Astegolimab

AstraZeneca’s investigational antibody for chronic obstructive pulmonary disease has succeeded in two late-stage studies, despite having previously failed in a mid-stage trial. And, unexpectedly, the company revealed Friday the drug yielded positive data in a relatively broad population, potentially increasing its market reach. The drugmaker said that tozorakimab, which targets interleukin-33, hit the primary endpoints in the twin OBERON and TITANIA trials, in both cases cutting the rate of moderate-to-severe COPD exacerbations — acute attacks of breathlessness, coughing and increased sputum production — compared with placebo. The company called these reductions statistically significant and highly clinically meaningful, though it did not give figures. The two trials are part of a four-study program called LUNA. According to the Friday data, tozorakimab succeeded in both trials’ primary populations of former smokers, as well as in their overall populations. The latter groups included a broader spectrum of patients, including former and current smokers with different levels of lung function and numbers of eosinophils in their blood. High levels of eosinophils, a type of white blood cell, are thought to spur inflammation in respiratory diseases. Subjects in the trials took a 300 mg dose of the antibody, injected once a month for a year on top of standard of care. Tozorakimab was well tolerated, AstraZeneca said, with a “favorable” safety profile. Analysts from Jefferies wrote in a same-day note that tozorakimab’s success in the overall populations could mean that their current projection for worldwide peak sales of the drug is now “potentially conservative, pending detailed data.” The forecast stands at $3 billion at present, and assumes success only in former smokers. They wrote that the broad efficacy could mean that the upper end of AstraZeneca’s target sales range for the drug of $3 billion to $5 billion may be achievable. AstraZeneca said that the data from the two studies will be showcased in greater detail at a medical meeting. One question is why these studies hit when an earlier Phase 2a trial called FRONTIER-4 flopped . That trial used a different endpoint — the amount of air exhaled during a forced breath, assessed at three months. But it also used a higher dose of 600 mg, given monthly. Other IL-33 blockers also have a history of disappointing in COPD. Sanofi and Regeneron’s itepekimab posted underwhelming, though technically successful, Phase 3 data last May. A month later, Roche’s astegolimab stumbled in a late-stage trial, though it hit in a Phase 2b. GSK is also pursuing this mechanism. An asset, codenamed GSK3862995B, is in a Phase 1 trial, with data possibly due next year. AstraZeneca believes tozorakimab could be the first drug in its class to gain approval. It works by blocking the signaling of certain forms of IL-33, which reduces both inflammation and the mucus dysfunction that can worsen COPD, the company said. Still, approval is not a done deal. The drug is in two more Phase 3 trials, named MIRANDA and PROSPERO. The former is testing the 300 mg dose of tozorakimab, but given every two weeks rather than every four. PROSPERO is a long-term extension trial consisting of patients who completed the OBERON or TITANIA trials, with a readout at 104 weeks. Data from both of these studies should come by mid-year. Tozorakimab is also in late-stage research as a therapy for severe viral lower respiratory tract disease, and is in a mid-stage trial in asthma.

AstraZeneca's tozorakimab met its primary endpoint in two replicate Phase III trials in chronic obstructive pulmonary disease (COPD), offering a clearer signal of efficacy for drugs targeting the IL-33 pathway after some inconsistent showings from competitors.The year-long OBERON and TITANIA studies, which enrolled a combined 2306 participants, tested the monoclonal antibody in patients with persistent COPD exacerbations despite inhaled standard of care. Participants were randomised to tozorakimab or placebo once every four weeks, on top of background therapy.Across both trials, AstraZeneca said tozorakimab demonstrated "statistically significant and highly clinically meaningful reductions" in the annualised rate of moderate-to-severe COPD exacerbations versus placebo. The benefit was seen in the primary population of ex-smokers, as well as in the broader population that included current smokers, all stages of lung function impairment, and all blood eosinophil counts.The drug was generally well tolerated and had a favourable safety profile, according to the company.Mixed IL-33 pathway readoutsThe twin successes stand out in part because they provide replicated evidence in a heterogeneous disease space where similar drug candidates have so far delivered a rather patchy track record."This marks a notable shift in sentiment, given limited conviction in the IL-33 mechanism following prior IL-33 failures from Sanofi and Roche," said Jefferies analysts, calling the results for tozorakimab "a positive surprise."Sanofi and Regeneron's IL-33 monoclonal antibody itepekimab yielded split results in the Phase III AERIFY-1 and AERIFY-2 trials last year, as did Roche's astegolimab — which targets ST2, a receptor for IL-33 — succeeding in the Phase IIb ALIENTO study, but falling short in the Phase III ARNASA trial (see – KOL Views Q&A: Itepekimab setback more instructive than destructive for IL-33 therapies in COPD and Spotlight On: Roche further muddies water with more "mixed" messages about IL-33 in COPD)."Today's…results deliver the first two confirmatory Phase III trials for an IL-33 biologic," said Sharon Barr, AstraZeneca's executive vice president for biopharmaceuticals R&D, in a release Friday. "Tozorakimab works in a fundamentally different way from other biologics, inhibiting the signalling of the reduced and oxidised forms of IL-33 to both decrease inflammation and disrupt the cycle of mucus dysfunction that are key disease drivers in COPD."Full results from OBERON and TITANIA will be shared at a future medical meeting.Upcoming dataThe studies form part of AstraZeneca's broader LUNA programme, which also includes the ongoing PROSPERO and MIRANDA trials. PROSPERO is a long-term extension study assessing severe exacerbations over 104 weeks in 1713 patients who completed OBERON or TITANIA, while MIRANDA is evaluating a more frequent dosing regimen in 1454 patients by administering the drug once every two weeks. Both are expected to report results this half.Beyond COPD, tozorakimab is also being tested in a Phase III study in severe viral lower respiratory tract disease and in a mid-stage asthma study.