AstraZeneca announced that its investigational compound olaparib will not progress into Phase III development for the maintenance treatment of serous ovarian cancer. In addition, AstraZeneca announced that the second RENAISSANCE Phase III study of TC-5214 for patients with major depressive disorder did not meet its primary end point. As a result, AstraZeneca will take pre-tax impairment charges totalling $381.5 million to R&D expense in the fourth quarter of 2011. The company confirms its expectation for full year Core EPS in the range of $7.20 to $7.40, but with the inclusion of these intangible impairments, Core EPS is likely to be in the lower half of this range.
The decision to discontinue olaparib's development in serous ovarian cancer was made following a review of an interim analysis of a Phase II study (study 19) which indicated that the previously reported progression free survival benefit is unlikely to translate into an overall survival benefit, the definitive measure of patient benefit in ovarian cancer. In addition, attempts to identify a suitable tablet dose for use in Phase III studies have not been successful. No new safety concerns were identified for patients.
With respect to TC-5214, the second of four Phase III efficacy and tolerability studies of the compound as an adjunct therapy to an antidepressant in patients with major depressive disorder who do not respond adequately to initial antidepressant treatment, did not meet its primary end point. The target measure was change in the Montgomery-Asberg Depression Rating Scale total score after eight weeks of treatment with TC-5214 as compared to placebo. TC-5214 was overall well tolerated in RENAISSANCE 2 and showed an adverse event profile generally consistent with prior clinical trials of TC-5214. Analyses of the full data set from the RENAISSANCE 2 are ongoing.
These results follow the recent announcement of top-line results of the RENAISSANCE flexible dose trial study 3, which also did not meet its primary endpoint. AstraZeneca will continue with the development of the two remaining fixed dose Phase III RENAISSANCE efficacy and tolerability studies and one long-term safety study. Regulatory filing targets will be reviewed following full results of the remaining studies which are expected in the first half of 2012. A potential New Drug Application filing in the US is planned for the second half of 2012, with an EU Marketing Authorisation Application targeted for 2015.
As a result of the termination of further development of olaparib in serous ovarian cancer, the company is taking an impairment of $285 million pre-tax charge. A further impairment of $96.5 million pre-tax charge will also be taken based on the lower probability of success for the remaining TC-5214 studies. The value of the remaining intangible assets held in relation to TC-5214 amount to $96.5 million.
These impairments will have an approximately $0.21 negative impact on the company's Core EPS in the fourth quarter. The company's Core EPS guidance remains unchanged at between $7.20 and $7.40 per share, although it is now likely that Core EPS will be in the lower half of this range.
About Olaparib
Olaparib is an oral PARP inhibitor that exploits DNA repair pathways to preferentially kill cancer cells. Human cells have a number of repair pathways to maintain normal DNA integrity. Olaparib inhibits PARP that is involved in one of these DNA repair pathways (Base Excision Repair). Inhibition of PARP results in a build-up of DNA damage in the cell, requiring repair via an alternative pathway called Homologous Recombination repair (HR). Cancer cells that already have a damaged HR pathway are limited in their ability repairing their DNA, overloading them with DNA damage and causing them to die. Importantly, normal (non-cancer) cells, that have full DNA repair capacity are unaffected by PARP inhibition, resulting in tumour selective cell killing.
The investigational cancer treatment olaparib was acquired when AstraZeneca bought KuDOS Pharmaceuticals in 2005.
About The RENAISSANCE Programme
The RENAISSANCE Programme consists of five randomised, double-blind, placebo controlled Phase III studies. In RENAISSANCE study 2, 1,320 patients with MDD were screened at 45 sites in the United States and 25 sites in India. Of the patients screened, 710 initially received one of seven serotonin reuptake inhibitor (SSRI) or serotonin/norepinephrine reuptake inhibitor (SNRI) on an open label basis for eight weeks to determine the extent of therapeutic response. At the end of the eight weeks, 319 patients who did not respond adequately, based on predefined criteria, were randomized into the double blind phase of the study and received either a flexible dose of TC-5214 or placebo, twice daily, while continuing the SSRI or SNRI therapy for an additional eight weeks. The dosage of TC-5214 was initially 2 mg/day and could be increased at the discretion of the investigator to 4 mg/day and 8 mg/day based on tolerability and therapeutic response.
In addition to RENAISSANCE 2 and RENAISSANCE 3 (previously reported), the RENAISSANCE Programme includes two fixed dose studies (RENAISSANCE 4 and RENAISSANCE 5) designed to evaluate the efficacy and tolerability of TC-5214 as an adjunct treatment to SSRI/SNRI therapy and RENAISSANCE 7, a long-term safety study in which patients receive TC-5214 or placebo, plus baseline SSRI or SNRI, for one year.
About Targacept and AstraZeneca Collaboration
In December 2009, AstraZeneca and Targacept signed a collaboration and license agreement for the global development and commercialisation of TC-5214. The initial goal for the collaboration is to develop TC-5214 as an adjunct treatment for MDD in patients with an inadequate response to an SSRI or SNRI. TC-5214 is also being studied in a Phase 2b 'switch' monotherapy trial, known as the EXPLORER study, in patients with MDD who do not respond adequately to initial treatment with a SSRI or SNRI.
About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialisation of prescription medicines for gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.