Alvotech biosimilars: FDA ustekinumab application rejection; adalimumab interchangeability designation re-submission

In October 2023, Iceland-based biosimilar manufacturer Alvotech, announced that the US Food and Drug Administration (FDA) has issued a complete response letter (CRL) for Alvotech’s Biologics License Application (BLA) for AVT04, a biosimilar candidate to Stelara (ustekinumab). As such, the application was not approved. This follows Alvotech’s September 2023 resubmission of a BLA for their high-concentration biosimilar formulation to AbbVie’s blockbuster arthritis treatment Humira (adalimumab), AVT02 [1], following receipt of a similar CRL.

FDA rejects application of AVT04 ustekinumab biosimilar
The October CRL regarding AVT04 noted that certain deficiencies, which were conveyed following the FDA’s inspection of the company’s Reykjavik facility that concluded in March 2023, must be satisfactorily resolved before the application can be approved. No other deficiencies in the application were noted by the FDA. In response, Alvotech has indicated that it will file a resubmission in due course.

Ustekinumab is indicated for the treatment of Crohn’s disease, psoriasis and psoriatic arthritis, and the originator is Janssen’s/Johnson & Johnson’s Stelara. It is a humanized monoclonal antibody that interferes with the triggering of the body’s inflammatory response through the suppression of certain cytokines. Specifically, it blocks interleukin IL 12 and IL 23 which help activate certain T cells. It binds to the p 40 subunit of both IL 12 and IL 23 so that they subsequently cannot bind to their receptors [4].

Alvotech’s AVT04 has been approved in Japan [2] and a marketing authorisation application has been submitted to the European Medicines Agency on 9 February 2023 [3].

AVT02 adalimumab biosimilar re-submits interchangeability designation
This is not the first time that such issues with the company’s facility have held back the approval of a biosimilar. In 2022, Alvotech’s high-concentration biosimilar formulation adalimumab formulation, AVT02, was issued a similar CRL [5]. However, Alvotech resubmitted its BLA to the FDA seeking an interchangeability designation for AVT02, in September 2023.

Adalimumab is a human monoclonal antibody that treats autoimmune diseases by inhibiting tumour necrosis factor (TNF), a soluble inflammatory cytokine. Adalimumab binds to TNF-alpha (TNF-α), preventing it from activating TNF receptors, which cause the inflammatory reactions associated with autoimmune diseases. Adalimumab is indicated for the treatment of rheumatoid, juvenile idiopathic and psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, psoriasis and ulcerative colitis [6].

If approved, AVT02 will compete with a number of other adalimumab biosimilars now approved for the US market.

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References
1. GaBI Online - Generics and Biosimilars Initiative. AVT02 biosimilarity with Humira proved in chronic plaque psoriasis treatment [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2023 Oct 31]. Available from: www.gabionline.net/biosimilars/research/avt02-biosimilarity-with-humira-proved-in-chronic-plaque-psoriasis-treatment
2. GaBI Online - Generics and Biosimilars Initiative. Japanese approval for first ustekinumab biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2023 Oct 31]. Available from:
www.gabionline.net/biosimilars/news/japanese-approval-for-first-ustekinumab-biosimilar
3. GaBI Online - Generics and Biosimilars Initiative. EMA accepts application for ustekinumab biosimilar AVT04 [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2023 Oct 31]. Available from: www.gabionline.net/biosimilars/news/ema-accepts-application-for-ustekinumab-biosimilar-avt04
4. GaBI Online - Generics and Biosimilars Initiative. Biosimilars of ustekinumab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2023 Oct 31]. Available from: www.gabionline.net/biosimilars/general/biosimilars-of-ustekinumab
5. GaBI Online - Generics and Biosimilars Initiative. FDA inspections in Iceland and Singapore for Alvotech and Strides [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2023 Oct 31]. Available from:
www .gabionline.net/pharma-news/fda-inspections-in-iceland-and-singapore-for-alvotech-and-strides
6. GaBI Online - Generics and Biosimilars Initiative. Biosimilars of adalimumab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2023 Oct 31]. Available from: www.gabionline.net/biosimilars/general/Biosimilars-of-adalimumab

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