Introduction
Daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), has been under intense scrutiny for its potential to treat anemia associated with chronic kidney disease (CKD). Here, we delve into the clinical trials, market analysis, and projections for this promising drug.
Clinical Trials Overview
Phase III Trials: ASCEND Program
The ASCEND program, comprising five pivotal Phase III trials, has been instrumental in evaluating the efficacy and safety of daprodustat. The ASCEND-ND and ASCEND-D trials, presented at the American Society of Nephrology’s Kidney Week 2021, demonstrated that daprodustat improved or maintained haemoglobin levels within target ranges for patients with CKD, both on and off dialysis. These trials also showed that daprodustat achieved non-inferiority in major adverse cardiovascular events (MACE) compared to erythropoiesis-stimulating agents (ESAs)[1][3].
Additional Trials and Findings
Other trials within the ASCEND program, such as the ASCEND-TD, ASCEND-NHQ, and ASCEND-ID trials, provided further evidence of daprodustat's efficacy. The ASCEND-TD trial supported the use of three-times weekly dosing, in addition to the once-daily regimen. The ASCEND-NHQ trial showed significant improvements in haemoglobin levels and quality of life for non-dialysis dependent patients. The ASCEND-ID trial confirmed the ability of daprodustat to maintain haemoglobin levels in high-risk incident dialysis patients[1].
FDA and Regulatory Approvals
US FDA Approval
In February 2023, daprodustat, marketed as Jesduvroq in the U.S., became the first oral treatment for CKD-related anemia approved by the FDA, but only for patients on dialysis. The FDA's Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted in favor of the drug's benefits outweighing the risks for dialysis patients, but not for non-dialysis patients[3].
European Market Decision
Despite a positive opinion from the European Medicines Agency (EMA) for treating anemia in dialysis-dependent patients, GSK decided not to commercialize daprodustat in Europe. This decision was based on the reduced market opportunity, the EMA's limited indication to dialysis patients, and the presence of rival drugs like roxadustat (Evrenzo) and vadadustat (Vafseo)[2].
Market Analysis
Market Opportunity and Competition
The initial projections for daprodustat and other HIF-PHI drugs were highly optimistic, with predictions of blockbuster sales. However, the landscape has changed significantly due to regulatory hurdles and competition. In Europe, the presence of roxadustat and vadadustat has limited the market potential for daprodustat. In the U.S., while Jesduvroq is approved, its use is restricted to dialysis patients, further reducing its market potential[2].
Sales Performance and Projections
GSK had initially predicted peak sales of around £500 million to £1 billion for Jesduvroq, but these projections are now unlikely to be met. The drug's limited approval and market restrictions, combined with the performance of rival drugs, have dampened sales expectations. For example, roxadustat generated only $23 million in sales across Japan and the EU in the 12 months ending in March 2023[2].
Safety and Efficacy Concerns
Cardiovascular Safety
A significant concern for daprodustat and other HIF-PHI drugs has been their cardiovascular safety profile. While the ASCEND trials showed non-inferiority in MACE compared to ESAs, the FDA's CRDAC did not support the use of daprodustat for non-dialysis patients due to safety concerns. This has been a recurring theme in the regulatory reviews of these drugs across different regions[1][3].
Quality of Life and Patient Outcomes
Despite the safety concerns, daprodustat has shown positive impacts on patient quality of life. The ASCEND-NHQ trial demonstrated improvements in haemoglobin levels and reduced fatigue, as measured by the SF-36 vitality score, for non-dialysis dependent patients[1].
Future Prospects and Challenges
Global Availability
Currently, daprodustat is available in the U.S. and Japan, but GSK has decided against seeking approvals in other territories. This limits the drug's global reach and potential market impact[2].
Regulatory Discrepancies
The discrepancies in regulatory approvals across the U.S., EU, and Japan highlight the challenges faced by HIF-PHI drugs. These differences in regulatory standards and safety assessments have significantly influenced the market trajectory of these drugs[2].
Key Takeaways
- Clinical Trials Success: Daprodustat has shown positive efficacy and safety results in Phase III trials, particularly in the ASCEND program.
- Regulatory Approvals: Approved in the U.S. for dialysis patients but not for non-dialysis patients; not to be commercialized in Europe.
- Market Challenges: Limited market opportunity due to competition and regulatory restrictions.
- Safety Concerns: Cardiovascular safety remains a concern, affecting broader approval and use.
- Patient Outcomes: Improvements in haemoglobin levels and quality of life for patients on dialysis.
FAQs
What is daprodustat, and how does it work?
Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that works by stabilizing hypoxia-inducible factors, leading to the transcription of erythropoietin and other genes involved in correcting anemia.
Which regions is daprodustat approved in?
Daprodustat is approved in the U.S. and Japan but will not be commercialized in Europe or other territories.
What are the primary concerns regarding daprodustat?
The primary concerns include cardiovascular safety and the limited market opportunity due to regulatory restrictions and competition.
How does daprodustat compare to other HIF-PHI drugs?
Daprodustat faces similar challenges as other HIF-PHI drugs like roxadustat and vadadustat, including regulatory discrepancies and safety concerns, but has shown positive efficacy results in clinical trials.
What are the implications of GSK's decision not to commercialize daprodustat in Europe?
GSK's decision reflects the reduced market potential and the presence of rival drugs, which will limit the global reach and sales of daprodustat.
How has the FDA's CRDAC vote impacted daprodustat's approval?
The FDA's CRDAC vote supported the use of daprodustat for dialysis patients but not for non-dialysis patients, restricting its approval and market potential.
Sources
- GSK announces positive Phase III efficacy and safety data for daprodustat in patients with anaemia due to chronic kidney disease. GSK.
- GSK scraps plan to launch oral anemia drug beyond US, Japan. FiercePharma.
- GSK reports outcome from US FDA Advisory Committee meeting on daprodustat for anaemia of CKD. GSK.
- Daprodustat by GSK for Anemia in Chronic Kidney Disease (Renal Anemia). Pharmaceutical Technology.
- Efficacy and Safety of Daprodustat for Treatment of Anemia of CKD. JAMA Internal Medicine.
