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The Orladeyo Resubmission Journey: From FDA CRL to Approval

Categories: Clinical Studies / Therapeutic Areas
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Hello Regulatory Scientists, 

Today, let’s explore the journey of Orladeyo (berotralstat) from receiving an FDA Complete Response Letter (CRL) to achieving approval. This case study provides valuable insights and lessons that can guide companies developing new drugs today. 

Regulatory History and Initial Submission 

Drug: Orladeyo (berotralstat) 
Mechanism of Action: Kallikrein inhibitor, which prevents attacks of hereditary angioedema (HAE) by inhibiting the kallikrein-kinin system 
Indication: Prevention of attacks in patients with hereditary angioedema (HAE) 
Initial Submission Date: March 2019 

The Complete Response Letter (CRL) 

CRL Date: December 2019 
CRL Concerns: 

  1. Efficacy Data: The FDA requested additional data to confirm the efficacy of Orladeyo, particularly over a longer duration. 
  1. Safety Data: Concerns were raised about the long-term safety profile, requiring more comprehensive data. 
  1. Risk Management Plan: Need for a robust risk management plan to monitor and mitigate potential adverse effects. 

Resubmission Strategy 

BioCryst Pharmaceuticals, the company behind Orladeyo, implemented a comprehensive strategy to address the FDA’s concerns: 

  1. Extended Clinical Trials: Conducted additional studies to gather more robust data on the efficacy of Orladeyo over a longer duration. 
  1. Enhanced Safety Monitoring: Provided more detailed safety data, focusing on long-term use and potential adverse effects. 
  1. Risk Management Plan: Developed a detailed risk management plan, including patient monitoring guidelines and educational materials for healthcare providers. 
  1. Continuous FDA Engagement: Maintained open lines of communication with the FDA to ensure alignment on the resubmission strategy and clarify any outstanding questions. 

Resubmission Date: June 2020 

Outcome 

Approval Date: December 2020 
Orladeyo was approved for the prevention of attacks in patients with hereditary angioedema, providing a new, oral treatment option for this rare condition. 

Lessons Learned 

The journey of Orladeyo from CRL to approval highlights several key lessons for drug developers: 

  1. Extended Efficacy Data: Providing long-term efficacy data is crucial to demonstrate the sustained benefits of the drug. 
  1. Comprehensive Safety Monitoring: Ensuring thorough understanding and communication of the long-term safety profile can help address regulatory concerns. 
  1. Effective Risk Management: Developing and implementing a detailed risk management plan can help mitigate potential adverse effects and ensure patient safety. 
  1. Continuous FDA Engagement: Maintaining open and ongoing communication with the FDA helps align development efforts with regulatory expectations. 
  1. Proactive Data Collection: Conducting additional studies and analyses proactively can address potential concerns before they become major issues. 

Relevance for Current Drug Developers 

For companies developing drugs today, the Orladeyo case underscores the importance of strategic planning and meticulous attention to detail in the regulatory process. Here are some takeaways to help avoid a CRL and achieve first-cycle approval: 

  1. Thorough Pre-Submission Preparation: Ensure that all aspects of your submission, including long-term efficacy and safety data, meet FDA standards. 
  1. Proactive Risk Management: Identify and address potential risks early in the development process to prevent issues from arising during FDA review. 
  1. Engage with the FDA Early and Often: Regular interactions with the FDA can provide valuable guidance and help steer the development process. 
  1. Invest in Comprehensive Data: Prioritize the collection of high-quality, detailed safety and efficacy data to support the submission. 
  1. Utilize Advisory Committees: Seek feedback from advisory committees to validate data and address potential concerns, even if formal hearings are not required. 

By learning from the Orladeyo resubmission experience, current drug developers can better navigate the regulatory landscape, avoid common pitfalls, and increase the likelihood of a successful first review cycle approval. 

Stay diligent and strategic, 

CERES Regulatory Services 

Picture of Asad Khan
Asad Khan