San Diego-based Anaptysbio Inc.’s phase II blowup with anti-IL-33 monoclonal antibody etokimab in chronic rhinosinusitis with nasal polyps (CRwNP), disclosed Aug. 10, followed the compound’s mid-stage atopic dermatitis (AD) fizzle in November of last year, and raised questions not only about the lead candidate but also about the target.
Patients in the CRwNP study called Eclipse were given etokimab every four or eight weeks and failed to achieve statistically significant improvement in their bilateral nasal polyps score (NPS), an endoscopic measure of nasal occlusion, and in their sino-nasal outcome test (SNOT-22), a patient reported quality-of-life assessment, vs. placebo at the eighth week. Both endpoints turned up statistically significant improvement over baseline levels of NPS and SNOT-22, the company noted, and blood eosinophil levels – a biomarker of etokimab’s mechanism – yielded statistically significant reduction relative to baseline in both treatment arms. The company said it will determine next steps for the etokimab program after reviewing the week 16 primary endpoint by the end of this year.
Meanwhile, some of the IL-33 faithful are taking pause. Scientific papers have held out promise for the approach, but such hopes may be dwindling. In June of last year, Regeneron Pharmaceuticals Inc., of Tarrytown, N.Y., rolled out phase II proof of concept (POC) data with its IL-33 antibody, REGN-3500, showing that monotherapy trimmed the loss of asthma control and improved lung function compared to placebo. The greatest improvement was seen in patients with blood eosinophil levels ≥300 cells/microliter. Patients treated in the POC study with Regeneron’s IL-4 binder Dupixent (dupilumab) monotherapy did numerically better than REGN-3500 across all endpoints, although the trial was not powered to show differences between active treatment arms. Dupixent gained its first approval in AD in March 2017. Asthma was added to the label in October of 2018.
Pairing REGN-3500 with Dupixent in the trial didn’t yield increased benefit compared to IL-4 monotherapy, either – a finding that caused an Anaptysbio sell-off as investor skepticism regarding IL-33 mounted. But another way to interpret the combo results favored etokimab: If the dual therapy had proven better than Dupixent alone, Anaptysbio might have been in even more trouble. Wall Street optimists urged etokimab backers to wait for more data before giving up. Maybe the target wasn’t to blame, but instead the Regeneron antibody. Thousand Oaks, Calif.-based Amgen Inc.’s IL-4-targeting AMG-317, for example, fell short in a phase II asthma trial, yet Dupixent, with the same mechanism, not only did the job but won approval.
Now that the other shoe dropped has dropped for etokimab in CRwNP, the picture is less bright. Anaptysbio had made known plans to try the product in asthma, but RBC Capital analyst Kennan MacKay pointed out in an Aug. 10 report that about 36% of CRwNP also have asthma, and the poor results in the former indication represent “another strong signal that etokimab is unlikely to have any therapeutic benefit for patients” with the latter. He removed all etokimab risk-adjusted sales/revenue estimates and development costs from his model.
IL-4 remains intriguing. Among the players in that space is Pieris Pharmaceuticals Inc., of Boston, with PRS-060 (AZD-1402), an inhaled IL-4 receptor alpha-chain antagonist for asthma in the works as part of the global partnership with London-based Astrazeneca plc. The drug brought about a robust fractional exhaled nitric oxide, or FeNO, reduction in mild asthmatics in a phase I multiple ascending-dose study. Astrazeneca is in charge of all subsequent clinical development of PRS-060, including the start of the phase IIa study, expected in the fourth quarter of this year. Pieris holds the option to co-develop and to co-commercialize PRS-060 after the completion of the phase IIa experiment, details of which haven’t been disclosed. Improvement in the first second of forced breath, or FEV1, likely will be an important endpoint, though, since an inverse connection between FeNO and higher FEV1 has been shown – and the EMA recently approved Dupixent based on using FeNO as an asthma biomarker.
Asked for details on FeNO from the phase I bid, Pieris CEO Stephen Yoder said during the Aug. 10 conference call on earnings that his firm is “not at liberty to say a lot. I can say that, yes, as we disclosed that at [the European Respiratory Society meeting] last year, we had been very busy looking at the dose response curve, which included lower dose cohorts to look at the effect of lower doses on PK/PD, as we significantly reduce the FeNO, even at the lowest disclosed doses. That work is certainly used to inform a better understanding” of the curve, he said, as the partners find “the most efficient way, all things considered, to drive towards a phase II and then ultimately a registration in moderate-to-severe asthmatics. We have not finally aligned with Astrazeneca on when we would disclose the data and in what format,” he expects they will be made public “at a conference, most likely next year, once the phase II has started,” he said.