly similar versions of innovator or reference biological agents-for their patients with inflammatory diseases. Although a switch from a reference product to a licensed biosimilar version (or vice versa) is a medical decision robustly supported by the stepwise accumulation of clinical trial evidence concerning comparable safety, immunogenicity, and efficacy between these products, a switch from one biosimilar to another biosimilar of the same reference product, or a cross-switch, is not. Similarity among biosimilars of a reference product is not a regulatory agency concern and therefore is unlikely to be investigated in randomized controlled trials in the foreseeable future. Yet in clinical practice, across a diverse range of patients, the option to cross-switch from one biosimilar to another can and does arise for valid reasons such as convenience or tolerability issues, or driven by third parties (e.g., payers). In the absence of clinical trial data, clinicians must attempt to objectively evaluate the emerging real-world cross-switching evidence within the context of what is known about the science underpinning a designation of biosimilar. That knowledge then needs to be integrated with what clinicians know about their patients and their disease on a case-by-case basis. This review aims to consolidate relevant emerging real-world data and other key information about biosimilar-to-biosimilar cross-switching for prescribing clinicians. In the absence of clear clinical guidelines addressing this topic at present, this review may serve to facilitate discretionary and educated treatment decision making.

BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy, Jan 20, 2016

Biopharmaceuticals have the potential to raise an immunogenic response in treated individuals, wh... more Biopharmaceuticals have the potential to raise an immunogenic response in treated individuals, which may impact the efficacy and safety profile of these drugs. As a result, it is essential to evaluate immunogenicity throughout the different phases of the clinical development of a biopharmaceutical, including post-marketing surveillance. Although rigorous evaluation of biopharmaceutical immunogenicity is required by regulatory authorities, there is a lack of uniform standards for the type, quantity, and quality of evidence, and for guidance on experimental design for immunogenicity assays or criteria to compare immunogenicity of biopharmaceuticals. Moreover, substantial technological advances in methods to assess immune responses have yielded higher immunogenicity rates with modern assays, and limit comparison of immunogenicity of biopharmaceuticals outside of head-to-head clinical trials. Accordingly, research programs, regulatory agencies, and clinicians need to keep pace with cont...

BioDrugs

A biosimilar is a biologic drug that is "highly similar to a reference (originator) product, with... more A biosimilar is a biologic drug that is "highly similar to a reference (originator) product, with no clinically meaningful differences between the two products in safety, purity, and potency". Regulatory approval of a biosimilar is based on analytical, structural, and functional comparisons with the reference product, comparative nonclinical (in vivo) studies, clinical pharmacokinetics and/or pharmacodynamics, and immunogenicity. In addition, comparative clinical efficacy and safety assessments are usually conducted and, taken together, comprise the "totality of the evidence" supporting biosimilarity. For a biosimilar to meet the additional designation of interchangeability in the United States (US), the applicant must demonstrate that the biological drug can be expected to produce the "same clinical result as the reference product in any given patient" and "if the biological drug is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological drug and the reference product is no greater than the risk of using the reference product without such alternation or switch". The challenges faced in conducting clinical studies to support a designation of interchangeability, as defined in the final interchangeability guidance from the US Food and Drug Administration, are considered. Potential alternative approaches to generating adequate and sufficient clinical data to support a designation of interchangeability are also presented.

Arthritis research & therapy, Jan 15, 2018

This double-blind, randomized, 78-week study evaluated the efficacy, safety, immunogenicity, phar... more This double-blind, randomized, 78-week study evaluated the efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics of PF-06410293, a candidate adalimumab biosimilar, versus adalimumab reference product (Humira) sourced from the EU (adalimumab-EU) in biologic-naïve patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) (10-25 mg/week). We report results for the first 26 weeks of treatment. Patients with active RA (N = 597) were randomly assigned (1:1) to PF-06410293 or adalimumab-EU, while continuing with MTX treatment. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 12. Therapeutic equivalence was concluded if the two-sided 95% confidence interval (CI) for the ACR20 difference between the two arms was entirely contained within the symmetric equivalence margin (±14%). Additionally, a two-sided 90% CI was calculated by using an asymmetric equivalence margin (-12%, 15%). Secondary efficacy endpoints to week 2...

Objectives The aim of this phase 3, double-blind study was to compare the radiographic and clinic... more Objectives The aim of this phase 3, double-blind study was to compare the radiographic and clinical effects of etanercept (ETN) versus methotrexate (MTX) over 52 weeks in Japanese subjects with active rheumatoid arthritis. Methods The study population comprised 550 subjects with inadequate response to C1 disease-modifying antirheumatic drugs who were randomized to treatment groups of ETN 25 mg twice weekly (BIW; n = 182), ETN 10 mg BIW (n = 192), or MTX (B8.0 mg/week; n = 176). Results Of the 550 subjects initially enrolled in the three treatment groups, 21.6 % discontinued the study; a significantly higher proportion of those who withdrew from the study due to lack of efficacy were in the MTX (21.6 %) group compared with the ETN 25 mg (3.3 %) and ETN 10 mg (6.8 %) groups (P \ 0.001). Mean change from baseline in the modified total Sharp score at week 52 (primary endpoint) was significantly lower in the ETN 25 mg [3.33; standard error (SE), 0.73] and ETN 10 mg (5.19; SE 0.93) groups than in the MTX group (9.82; SE 1.16; P \ 0.0001 vs. either ETN group). Compared with subjects receiving MTX, significantly higher percentages of subjects treated with ETN 25 and 10 mg achieved American College of Rheumatology (ACR) ACR20 and ACR50 response rates at all time points (P \ 0.01). ETN was well-tolerated, with no unexpected safety findings. Conclusions ETN 25 mg BIW and ETN 10 mg BIW slowed radiographic progression and improved clinical outcomes more effectively than MTX in this Japanese population.

Objective. Assess the efficacy of etanercept in early active NSAID–refractory nonradiographic axi... more Objective. Assess the efficacy of etanercept in early active NSAID–refractory nonradiographic axial spondyloarthritis (nr-axSpA).Methods. Patients satisfied ASAS axSpA classification criteria without fulfilling modified NY radiographic criteria for ankylosing spondylitis (by central reading), had symptom duration >3 months and <5 years, Bath Ankylosing Spondylitis Disease Activity Index ≥4, and failed ≥2 NSAIDs. Patients were randomized to etanercept 50 mg/week or placebo and continued background NSAID for 12 weeks (double-blind); patients enrolled in the subsequent open-label period received etanercept 50 mg/week. Primary endpoint was ASAS40 at week 12. Sacroiliac joint/spine MRIs were performed at baseline and week 12.Results. In randomized patients (etanercept, n=106; placebo, n=109) at baseline, mean age (standard deviation) was 32.0 (7.8), 154/210 (72%) were HLA-B27 positive, and 174/215 (81%) were MRI sacroiliitis positive. ASAS40 at 12 weeks was achieved by a significan...

Journal of the National Medical Association, 2004