Relative bioavailability, immunogenicity, and safety of two adalimumab-adbm formulations in healthy volunteers: a double-blind, randomized, single-dose, parallel-arm Phase I trial (VOLTAIRE-HCLF).

OBJECTIVE: VOLTAIRE-HCLF compared the relative bioavailability of citrate-free high-concentration and reference formulations of the biosimilar adalimumab-adbm (Cyltezo®), including pharmacokinetic (PK) profiles, immunogenicity, and safety profiles in healthy volunteers. METHODS: Healthy volunteers (N = 200) aged 18-55 years and with body mass index of 18.5-29.9 kg/m2 and no prior exposure to adalimumab were randomized in a 1:1 ratio to receive a single subcutaneous injection of either adalimumab-adbm 40 mg/0.4 mL (high-concentration formulation) or 40 mg/0.8 mL (reference formulation). Participants completed 13 follow-up visits over 57 days, followed by a safety follow-up period of up to 70 days. RESULTS: The main PK parameters were similar for the high-concentration and reference groups. For all primary endpoints, the geometric mean ratios and 90% confidence intervals of AUC0-1344, AUC0-∞, and Cmax for both groups were entirely within the standard 80-125% bioequivalence acceptance range at 101.88% (93.31-111.23%), 105.38% (95.06-116.81%), and 91.29% (84.38-98.76%), respectively. There were no differences in the proportion of anti-drug antibody-positive participants or in the distribution of anti-drug antibody titers between the two formulations at any time point after drug dosing. Participants who were given the high-concentration formulation of adalimumab-adbm experienced a lower incidence of adverse events and local reactions than those who were given the reference formulation. CONCLUSIONS: Overall, the high-concentration and reference adalimumab-adbm formulations had highly similar PK and immunogenicity profiles and were safe and well tolerated. CLINICAL TRIAL REGISTRATION: NCT05203289.

Future Evolution of Biosimilar Development by Application of Current Science and Available Evidence: The Developer's Perspective.

Biosimilars have been available in the USA for over a decade, and in Europe for almost two decades. In that time, biosimilars have become established in the treatment landscape for a wide range of diseases, facilitating patient access and affordability of healthcare. However, patients can still struggle to access biological therapies in some markets. There is a need to streamline the process of developing biosimilars without compromising their quality, safety, or efficacy. This opinion piece considers the efficiencies that could be achieved within the biosimilar approval process. In clinical trials for biosimilars, clinical efficacy endpoints have been shown to be less sensitive measures of biosimilarity than biochemical, biophysical, and biological functional assays. Additional clinical efficacy studies comparing potential biosimilars and reference products do not add information that is useful for regulatory purposes. Large clinical studies of biosimilars with immunogenicity endpoints are of limited value, given the quality control processes in place for all biologics, including biosimilars. The expectation for multiple-switch studies for US interchangeability designation should be reconsidered immediately, and the category should be eliminated in the future. As biosimilars are typically approved globally based on a single set of clinical trials, and all subsequent manufacturing changes are already carefully monitored by regulatory authorities, comparative pharmacokinetic testing of EU and US reference products is unnecessary. Manufacturers and regulators could take greater advantage of existing real-world evidence. Streamlining biosimilar development would enable biosimilar development of more and a wider variety of biological drugs, accelerating biosimilar development without impacting patient safety or effectiveness.

An online survey among US patients with immune-mediated conditions: Attitudes about biosimilars.

BACKGROUND: Few surveys about biosimilars have been conducted among US patients. OBJECTIVE: To evaluate attitudes about biosimilars among patients with rheumatoid arthritis (RA), psoriasis and/or psoriatic arthritis (PsO/A), and/or inflammatory bowel disease (IBD). METHODS: WebMD, LLC fielded a 16-item online survey to members of the US Dynata consumer panel meeting these criteria: aged 18 years or older; self-reported specialist diagnosis of RA, PsO/A, or IBD of at least 1 year; and not currently receiving an infliximab biosimilar. A quota of 500 was set, stratified by region and condition. The survey was exempt by the institutional review board, exploratory, and not registered. RESULTS: Overall, 44% (n = 221) of patients were on a biologic; 56% (n = 279) were not on a biologic (40% [n = 199] were biologic naive and 16% [n = 80] used biologics in the past). Among all patients, 66% were unaware of biosimilars and 24% were aware (10% unsure). After being shown the US Food and Drug Administration definition of a biosimilar, main concerns were side effects (59%), long-term safety (50%), and not knowing a lot (46%). Among current users, 43% would switch to a biosimilar and 26% would not (32% unsure). Of those unwilling to switch, 51% were concerned about side effects, 42% about financial support, and 40% about efficacy. When those not on a biologic were asked if their doctor prescribed an original anti-tumor necrosis factor α but their insurance required its biosimilar, 49% would switch and 8% would not (43% unsure). 51% of patients surveyed thought pharmacist-level substitution of an interchangeable biosimilar was acceptable with notification. Survey findings were consistent among the RA, PsO/A, and IBD subgroups. CONCLUSIONS: Although two-thirds of patients surveyed were unaware of biosimilars, the majority were potentially receptive to biosimilar treatment after being provided with the definition of a biosimilar. Patients expressed a desire to know more about biosimilars in general, how they compare with original biologics, their benefits, and cost. DISCLOSURES: This study was funded by Boehringer Ingelheim Pharmaceuticals Inc. (BIPI). WebMD, LLC, fielded the survey. BIPI was given the opportunity to review the article for medical and scientific accuracy and intellectual property considerations. Dr Gibofsky is a consultant/advisor for AbbVie Inc., Biosplice Therapeutics, Lilly, Novartis Pharmaceuticals Corporation, and Pfizer Inc., and he is on the speakers' bureau for AbbVie Inc., Amgen, Lilly, and Pfizer Inc., and has stock ownership in AbbVie Inc., Amgen, Bristol-Myers Squibb Company, Horizon Pharma plc, and Pfizer Inc. Dr Peyrin-Biroulet reports that he has received personal consulting fees from Merck Sharp & Dohme, AbbVie, Janssen, Takeda, Celltrion, Pfizer, Bristol-Myers Squibb Company, Pharmacosmos, Shire, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, UCB-Pharma, Hospira, BIPI, and Lilly. Dr McCabe is an employee of BIPI. Dr McGrath was an employee of BIPI at the time the survey was conducted. Mr Jacobson, Mr Franklin, and Ms O'Hara-Levi report no disclosures.

Pharmacist biosimilar survey reveals knowledge gaps.

BACKGROUND: Biosimilars are of increasing significance to pharmacy practice, with the potential to improve patient access to biologic therapies and help reduce overall health care costs. OBJECTIVES: This web-based survey assessed pharmacists' understanding of biosimilars, including interchangeability. METHODS: WebMD LLC fielded a survey including true or false and Likert-type questions to the Medscape pharmacist and certified pharmacy technician (CPT) panel in March 2021. Those practicing in community, home care or infusion, hospital or health system, managed care, outpatient, or specialty pharmacy settings and currently providing prescription services, or formulary or benefit management related to biologic products were included, to a quota of 500 responses. Results were analyzed descriptively. RESULTS: Data are reported for 507 of 992 respondents (265 did not meet eligibility criteria, 220 responded after the survey closed), including 498 pharmacists and 9 CPTs. These respondents worked in a community setting (66%), outpatient or ambulatory or other setting (16%), hospital or health system setting (14%), or managed care (5%). Overall, 87% and 91% of respondents knew that the biosimilar had equivalent efficacy and safety, respectively, to its reference product. Only 20% understood that a pharmacist can substitute a Food and Drug Administration-approved interchangeable without approval of the prescriber. However, 53% responded that they felt it was appropriate for a pharmacist to dispense an interchangeable in place of its reference product without authorization from the prescriber if consistent with state law; a numerically smaller proportion of community pharmacists understood this concept than the other groups (50% vs. 54%-61%). Only 11% of respondents knew that no biosimilars were designated as interchangeable at the time of the survey, with a numerically greater proportion of managed care pharmacists showing awareness than other groups. Slightly more than 50% of respondents felt that they were moderately or very comfortable in responding to patients' biosimilar questions. CONCLUSION: Gaps remain in pharmacists' understanding and comfort with key concepts about biosimilar products, including interchangeability, suggesting the need for further education.

Switching Between Adalimumab Reference Product and BI 695501 in Patients with Chronic Plaque Psoriasis (VOLTAIRE-X): A Randomized Controlled Trial.

BACKGROUND: BI 695501 is an FDA-approved biosimilar to adalimumab reference product (RP). VOLTAIRE-X was a randomized clinical trial to assess outcomes with a biosimilar monoclonal antibody in line with the FDA requirements for designation as an 'interchangeable' biosimilar. OBJECTIVE: The aim of this study was to assess whether multiple switches between adalimumab RP and BI 695501 lead to equivalent pharmacokinetics and a similar safety and immunogenicity profile compared with continuous adalimumab RP. METHODS: We conducted a phase III, double-blind, randomized controlled trial between July 19, 2017, and April 16, 2019. There were 49 investigational sites across Europe and North America. Of 323 screened patients with moderate-to-severe chronic plaque psoriasis, 259 were treated with adalimumab RP during the run-in period. Of these, 118 and 120 were randomized to the continuous or switching arms, respectively. Interventions consisted of a run-in period with adalimumab RP 80 mg subcutaneously (SC) on Day 1, then 40 mg SC every other week (EOW) Weeks 2-12. Patients were then randomized to receive adalimumab RP 40 mg EOW Weeks 14-48 (continuous arm) or BI 695501 40 mg Weeks 14 and 16, adalimumab RP 40 mg Weeks 18 and 20, and BI 695501 40 mg EOW Weeks 22 to 48 (switching arm); all interventions were given SC. Primary endpoints were pharmacokinetics parameters, area under the plasma concentration-time curve (AUCτ,30-32) and maximum observed drug plasma concentration (Cmax,30-32), measured after the third switch during the Week 30-32 dosing interval. RESULTS: 238 patients (mean [standard deviation] age 44.9 [13.8]; 66.0% male) were treated in the switching (n = 118) or continuous arms (n = 120). Adjusted mean Cmax,30-32 was 7.08 and 7.00 µg/mL in the switching and continuous treatment arms, respectively; adjusted mean AUCτ,30-32 was 2025.8 and 1925.9 µg h/mL. Point estimate for mean ratio for AUCτ,30-32 was 105.2% (90.2% confidence interval [CI] 96.6-114.6), and 101.1% (90.2% CI 93.3-109.7) for Cmax,30-32. Both CIs were within a predefined bioequivalence range of 80.0-125.0%. Treatment-emergent adverse events led to discontinuation in 0.8% and 1.7% of patients in the switching and continuous treatment arms, and Psoriasis Area and Severity Index (PASI) scores were highly similar in the two arms across the entire trial period. CONCLUSIONS: Pharmacokinetic equivalence was demonstrated, with highly similar efficacy and immunogenicity, and comparable safety observed in patients with chronic plaque psoriasis who received either adalimumab RP continuously or who switched between adalimumab RP and BI 695501. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03210259 (registered July 2017); Eudract.ema.europa.eu: 2016-002254-20.

US rheumatologists' beliefs and knowledge about biosimilars: a survey.

OBJECTIVES: We sought to evaluate perceptions of biosimilar products among US rheumatologists who prescribe TNF-α inhibitors, given that 10 TNF-α inhibitor biosimilars and two rituximab biosimilars have Food and Drug Administration (FDA) approval. METHODS: A 19-question self-administered online survey was conducted from 6 May to 1 June 2019, and fielded by WebMD, LLC. Rheumatologists (n = 9050) who were members of Medscape.com and its partner panels were invited to participate. Likert and other rating scales were used to collect responses, which were summarized descriptively. RESULTS: Responses were obtained from 320 board-certified US rheumatologists, 85% of whom were fellows of the ACR. Nearly all respondents were familiar with the FDA definition of a biosimilar product and were aware that an infliximab biosimilar was FDA approved; fewer realized that adalimumab, etanercept and rituximab biosimilars were also FDA approved. Most respondents (84%) were aware that an approved biosimilar was not automatically deemed interchangeable by the FDA. Rheumatologists were more likely to initiate biosimilar treatment for a biologic treatment-naïve patient with RA (73%) than they were to switch to the biosimilar for a patient with RA doing well on the reference product (35%). CONCLUSIONS: The results of this survey suggest that US rheumatologists have a good understanding and acceptance of biosimilar products, particularly for the initiation of treatment in biologic-naïve individuals. They were hesitant to switch from a reference product to a biosimilar for a patient doing well on the reference product. Additional education on biosimilars is required to help inform treatment decisions by rheumatologists. A plain language summary of this article has been uploaded as supplementary material, available at Rheumatology online.

The Importance of Countering Biosimilar Disparagement and Misinformation.

Biosimilar use is limited in some healthcare systems because biosimilars are not well understood by many healthcare professionals and patients. The knowledge gap is exacerbated by disparagement of biosimilars and dissemination of misinformation, whether intentional or otherwise. There are several different types of disparagement and misinformation directed towards biosimilars as a class, including statements about biosimilar science or policy that are factually incorrect; misleading information, where the information is correct, but is provided out of context; incomplete information, where only partial or a limited set of facts are provided; creation of a false narrative, especially in scientific and medical literature, that provides a set of references to support incorrect conclusions; and negative message framing of factual statements to create a negative perception. Disparagement and misinformation about biosimilars can be countered by educational efforts, appropriate oversight, and regulatory activities with the option of enforcement action by governmental agencies, if warranted. Balanced educational materials about biosimilars should be made easily accessible. Physicians, nurses, pharmacists, and patient advocacy groups should work together to provide patients with consistent, positive messages about the value of biosimilars.

Fosdagrocorat (PF-04171327) versus prednisone or placebo in rheumatoid arthritis: a randomised, double-blind, multicentre, phase IIb study.

Objectives: Glucocorticoids have anti-inflammatory, transrepression-mediated effects, although adverse events (AEs; transactivation-mediated effects) limit long-term use in patients with rheumatoid arthritis (RA). We evaluated the efficacy and safety of fosdagrocorat (PF-04171327), a dissociated agonist of the glucocorticoid receptor, versus prednisone or placebo. Methods: In this 12-week, phase II, randomised controlled trial, 323 patients with moderate to severe RA were randomised 1:1:1:1:1:1:1 to fosdagrocorat (1 mg, 5 mg, 10 mg or 15 mg), prednisone (5 mg or 10 mg) or placebo, once daily. The primary endpoints (week 8) were American College of Rheumatology 20% improvement criteria (ACR20) responses, and percentage changes from baseline in biomarkers of bone formation (procollagen type 1 N-terminal peptide [P1NP]) and resorption (urinary N-telopeptide to urinary creatinine ratio [uNTx:uCr]). Safety was assessed. Results: ACR20 responses with fosdagrocorat 10 mg and 15 mg were superior to placebo, and fosdagrocorat 15 mg was non-inferior to prednisone 10 mg (week 8 model-predicted ACR20 responses: 47%, 61%, 69% and 73% vs 51%, 71% and 37% with fosdagrocorat 1 mg, 5 mg, 10 mg and 15 mg vs prednisone 5 mg, 10 mg and placebo, respectively). Percentage changes from baseline in P1NP with fosdagrocorat 1 mg, 5 mg and 10 mg met non-inferiority criteria to prednisone 5 mg. Corresponding changes in uNTx:uCr varied considerably. All fosdagrocorat doses reduced glycosylated haemoglobin levels. AEs were similar between groups; 63 (19.5%) patients reported treatment-related AEs; 9 (2.8%) patients reported serious AEs. No patients had adrenal insufficiency, treatment-related significant infections or laboratory abnormalities. No deaths were reported. Conclusion: In patients with RA, fosdagrocorat 10 mg and 15 mg demonstrated efficacy similar to prednisone 10 mg and safety similar to prednisone 5 mg. Trial registration number: NCT01393639.

Awareness, Knowledge, and Perceptions of Biosimilars Among Specialty Physicians.

INTRODUCTION: The Biosimilars Forum conducted a survey through an independent organization from November 20, 2015 to January 4, 2016 in order to assess current levels of awareness, knowledge, and perceptions of biosimilars among US specialty physicians who already prescribe biologics. The survey was intended to provide a baseline level of knowledge about biosimilars and will be repeated in 2-3 years in order to monitor trends over time. METHODS: A 19-question survey was created by the Biosimilars Forum and was administered by an independent third party. RESULTS: Responses were obtained from 1201 US physicians across specialties that are high prescribers of biologics, including dermatologists, gastroenterologists, hematologist-oncologists, medical oncologists, nephrologists, and rheumatologists. CONCLUSIONS: The results of this survey highlight a significant need for evidence-based education about biosimilars for physicians across specialties. Five major knowledge gaps were identified: defining biologics, biosimilars, and biosimilarity; understanding the approval process and the use of "totality of evidence" to evaluate biosimilars; understanding that the safety and immunogenicity of a biosimilar are comparable to the originator biologic; understanding the rationale for extrapolation of indications; and defining interchangeability and the related rules regarding pharmacy-level substitution. FUNDING: Biosimilars Forum.

Predicting the probability of successful efficacy of a dissociated agonist of the glucocorticoid receptor from dose-response analysis.

PF-04171327 is a dissociated agonist of the glucocorticoid receptor (DAGR) being developed to retain anti-inflammatory efficacy while reducing unwanted effects. Our aim was to conduct a longitudinal dose-response analysis to identify the DAGR doses with efficacy similar to or greater than prednisone 10 mg once daily (QD). The data included were from a Phase 2, randomized, double-blind, parallel-group study in 323 subjects with active rheumatoid arthritis on a background of methotrexate. Subjects received DAGR 1, 5, 10 or 15 mg, prednisone 5 or 10 mg, or placebo QD for 8 weeks. The Disease Activity Score 28-4 calculated using C-Reactive Protein (DAS28-4 CRP) was the efficacy endpoint utilized in this dose-response model. For DAGR, the maximum effect (Emax) on DAS28-4 CRP was estimated to be -1.2 points (95 % CI -1.7, -0.84), and the evaluated dose range provided 31-87 % of the Emax; for prednisone 5 and 10 mg, the estimated effects were -0.27 (95 % CI -0.55, 0.006) and -0.94 point (95 % CI -1.3, -0.59), respectively. Stochastic simulations indicated that the DAGR 1, 5, 10 and 15 mg have probabilities of 0.9, 29, 54 and 62 %, respectively, to achieve efficacy greater than prednisone 10 mg at week 8. DAGR 9 mg estimated probability was 50 % suggesting that DAGR ≥9 mg QD has an effect on DAS28-4 CRP comparable to or greater than prednisone 10 mg QD. This work informs dose selection for late-stage confirmatory trials.

Efficacy of low-dose celecoxib in patients with acute pain.

UNLABELLED: The sore throat pain model was used to evaluate single-dose effects of celecoxib 50 and 100 mg over 6 hours in the treatment of acute pharyngeal pain. Multiple-dose effects of 50-mg bid and 100 mg followed by 50 mg over 6 to 24 hours were also evaluated. Under double-blind, randomized, placebo-controlled conditions, 269 adults with confirmed acute pharyngitis rated throat pain intensity, throat soreness, difficulty swallowing, and sore throat pain relief over 24 hours. For the primary efficacy analysis (SPID2), patients receiving celecoxib 100 mg during the first 2 hours after the first dose had significantly higher mean scores than patients in the placebo group (P < .0003). Efficacy was also demonstrated for celecoxib 50 and 100 mg compared with placebo for all end points (including total pain relief, summed pain intensity differences, total reduction of throat soreness, and difficulty swallowing) at all time points after the first dose and after the second 50-mg dose (P < .01). There were no differences between the dosage regimens, although a supplementary 50-mg dose of celecoxib 6 to 12 hours after the first dose appeared to provide additional efficacy over 24 hours. No serious adverse events (AEs) or discontinuations due to an AE were reported. The results of this study demonstrate that in this pain model, celecoxib is a well tolerated and efficacious analgesic in 50- and 100-mg doses. PERSPECTIVE: In a double-blind, randomized, placebo-controlled trial utilizing the sore throat pain model, low-dose celecoxib (50- and 100-mg doses) was well tolerated and provided effective analgesia in patients with acute pain.

Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To demonstrate the long-term efficacy of anakinra, a human recombinant interleukin-1 receptor antagonist, in patients with rheumatoid arthritis (RA), and to assess the long-term safety of anakinra at different daily doses. METHODS: The efficacy and safety of anakinra were previously demonstrated in a double-blind, placebo-controlled, 24-week evaluation in 472 patients with active RA. Of 345 patients who completed the placebo-controlled phase of the study, 309 continued in a 52-week, multicenter, double-blind, parallel-group extension phase of the study. Patients received subcutaneous injections of anakinra (30, 75, or 150 mg) once daily. Efficacy was assessed among the 309 patients for the first 24 weeks of the extension phase (48 weeks total therapy), using the American College of Rheumatology composite score (ACR20), its components, and radiographs of the hands and wrists. Safety was assessed in all 472 patients over the entire 52-week extension phase (76 weeks total exposure). RESULTS: A total of 218 patients completed the extension phase. Of the 91 patients who withdrew prematurely, 46 did so following adverse events, and 26 withdrew because of lack of efficacy. Among patients receiving anakinra who entered the extension phase, the level of improvement was maintained for 48 weeks. The ACR20 response was 51% at week 24 and 46% at week 48, and this effect was consistent across all dose groups. The durability of the response to anakinra was further demonstrated in an evaluation of the sustained ACR20 response, which was similar during the first and second 24-week periods (36% and 42%, respectively). At week 48, ACR50 and ACR70 responses were demonstrated in 18% and 3% of patients, respectively, who continued taking anakinra (all dose groups) and in 20% and 1% of patients, respectively, who were originally receiving placebo and then were randomized to all doses of anakinra. Anakinra was well tolerated for 76 weeks. The only side effects that appeared to be treatment-related were skin reactions at the injection site. There was no evidence of decreased tolerance, an increased number of withdrawals, or an increased incidence of clinical complications associated with extended anakinra therapy. CONCLUSION: The clinical benefits of treatment with daily self-administered subcutaneous injections of anakinra in a cohort of patients with active RA were maintained for up to 48 weeks. Anakinra was well tolerated over 76 weeks. These observations support the long-term use of anakinra for the treatment of patients with RA.

Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of anakinra in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: Patients with moderate-to-severe active RA who were receiving MTX for 6 consecutive months, with stable doses for > or = 3 months (those with disease duration of >6 months but <12 years) were randomized into 6 groups: placebo or 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg of anakinra administered in a single, daily, subcutaneous injection. The primary efficacy end point was the proportion of subjects who met the American College of Rheumatology 20% improvement criteria (attained an ACR20 response) at week 12. RESULTS: A total of 419 patients were randomized in the study. Patient demographics and disease status were similar in the 6 treatment groups. The ACR20 responses at week 12 in the 5 active treatment plus MTX groups demonstrated a statistically significant (P = 0.001) dose-response relationship compared with the ACR20 response in the placebo plus MTX group. The ACR20 response rate in the anakinra 1.0-mg/kg (46%; P = 0.001) and 2.0-mg/kg (38%; P = 0.007) dose groups was significantly greater than that in the placebo group (19%). The ACR20 responses at 24 weeks were consistent with those at 12 weeks. Similar improvements in anakinra-treated subjects were noted in individual ACR components, erythrocyte sedimentation rate, onset of ACR20 response, sustainability of ACR20 response, and magnitude of ACR response. Anakinra was safe and well tolerated. Injection site reaction was the most frequently noted adverse event, and this led to premature study withdrawal in 7% (1.0-mg/kg group) to 10% (2.0-mg/kg group) of patients receiving higher doses. CONCLUSION: In patients with persistently active RA, the combination of anakinra and MTX was safe and well tolerated and provided significantly greater clinical benefit than MTX alone.