Fenebrutinib Versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double‐Blind, Phase <scp>II</scp> Trial

Fenebrutinib Versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double‐Blind, Phase II Trial

Arthritis & Rheumatology (2020)

Stanley Cohen Katie Tuckwell Tamiko R. Katsumoto Rui Zhao Joshua Galanter Chin Lee Julie Rae Balázs I. Tóth Nandhini Ramamoorthi Jason A. Hackney Alberto Berman Nemanja Damjanov D. Fedkov Sławomir Jeka Leslie W. Chinn Michael J. Townsend Alyssa Morimoto Mark C. Genovese

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Background

Adalimumab, an anti-TNF-α monoclonal antibody, is effective in active rheumatoid arthritis (RA). There is a relationship between adalimumab concentration and clinical response but it has never been quantified individually.

Objectives

To describe the individual relationship between adalimumab concentration and disease activity in RA patients and to select an adalimumab target concentration necessary to reach either a low disease activity or clinical remission.

Methods

We measured adalimumab concentration in 127 samples from 30 RA patients who received 40 mg subcutaneously every other week. Disease activity score (DAS 28) were available at baseline, and at weeks 6, 12, 24 and 52. The relationship between adalimumab concentrations and DAS 28 was described by pharmacokinetic-pharmacodynamic (PK-PD) modelling using a direct inhibitory model.

Results

Median adalimumab concentrations increased over all the year whereas median DAS 28 decreased. At steady state, median adalimumab concentration [min-max] was 7.8 mg/L [1.8-15.0] and median DAS 28 was 2.9 [0.8-6.3]. The concentration-response relationship of adalimumab was well described by the direct inhibitory model. For a typical patient, adalimumab concentration required to decrease baseline DAS28 by 2 was 11.8 mg/L. The relationship between baseline DAS 28 and adalimumab concentration at steady state is displayed in figure 1. It shows that, if baseline DAS 28 is 6, the steady state adalimumab concentration necessary to achieve a low disease activity is 10 mg/L with 25%>75% confidence interval of 5-20 mg/L. To achieve remission, the required adalimumab concentration is 15 mg/L [8-30 mg/L].

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Conclusions

This is the first study describing the individual concentration-effect relationship of adalimumab in RA. This model can be used to select the target concentration of adalimumab when therapeutic drug monitoring is applied.

Acknowledgements

Pr. Christian Marcelli. CHU Caen, Pr. René-Marc Flipo. CHU Lille, Pr. Patrice Fardellone. CHU Amiens

Disclosure of Interest

None Declared

Pharmacodynamics

Therapeutic Drug Monitoring

10.1136/annrheumdis-2013-eular.1292

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Adalimumab for Crohn's disease in New Zealand--a prospective multicentre experience.

PubMed (2014)

Gareth Thomas Timothy Lewis-Morris David Rowbotham Cathryn Whiteside Stephne Joyce

Adalimumab is an effective treatment for Crohn's disease (CD). We aimed to describe the early patterns of use, efficacy and response to adalimumab in four regions of New Zealand.Prospectively collected CDAI data were used to examine adalimumab continuation rates in CD patients. Reasons for adalimumab cessation were determined and phenotypic characteristics of those remaining on adalimumab were examined.194 patients (100 female) from four centres were included. Indications for adalimumab included CDAI>300 (59.8%), extensive small intestinal disease (21.1%), stoma with active disease (4.6%), risk of short gut syndrome (7.7%) and other (6.7%). The mean follow-up was 20 months (252.8 patient years of data). Adalimumab continuation rates at 6, 12, 24 and 30 months were 92.7%, 87.3%, 76.6% and 67.4%, respectively. Patients with penetrating disease behaviour were more likely to continue on adalimumab (p<0.005). There was a significant reduction in mean CDAI from 357 to 110 (p<0.0001) over a 6-month period. The mean (range) number of days spent in hospital per patient in the year prior and after adalimumab initiation were 3.5 (0-38) days and 1.9 (0-67) days, respectively (p<0.0001).Adalimumab continuation rate in this multicentre CD population was higher than other populations. This may be due to adalimumab being used more commonly as the initial biologic drug in New Zealand.

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Adalimumab in the treatment of rheumatoid arthritis

World Clinical Drugs (2012)

Wang Niansong

Biological agents for the treatment of rheumatic diseases have made a major breakthrough over the past decade.Since the discovery of adalimumab,a tumor necrosis factor(TNF)-α inhibitor,the rheumatoid arthritis therapy has been made significant progress.This article reviews related progress in the treatment of rheumatoid arthritis with adalimumab.

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P607 Higher adalimumab serum levels do not increase the risk of adverse events in patients with inflammatory bowel disease

Journal of Crohn s and Colitis (2019)

Neeraj Narula Brian Lauzon J Marshall

The relationship between serum adalimumab concentrations and adverse events in patients with inflammatory bowel disease (IBD) is unknown. We aimed to determine whether patients with IBD using adalimumab are at increased risk of adverse events if they have high adalimumab serum levels compared with those with lower adalimumab levels. This was a retrospective study of 133 IBD patients with at least one measurement of serum adalimumab level available. The cohort was divided according to the median adalimumab level of 9.8 μg/ml. The primary outcome was the rate of overall adverse events between the two groups. Secondary outcomes included the rate of infections, dermatologic reactions, injection-site reactions, and other adverse events in both groups. Rates of discontinuation of adalimumab due to adverse events was also evaluated. Multi-variate logistic regression analysis was also performed to evaluate the relationship between adalimumab levels and adverse events. A total of 27 adverse events were reported in 133 patients in the overall cohort. In patients with higher adalimumab levels, there were 17 adverse events reported in a total of 66 patients, which was not significantly different than the 10 adverse events reported in 67 patients with lower adalimumab levels (25.7% vs. 14.9%, p = 0.12). Stratification of patients into adalimumab level tertiles did not show any difference in the rate of adverse events between the three groups. After adjustment for potential covariates, IBD patients with higher adalimumab levels did not have higher odds of an adverse event than patients with lower levels (OR 1.94, 95% CI 0.81–4.64). There does not appear to be an increased risk of adverse events in IBD patients with higher adalimumab levels.

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10.1093/ecco-jcc/jjy222.731

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THU0211 Six months after treatment discontinuation tnf is still in complex with adalimumab

Annals of the Rheumatic Diseases (2018)

M. l’Ami Lea C. Berkhout Michael T. Nurmohamed Ronald van Vollenhoven Maarten Boers

Background

Many patients with rheumatoid arthritis (RA) are successfully treated with tumour necrosis factor inhibitors (TNFi). We recently developed a novel assay that can quantify TNF in the presence of large amounts of TNFi, i.e. a 'drug-tolerant' assay. We showed in RA patients that TNF levels increased and stabilised during adalimumab treatment due to complex forming between TNF and adalimumab. In the presence of adalimumab, all TNF was in complex and biologically inactive. Once in remission, some patients can discontinue the TNFi for a prolonged period. It is unclear how long adalimumab levels are detectable and TNF complexes are formed after the last adalimumab administration.

Objectives

To investigate adalimumab levels and complexed TNF levels 6 months after the last adalimumab administration.

Methods

TNF and adalimumab levels were measured using a novel drug-tolerant competition enzyme-linked immunosorbent assay (ELISA), and a regular ELISA, respectively, in 11 consecutive RA patients with stable low disease activity (disease activity score of 28 joints<3.2) who discontinued adalimumab for 6 months (prior dose: 40 mg every 2 weeks). Blood samples were drawn prior to adalimumab discontinuation and 3 and 6 months thereafter.

Results

After the last adalimumab administration, mean adalimumab level decreased from 5.5 (SD 2.9) to 0.55 (0.52) and 0.11 (0.13) μg/mL at 3 and 6 months after treatment discontinuation, respectively (figure 1A). In contrast, complexed TNF levels remained stable for prolonged periods of time: in 8 patients TNF levels at 3 months were indistinguishable from levels seen at baseline, on standard-dose adalimumab (figure 1B). After 6 months, TNF still remained stable in patients with adalimumab concentrations above 0.1 µg/mL (n=4). Overall, mean TNF levels decreased from median 381 (inner quartiles 16; 707) to 290^{2; 755} and 83^{2; 532} pg/mL at 3 and 6 months after treatment discontinuation, respectively. In 5 patients, TNF levels decreased significantly. In those patients, adalimumab levels dropped to, or below the detection limit.

Conclusions

This is the first study showing that TNF is still in complex with adalimumab in the majority of patients 6 months after the last administration. Therefore, one may wonder at which point in time a patient has truly discontinued adalimumab treatment.

Disclosure of Interest

M. l'Ami: None declared, L. Berkhout: None declared, M. Nurmohamed Grant/research support from: Pfizer, AbbVie, Roche, BMS, MSD, Mundipharma, UCB, Janssen, Menarini, Eli Lilly, Sanofi, and Celgene, Speakers bureau: Pfizer, AbbVie, Roche, BMS, MSD, Mundipharma, UCB, Janssen, Menarini, Eli Lilly, Sanofi, and Celgene, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, UCB, Consultant for: AbbVie, AstraZeneca, Biotest, BMS, Celgene, GSK, Janssen, Lilly, Novartis, Pfizer, UCB, M. Boers: None declared, J. Ruwaard: None declared, F. Hooijberg: None declared, T. Rispens Grant/research support from: Genmab, Speakers bureau: Pfizer, AbbVie and Regeneron, G. Wolbink Speakers bureau: Pfizer, UCB, AbbVie, Biogen, BMS

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TNF inhibitor

10.1136/annrheumdis-2018-eular.5526

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Safety of Placebo Controls in Pediatric Hypertension Trials

Hypertension (2008)

P. Brian Smith Jennifer S. Li M. Dianne Murphy Robert M. Califf Daniel K. Benjamin

Many clinical trials, including those in pediatric populations, use a placebo arm for medical conditions for which there are readily available therapeutic interventions. Several short-term efficacy trials of antihypertensive medications performed in response to Food and Drug Administration–issued written requests have used a placebo arm; whether the use of a placebo arm is safe in children with hypertension is unknown. We sought to define the rates of adverse events in 10 short-term antihypertensive trials to determine whether these trials resulted in increased risk to pediatric patients receiving placebo. We combined patient-level data from 10 antihypertensive efficacy trials performed in pediatric patients that were submitted to the Food and Drug Administration from 1998 to 2005. We determined the number and type of all of the adverse events reported during the placebo-controlled portion of the clinical trials and compared these numbers between the patients who received placebo and those who received active drug. Among the 1707 children in the 10 studies, we observed no differences in the rates of adverse events reported between the patients who received placebo and those who received active drug. Only 5 patients suffered a serious adverse event during the trials; none were thought by the investigators to be related to study drug, and only 1 occurred in a patient receiving placebo. Short-term exposure to placebo in pediatric trials of antihypertensive medications appears to be safe.

10.1161/hypertensionaha.107.104950

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강직성 척추염 환자에서 Adalimumab 치료 후 관찰된 천장관절염의 회복 1예 Running title: 강직성 척추염에서 Adalimumab 치료와 천장관절염의 회복

전북의대논문집 (2012)

강성욱 김대호 홍성훈 정상완 김소미

강직성 척추염은 몸통 뼈대와 큰 말초 관절 그리고 근육힘줄뼈 부착부위에 발생하는 만성 염증성 류마티스 질환이다. Adalimumab은 anti-tumor necrosis factor(TNF) 중 하나로 강 직성 척추염의 치료에 투여한다. Adalimumab 이 강직성 척추염의 징후와 증상의 치료에 효과적이기는 하지만, 강직성 척추염 환자에 서 뼈의 발생 혹은 재형성과 TNF 사이의 뚜렷한 연관성은 아직 밝혀지지 않았다. 그 리고adalimumab 치료 후에 이전에 손상되었던 천장관절의 회복이 영상의학적으로 증명 된 적은 극히 드물다. 여기서 우리가 소개하는 29세 남자는 이전에 천장관절의 염증성 변화를 보이는 강직성 척추염을 진단 받았던 자로, adalimumab 치료 전후에 영상의학적 변화를 비교해 보았다. 컴퓨터 단층촬영 영 상에서 adalimumab 치료 후 양측 천장관절 의 관절강이 좁아진 소견없이 미란성 변화들 이 거의 회복된 것을 볼 수 있었다. 이것은 adalimumab 치료 후에 강직성 척추염의 징 후 와 증상의 호전뿐만 아니라 이와 함께 천 장관절의 골미란이 관절강이 좁아지는 소견 없이 회복된 첫 번째 증례라고 할 수 있다.

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

Dermatology and Therapy (2023)

Alan Menter

This Summary of Research overviews the results of the VOLTAIRE-X study (NCT03210259), which looked at what happened when people with plaque psoriasis continually took the adalimumab reference product (adalimumab RP; known by the brand name Humira

Biosimilar

10.1007/s13555-023-00995-z

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Higher adalimumab serum levels do not increase the risk of adverse events in patients with inflammatory bowel disease

Scandinavian Journal of Gastroenterology (2019)

Neeraj Narula Brian Lauzon John K. Marshall

Background: The relationship between serum adalimumab concentrations and adverse events in patients with inflammatory bowel disease (IBD) is unknown. We aimed to determine whether patients with IBD using adalimumab are at increased risk of adverse events if they have higher adalimumab serum levels compared to those with lower adalimumab levels.Methods: This was a retrospective study of 191 IBD patients with at least one serum adalimumab level measurement available. The cohort was divided using a cutoff level of 10 mcg/mL. The primary outcome was the rate of overall adverse events between the two groups. Secondary outcomes included rate of infections, dermatologic reactions, injection-site reactions and other adverse events in both groups. Rates of discontinuation of adalimumab due to adverse events were evaluated. Multivariate logistic regression analysis was performed to evaluate the relationship between adalimumab levels and adverse events.Results: A total of 41 adverse events were reported in 191 patients in the overall cohort. Among 86 patients with higher adalimumab levels, 22 adverse events were reported, vs. 19 adverse events among 105 patients with lower adalimumab levels (25.6% vs. 18.1%, p = .21). Analysis according to adalimumab level tertiles also did not show significant differences in the rates of adverse events. A multivariate forward selection model also did not find higher odds of an adverse event in IBD patients with higher adalimumab levels compared to lower levels (OR 1.54, 95% CI 0.77–3.08).Conclusions: There does not appear to be a relationship between adalimumab exposure and risk of adverse events in IBD patients.

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10.1080/00365521.2019.1621367

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