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Adalimumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetTNF alpha
Clinical data
Trade namesHumira
Other namesD2E7
Biosimilarsadalimumab-aacf,[1] adalimumab-aaty,[2] adalimumab-adaz,[3] adalimumab-adbm,[4] adalimumab-afzb,[5] adalimumab-aqvh,[6] adalimumab-atto,[7] adalimumab-bwwd,[8] adalimumab-fkjp,[9] adalimumab-ryvk,[10] Abrilada,[11] Amgevita,[12] Amsparity,[13] Ardalicip,[14] Cadalimab,[15] Ciptunec,[14] Cyltezo,[16] Exemptia,[17] Hadlima,[8] Halimatoz,[18] Hefiya,[19] Hukyndra,[20] Hulio,[21] Hyrimoz,[22] Idacio,[23] Imraldi,[24] Kromeya,[25] Libmyris,[26] Mabura, Simlandi,[27][10] Solymbic,[28] Trudexa,[29] Yuflyma,[2][30] Yusimry[6]
AHFS/Drugs.comMonograph
MedlinePlusa603010
License data
Pregnancy
category
Routes of
administration		Subcutaneous
Drug classTNF inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability64% (subcutaneous), 0% (by mouth)
Elimination half-life10–20 days
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
ECHA InfoCard100.224.376 Edit this at Wikidata
Chemical and physical data
FormulaC6428H9912N1694O1987S46
Molar mass144190.64 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Adalimumab, sold under the brand name Humira and others, is a disease-modifying antirheumatic drug and monoclonal antibody used to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, and uveitis.[43][44][45] It is administered by subcutaneous injection (injection under the skin).[43] It works by inactivating tumor necrosis factor-alpha (TNFα).[43]

Common side effects include upper respiratory tract infections, pain at the site of injection, rash, and headache.[43] Other side effects may include serious infections, cancer, anaphylaxis, reactivation of hepatitis B, new onset or exacerbation of demyelinating diseases (such as multiple sclerosis), heart failure, liver failure, and aplastic anemia.[43] Use during pregnancy is not recommended, but some sources show use during breastfeeding may be safe.[31][44]

Adalimumab was approved for medical use in the United States in 2002.[43][46] It is on the World Health Organization's List of Essential Medicines.[47] It is available as a biosimilar medication.[48] In 2023, it was the 244th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[49][50]

Medical uses

[edit]

In the US and the EU, adalimumab is indicated for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult and pediatric Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, and uveitis.[41][51][42] In the EU it is also indicated for chronic aggressive progressive pulmonary and bone sarcoidosis.[42]

Rheumatoid arthritis

[edit]

Adalimumab has been shown to reduce the signs and symptoms of moderate to severe rheumatoid arthritis in adults. It may be used alone or in combination with disease-modifying antirheumatic drugs.[52] It has also been shown to have efficacy in moderate to severe polyarticular juvenile idiopathic arthritis in children four years and older, and is indicated for the treatment of that condition. In rheumatoid arthritis, it is indicated for use alone, or with methotrexate or similar medicines, in the United States since 2002.[53] It has a similar effectiveness as methotrexate and, in combination, nearly doubles the response rate of methotrexate alone.[54]

Juvenile idiopathic arthritis

[edit]

Adalimumab has been shown to reduce the signs and symptoms of moderate to severe polyarticular juvenile idiopathic arthritis in children aged four years and older.[55][56][57]

Ankylosing spondylitis

[edit]

Adalimumab has been shown to reduce the signs and symptoms of, and is approved for treatment for, ankylosing spondylitis in adults.[58]

Crohn's disease

[edit]

Adalimumab has been shown to reduce the signs and symptoms of moderate to severe Crohn's disease.[48][59][60] It has been approved for that use in the UK since 2009.[61]

Ulcerative colitis

[edit]

Adalimumab may be effective and well tolerated in ulcerative colitis. It was approved by the US Food and Drug Administration (FDA) for treatment of moderate to severe cases in adults.[62][63]

Plaque psoriasis

[edit]

Adalimumab has been shown to treat moderate to severe chronic plaque psoriasis in adults who have the condition in many areas of their body and who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).[64] Adalimumab has been shown to be effective therapy when used either continuously or intermittently in patients with moderate to severe psoriasis.[65]

Hidradenitis suppurativa

[edit]

Adalimumab was approved for hidradenitis suppurativa in 2015.[45][66][67]

Non-infectious uveitis

[edit]

Adalimumab is indicated for the treatment of non-infectious uveitis (inflammation of the layer beneath the white of the eyeball).[41][42]

Mechanism of action

[edit]

Adalimumab is a monoclonal antibody. It works by binding to and inhibiting Tumor necrosis factor alpha (TNF-alpha) and inducing apoptosis in mononuclear cells expressing TNF.[68]

Adverse effects

[edit]

The US FDA label contains a boxed warning about serious infections and malignancies.[41]

There is strong evidence that adalimumab increases risk of serious infections, such as tuberculosis, and it has also been reported to increase the risk of developing various cancers.[69] However, such an association may reflect an increased risk of developing malignancies inherent in the conditions being treated, and not with adalimumab itself. A systematic review published in 2018, found no increased cancer incidence rate in patients with chronic inflammatory disorders treated with adalimumab and other TNF inhibitors, as compared to those who were not, with a possible exception for non-melanoma skin cancer.[70]

Injection site reactions such as redness and pain are very common, and may occur in up to 80% of cases.[71]

History

[edit]

Adalimumab was the first fully human monoclonal antibody approved by the US Food and Drug Administration (FDA).[72] It is derived from phage display.[72][73]

Adalimumab was discovered as a result of a collaboration between BASF Bioresearch Corporation and Cambridge Antibody Technology, U.K., itself a collaboration of the government-funded Medical Research Council and three academics, which began in 1993.[72][74]

Initially named D2E7,[75] it was then further manufactured at BASF Bioresearch Corporation, developed by BASF Knoll (BASF Pharma), and ultimately manufactured and marketed by Abbott Laboratories after Abbott's acquisition of BASF Pharma. On 1 January 2013, Abbott split into two companies, one retaining the Abbott name and the other named AbbVie.[76] As a result, AbbVie took over development and marketing of Humira.[77][78] The brand name Humira stands for "human monoclonal antibody in rheumatoid arthritis", and was named by one of Abbott's employees, Richard J. Karwoski, who was also responsible for leading the effort to get Humira approved by the FDA.

It is the third TNF inhibitor, after infliximab and etanercept, to be approved in the United States.[72] It is constructed from a fully human monoclonal antibody, while infliximab is a mouse-human chimeric antibody[79] and etanercept is a TNF receptor-IgG fusion protein.[80]

The drug candidate was discovered initially using CAT's phage display technology and named D2E7.[75] The key components of the drug were found by guiding the selection of human antibodies from phage display repertoires to a single epitope of an antigen TNF alpha.[81] The ultimate clinical candidate, D2E7, was created and manufactured at BASF Bioresearch Corporation and taken through most of the drug development process by BASF Knoll, then further development, manufacturing and marketing by Abbott Laboratories, after Abbott acquired the pharmaceutical arm of BASF Knoll.[82]

Since 2008, adalimumab had been approved by the FDA for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, moderate to severe chronic psoriasis and juvenile idiopathic arthritis. Although only approved for ulcerative colitis from late 2012, by the FDA in the disease's management, it had been used for several years in cases that have not responded to conventional treatment at standard dosing for Crohn's disease.[citation needed]

Adalimumab, sold under the brand name Humira, was approved for use in the United States in 2002.[46][83]

Adalimumab, sold under the brand names Humira and Trudexa, was approved for use in the European Union in September 2003.[42][84]

Research

[edit]
  • 1999: Preliminary results of early clinical trials with the fully human anti-TNFα monoclonal antibody D2E7[75]
  • 2001, June: Results from ARMADA, a double-blind, placebo-controlled clinical trial involving 271 patients with active rheumatoid arthritis despite treatment with methotrexate are announced. Results show that 50% of patients demonstrate a 50% improvement in American College of Rheumatology (ACR) score.[85]
  • 2002: Broke ground on a new biologics manufacturing facility.[86]
  • 2002: Adalimumab results from five separate trials show that it is effective at reducing signs and symptoms of rheumatoid arthritis and had a rapid onset of action and sustained efficacy. Adalimumab was safe and effective when given alone or in combination with MTX as a subcutaneous injection.[87]
  • 2002: Humira approved by the US Food and Drug Administration (FDA) for treatment of rheumatoid arthritis.[86]
  • 2003: Launched Humira for rheumatoid arthritis and continued clinical studies for additional indications.[86]
  • 2005: Launched Humira for psoriatic arthritis. Exceeded US$1 billion in annual sales for the first time.[86]
  • 2005: Eisai submits new drug application for adalimumab (D2E7) in Japan.[88]
  • 2006: Submitted Humira for the Crohn's disease indication and launched it for AS. Exceeded US$2 billion in annual sales.[86]
  • 2007: Launched Humira for Crohn's disease in the United States,[86] submitted Humira for global regulatory approval for psoriasis — the fifth Humira disease indication, achieved more than US$3 billion in worldwide Humira sales.[89]
  • 2007: Abbott opens new biotechnology manufacturing facility in Puerto Rico[90]
  • 2008: Launched Humira for plaque psoriasis[91]
  • 2009: Five-Year data demonstrate initial use of humira plus methotrexate may prevent further joint damage in early rheumatoid arthritis patients [92][93]
  • 2012: Humira could be associated with a significant decrease in vascular inflammation, a major risk factor of cardiovascular disease[94]
  • 2013: Because of the split of Abbott, Humira rights are now owned by AbbVie.[76][77]
  • 2014: Humira recognized by IMS Health as the "world's best selling drug".[95]
  • 2014: In December 2014, Indian drugmaker Cadila Healthcare declared the launch of the first adalimumab biosimilar at a fifth of its US price. The generic was launched under the brand name Exemptia.[96]
  • 2015: Launched Humira for moderate to severe hidradenitis suppurativa, an orphan indication. No other treatment has been[when?] rigorously tested and found to be safe and effective in treating this condition.[45]

Society and culture

[edit]

Economics

[edit]

The UK NHS in 2019 listed Humira, Amgevita, Hulio, Hyrimoz, Idacio, and Imraldi as biosimilars available on (almost free) prescription, to be updated in February 2022.[97] The annual cost of adalimumab, the costliest NHS drug, was expected to drop from £400m to £100m by 2021, the biggest saving in NHS history from a single drug negotiation.[98]

The best-selling drugs list published by Genetic Engineering & Biotechnology News, shows that Humira occupied the #1 position for 2015 (US$14.012 billion) and 2016 (US$16.078 billion)[99] From 2012 until the US patent expired in 2016, Humira led the list of top-selling pharmaceutical products, and in 2016, it had US$16 billion of global sales.[99] AbbVie reported that Humira achieved US$18.427 billion of sales in 2017.[100] Humira had the largest worldwide drug sales in 2019 and 2020 of US$19.7bn and US$20.4bn respectively.[101]

Biosimilars

[edit]
See also: Biosimilars

From 2014, biosimilars were manufactured by several companies and sold at a lower price than before patent expiry.[96]

In 2014, Indian drugmaker Cadila Healthcare declared the launch of the first adalimumab biosimilar at a fifth of its US price. The generic was launched under the brand name Exemptia.[96] In 2016, Indian drugmaker Torrent Pharmaceuticals launched its biosimilar for adalimumab, called Adfrar. It is the second generic biosimilar of adalimumab.[102]

In September 2016, the FDA approved Amgen's biosimilar adalimumab-atto, sold under the brand name Amjevita.[7][103][104][105][106][107]

In August 2017, the FDA approved German pharmaceutical company Boehringer Ingelheim's biosimilar, Cyltezo.[4][103][108][109][110][111]

In 2017, the biosimilars Amgevita,[12] Solymbic,[28] Imraldi,[24] and Cyltezo[16] were approved for use in the European Union.

In 2018, the biosimilars Halimatoz,[18] Hefiya,[19] Hyrimoz,[22] and Hulio[21] were approved for use in the European Union.

From 2018, Adalimumab biosimilars became available in the European Union,[112] allowing the National Health Service to make record-breaking cost-savings,[113] as this is the single most expensive drug used in NHS hospitals, costing more than £400 million a year for about 46,000 patients.[114]

In October 2018, adalimumab-adaz (Hyrimoz) was approved for use in the United States.[3][103][115]

In April 2019, Idacio[23] and Kromeya[25] were approved for use in the European Union.

In July 2019, adalimumab-bwwd (Hadlima), produced by Samsung Bioepsis, was approved for use in the US.[8][103][116][117]

In November 2019, adalimumab-afzb (Abrilada) was approved in the United States.[5][103][118][119][120] It is the 25th biosimilar approved by the FDA.[121]

In February 2020, the biosimilar Amsparity was approved for use in the European Union.[13]

In June 2020, the biosimilar Idacio was approved for use in Australia.[36]

In July 2020, adalimumab-fkjp (Hulio) was approved for use in the United States.[9][103][122]

In August 2020, the biosimilar Cadalimab was launched in India by Cadila Pharmaceuticals.[15][123]

In October 2020, Idacio was approved for medical use in Canada.[124]

In November 2020, Amgevita, Hulio, and Hyrimoz were approved for medical use in Canada.[125][126][127]

In February 2021, Yuflyma was approved for medical use in the European Union.[30]

In January 2021, Abrilada was approved for medical use in Canada.[11]

In November 2021, the biosimilars Libmyris and Hukyndra were approved for medical use in the European Union.[26][20]

In December 2021, adalimumab-aqvh (Yusimry) was approved for medical use in the United States.[6][103][128]

In December 2021, Yuflyma was approved for medical use in Canada.[129]

In January 2022, Simlandi was approved for medical use in Canada.[27][130]

In December 2022, Adalimumab-aacf (Idacio) was approved for medical use in the United States.[1][103][131]

In January 2023, the CHMP recommended that the high-concentration 100mg/ml Hyrimoz biosimilar be granted a pan-European marketing authorization for all indications covered by the reference medicine, including Crohn's disease, plaque psoriasis, ulcerative colitis, rheumatoid arthritis and uveitis.[132]

In January 2023, Simlandi was approved for medical use in Saudi Arabia.[133]

In May 2023, Adalimumab-aaty (Yuflyma) was approved for medical use in the United States.[2][103][134][135]

In July 2023, when Humira's regulatory exclusivity lapsed, a number of biosimilars such as Hadlima, Hyrimoz, Cyltezo, and Celltrion were launched in the US.[103][136][137][138]

In February 2024, adalimumab-ryvk (Simlandi) was approved for medical use in the United States.[103][139][10]

Royalty litigation

[edit]

In March 2003, Cambridge Antibody Technology (CAT) stated its wish to "initiate discussions regarding the applicability of the royalty offset provisions for Humira" with Abbott Laboratories in the High Court of London. In November 2004, the trial began, and in December 2004, Justice Hugh Laddie ruled for CAT.

A short version of the full statement of the proceedings was released.[140] In it Justice Laddie remarked, "Abbott was in error when it made its first royalty payment to CAT calculated on the basis that only 2% of the Net Sales was due. It should have calculated on the basis of the full royalty of just over 5% and should have paid and continued to pay CAT accordingly." Justice Laddie went on to observe "...that the construction advanced by Abbott does violence to the language of the agreements, renders them obscure and makes little or no commercial sense. For this reason CAT wins the action."[141]

Abbott was required to pay CAT US$255 million, some of which was to be passed to its partners in development.[142] Of this sum, the Medical Research Council received US$191 million, and in addition, Abbott was asked to pay the MRC a further US$7.5 million over five years from 2006, providing that Humira remains on the market. The MRC also is to receive a further £5.1 million (sterling) in respect of past royalties.[143]

Patent litigation

[edit]

In May 2009, Johnson & Johnson's Centocor unit, the maker of infliximab, won a ruling for $1.67 billion from Abbott Laboratories for patent infringement on the process for making Humira.[144][145] However, in 2011, the judgment was overturned by the United States Court of Appeals for the Federal Circuit.[146][147] In June 2020, a class action lawsuit filed by United Food and Commercial Workers Local 1500 (UFCW Local 1500) against AbbVie, alleging that the drug manufacturer used a patent thicket over 100 strong to maintain a monopoly on Adalimumab, was dismissed by the Northern District Court in Illinois.[148] The dismissal was affirmed by the Seventh Circuit Court of Appeals on 1 August 2022.[149]

AbbVie has extensively used the US patent system to delay competitors from entering the market, a process commonly known as "evergreening".[150] It filed 311 patents for Humira, of which 165 were granted. AbbVie sued Amgen, the manufacturer of Amjevita, in 2016 for violating 10 of its patents. Amgen agreed to delay sales until 2023, which allowed AbbVie to drive up prices of Humira. Between 2016 and 2023, the price of Humira went up by 60%, during which time AbbVie made $114 billion in revenue from Humira.[151]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Adalimumab

View on Grokipedia
from Grokipedia
Adalimumab is a recombinant fully human monoclonal antibody that specifically binds to alpha (TNF-α), a pro-inflammatory central to the of various autoimmune and inflammatory conditions. Administered subcutaneously, it neutralizes soluble and membrane-bound TNF-α, thereby disrupting downstream inflammatory signaling pathways without directly causing cell death. Marketed as Humira by , it was first approved by the U.S. in December 2002 for reducing signs and symptoms, inducing major clinical response, inhibiting structural damage progression, and improving physical function in adults with moderately to severely active , either as monotherapy or in combination with or other non-biologic disease-modifying antirheumatic drugs. Subsequent approvals expanded its indications to include polyarticular , , , adult , , moderate to severe plaque , , and , reflecting its broad utility in TNF-α-mediated diseases. Clinical studies, including randomized controlled trials, have shown adalimumab to achieve significant reductions in disease activity scores, remission rates, and radiographic progression in and similar conditions, often outperforming and comparable to other TNF inhibitors in head-to-head comparisons. Its efficacy stems from high-affinity binding to TNF-α, preventing interaction with receptors p55 and p75, which causal mechanisms link to reduced cascades, leukocyte migration, and tissue damage in empirical models of . Despite these benefits, adalimumab's immunosuppressive effects elevate risks of serious infections, including bacterial , opportunistic fungal infections, and reactivation of , necessitating screening and prophylaxis in at-risk patients; reactions, malignancy (e.g., ), and demyelinating disorders have also been observed in post-marketing surveillance. As the world's top-selling drug for over a , it generated approximately $200 billion in global revenue by 2022, a figure attributable to AbbVie's strategy of amassing over 100 s—often termed a "patent thicket"—covering formulations, manufacturing processes, and methods of use, which delayed U.S. competition until 2023 despite earlier European approvals. This approach, involving litigation against multiple developers, has been empirically linked to prolonged market exclusivity and elevated prices, though it secured exclusivity under biologic laws; entry has since introduced alternatives, potentially lowering costs but facing ongoing disputes.

Pharmacology

Mechanism of action

Adalimumab is a fully human recombinant of the immunoglobulin G1 (IgG1) subclass that specifically targets alpha (TNF-α), a pro-inflammatory central to immune dysregulation in various autoimmune conditions. It binds with high affinity ( approximately 6 × 10^{-11} M) to both the soluble and transmembrane forms of TNF-α, forming stable complexes that prevent the cytokine from engaging its cognate receptors. This binding neutralizes TNF-α's biological activity by competitively inhibiting its interaction with (TNFR1, p55) and TNFR2 (p75) on cell surfaces, thereby disrupting ligand-induced receptor trimerization and activation. The blockade of TNF-α signaling cascades inhibits multiple downstream inflammatory processes, including the of nuclear factor kappa B (NF-κB) pathway, which normally translocates to the nucleus upon receptor ligation to promote transcription of genes encoding additional (e.g., interleukin-1 and interleukin-6), adhesion molecules, and matrix metalloproteinases. studies using human cell lines, such as endothelial cells and fibroblasts, have demonstrated that adalimumab reduces TNF-α-induced NF-κB nuclear translocation and subsequent production, confirming its capacity to attenuate acute responses at the molecular level. Animal models of further corroborate this, showing decreased endothelial and leukocyte recruitment following adalimumab administration. Adalimumab's specificity for TNF-α distinguishes it from non-selective immunosuppressants, as it does not directly interfere with other cytokine pathways (e.g., IL-6 or IFN-γ signaling), allowing targeted modulation in TNF-driven pathologies while preserving broader immune competence. Additionally, as an IgG1 antibody, adalimumab can mediate (ADCC) and (CDC) against cells expressing membrane-bound TNF-α, such as activated monocytes and lymphocytes, contributing to the lysis of TNF-producing cells . This dual mechanism—neutralization plus effector functions—underpins its efficacy without inducing global T-cell or B-cell suppression observed with agents like corticosteroids.

Pharmacokinetics and pharmacodynamics

Adalimumab is administered via subcutaneous injection, with an absolute of approximately 64% following a single 40 mg dose. Peak serum concentrations are achieved at a mean time of 131 hours (range 56–264 hours), with maximum levels around 4.7 μg/mL in healthy . The demonstrate linearity across doses from 0.5 to 10 mg/kg after intravenous administration, extending to subcutaneous regimens that support fixed dosing such as 40 mg every two weeks for steady-state exposure. Systemic clearance averages 12 mL/h, and the volume of distribution approximates the vascular compartment due to its high molecular weight. The steady-state elimination ranges from 10 to 20 days, enabling biweekly or less frequent dosing while maintaining therapeutic concentrations. occurs primarily through proteolytic via reticuloendothelial clearance, with no involvement of enzymes. Elimination is influenced by factors such as body weight, where higher mass correlates with increased clearance, and the development of anti-drug antibodies, which can accelerate clearance by up to twofold and reduce serum exposure by neutralizing the drug or enhancing its immunogenicity-mediated removal. Pharmacokinetic concentrations of adalimumab are typically measured using sandwich ELISA assays with TNF-α as the capture reagent and an anti-human IgG Fc-specific antibody (often HRP-conjugated) as the detection reagent. Fcγ receptors are not commonly used for detection in standard PK assays but are relevant for functional assays or Fcγ receptor binding studies. Pharmacodynamically, adalimumab's extended facilitates prolonged neutralization of soluble and membrane-bound TNF-α, with suppression durations aligning with its pharmacokinetic profile to sustain effects over 2–4 weeks per dose. This temporal correlation supports dose-response relationships observed in early-phase trials, where steady-state concentrations above 5 μg/mL were associated with maximal TNF inhibition and downstream reductions persisting through dosing intervals. Concomitant use mitigates anti-drug formation, preserving pharmacokinetic stability and enhancing pharmacodynamic consistency by minimizing clearance variability.

Clinical indications and efficacy

Rheumatoid arthritis

Adalimumab received U.S. (FDA) approval in 2002 for treating moderately to severely active (RA) in adults who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs), and it can be administered as monotherapy or in combination with (MTX) or other non-biologic DMARDs. As the first (TNF) inhibitor approved for RA, it established a benchmark for biologic therapy, with combination use alongside MTX recommended to enhance efficacy and mitigate . In the ARMADA trial, a phase III randomized controlled trial (RCT) of 271 patients with active despite MTX treatment, adalimumab (40 mg every other week) plus MTX yielded ACR20 response rates of 60%, ACR50 rates of 42%, and ACR70 rates of 23% at 24 weeks, compared to 13%, 6%, and 1% with plus MTX, respectively. The PREMIER trial, involving 799 patients with early aggressive (disease duration <3 years), demonstrated that adalimumab plus MTX achieved ACR20 rates of 68%, ACR50 rates of 49%, and ACR70 rates of 32% at 52 weeks, outperforming MTX monotherapy (ACR20: 61%; ACR50: 41%; ACR70: 21%) and adalimumab monotherapy (ACR20: 62%; ACR50: 41%; ACR70: 23%). Radiographic assessments in these trials showed adalimumab plus MTX reduced progression of structural damage by 60-78% over 1-2 years relative to MTX alone, as measured by modified Total Sharp Scores, with combination therapy inhibiting mean annual progression to near zero in early cohorts. Long-term open-label extensions of these RCTs confirmed sustained , with ACR response rates maintained or improved through 5 years; for instance, in a 5-year of patients completing the ReACT study (which included adalimumab initiators), low disease activity persisted in over 50% of completers, alongside continued inhibition of radiographic progression. Historically positioned as a first-line for moderate-to-severe , adalimumab's role has evolved with emerging therapies, though it remains a foundational option. indicates primary non-response rates of 20-30% among patients initiating anti-TNF therapy like adalimumab, often prompting switches to alternative biologics or targeted synthetics within 6-12 months.

Other autoimmune and inflammatory conditions

Adalimumab is indicated for active in adults with inadequate response to disease-modifying antirheumatic drugs. In the phase III , 58% of patients achieved an ACR20 response at week 24 compared to 14% on , with sustained efficacy over two years including inhibition of radiographic progression. For , adalimumab yields ASAS40 responses in 45-59% of TNF inhibitor-naïve patients at 24 weeks, outperforming by reducing spinal and improving function in pivotal studies. In moderate-to-severe plaque , the REVEAL trial demonstrated PASI75 achievement in approximately 80% of patients at week 16 with adalimumab versus 18% on , with responses maintained long-term in responders. Adalimumab treats moderately to severely active . The CHARM trial showed induction of clinical response, defined as a CDAI reduction of at least 70 points from baseline, in 58% of patients after open-label dosing at weeks 0 and 2.01947-0/fulltext) For maintenance, weekly or every-other-week dosing sustained remission in 40-47% at week 56 versus 12% on . In , approvals stem from ULTRA trials where adalimumab achieved mucosal healing (Mayo endoscopic subscore of 0 or 1) in 41.7% of patients at week 8 versus 17.9% on in pooled analyses, alongside clinical remission rates of 16.5-17.3% post-induction. For , phase III PIONEER trials reported HiSCR rates—defined as at least 50% reduction in and inflammatory nodule count with no or draining increase—of 42-59% at week 12 with weekly adalimumab versus 26-28% on . Adalimumab is effective in polyarticular for patients aged 2 years and older. Pediatric trials showed ACR30 responses in up to 94% and ACR70 in approximately 70% when combined with , with long-term data confirming sustained joint improvement and tolerability. In noninfectious , the VISUAL I and II trials established adalimumab's role in reducing treatment failure risk by 43-54% versus at week 80, achieving uveitis quiescence and enabling corticosteroid tapering while preserving .

Evidence from clinical trials and real-world data

Network meta-analyses of randomized controlled trials have positioned adalimumab as one of the more effective (TNF) inhibitors for achieving clinical remission in (RA), with comparable or superior rankings to and in terms of American College of Rheumatology (ACR) response criteria at 24 weeks. Similar analyses for (IBD), including and , rank adalimumab highly among anti-TNF agents for induction and maintenance of remission, though with moderate confidence in estimates relative to . These syntheses highlight adalimumab's efficacy within its class but note variability due to differences in patient populations and trial designs, such as responder potentially underestimating long-term effects. Head-to-head comparisons reveal limitations against newer agents; in the phase 3 SELECT-COMPARE trial for patients with inadequate response, (a ) demonstrated superior efficacy to adalimumab, with higher rates of clinical remission (26% vs. 13% at week 12) and low disease activity, sustained through 5 years. Placebo-controlled trials provide causal for TNF inhibition's role, as adalimumab consistently outperformed in pivotal phase 3 studies across indications, achieving response rates 20-40% higher (e.g., ACR20 in , clinical response in ), countering assertions that outcomes stem primarily from placebo effects. Real-world evidence from registries like Corrona corroborates trial but shows moderate persistence, with 1-year retention rates of 50-60% in and cohorts, declining to around 50% at 2 years due to secondary loss of response. Annual loss of response rates range from 10-20%, often linked to and requiring dose escalation in 20-30% of cases, though persists long-term (up to 10 years) in continuers. Predictors of sustained response include early disease onset and lower baseline TNF levels, with observational data emphasizing the need for to mitigate -driven failures. Overall, while trials establish robust initial , real-world attrition underscores limitations in durability, independent of safety concerns.

Safety profile and adverse effects

Common adverse reactions

The most frequently reported adverse reactions to adalimumab in clinical trials across rheumatoid arthritis and other indications, occurring in more than 10% of patients, include upper respiratory tract infections, injection-site reactions, , and . Upper respiratory infections were observed in approximately 17% of patients, while affected about 11%. These infection rates reflect mild, self-limiting events similar to background population incidences in immunocompromised cohorts, with no established causal excess beyond placebo groups in controlled studies. Injection-site reactions, such as , pain, itching, hemorrhage, or swelling, occurred in around 20% of adalimumab-treated patients in placebo-controlled trials, typically manifesting as localized, transient responses that decreased in frequency with repeated dosing. was reported in 5-12% of cases, and in approximately 6%, both generally mild and not requiring treatment discontinuation. These events exhibit dose dependency but resolve spontaneously in over 90% of instances without interrupting therapy, as evidenced by pooled data from global databases encompassing tens of thousands of patient-years.
  • Infections: Predominantly upper respiratory (17%) and (11%), with nasopharyngitis also common; rates align with comparator arms in trials.
  • Injection-site reactions: (most prevalent subtype at ~43% of such events), pain (~12%), and pruritus (~6%); mild and self-resolving.
  • Neurological and dermatological: (5-12%) and (6%); infrequent basis for withdrawal (<1%).
Empirical analyses from over 30,000 patient-years indicate these common reactions do not exceed expected background rates when adjusted for underlying activity and comorbidities, supporting their classification as non-serious and manageable.

Serious risks and long-term concerns

Adalimumab carries black-box warnings for serious infections and , reflecting elevated risks observed in clinical trials and post-marketing . Patients treated with adalimumab face an increased incidence of serious infections leading to hospitalization or , with pooled odds ratios from meta-analyses of TNF inhibitors indicating approximately twofold higher compared to non-biologic therapies (OR 2.0, 95% CI 1.3-3.1). This stems causally from TNF-alpha's essential role in immune defense against intracellular pathogens, as inhibition disrupts integrity and function, predisposing to bacterial dissemination. reactivation is particularly prominent, with epidemiological data showing heightened incidence in endemic areas or latent carriers, independent of baseline screening efficacy. Malignancy risks include lymphomas, where rheumatoid arthritis cohorts exhibit 3-4 times the background rate even without biologics, though adalimumab exposure yields standardized incidence ratios around 2.9 versus the general population—attributable largely to underlying disease inflammation rather than direct drug causation beyond RA's inherent lymphoma predisposition. Non-melanoma skin cancers show modest elevation (OR 1.5, 95% CI 1.2-1.8) in some registries, but overall solid tumor rates do not exceed expectations adjusted for RA duration and severity. Rare but serious concerns encompass (incidence <1%, often linked to reactivation), demyelinating disorders (0.1-1% reported, with optic neuritis or multiple sclerosis-like events prompting discontinuation), and heart failure exacerbation, contraindicated in NYHA class III/IV due to observed worsening in trials. Long-term registry data from over 23,000 patients across global trials reveal no net increase in overall mortality, with opportunistic infections (e.g., , ) occurring at rates below 0.1 events per 100 patient-years, underscoring the need for sustained monitoring of atypical pathogens over amplified cancer apprehensions unsubstantiated by adjusted epidemiological controls.

Development and regulatory history

Discovery and early development

Adalimumab, originally designated D2E7, emerged from a 1993 collaboration between Cambridge Antibody Technology (CAT) and BASF Pharma, leveraging CAT's platform to generate a fully targeting alpha (TNF-α). CAT's library, developed in 1991, enabled the selection of high-affinity fragments against TNF-α, yielding D2E7 as a lead candidate capable of neutralizing soluble and membrane-bound TNF-α with subnanomolar potency in preclinical assays. This approach marked the first application of to produce a fully therapeutic , prioritizing reduced over chimeric or humanized alternatives like . Early development focused on rheumatoid arthritis (RA), with phase I trials initiating in 1997 under BASF Knoll to assess safety, pharmacokinetics, and TNF neutralization in healthy volunteers and RA patients. These trials confirmed dose-dependent TNF-α blockade, with subcutaneous administration achieving rapid bioavailability and sustained serum levels sufficient for clinical efficacy, paving the way for phase II proof-of-concept studies by 2000 that demonstrated significant reductions in RA disease activity scores versus placebo. In 2001, Abbott Laboratories acquired BASF Knoll Pharmaceuticals for approximately $6.9 billion, integrating D2E7 into its immunology pipeline and accelerating advancement toward phase III evaluation. Pre-approval pivotal data from the ARMADA trial, a phase III study completed in 2002, established adalimumab's superiority over monotherapy in reducing joint damage and symptoms in moderate-to-severe patients, with American College of Rheumatology response rates exceeding 60% at 24 weeks when combined with . These findings, supported by radiographic evidence of halted structural progression, underscored the antibody's causal role in interrupting TNF-driven inflammation, informing its initial FDA approval in December 2002—later inherited by following Abbott's 2013 spin-off.

FDA approvals and global regulatory milestones

The U.S. Food and Drug Administration (FDA) granted initial approval to adalimumab on December 31, 2002, for the treatment of moderate to severe in adults, based on pivotal phase 3 clinical trials (e.g., ARMADA and studies) that met efficacy endpoints such as American College of Rheumatology 20% response criteria (ACR20) in 48-62% of patients versus 9-26% on , alongside radiographic evidence of reduced joint damage progression. Subsequent FDA approvals expanded indications, supported by randomized controlled trials demonstrating statistically significant improvements in activity scores, remission rates, and quality-of-life measures over comparators or :
IndicationApproval DateKey Evidence Threshold
September 26, 2005ACR20 response in 58% of patients versus 14% ( trial).
and January 18, 2008 (AS); August 2008 (JIA extension)ASAS 20 response in 48% versus 13% (ATLAS trial); JIA trials showed 74% ACR pediatric 30 response.
Crohn's diseaseFebruary 2007 (adults); May 2014 (pediatrics 6-17 years)CDAI reduction ≥70 in 59% versus 35% (CHARM trial); pediatric extrapolation from adult data plus .
Plaque September 2008PASI 75 response in 71% versus 7% (REVEAL trial).
Ulcerative colitis (UC)September 2012Clinical remission in 17% versus 9% (ULTRA 2 trial).
September 10, 2015HiSCR achievement in 50% versus 27% (PIONEER trials).
Non-infectious intermediate, posterior, and panuveitisJune 30, 2016Ocular quiescence in 60% versus controls (VISUAL trials); first non-corticosteroid biologic approved for this.
The (EMA) authorized adalimumab on September 8, 2003, initially for , with parallel expansions for other indications mirroring FDA timelines, such as and by 2007, supported by bridging studies confirming similar and efficacy in European populations. By the mid-2010s, adalimumab achieved regulatory approval in over 100 countries worldwide, including key markets like (2003 initial) and (2004), facilitated by prequalification and mutual recognition procedures that relied on shared pivotal trial data demonstrating consistent risk-benefit profiles across diverse ethnic groups. Post-approval, the FDA imposed commitments including long-term observational studies to monitor serious adverse events like tuberculosis reactivation and malignancies, with pediatric extensions requiring pharmacokinetic modeling and efficacy extrapolation from adult trials where direct studies were infeasible; similar pharmacovigilance obligations applied under EMA's , emphasizing infection screening protocols prior to initiation. These milestones underscored adalimumab's role as a benchmark , with approvals predicated on hazard ratios for key endpoints (e.g., 0.5-0.7 for radiographic progression in ) outperforming standards of care at the time.

Commercialization and market dynamics

Brand development by AbbVie

AbbVie was established as a spin-off from in 2013, inheriting the rights to Humira (adalimumab), which became the cornerstone of its portfolio and accounted for approximately half of its initial sales projections. Following the separation, AbbVie prioritized Humira's expansion through enhanced manufacturing capabilities and global marketing strategies, positioning it as the reference biologic for TNF inhibitors in autoimmune diseases. To support growing demand, AbbVie invested in production infrastructure, including expansions for biologic manufacturing that improved yield and supply reliability for adalimumab, enabling sustained global distribution as indications broadened. These efforts underpinned Humira's role in driving AbbVie's revenue, with the company leveraging direct-to-consumer campaigns and physician education to reinforce its market dominance. AbbVie introduced delivery device innovations, such as the Humira Pen , which simplified self-administration compared to prefilled syringes and demonstrated higher patient preference in usability trials. This advancement correlated with improved adherence rates, as studies showed use positively influenced persistence in biologic therapies for inflammatory conditions. Under AbbVie's stewardship, Humira achieved unprecedented commercial success, with global net revenues peaking at $20.7 billion in 2021, reflecting its leadership in prior to entries. This milestone solidified Humira as the world's top-selling pharmaceutical, driven by AbbVie's focused branding and indication expansions.

Pricing, sales, and economic impact

In the , the for a monthly supply of adalimumab (branded as Humira) exceeded $6,900 prior to widespread entry in 2023. Net prices, accounting for rebates and discounts to payers, averaged approximately $2,800 per prescription in late 2023, down from higher levels in prior years due to competitive pressures. These figures reflect a model where gross revenues supported manufacturer negotiations with benefit managers, though patient out-of-pocket costs varied widely based on coverage. Global revenues from adalimumab surpassed $200 billion in cumulative sales by the end of 2023, establishing it as the highest-grossing pharmaceutical product in . Annual worldwide sales peaked at over $21 billion in before declining to $14.4 billion in 2023 amid patent expirations. These earnings, primarily from , funded extensive across therapies while drawing scrutiny for contributing to elevated healthcare expenditures during periods of market exclusivity. Health economic evaluations indicate adalimumab provides value in treating , with incremental cost-effectiveness ratios (ICERs) often below $50,000 per (QALY) gained compared to conventional disease-modifying antirheumatic drugs. Such analyses account for QALY improvements from reduced disease progression and disability, though high upfront costs during monopoly phases have prompted debates over pricing sustainability; proponents argue revenues recouped investments in biologic exceeding $10 billion for adalimumab alone. Following patent expirations, market competition drove list price reductions of 80-90% in various regions, enhancing affordability without reliance on regulatory . This , observed in post-2018 and the U.S. after 2023, demonstrates how entry can lower net spending by up to 50% overall while maintaining access for patients with autoimmune conditions.

Biosimilars: Entry, uptake, and competition effects

The first adalimumab , Amjevita (adalimumab-atto), launched in the United States on January 31, 2023, following the expiration of key Humira patents. By late 2024, ten had received FDA approval, including Simlandi (adalimumab-ryvk) in February 2024, enabling broader market entry for interchangeable and non-interchangeable options. Despite these approvals, uptake remained modest, reaching approximately 2% of the market in early 2024 and climbing to 22% by October 2024, with some reports citing 23% share by November 2024; this limited penetration has been linked to AbbVie's rebate agreements with pharmacy benefit managers, which incentivize continued Humira prescriptions over lower-cost alternatives. Real-world switching dynamics reveal challenges in adoption, with Truveta analysis of electronic health records indicating that 13% of patients who transitioned from Humira to a subsequently switched back to the originator, often within 30 days citing early dissatisfaction or adverse events. However, multiple studies affirm equivalence, showing no significant differences in efficacy, safety, or upon switching; for instance, non-medical switches maintained control and retention rates comparable to Humira in cohorts with inflammatory conditions. Interchangeability designations, such as for Cyltezo (adalimumab-adbm) approved by the FDA in October 2021 with expansions confirmed in subsequent formulations, facilitate pharmacy-level substitution without prescriber intervention, potentially accelerating uptake where state laws permit. Competition from biosimilars has driven projected U.S. savings exceeding $19.5 billion over five years, representing over half of anticipated biosimilar-driven reductions in the adalimumab market, though actual savings per averaged $4,505 annually in 2024 after rebates. These effects underscore biosimilars' role in price deflation—up to 85% list price reductions in some cases—but highlight barriers from entrenched commercial contracts, with originator retention exceeding 70-80% in many payer networks as of mid-2025.

Patent extension strategies

AbbVie employed extensive secondary patenting strategies for adalimumab, filing over 300 patent applications in the United States, with 165 granted, many covering formulations, manufacturing processes, and delivery devices rather than the core composition-of-matter patent that expired in 2016. These "evergreening" tactics, including patents on stabilized high-concentration formulations and auto-injector improvements, created a dense thicket that extended effective exclusivity beyond the original term, deterring entry through infringement risks. Critics, including advocacy groups like I-MAK, argue this approach exemplifies anti-competitive layering, as approximately 90% of Humira-related patents were filed post-FDA approval in 2002, prioritizing market defense over novel innovation. A key example involved the citrate-free introduced in 2014, which reduced injection-site by eliminating citrate buffer and enabling a smaller injection volume (0.4 mL versus 0.8 mL), patented under U.S. No. 8,916,157 and equivalents. This reformulation, alongside device patents for pre-filled syringes and pens, faced opposition in , where the upheld related claims amid challenges prior to the 2018 compound expiry, though launched shortly thereafter. In the U.S., settled patent disputes with multiple developers (e.g., , Bioepis), stipulating market entry no earlier than January 2023, which delayed competition despite FDA approvals starting in 2016 and preserved originator dominance until that date. From a causal perspective, these strategies empirically safeguarded recoupment of substantial upfront R&D and clinical —Humira's development and global trials spanned over a with costs exceeding traditional small-molecule benchmarks—while funding AbbVie's broader , as the drug's cumulative revenues surpassed $200 billion by 2023, enabling acquisitions and further . Proponents contend such protections were necessary incentives in biologics' high-risk, high-cost landscape, where without extended exclusivity, diffusion of the therapy might have lagged, as evidenced by Humira's rapid uptake in treating and other indications post-launch. However, independent analyses highlight that secondary patents often yield marginal benefits relative to their extension value, raising questions about net societal welfare under current IP regimes.

Litigation outcomes and implications

In antitrust litigation challenging AbbVie's settlements with developers for adalimumab, the U.S. (FTC) alleged reverse-payment agreements that delayed market entry, but withdrew its claims in July 2021 following a ruling limiting the agency's authority to seek monetary remedies. Private suits by direct and indirect purchasers similarly claimed Sherman Act violations through no-cash reverse payments, such as cross-licenses for non-U.S. markets, but the Seventh Circuit Court of Appeals affirmed dismissal in August 2022, holding that such arrangements did not constitute unlawful restraints absent evidence of fraud on the U.S. and Trademark Office (PTO) under Walker Process standards. Plaintiffs failed to plead that AbbVie's patents were obtained via knowing misrepresentation to the PTO, a prerequisite for claims tied to patent enforcement. Amgen's disputes with AbbVie, resolved via a 2017 global settlement granting country-specific licenses, permitted U.S. launch of its adalimumab biosimilar (AMJEVITA) no earlier than January 31, 2023, aligning with outcomes in parallel suits by other developers like Samsung Bioepis. No antitrust convictions resulted from these cases, though scrutiny persisted over settlement terms that coordinated delayed entry among competitors. Post-2023 biosimilar launches proceeded without further U.S. court injunctions blocking entry, as settlements predefined resolution dates upon patent expirations or licenses. These outcomes underscore that enforcement, including thickets of secondary patents and negotiated delays, withstands antitrust challenge when grounded in valid PTO grants and arms-length settlements, fostering incentives without requiring judicial intervention via compulsory licensing. Courts rejected arguments equating aggressive litigation with per se illegality, affirming that market competition emerges through licensed entry rather than indefinite exclusion, as evidenced by multiple adalimumab s gaining U.S. approval and sales starting in 2023. This framework balances originator rewards for high-risk biologic development against eventual access, countering proposals for government-mandated licensing that could undermine voluntary resolution and long-term R&D investment.

Ongoing research and limitations

Comparative efficacy with newer therapies

In rheumatoid arthritis, the SELECT-COMPARE trial demonstrated that , a (JAK) inhibitor, achieved superior clinical responses compared to adalimumab, including higher rates of DAS28-CRP remission and ACR50 responses at week 12, with sustained advantages observed through 5 years of follow-up. In patients who had failed prior therapy, the SELECT-SWITCH trial (reported October 2025) further showed upadacitinib's superiority over adalimumab for the primary endpoint of clinical remission. These findings indicate that JAK inhibitors can outperform in achieving deeper and more durable remission, particularly in biologic-experienced populations. In , particularly , vedolizumab, an inhibitor, exhibited superior efficacy to adalimumab in head-to-head comparisons, with clinical remission rates of 31.3% versus 22.5% at week 52. Network meta-analyses corroborate this, ranking vedolizumab ahead of adalimumab for maintaining clinical remission ( 1.50, 95% CI 1.11–2.03). For , indirect comparisons via network meta-analysis position ustekinumab, an IL-12/23 inhibitor, and other newer agents as comparable or superior to adalimumab in inducing and maintaining response, though direct head-to-head data remain limited. Long-term retention rates for adalimumab in typically decline to 40–50% at 5 years, often due to loss of efficacy, highlighting its foundational but plateaued role in disease modification. Biosimilars of adalimumab have shown pharmacokinetic and clinical equivalence to the reference product in randomized trials, without evidence of superior efficacy. TNF inhibition remains mechanistically pivotal for interrupting core inflammatory cascades, yet newer therapies targeting JAK-STAT or specific interleukins empirically extend benefits to TNF non-responders by engaging distinct pathways.

Emerging applications and challenges

Adalimumab is under investigation for additional indications such as , where phase III trials have evaluated its efficacy in managing intestinal manifestations refractory to conventional therapies. In a multicenter phase III study involving Japanese patients, adalimumab achieved clinical remission in a significant proportion, with long-term extension data confirming sustained response rates over two years and an acceptable safety profile. These findings support its potential expansion beyond approved uses, though broader phase III confirmation in diverse populations remains needed to address data gaps in non-Asian cohorts. Biosimilar switching studies highlight high treatment persistence, with real-world evidence showing 84-91% of patients continuing therapy at 12 months post-switch from reference adalimumab, indicating comparable and . Such interchangeability data addresses concerns over loss of response, yet variability in persistence (e.g., 60-70% in some cohorts) underscores the need for larger, indication-specific trials. Key challenges include , with anti-drug antibodies developing in 10-30% of patients across indications like and , leading to reduced serum levels, loss of response, and increased clearance via immune complex formation. These antibodies arise due to the drug's immunogenicity profile, exacerbated by factors such as lack of concomitant immunosuppressants, and can necessitate dose adjustments or switching, though mitigates risks only partially. In low- and middle-income countries, persistent high costs—despite biosimilars—limit access, with biologic pricing barriers restricting uptake even in upper-middle-income settings without robust reimbursement. Future directions emphasize real-world evidence for personalized dosing, as precision-guided strategies using therapeutic drug monitoring have demonstrated improved outcomes in inflammatory bowel disease by optimizing trough levels and minimizing under- or over-dosing. Subcutaneous formulations of alternative TNF inhibitors, such as infliximab biosimilars, are being compared for potential superiority in high-inflammatory burden scenarios, offering pharmacokinetic advantages like sustained exposure without intravenous requirements. Ongoing needs include expanded real-world datasets to refine immunogenicity predictors and dosing algorithms, prioritizing causal factors like patient genetics over empirical trial extrapolations.

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