FDA Grants Orphan Drug Status to Sanofi's Rilzabrutinib for SCD

The US Food and Drug Administration (FDA) has granted orphan drug designation to rilzabrutinib, a novel oral Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of sickle cell disease.

This investigational drug is designed to reduce vaso-occlusive crises (VOCs), a hallmark of sickle cell disease that may arise from inflammation and immune system dysregulation.

The orphan drug designation applies to investigational therapies intended for the treatment of rare medical conditions affecting fewer than 200,000 individuals in the United States.

This designation is an important regulatory milestone that provides several incentives to support drug development, including tax credits, user fee waivers, and a potential seven-year marketing exclusivity period upon approval.

A Fourth Orphan Drug Designation for Rilzabrutinib

Expanding Potential in Rare Disease Therapeutics

This is the fourth orphan drug designation granted to rilzabrutinib. Karin Knobe, MD, PhD, Global Head of Development for Rare Diseases at Sanofi, highlighted the company’s dedication to rare disease communities.

She stated, “Receiving our fourth orphan drug designation for rilzabrutinib reinforces our continued dedication to developing medicines to address the unmet medical needs of people living with rare diseases. People with sickle cell disease often live with severe episodes of pain from vaso-occlusive crises and other complications that can significantly impact both quality of life and life expectancy.”

Addressing the Burden of Vaso-Occlusive Crises

Knobe emphasized the urgent need for innovative treatments that go beyond pain management. She noted that modulating immune system responses could offer a new way to address disease pathogenesis and reduce VOC frequency.

Current Regulatory Status and Clinical Development

Rilzabrutinib is currently under regulatory review in the US, EU, and China for its use in immune thrombocytopenia (ITP), another rare immune-mediated condition. In the US, the therapy has been granted fast track designation, with the FDA’s target action date for a decision on ITP set for August 29, 2025.

Previous Orphan Drug Designations

In addition to its new designation for sickle cell disease, rilzabrutinib holds orphan drug status in:

• Immune thrombocytopenia (ITP) – US, EU, Japan
• Warm autoimmune hemolytic anemia (wAIHA) – US, EU
• IgG4-related disease (IgG4-RD) – US

Emerging Data from Sickle Cell Disease Research

Promising Preclinical Evidence

Preclinical data shared at ASH 2024 showed that rilzabrutinib helped reduce both inflammation and vaso-occlusion in transgenic mice with sickle cell disease. Vaso-occlusion refers to the blockage of small blood vessels, a major contributor to acute pain episodes and organ damage in patients.

These findings suggest that rilzabrutinib’s mechanism may translate into clinical benefit by interrupting immune-mediated drivers of vascular blockage, which are not adequately addressed by current standard-of-care therapies.

Mechanism of Action: Multi-Immune Modulation

Rilzabrutinib is an oral, reversible inhibitor of Bruton's tyrosine kinase, a critical signaling molecule in multiple immune cells, including B cells and macrophages. It has been engineered using Sanofi’s proprietary Tailored Covalency technology, which enables selective inhibition of BTK while potentially minimizing off-target effects and unwanted immune suppression.

This multi-immune modulation approach aims to restore immune balance and reduce inflammation across a spectrum of rare immune-mediated or inflammatory conditions. It also positions rilzabrutinib as a potential alternative to broad immunosuppressants, which often carry a high risk of side effects.

Understanding the Disease: Sickle Cell Explained

Sickle cell disease is a group of rare inherited blood disorders characterized by misshapen red blood cells. These cells typically form a sickle or crescent shape, making it difficult for them to travel through small blood vessels. The resulting blockages can cause:

• Severe pain episodes (vaso-occlusive crises)
• Increased risk of infections
• Organ damage affecting the lungs, eyes, kidneys, and brain
• Reduced quality of life and life expectancy

Prevalence and Demographics in the US

• More than 100,000 people are affected by sickle cell disease in the US
• Approximately 90% of affected individuals are African American
• 3% to 9% are Hispanic or Latino
• 1 in 365 African American babies are born with the condition
• 1 in 13 African American babies are carriers of the sickle cell trait

Patients with sickle cell disease in the US have a life expectancy that is, on average, 20 years shorter than the general population. These statistics highlight the urgent need for effective therapies that address both the symptoms and underlying causes of the disease.

A Step Forward in Rare Disease Innovation

While the safety and efficacy of rilzabrutinib are still under investigation and have not been confirmed by any regulatory authority, the continued expansion of its orphan drug designations reflects growing confidence in its potential to transform care in multiple underserved diseases.

With multiple regulatory reviews underway and preclinical data supporting its role in modulating inflammatory and immune pathways, rilzabrutinib is emerging as a promising candidate in the landscape of rare disease drug development.

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