Date: 2012-12-13
Type of information: Granting of a Market Authorisation in the EU
Product name: Xofigo®/Alpharadin®
Compound: radium-223 dichloride
Therapeutic area: Cancer - Oncology
Action mechanism: Alpharadin® (radium-223 chloride) is containing an alpha-particle emitting nuclide. This compound mimics many of the behaviors of calcium in the bone to target areas of high bone turnover in and around bone metastases.
Company: Bayer HealthCare (Germany)
Disease: castration-resistant prostate cancer (CRPC) patients with bone metastases
Latest news: * On November 15, 2013, Bayer HealthCare has announced that the European Commission (EC) has granted marketing authorisation for Xofigo® 1000 kBq/ml, solution for injection (radium Ra 223 dichloride) for the treatment of adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases. This decision follows a positive recommendation from the European Committee for Medicinal Products for Human Use (CHMP) in September of this year. In September 2009, Bayer has signed an agreement with Algeta ASA (Oslo, Norway) for the development and commercialization of radium-223. Under the terms of the agreement, Bayer will develop, apply for global health authority approvals, and commercialize radium-223 globally. Algeta will co-promote radium-223 with Bayer in the US. The ALSYMPCA trial was initiated by Algeta in June 2008.
* On September 20, 2013, Algeta and Bayer have announced that Bayer has received a positive opinion from the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) recommending radium Ra 223 dichloride (radium-223) for approval with a proposed indication for the treatment of adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases. The CHMP recommendation is based on data from the pivotal phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) trial. The benefits with Xofigo® are its ability to improve survival and to delay skeletal-related events (such as pathological fractures, spinal cord compression and use of radiation to relieve symptoms or surgery to treat complications). The most common side effects are diarrhoea, nausea, vomiting and thrombocytopenia. A pharmacovigilance plan for Xofigo® will be implemented as part of the marketing authorisation.
* On May 30, 2013, Algeta has announced that Xofigo® (radium Ra 223 dichloride) injection, recently approved by the FDA for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease, has been launched in the United States and the first sale has been made.The first commercial sale of Xofigo triggers a € 50 million milestone payment to Algeta from Bayer under the terms of the 2009 development and licensing agreement. Bayer has worldwide exclusive marketing rights for Xofigo.
* On May 15, 2013, the FDA approved radium Ra 223 dichloride (Xofigo® Injection, Bayer HealthCare Pharmaceuticals Inc.) for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.
The approval was based on a double-blind, randomized, placebo-controlled trial in patients with metastatic castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease. Patients were allocated 2:1 to Xofigo®, 50 kBq/kg (1.35 microcurie/kg), intravenously, every 4 weeks for 6 cycles plus best standard of care (N=541) or to matching placebo plus best standard of care (N=268). Best standard of care included local radiotherapy, corticosteroids, anti-androgens, estrogens, estramustine or ketoconazole. All patients were to continue androgen deprivation therapy. The median age was 71 years, 94% were Caucasian, 86% had an ECOG performance status of 0-1, and 58% had received prior docetaxel. Fifty-four percent of patients used opiate and 44% used non-opiate pain medications. Overall survival (OS) was the primary endpoint.
At the pre-specified interim analysis, a statistically significant improvement in OS was demonstrated [HR 0.70 (95% CI: 0.55, 0.88), p = 0.00185]. The median OS was 14.0 and 11.2 months in the Xofigo and placebo arms, respectively. The improvement in OS was supported by a delay in time- to- first symptomatic skeletal event favoring the Xofigo® arm.
The most common (> 10%) adverse reactions in patients receiving Xofigo® were nausea, diarrhea, vomiting, and peripheral edema. The most common (> 10%) hematologic laboratory abnormalities were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia. Two percent of patients on the Xofigo® arm experienced bone marrow failure or ongoing pancytopenia. No patients on the placebo arm experienced bone marrow failure or pancytopenia.
The recommended dose and schedule for Xofigo® is 50 kBq/kg (1.35 microcuries/kg) administered by slow intravenous injection over 1 minute every 4 weeks for 6 doses.
* On February 13, 2013, Bayer HealthCare has announced that the FDA has granted priority review to the New Drug Application (NDA) filed in December 2012 for the investigational oncology compound radium-223 dichloride (radium-223). The application is under review for the treatment of castration-resistant prostate cancer (CRPC) patients with bone metastases. In January 2013, the U.S. Nuclear Regulatory Commission (NRC) issued a licensing decision on the medical use of radium-223. The decision states that U.S. medical sites can procure and administer radium-223 under 10 CFR Part 35, Subpart E, which includes 10 CFR § 35.300.
* On December 14, 2012, Bayer HealthCare has announced that the company has submitted a Marketing Authorization Application to the FDA for radium-223 dichloride (radium-223) for the treatment of castration-resistant prostate cancer (CRPC) patients with bone metastases.
* On December 12, 2012, Bayer HealthCare has announced that the company has submitted a Marketing Authorization Application to the European Medicines Agency (EMA) for radium-223 dichloride (radium-223) for the treatment of castration-resistant prostate cancer (CRPC) patients with bone metastases.
The submission is based on data from the pivotal Phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) trial. In the study, radium-223 significantly increased overall survival by 44 percent (HR=0.695, p=0.00007), resulting in a 30.5 percent reduction in the risk of death compared to placebo. The median overall survival (OS) benefit in patients with radium-223 was 3.6 months, based on 14.9 months OS with radium-223 plus best standard of care (BSoC) vs. 11.3 months with placebo plus BSoC. Updated results and analysis were presented at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) in June 2012 and at at the ESMO 2012 Congress in October 2012.
The most common hematologic adverse events for patients treated with radium-223 and best standard of care (BSoC) and compared to placebo and BSoC included anemia (31% vs. 31%), neutropenia (5% vs. 1%) and thrombocytopenia (12% vs. 6%). With respect to Grade 3 and 4 adverse events, the most common events included anemia (13% vs. 13%), neutropenia (2% vs. 1%) and thrombocytopenia (6% vs. 2%). The most common non-hematologic adverse events in patients treated with radium-223 and BSoC compared to placebo and BSoC included bone pain (50% vs. 62%), nausea (36% vs. 35%), diarrhea (25% vs. 15%) and vomiting (19% vs. 14%). With respect to Grade 3 to 4 adverse events, the most common events included bone pain (21% vs. 26%).
Patents:
Submission of marketing authorization application USA : 2012-12-14
Submission of marketing authorization application UE: 2012-12-12
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2013-05-15
UE authorization: 2013-11-15
Favourable opinion UE: 2013-09-19
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: OTC status: Other news:
