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New antibody drug approved in 2021: Anifrolumab-fnia
New antibody drug approved in 2021: Anifrolumab-fnia. On July 30, 2021, the US Food and Drug Administration (FDA) approved anifrolumab-fnia (trade name SAPHNELO) for the first time for the treatment of adult patients with moderate to severe systemic lupus erythematosus (SLE) who are receiving standard therapies .
Anifrolumab is a fully human monoclonal antibody targeting subunit 1 of type I IFN receptor, which can block the activity of type I IFN. Type I IFN such as IFN-α, IFN-β and IFN-κ are cytokines involved in regulating the inflammatory pathway of SLE. This approval is based on the efficacy and safety data of two phase 3 clinical trials named TULIP (NCT02446912 and NCT02446899) and phase 2 clinical trials named MUSE (NCT01438489).
The recommended dose of anifrolumab is 300 mg intravenously every 4 weeks.
Anifrolumab was granted global rights by AstraZeneca in 2004 through an exclusive license and cooperation agreement with Medarex. The license of anifrolumab for the treatment of SLE is also undergoing regulatory review in the European Union and Japan. In China, AstraZeneca has obtained an implied license for the clinical trial application for Saphnelo injection submitted by AstraZeneca according to category 1 of therapeutic biological products, and it is planned to be developed for moderate to moderate to Treatment of severely active systemic lupus erythematosus.
Pharmacodynamics and pharmacokinetics
Anifrolumab is a humanized IgG1 monoclonal antibody that binds to type I interferon receptor (IFNAR) subunit 1 and has a high specific affinity. This combination inhibits type I interferon signaling, thereby blocking the biological activity of type 1 interferon.
Anifrolumab also induces the internalization of IFNAR1, thereby reducing the level of IFNAR1 on the cell surface. Blocking receptor-mediated type I interferon signaling can inhibit interferon-responsive gene expression and downstream inflammation and immune processes.
In addition, inhibition of type I interferon can also block plasma cell differentiation and normalize peripheral T cell subsets. Type I interferon plays an important role in the pathogenesis of SLE. About 60-80% of adult patients with active SLE express type I interferon to induce increased gene levels.
Anifrolumab showed a non-linear PK in the dose range of 100 mg to 1000 mg. After intravenous injection of 300 mg of Anifrolumab every 4 weeks, it reached a steady state on day 85. The accumulation rates of Cmax and Ctrough are about 1.36 and 2.49, respectively. Based on population PK analysis, the volume of distribution of a typical SLE patient (69.1 kg) at steady state is about 6.23 L, and the systemic clearance (CL) is 0.193 L/day.
In three 52-week multicenter, randomized, double-blind, placebo-controlled studies (NCT01438489, NCT02446912, and NCT02446899), the safety and effectiveness of SAPHNELO were evaluated. According to the classification criteria of the American College of Rheumatology, the patient was diagnosed with SLE. All patients were adults ≥18 years of age, with moderate to severe SLE, disease activity index 2000 (SLEDAI-2K) score ≥6 points.
The efficacy endpoint of SAPHNELO is based on the Comprehensive Lupus Assessment (BICLA) and SLE Responder Index (SRI-4) of the British Isles Lupus Assessment Panel, determined based on the clinical response assessment of the composite endpoint.
Clinical trial 1 (NCT01438489) randomly enrolled 305 patients (1:1:1) who received Anifrolumab 300 mg, 1000 mg, or placebo for 52 weeks. The primary endpoint was a comprehensive assessment of SRI-4 and oral corticosteroid (OCS) status at 24 weeks.
Clinical trial 2 (NCT02446912) and clinical trial 3 (NCT02446899) are similar in design. In trial 2, 457 patients were randomly selected to take 150 mg, 300 mg Anifrolumab, or placebo (1:2:2). Trial 3 randomly selected 362 patients (1:1) who received 300mg Anifrolumab or placebo. The primary endpoint is the improvement in disease activity status assessed at 52 weeks, the previous trial used SRI-4 to evaluate, and the second trial used BICLA to evaluate. The secondary efficacy endpoints common in the two studies are the reduction in maintenance of OCS, the improvement in skin SLE activity and the onset rate.
BICLA is the primary endpoint of Trial 3. Compared with placebo, 300 mg Anifrolumab showed a statistically significant and clinically significant effect in terms of overall disease activity, with great improvements in all aspects of the composite endpoint. In trials 1 and 2, BICLA was a pre-specified analysis. The results of BICLA are shown in the table below.
The graph below shows the proportion of BICLA responders during the 52-week treatment period in Trial 3.
SRI-4 is the primary endpoint of Trial 2. Anifrolumab treatment did not result in a statistically significant improvement compared to placebo. In trials 1 and 3, SRI-4 was the pre-specified analysis. The SRI-4 results are shown in the table below.
In Trial 3, 47% of patients used OCS ≥ 10 mg/day at baseline. Anifrolumab can reduce OCS use by at least 25%. OCS ≤ 7.5 mg/day at week 40 and maintained until week 52 (p =0.004). Compared to the placebo group, more patients in the Anifrolumab group achieved this level of steroid reduction (52% vs 30%). In trials 1 and 2, compared with placebo, Anifrolumab had a consistent trend in reducing the effect of OCS use, but the difference was not statistically significant.
The most common adverse drug reactions (incidence ≥5%) of Anifrolumab are nasopharyngitis, upper respiratory tract infection, bronchitis, infusion-related reactions, herpes zoster, and cough.
Like all therapeutic proteins, Anifrolumab is immunogenic. In trials 2 and 3, of the 352 treated patients, anti-antibodies were detected in 6 (1.7%) patients.
(source:internet, reference only)