With a year-old phase III failure dogging it, Astrazeneca plc's phase III Tulip 2 clinical trial of anifrolumab for treating systemic lupus erythematosus (SLE) met its primary endpoint by reducing disease activity vs. placebo.

The positive data is a tentative yet large step toward what's been an elusive potential lupus treatment, as there has been only one FDA approval for the disease in the past 60 years. The trial used the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) at week 52. Last year's failed anifrolumab Tulip 1 used a different measure, the SLE responder index 4. BICLA mandates improvement in all diseased organs as baseline with no new flares. The positive BICLA response in Tulip 2 was consistent with a pre-specified analysis of Tulip 1 and anifrolumab's safety profile was consistent with previous trials.

As with data from the failed Tulip 1, no further data from Tulip 2 was released. That didn't dampen the Street's enthusiasm as Astrazeneca shares (NYSE:AZN) closed up 1.38% on Thursday.

Flops line the route toward a successful lupus treatment. For instance, Tulip 2 could have suffered the same fate as UCB SA and Biogen Inc.'s phase IIb stumble last October as its study of dapirolizumab pegoylated Fab for adults with moderately to severely active SLE failed to meet its primary endpoint. The patients, despite receiving corticosteroids, antimalarials and nonbiological immunosuppressants, were measured on BICLA, same as Tulip 2, at 24 weeks for a dose response and missed the endpoint (p=0.06).

There's also Neovacs SA's misfire as two co-primary endpoints went awry in a phase IIb trial of interferon-alpha-kinoid (IFNalpha kinoid) in SLE. IFNalpha kinoid is a therapeutic vaccine designed to train a polyclonal, neutralizing antibody response on interferon-alpha. The cytokine is considered a key culprit in the pathogenesis of SLE, a notoriously complex and difficult-to-manage autoimmune disease that can affect many different organs and tissues throughout the body. IFNalpha kinoid comprises an inactivated form of IFN-alpha2b tethered to an immunogenic carrier protein, keyhole limpet hemocyanin. (See BioWorld, July 5, 2018.)

Success has been elusive

The last FDA approval, in 2011, was Benlysta (belimumab), from Human Genome Sciences Inc. and Glaxosmithkline plc. Benlysta is a recombinant, fully human, IgG1λ monoclonal antibody delivered via intravenous infusion for patients with active, autoantibody-positive SLE who are receiving standard therapy, including corticosteroids, antimalarials, immunosuppressives and nonsteroidal anti-inflammatory drugs. (See BioWorld, March 11, 2011.)

Glaxosmithkline's intravenous formulation of Benlysta (belimumab), a B-lymphocyte stimulator-specific inhibitor, was approved for children as young as 5 in April. The proportion of children achieving a clinically meaningful improvement in disease activity, as assessed by the SLE responder index response rate, was numerically higher in patients receiving belimumab plus standard therapy (52.8%) compared with placebo plus standard therapy (43.6%) at week 52.

The previous approval was when Dwight Eisenhower was in the Oval Office as Plaquenil (hydroxychloroquine) and corticosteroids received the FDA's nod in 1955.

Astrazeneca's anifrolumab is a fully human monoclonal antibody that binds to subunit 1 of the type I interferon receptor. It blocks all type I interferons' activity, including IFN-alpha, IFN-beta and IFN-omega. Type I interferons are cytokines involved in the inflammatory pathways. Between 60% and 80% of adults with SLE have an increased type I interferon gene signature, correlating with disease activity.

Tulip 2 randomized 373 eligible patients (1:1) to receive a fixed-dose intravenous infusion of 300 mg anifrolumab or placebo every four weeks and assessed the effect of anifrolumab in reducing disease activity, as measured by the BICLA. The BICLA was chosen as the primary endpoint for Tulip 2 following a full evaluation of Tulip 1 and is an established measurement for disease activity in adults with SLE.

Tulip 1 randomized 460 eligible patients (1:2:2) to receive a fixed-dose intravenous infusion of 150 mg anifrolumab, 300 mg anifrolumab or placebo every four weeks. Tulip 1 assessed the effect of anifrolumab in reducing disease activity, as measured by the SLE responder index 4.

There's more coming as Tulip also has a phase III long-term extension trial in SLE and a phase II trial in lupus nephritis.

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