AstraZeneca Sees SOURCE Tezepelumab Failure In Asthma
Comes After Delay For Roxadustat In The US
Executive Summary
The SOURCE failure is a reversal for the novel Amgen-partnered TSLP inhibitor after NAVIGATOR success last month, and comes just days after the US FDA requested more analyses of the pivotal data for the kidney disease anemia therapy roxadustat.
AstraZeneca PLC has had a disappointing few days with two novel products, with the topline failure of the Phase III SOURCE study of its asthma candidate tezepelumab coming on top of a US approval delay for the anemia in kidney disease therapy roxadustat, announced on 18 December. The UK company had better news, however, with the expanded US approval for Tagrisso (osimertinib) for early-stage EGFR mutant non-small cell lung cancer on the ADUARA study on 21 December.
The initial data from SOURCE show that the potential first-in-class thymic stromal lymphopoietin (TSLP) inhibitor, being jointly developed with Amgen, Inc., missed the primary endpoint of reduction in daily oral corticosteroid (OCS) treatment, without loss of asthma control, in 150 asthma patients who require maintenance OCS use on top of standard of care (SoC).
Mene Pangalos, head of biopharmaceuticals R&D, said AstraZeneca’s initial analysis of SOURCE indicated that the trial design may have contributed to the primary endpoint result. Further analysis is underway. In the trial, patients were randomized to receive tezepelumab 210mg every four weeks or placebo as add-on therapy, with patients maintained on their currently prescribed OCS plus LABA (long-acting beta 2 agonist), with or without other asthma controller therapy.
Despite the setback, Pangalos is confident that the drug will succeed, saying the totality of the evidence, particularly given the recent data from the registrational NAVIGATOR trial, plus the Phase IIb PATHWAY study means tezepelumab still has the potential “to improve care for a broad population of severe asthma patients.” Tezepelumab’s effect on other efficacy parameters was similar to those observed in previous trials, including NAVIGATOR.
The topline data from NAVIGATOR, reported last month, showed that when tezepelumab was added to SoC in a broad population of severe uncontrolled asthmatics, the human monoclonal antibody was associated with a significant and clinically meaningful reduction in the annualized asthma exacerbation rate over 52 weeks, compared with placebo, including in patients with low eosinophil levels.
Regulatory filings are expected for tezepelumab in the first half of 2021. There are around 34 million people worldwide with severe asthma, the companies estimate.
Under a 2012 collaboration which was amended in early 2020, AstraZeneca and Amgen will jointly commercialize tezepelumab in the US and Canada, while AstraZeneca will solely market it in other countries. The US Food and Drug Administation in 2018 granted breakthrough therapy designation to the product for patients with severe asthma without an eosinophilic phenotype.
The product is one of number of pipeline assets that are crucial to Amgen’s plans to combat declining revenues for multiple blockbusters facing biosimilar and generic competition, such as Neulasta (pegfilgrastim) and Neupogen (filgrastim) for neutropenia, anemia therapy Epogen (epoetin alfa) and Sensipar (cinacalcet) for hyperparathyroidism. SC143199
Roxadustat FDA Delay
Meanwhile, AstraZeneca and its partner FibroGen announced on 18 December that they needed to provide additional clarifying analyses to gain the approval from the FDA for roxadustat, their oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor for patients with anemia of chronic kidney disease (CKD).
The FDA wants the clinical data analyses to complete its review of the roxadustat new drug application and the two companies said they would submit them as soon as possible to assist with the labelling discussions. The NDA was based on a pivotal Phase III program in more than 8,000 patients.
It appears the issue surrounds the safety component of the label and a possible need for a black box warning.
Roxadustat is the lead product in this new class of anemia therapies, and having a label showing a better safety profile than existing standard erythropoiesis-stimulating agents (ESAs) will be a key differentiator.
ESAs, such as Amgen’s Epogen (epoetin alpha), are well-established treatments for several classes of anemia, but the injectable drugs are linked with thromboses and cardiovascular events.
On 21 December, AstraZeneca told analysts that the delay did not change its expectations for the drug’s overall commercial opportunity.
Analysts at SVB Leerink said in a 21 December note, “While AstraZeneca did not provide details about the FDA's request during the call, management comments suggest to us that it may be related to roxa's cardiovascular event analysis … rather than efficacy or manufacturing issues.”
Considering cardiovascular events are the leading cause of death in all CKD patients, they believe that the FDA is taking care to validate the adjudication of the cardiovascular events in the active and control arms of the trials, including both major adverse cardiac and other events. “Small differences in the determination of such events can have a significant difference in the perceived risk-benefit for any medicine in CKD, and are also necessary to reach agreement between agency and sponsor on safety labelling ,” the analysts said. They now expect a Q3 2021 launch for the product, which Astra Zeneca had previously suggested would likely come in April based on a December approval to give time for payer and CMS/Medicare negotiations.
Both AstraZeneca and Fibrogen are hopeful that they can respond to the FDA’s request swiftly and a decision could come before the 20 March deadline. No advisory panel meeting is expected.
Roxadustat is already approved in China, Japan (as Evrenzo) and Chile for the treatment of anemia in CKD in both non-dialysis and dialysis-dependent adult patients.
An EU Marketing Authorisation Application as Evrenzo for the treatment of anemia in CKD was submitted by Astellas Pharma Inc and accepted for review in May 2020. Astellas has rights to the product in CIS countries, Europe, Japan, Middle East and South Africa.