Favorable Equivalency Studies of Candidate Biosimilar AVT04 and Reference Ustekinumab

In February of this year, Alvotech announced that a marketing authorization application filing for AVT04 was accepted by the European Medicine Agency and had a biologics license application accepted for review by the US FDA in January 2023.¹

One team of investigators assessed bioequivalence between AVT04 and reference product (RP) ustekinumab in a pharmacokinetic (PK) study in healthy volunteers.² Reference ustekinumab is approved in the European Union and licensed in the United States.

Investigators conducted a double-blind, 3-arm, parallel-group study of 298 randomized participants in a 1:1:1 ratio; 98 received AVT04, 99 received EU-RP and 97 received US-RP as a single 45 mg subcutaneous injection on day 1.

The primary endpoint was the comparison of PK parameters of maximum serum concentration (Cmax) and area under the concentration-time curve from time zero to infinity (AUCinf) between AVT04 and both RPs, and between EU-RP and US-RP. Further endpoints included additional PK parameters, safety, tolerability, and immunogenicity.

Results showed that mean serum concentration-time profiles were similar for AVT04, EU-RP, and US-RP Mean values of the primary PK endpoints AUCinf and Cmax were similar.

After protein content normalization, the 90% CI of the geometric mean ratios were contained within the prespecified margins of 80% and 125% in all 6 pairwise comparisons:

• Cmax: 95% CI, 95.5-110.7 for AVT04/EU-RP; 95% CI 91.5-106.2 for AVT04/US-RP; and 95% CI, 96.8-112.4 for US-RP/EU-RP
• AUC0-inf: 95% CI, 101.5-18.8 for AVT04/EU-RP; 95% CI, 95.9-112.6 for AVT04/US-RP; and 95% CI, 97.6-114.4 for US-RP/EU-RP

Further results supported bioequivalence, with the additional mean systemic PK parameters in the AVT0 group found to be comparable with the EU-RP and US-RP treatment groups. The frequency of anti-drug antibodies, neutralizing antibodies, and local administration site reactions between treatment groups were similar.

“AVT04 was safe and well-tolerated, with a safety and immunogenicity profile similar to EU-RP and US-RP,” they concluded.

The investigators found that the analysis of bioequivalence supported the evaluation of PK similarity between AVT04 and EU-RP and US-RP.

A second poster assessed therapeutic equivalence between candidate biosimilar AVT04 and reference ustekinumab (Stelara).³ Ustekinumab is a safe and effective treatment for psoriasis, and biosimilars to the originator may increase treatment accessibility. Investigators evaluated therapeutic equivalence of AVT04 and RP in a confirmatory efficacy and safety study in patients with moderate-to-severe chronic plaque psoriasis.

Investigators randomized 581 subjects in a double-blind, 2-arm, parallel group, active control study at a 1:2 ratio to receive AVT04 (n = 194) or RP (n = 387), 45 mg (≤100kg) or 2 x 45 mg (>100 kg) subcutaneously on day 1, followed by the same dose 4 weeks later. The primary endpoint consisted of percentage improvement in Psoriasis Area and Severity Index (PASI) to week 12, static Physician’s Global Assessment (sPGA), Dermatology Life Quality Index (DLQI) safety, tolerability, and immunogenicity. The study continues to week 52.

At week 12, the 2-sided 95% Cis between treatment groups were within predefined equivalence margins of 10% (95% CI, ­–2.63 to 3.50), supporting the therapeutic equivalence assessment. DLQI score (12.5- vs 11.4-point improvement in the AVT04 vs RP groups, respectively) and sPGA (78.4% vs 80.5% achieving “clear” or “mostly clear” in AVT04 vs RP-treated groups, respectively) supported this assessment. The safety, tolerability, and immunogenicity profiles of AVT04 and RP were also similar.

“Analysis of percent change in PASI scores to Week 12 supports the assessment of therapeutic equivalence between AVT04 and RP. AVT04 was safe and well-tolerated, with a safety and immunogenicity profile similar to that observed for RP,” researchers concluded.

References

1. Alvotech to present clinical study data for AVT04, a proposed biosimilar to Stelara®, at 2023 American Academy of Dermatology (AAD) annual meeting. News Release. GlobeNewswire; March 17, 2023. Accessed March 20, 2023. https://www.globenewswire.com/news-release/2023/03/17/2629525/0/en/Alvotech-to-Present-Clinical-Study-Data-for-AVT04-a-Proposed-Biosimilar-to-Stelara-at-2023-American-Academy-of-Dermatology-AAD-Annual-Meeting.html

2. Berti F, Wynne C, Stroissnig H, et al; Assessment of bioequivalence between candidate biosimilar AVT04 and reference ustekinumab. Presented at: AAD 2023; March 17-21, 2023.

https://eposters.aad.org/abstracts/42601

3. Stroissnig H, Feldman S, Berti F, et al; Assessment of therapeutic equivalence between candidate biosimilar AVT04 and reference ustekinumab. Presented at: AAD 2023; March 17-21, 2023. https://eposters.aad.org/abstracts/42913