223Ra-Radium Dichloride (Xofigo)

Description

²²³Ra-Radium Dichloride (Xofigo), also known as Radium-223 dichloride, BAY88-8223, or Xofigo® (formerly ²²³Ra-Alpharadin), is a radioactive salt developed by Algeta ASA. It targets cancers that commonly metastasize to the bone. Unlike earlier radiotherapeutics, which were limited to pain palliation, ²²³Ra has demonstrated a significant improvement in overall survival (OS) in phase III trials, establishing its role as a therapeutic agent.

In 2009, Bayer Healthcare Pharmaceuticals Inc. acquired Xofigo from Algeta for approximately $800 million (€615 million) and a significant royalty agreement. Bayer subsequently gained global health authority approvals, commercialized Xofigo, and acquired Algeta outright in 2014.

• Regulatory Milestones:
  • US FDA Approval: May 15, 2013.
  • European Medicines Agency (EMA) Approval: November 2013.
  • Japan Approval: March 2016.

Clinical Applications

Xofigo is approved in over 40 countries, including the US, EU, and Japan, for:

• Castration-Resistant Prostate Cancer (CRPC):
  • Specifically in patients with symptomatic bone metastases and no known visceral metastatic disease.

Mechanism of Action:

• Radium-223 mimics calcium and targets bone mineral hydroxyapatite at areas of increased bone turnover, such as metastases.
• The high linear energy transfer of alpha particles induces double-strand DNA breaks in tumor cells, providing a localized anti-tumor effect.
• The short range of alpha particles (<100 µm) minimizes damage to surrounding healthy tissue.

Clinical Trial Evidence:

• The ALSYMPCA trial (921 patients, 100 centers, 19 countries) demonstrated:
  • A 30.5% reduction in the risk of death compared to placebo.
  • Median OS of 14.9 months with ²²³Ra versus 11.3 months with placebo.

Dosage:

• Administered as 50 kBq (1.35 µCi) per kg of body weight every 4 weeks for six injections.
• Each vial contains 6 mL of 1 MBq/mL solution (total 0.16 mCi or 6 MBq per vial).

Production and Costs

• A dedicated manufacturing facility in Indianapolis, operated by Cardinal Health, was completed in 2017.
• Cost:
  • US: ~$69,000 for six injections.
  • Europe: €35,000–€40,000.

Market Performance and Sales

• Initial market potential was estimated at €800 million ($1 billion) annually by 2017.
• Actual sales have not exceeded $500 million annually, primarily due to high costs and limited patient benefit.
• 2021 Sales: €130 million for the first half of the year.

Competition

223Ra-Radium Dichloride (Xofigo) is unique as the only bone-targeted agent with demonstrated OS benefits, albeit modest (3 months). However, new CRPC treatments (e.g., Provenge, Zytiga, Xtandi) present competition. Other bone-targeted radiopharmaceuticals, such as:

• ¹⁵³Sm-Lexidronam (Quadramet), ⁸⁹Sr-Sodium Chloride (Metastron), and ³²P-Sodium Phosphate lack OS benefits but share palliative roles.

Emerging therapies like ¹⁸⁸Re-HEDP and ¹⁷⁷Lu-PSMA/²²⁵Ac-PSMA analogues are anticipated to challenge Xofigo’s market share, offering potential improvements in survival.

Challenges and Opportunities

• Side Effects: EMA warnings (2017) noted increased post-treatment fractures, even in monotherapy settings. These findings contributed to stagnating sales.
• Market Dynamics:
  • Alpha-emitter products, such as ²²³Ra, have spurred broader pharmaceutical interest in nuclear medicine.
  • The high price ($69,000 per treatment course) aligns with similar therapies but limits accessibility.
  • Reimbursement policies and funding decisions are critical to sustaining growth.

Future Prospects:

• Continued development of Bayer’s radiotherapeutic pipeline, including ²²⁷Th-labeled molecules, depends on market performance and clinical outcomes.
• Advancements in ¹⁷⁷Lu-PSMA and ²²⁵Ac-PSMA analogues could overshadow Xofigo’s therapeutic role.

Conclusion

²²³Ra-Radium Dichloride (Xofigo) represents a breakthrough in nuclear medicine with its ability to extend survival in CRPC patients with bone metastases. However, challenges in pricing, side effects, and competition may limit its long-term market dominance. As new therapies emerge, Xofigo’s future will depend on its ability to adapt to an evolving therapeutic landscape while maintaining its role in specialized cancer care.