Corvus Pharmaceuticals has announced that the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), has initiated a Phase 2 clinical trial investigating soquelitinib for the treatment of autoimmune lymphoproliferative syndrome (ALPS), a rare genetic disease that typically begins in early childhood.
The trial will be led by V. Koneti Rao, MD, FRCPA, Senior Research Physician at the Primary Immune Deficiency Clinic (ALPS Clinic) at NIH Clinical Center, who previously presented preclinical data supporting soquelitinib's potential in ALPS patients. Additional trial sites include Children's Hospital of Philadelphia and Texas Children's Cancer and Hematology Center.
Understanding ALPS and Current Treatment Challenges
ALPS is a rare genetic disorder most commonly caused by mutations in the Fas gene, which provides instructions for making a protein involved in programmed cell death (apoptosis). When this protein is defective or missing, T cells accumulate abnormally, disrupting immune system function and leading to characteristic symptoms including enlarged lymph nodes, splenomegaly, and low blood counts (cytopenias).
"ALPS typically begins to manifest by age two and most patients live into adulthood with burdensome symptoms often related to refractory autoimmune cytopenias," explained Dr. Rao. "This requires ongoing surveillance and the risk for potentially fatal conditions such as infection, hemorrhage and malignant lymphoma."
Currently, there is no cure for ALPS. Management typically involves corticosteroids like prednisone and other immunosuppressive medications to address symptoms and complications. These approaches often come with significant side effects and do not address the underlying disease mechanism.
Trial Design and Endpoints
The Phase 2 clinical trial (NCT06730126) will enroll up to 30 patients aged 16 or older with confirmed ALPS-FAS based on genetic testing. The study will evaluate two dosing cohorts, with patients receiving soquelitinib at either 200 mg or 400 mg twice daily for up to 360 days.
The primary endpoint focuses on efficacy as determined by reductions in splenomegaly and lymph node volumes, measured by computed tomography (CT) or positron emission tomography/computed tomography (PET/CT). The trial will also assess improvements in cytopenias through complete blood count (CBC) measurements.
"Improvements in cytopenias can improve quality of life and overall health, and they also serve as a valuable biomarker associated with ALPS disease activity," noted the company in its announcement. Secondary endpoints include safety and tolerability assessments.
Mechanism of Action: ITK Inhibition
Soquelitinib (formerly CPI-818) is an investigational oral small molecule drug designed to selectively inhibit interleukin-2-inducible T cell kinase (ITK), an enzyme predominantly expressed in T cells that plays a crucial role in T cell and natural killer cell immune function.
Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus, highlighted the scientific rationale: "There is compelling preclinical evidence that soquelitinib may address the immune dysregulation in T cells that is a hallmark of the disease. It also bridges the biology of T cell lymphomas and autoimmunity, highlighting the role that ITK inhibition may play in restoring immune balance in lymphoma and immune disease."
The drug has been shown to affect T cell differentiation, inducing the generation of Th1 helper cells while blocking the development of both Th2 and Th17 cells and their associated cytokines. Recent studies have demonstrated that ITK controls a switch between the differentiation of Th17 proinflammatory cells and T regulatory suppressor cells, with ITK inhibition shifting toward T regulatory cell differentiation.
Expanding Clinical Development Program
This ALPS trial marks the third indication under clinical development for soquelitinib. The drug is also being evaluated in:
- A registrational Phase 3 trial for peripheral T cell lymphoma (PTCL)
- A Phase 1 trial for atopic dermatitis (AD)
Additionally, Corvus plans to initiate a Phase 1 clinical trial of soquelitinib in patients with solid tumors in the second quarter of 2025, further expanding the potential applications of ITK inhibition.
Expert Perspective
"Developing safe and effective targeted treatments to address ALPS and related disorders is a priority at the NIAID since this condition was first discovered in NIAID in the early 1990s," said Dr. Rao. "We look forward to investigating the potential of ITK inhibition with soquelitinib to improve immune system balance and reduce the buildup of dysfunctional T cells in lymph nodes and spleens and autoantibodies that drive the disease."
The initiation of this trial represents a significant step forward in addressing an unmet medical need for patients with ALPS, potentially offering a targeted approach to a disease that currently lacks effective treatment options.
