First patients dosed in Grifols Phase III immunoglobulin trials

Grifols Doses First Patients in Two Phase III Immunoglobulin Trials

Grifols has initiated two separate Phase III clinical trials, SIGMA and XPERT, to support the US label expansion of its immunoglobulin therapies, Gamunex-C and Xembify. The SIGMA trial involves 50 participants with secondary immunodeficiency (SID), assessing the intravenous immunoglobulin Gamunex-C in combination with standard medical treatment. Concurrently, the XPERT trial is evaluating the subcutaneous immunoglobulin Xembify in approximately 40 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), comparing its pharmacokinetics, safety, and efficacy against Gamunex-C as maintenance therapy across US and European sites.

• The open-label, multi-centre, single-arm SIGMA trial is assessing Gamunex-C, an intravenous immunoglobulin (IVIg), in 50 participants with secondary immunodeficiency (SID). This includes individuals with hypogammaglobulinaemia and a history of B-cell chronic lymphocytic leukaemia, multiple myeloma, or non-Hodgkin lymphoma. The primary objective is to demonstrate a rate of serious bacterial infections less than one per participant per year.
• The multi-centre XPERT trial is evaluating the subcutaneous immunoglobulin (SCIg) Xembify in approximately 40 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Conducted across 20 sites in the US and Europe, the study aims to establish Xembify's non-inferiority to Gamunex-C, which is already indicated for CIDP in the US, by comparing their pharmacokinetics, safety, and efficacy as maintenance therapy.
• These Phase III trials are part of Grifols' ongoing immunoglobulin research program, which also includes the EXCELL trial, underscoring the company's commitment to providing flexible and convenient treatment options for patients. Additionally, Grifols' subsidiary GigaGen recently commenced a Phase I trial for GIGA-2339, a recombinant polyclonal drug candidate aimed at treating hepatitis B virus infection, further diversifying the company's pipeline.

Addressing Key Challenges in Secondary Immunodeficiency Treatment

Managing secondary immunodeficiency (SID) presents a distinct set of clinical challenges, particularly given the heterogeneity of underlying causes and the frequent difficulty in identifying affected patients. These limitations span diagnostic recognition, vaccination efficacy, and the practical constraints of definitive treatment.

• Diminished vaccine responsiveness: Immunocompromised SID patients often show reduced immunogenic response to vaccination, although studies still demonstrate meaningful protective effects—reducing complications, hospitalizations, treatment costs, and mortality.

• Restrictions on vaccine selection: Live vaccines are contraindicated in patients with severe immune impairment, limiting options to killed vaccines, which are highly recommended for SID patients.

• Diagnostic gaps and underrecognition: Up to 20% of patients with persistent symptoms, frequent exacerbations despite appropriate medical therapy, or other sinopulmonary conditions may harbor an underlying immunodeficiency that goes unidentified without targeted testing (e.g., CBC with differential, immunoglobulin levels, and pre-/post-vaccination pneumococcal titres).

• Atypical and severe clinical presentations: SID patients may present with atypical symptoms or unusual pathogens, and are at risk for severe complications—such as orbital or intracranial spread of disease—particularly in the context of acute bacterial rhinosinusitis.

• Limited reversibility of the underlying cause: While addressing the root cause of immunodeficiency is the optimal therapeutic goal, this is frequently impractical or unachievable in many SID patients, necessitating long-term supportive management instead.

• Reliance on immunoglobulin replacement for non-responders: In patients who fail diagnostic vaccination challenges (antibody failure), immunoglobulin replacement therapy becomes the mainstay of treatment—an intensive, ongoing intervention rather than a curative solution.

• Need for specialized, multidisciplinary care: Patients with comorbid chronic rhinosinusitis (CRS) and SID require more complex management than immunocompetent counterparts, including pneumococcal vaccination, judicious prophylactic and therapeutic antibiotic use, immunoglobulin replacement, and consideration of endoscopic sinus surgery.

• Variability in defining immune impairment: Although criteria exist to distinguish high- versus low-level immune impairment across different disease entities, this variability complicates standardized treatment decision-making across the SID population.

SIGMA Trial Design: Gamunex-C for Secondary Immunodeficiency

Recent non-interventional and retrospective studies have evaluated the use of immunoglobulin replacement therapy (IgRT) for treating secondary immunodeficiency (SID), particularly in patient populations with hematological malignancies. These analyses focus on key efficacy and safety endpoints, including infection rates, serum IgG levels, and treatment-related outcomes, providing real-world evidence on the role of IgRT in managing SID.