Explore chapters and articles related to this topic
Progressive multifocal leukoencephalopathy
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Eric M. L. Williamson, Joseph R. Berger
Efalizumab is an anti-CD11a IgG1 antibody no longer on the market due to its own unique association with PML, despite demonstrated efficacy in moderate to severe plaque psoriasis [184]. It targets psoriasis pathogenesis at multiple levels by inhibiting the initial T-cell activation in lymph nodes, preventing binding of T-cells to endothelial cells and blocking trafficking of T-cells from the circulation into the psoriatic skin, preventing their reactivation in the dermal and epidermal layer [185]. More than 6000 patients had been treated with efalizumab before its removal from the European and US markets in the spring of 2009; of these, only 166 patients had received more than 3 years of therapy. Four patients ranging in age from 47 to 73 years old that were treated with efalizumab for more than 3 years for psoriasis were reported to have developed PML before the removal of the drug—PML was subsequently confirmed in three cases and suspected in one. As with MS and Crohn’s disease, PML had not previously been observed complicating psoriasis. But, unlike natalizumab, the efficacy of, or need for the therapy to be available, was not thought to justify the risk.
Angiogenesis and Roles of Adhesion Molecules in Psoriatic Disease
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Asmita Hazra, Saptarshi Mandal
Humanized monoclonal antibody efalizumab (marketed as Raptiva by Genentech) is a full-length IgG1κ against the αL (CD11a) integrin subunit. It was previously on the market for psoriasis but was withdrawn in 2009 because of a rare association of progressive multifocal leukoencephalopathy (PML) due to reactivation of a polyoma virus, John Cunningham virus (JCV). Multicenter randomized controlled trials had shown that efalizumab was effective in psoriasis; for example, subcutaneous efalizumab (1 or 2 mg/kg/week) was significantly superior to placebo. Adverse events, including headache, chills, pain, and fever, were more common in patients receiving efalizumab, but serious adverse events and infections were not statistically more common than in those receiving placebo. One must wonder why this drug was not continued even though the percentage of PML was not more than that of natalizumab, which is continuing for multiple sclerosis.
Psoriasis of the Nails
Published in John Y. M. Koo, Ethan C. Levin, Argentina Leon, Jashin J. Wu, Mark G. Lebwohl, Mild to Moderate Psoriasis, 2014
Ashley A. Keyes, Richard K. Scher, Gabriele B. Poindexter, Maithily A. Nendedkar-Thomas
Efalizumab is a humanized monoclonal antibody against the CD11 portion of the LFA-1 molecule on T cells. It prevents binding to intercellular adhesion molecule (ICAM) on the antigen-presenting cell and prevents T-cells from migrating to the skin [92]. Because it does not actually destroy the activated pathogenic T cells, the psoriasis can actually worsen upon cessation of the drug due to a sudden influx of T cells into the skin. Efalizumab was FDA approved for the treatment of psoriasis; however, it was withdrawn from the market in 2009 due to increased risk of developing progressive multifocal leukoencephalopathy [93].
How not to discover a drug - integrins
Published in Expert Opinion on Drug Discovery, 2021
Efalizumab is an anti-αLβ2 monoclonal antibody that was approved for the treatment of plaque psoriasis [153–155]. While there was evidence of it being effective it was soon found to be associated with an increased risk of PML [156] and was subsequently withdrawn from the market. However, lifitegrast (see Figure 3), a small molecule αLβ2 antagonist, was approved for use in the treatment of dry eye disease by FDA [157]. Early success with lifetegrast ($400 million sales in 2018) supported its sale by Takeda to Novartis for over 3 USD billion. However, while approved in US, the EMA have recently refused to grant approval. This is based on lack of evidence for benefit, primarily because the PIII studies were performed against placebo rather than artificial tears. While this is not a rejection of the drug it does mean that further studies will be necessary if they are to seek EMA approval.
Targeting the cutaneous lymphocyte antigen (CLA) in inflammatory and neoplastic skin conditions
Published in Expert Opinion on Biological Therapy, 2020
Alvise Sernicola, Irene Russo, Micol Silic-Benussi, Vincenzo Ciminale, Mauro Alaibac
Efalizumab, a monoclonal antibody against the CD11a subunit of LFA-1 expressed on T-cell surface and involved in T-cell extravasation to the skin [94–96], was formerly available for the treatment of plaque psoriasis [97]. Blocking the interaction of LFA-1 with CD54 (ICAM-1) on activated endothelial cells proved effective in improving skin lesions of AD [98] and psoriasis with concurrent observation of increased CLA+ effector memory T-cell numbers in peripheral blood [99–101]. Furthermore, a rebound in psoriasis often followed drug discontinuation as migration from blood back to the skin of CLA+ T-cells occurred once efalizumab-mediated restraints on extravasation were relieved [102]. Efalizumab was demonstrated to correlate with the risk of PML and was withdrawn from the market in 2009 [103]. PML is a demyelinating disease of the central nervous system caused by human polyomavirus JCV. The suggested pathogenesis in patients treated with efalizumab involves reactivation of JCV from latently infected lymphoid cells and trafficking of the virus into the brain [104]. Therapeutic interference with the skin homing of T-cells is therefore limited by the risk of potential severe adverse reactions, requiring a careful evaluation of the risk and benefit ratio in cutaneous immune disorders and may be a more appropriate approach for the treatment of MF and other CTCLs, that is a current area of unmet therapeutic need.
Efficacy and survival of biologic agents in psoriasis: a practical real-life 12-year experience in a French dermatology department
Published in Journal of Dermatological Treatment, 2019
Hélène Roche, Kevin Bouiller, Eve Puzenat, Elise Deveza, Blandine Roche, Fabien Pelletier, Alison van de Laak, Anne Sophie Dupond, Charlée Nardin, François Aubin
All consecutive patients treated with biologics for psoriasis vulgaris between January 2005 and December 2016 were analyzed. Patients treated with efalizumab, participating in clinical trials, or receiving concomitant treatment with another systemic therapy for psoriasis were excluded. Eligibility for biologics was regulated by the national guidelines of the Haute Autorité de Santé (https://www.has-sante.fr) and requires moderate to severe psoriasis (Psoriasis Area and Severity Index [PASI] > 10 or Dermatology Life Quality Index >10 or affected body surface area >30%) in whom at least 2 systemic treatments including phototherapy, methotrexate or cyclosporin) previously failed or who have contraindications or toxicity to the previous treatments. The choice of drug was the decision of the physician. Data were organized as treatment courses comprising a period of continuous treatment with a given biologic. Thus, one patient may receive several treatment courses of different durations. The decision of drug discontinuation (adverse event, lack or loss of efficacy, patient’s decision, lost to follow-up, other) was based on clinical judgment of efficacy most often measured by the Physician’s Global Assessment and safety rather than objective measurement of disease activity.