Access to Radium-223 Restored Following Brief Suspension

Bayer HealthCare Pharmaceuticals restored access to radium-223 dichloride (Xofigo) following a temporary suspension in production to adjust its manufacturing process to meet certain quality standards that the company has in place.

Bayer HealthCare Pharmaceuticals restored access to radium-223 dichloride (Xofigo) following a temporary suspension in production to adjust its manufacturing process to meet certain quality standards that the company has in place.

"Some of the product did not meet the quality standards that we have in place, and therefore we made the decision not to distribute that into the market for patient use," Shannon Campbell, vice president and general manager of Oncology at Bayer, said in an interview withTargeted Oncology. "Xofigo has resumed production. We have supply here in the US now and we have begun patient treatments again starting this week."

The FDA reported a shortage of the novel radiopharmaceutical on October 7, 2014. The alpha-particle emitting agent has an 11-day half-life and a 28-day shelf life, resulting in quick exhaustion of the supply.

"As we looked back at the batches that were involved, we have quality standards in place, and what we found were there were some small fibrous particles that were present in some of the vials," Campbell said. "That triggered a very thorough, investigative process, and it was really through that process that we determined that the fibrous particles were actually coming from the stoppers, which are the parts that are used to seal the vials while they're transported."

Following the discovery of the particles, Bayer worked with the FDA to put a filtering process in place for preparing patient-ready dose syringes. In the US, the primary distributor for radium-223 is Cardinal Health, who will place a filter between the vial and syringe during dose withdrawal. This step will not alter the therapeutic profile, Bayer noted.

"What we have done, together in consultation with the FDA, is put in place a program of both corrective as well as preventive measures to resume production and ensure that the quality standards that we have in place can be met," Campbell said.

Radium-223 gained approval from the FDA in May 2013 as a treatment for men with symptomatic metastatic castration-resistant prostate cancer (mCRPC) that had spread to the bones but not to any other organs based on findings from the phase III ALSYMPCA trial.

In this study, patients with mCRPC were randomized in a 2:1 ratio to best supportive care with radium-223 (n = 541) or placebo (n = 268). Radium-223 was administered at 50 kBq/kg every 4 weeks for 6 cycles. Best standard of care included local radiotherapy, corticosteroids, antiandrogens, estrogens, estramustine, or ketoconazole.

At an interim analysis, the median OS was 14 months with radium-223 and 11.2 months with placebo (HR = 0.70; 95% CI, 0.55-0.88;P= .00185). The time to the first skeletal-related event was a median of 15.6 months in the radium-223 arm versus 9.8 months with placebo (HR = 0.658; 95% CI, 0.52-0.83;P= .00037).

"Given that we're just resuming supply right now, what we're doing is working really hard to ensure that all existing patients and patients who may have had delayed treatment as a result of this drug shortage have the opportunity to get all of their treatments rescheduled," Campbell said. "We're working with the physicians and clinical investigators to really manage that situation with the goal of getting all existing patients rescheduled as quickly as possible."

A recent analysis published inLancet Oncologydemonstrated that radium-223 is effective and well tolerated regardless of prior docetaxel administration in patients with CRPC who have symptomatic bone metastases. This analysis was based on a subset of patients who received docetaxel prior to randomization in the ALSYMPCA trial.

In the trial, 57% of enrolled patients received docetaxel prior to randomization to radium-223 (n = 352) or placebo (n = 174). The median OS was similar between the two groups of patients. The HR for OS in those receiving prior docetaxel was 0.70 (95% CI, 0.56—0.88;P= .002). In untreated patients, the HR was 0.69 (0.52—0.92;P= .01).

Treatment with radium-223 following docetaxel demonstrated an extension in the time to first symptomatic skeletal event compared with placebo. However, a statistically significant extension was not observed in those who were not previously treated with docetaxel.

For patients treated with radium-223, grade 3/4 adverse events were observed in 62% with prior docetaxel compared with 54% in those who were chemotherapy-naive. Those treated with docetaxel had a higher incidence of grade 3/4 thrombocytopenia (9% vs 3% with placebo). The incidence of thrombocytopenia was similar in patients who were not treated with docetaxel between the radium-223 and placebo arms (3% vs 1%).

Given the short duration of the shortage, it is unlikely that an impact on outcomes will be noted. The FDA recommended schedule for radium-223 is every 4 weeks for 6 doses. In clinical trials, 8 weeks occasionally passed between cycles.

"Given that we've been out for about 4 weeks, we know that there may be patients who as a result of the delay may have been switched to alternative treatments. For those patients, yes, if certain conditions are met, those patients are eligible for reimbursement for certain costs," Campbell added. "For details around that and to understand the eligibility requirement around that contact the Bayer call center, at 1-888-842-2937."