Date: 2016-06-02
Type of information: Results
phase: 2-3
Announcement: results
Company: Intercell now Valneva (France - Austria) Novartis (Switzerland)
Product: Pseudomonas aeruginosa vaccine IC43/VLA43
Action
mechanism: vaccine. Valneva’s vaccine candidate IC43 is a recombinant subunit vaccine consisting of two outer membrane proteins (OprF and OprI) of Pseudomonas aeruginosa. These outer membrane proteins have been shown to be disease-relevant targets in numerous preclinical and several early clinical trials.
Disease: Pseudomonas aeruginosa infection
Therapeutic area: Infectious diseases
Country: Austria, Belgium, Czech Republic, Germany, Hungary, Spain
Trial
details: The current pivotal Phase II/III efficacy trial follows a previous randomized, placebo-controlled exploratory Phase II trial in which lower all-cause mortality rates were observed for the vaccine candidate at several dosage levels compared to placebo.The pivotal Phase II/III trial is a randomized, placebo-controlled double-blind study of IC43 expected to enrol a total of 800 ventilated intensive-care unit patients in approximately 40 study sites. Patients are vaccinated twice with either the Pseudomonas aeruginosa vaccine candidate or placebo at a 7-day interval in addition to the standard of care for ICU patients. The Pseudomonas aeruginosa vaccine candidate is used as a non-adjuvanted product formulation which was found to lead to the highest observed survival rates in the previous Phase II clinical study. The primary objective of the Phase II/III trial is to compare all-cause mortality rates at day 28 after first vaccination between the two study groups. Secondary objectives include comparison of infection related mortality rates and Pseudomonas aeruginosa infection rates between the groups and to investigate the vaccine candidate’s immunogenicity, safety and tolerability. The study has previously received positive scientific advice from the European Medicines Agency (EMA). (NCT01563263)
Latest
news: * On April 1, 2011, Intercell has agreed with Novartis to advance Intercell's investigational Pseudomonas aeruginosa vaccine into a confirmatory clinical efficacy trial in ventilated ICU (Intensive Care Unit) patients. * On June 2, 2016, Valneva announced Phase II/III results for its Pseudomonas aeruginosa vaccine candidate (VLA43).
The current Phase II/III study was a randomized, placebo-controlled, double-blind study of VLA43. It was conducted in 800 mechanically ventilated Intensive Care Unit (ICU) patients at 52 trial sites in 6 European countries. Patients were vaccinated twice with either the Pseudomonas aeruginosa vaccine candidate or a placebo at a 7-day interval, in conjunction with standard of care treatments for ICU patients.
While the trial confirmed good immunogenicity and an acceptable safety profile of the vaccine candidate, the primary endpoint of the Phase II/III trial was not met. Findings from a previous Phase II study that had shown a strong reduction in all-cause mortality were therefore not confirmed.
Overall survival, a secondary endpoint in the study, also did not differ between the VLA43 treatment group and the placebo group. Further study results on secondary endpoints, including Pseudomonas aeruginosa infection rates and sepsis-related mortality, will become available over the coming months and may provide additional insights into the clinical trial outcome and secondary endpoints. Valneva announced that "this outcome will not affect the key strategic direction the company has taken since the creation of Valneva". Valneva said that it is unlikely that GSK will exercise its option to the program under the Strategic Alliance Agreement (SAA). Valneva now expects to bring two vaccine candidates into Phase I in the short term.* On March 24, 2014, Valneva has announced the continuation of the current phase II/III clinical trial of its Pseudomonas aeruginosa vaccine candidate IC43. Valneva and its co-development partner decided to continue the trial following different assessments including analyses conducted by a Data Monitoring Committee (DMC) and consultation with two European regulatory agencies and experts. The continuation decision was taken since the interim analysis showed a clinically meaningful reduction in all-cause mortality rates for the vaccine group as compared to placebo and no safety concerns were observed. These findings were in-line with previous Phase II results. Valneva expects to resume recruitment for the trial in the second quarter of 2014. In addition to the 394 patients already enrolled, another 400 ventilated intensive care patients are planned initially to be enrolled in this second phase of the study in 40 different sites. Preliminary results are expected at the end of 2015 / early 2016.Although the difference on all-cause mortality between vaccine and placebo groups on day 28 (primary endpoint) at interim analysis was smaller than initially pre-specified, the development partners concurred to progress with the original sample size to potentially achieve statistical significance in this pivotal trial earlier on a potential route to licensure. The company is however also considering the option to extend the study further if needed and justified.* On October 30, 2013, Valneva has provided an update on the Phase II/III efficacy study interim analysis of its Pseudomonas aeruginosa vaccine candidate. The development partners – Valneva and Novartis Vaccines & Diagnostics have initiated discussions on trial continuation in agreement with the recommendations of a Data Monitoring Committee (DMC) following their data review on the primary efficacy endpoint and safety data from 394 patients. Although the stringent pre-specified futility criterion in regards to the primary efficacy endpoint was formally met, the difference in all-cause mortality rates (at Day 28) between the vaccine and placebogroup in this randomized, placebo controlled double blind study, was considered clinically meaningful and in line with the trend observed in the previous study. Additionally there were no concerns with regard to the observed safety profile. Possible protocol modifications, if needed, will be discussed with the DMC to enable re-initiation of the trial, which is anticipated today for early 2014.IC43 is targeted for ventilated Intensive Care (ICU) patients, who are only vaccinated at hospital admission and are at particular risk of life threatening Pseudomonas infections. The primary endpoint of the Phase II/III trial is the mortality rate from all causes of death (all-cause mortality) on Day 28. The futility analysis for the primary endpoint midway through the study, conducted in critically ill patients (or people), was factored into its design to allow early discontinuation , in case it would appear unlikely to see a meaningful vaccine effect when the study has been completed.The Pseudomonas aeruginosa program is part of a Strategic Alliance Agreement with Novartis Vaccines and Diagnostics, who is also co-financing the current Phase II/III pivotal efficacy trial. Valneva will give an update to its share- and stakeholders (including holders of preferred shares, the value of which is exclusively linked to the Pseudomonas vaccine) on next steps, impacts on its R&D strategy and other business implications in due course.
The planned double blind study is powered to show a clinically meaningful and statisticallysignificant reduction in overall mortality between the vaccine and control group and envisages enrolling about 800 subjects.
The trial is expected to be conducted in various countries, predominantly in the EU, involving up to 50 study sites. Two study groups, both receiving standard of care in addition to vaccine or placebo, will be compared. The subjects in the vaccine group which will comprise about 400 ventilated ICU patients will be vaccinated twice within a 7-day interval with the nonadjuvanted product formulation that was found to most impact observed survival.
Primary endpoint of the trial will be mortality at day 28 after first vaccination in both study groups.
Secondary objectives are to investigate Pseudomonas aeruginosa infections, infection?related mortality as well as immune response to the vaccine candidate and its safety and tolerability.
The study is subject to final regulatory concurrence and its start is planned for first half of 2012. Intercell will execute the trial and the costs will be shared with Novartis. This program is one of the development programs under the strategic alliance concluded between Intercell and Novartis in July 2007.
Next steps for the program will be decided based upon data from the planned efficacy trial, taking into consideration the Novartis option rights and the Intercell right to choose either profit'sharing or to receive milestones and royalties.
