FDA Fast-Tracks MALT1 Inhibitor in Relapsed/Refractory Waldenström Macroglobulinemia

US FDA

• SGR-1505 has received fast track designation from the FDA for the treatment of adult patients with Waldenström macroglobulinemia (WM) who have progressed after at least 2 prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor.
• SGR-1505 is an investigational mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) inhibitor.
• An ongoing phase 1 trial (NCT05544019) of SGR-1505 has demonstrated a favorable safety profile and good tolerability in patients with relapsed/refractory B-cell malignancies, including WM.

An investigational MALT1 inhibitor, SGR-1505, has received fast track designation from the FDA for the treatment of adult patients with WM who have progressed after at least 2 prior lines of therapy, including a BTK inhibitor. This designation underscores the significant unmet medical need in this patient population, particularly those who have developed resistance to existing therapies.¹

Waldenström macroglobulinemia is a rare, indolent B-cell lymphoma characterized by the overproduction of monoclonal IgM paraprotein. While BTK inhibitors have revolutionized the treatment landscape for WM, a growing number of patients experience treatment failure and disease progression, often due to acquired resistance mechanisms. This creates a critical need for novel therapeutic strategies that can offer durable responses and improved outcomes for these heavily pretreated individuals.

“We are excited to receive fast track designation for SGR-1505, which underscores the significant need in patients with Waldenström macroglobulinemia,” said Karen Akinsanya, PhD, president, head of therapeutics research and development and chief strategy officer, partnerships at Schrödinger Inc, in a press release. “Despite the continued therapeutic advances in the treatment of hematologic malignancies, treatment failure and disease progression due to BTK resistance remains a challenge for a growing number of patients. This unmet need represents an opportunity for novel mechanisms such as MALT1 as monotherapy and as part of new combination regimens.”

The MALT1 inhibitor targets a pivotal enzyme in the NF-κB signaling pathway, which is aberrantly activated in various B-cell malignancies, including WM. MALT1 acts downstream of BTK, suggesting its potential to overcome BTK inhibitor resistance by inhibiting a crucial component of the same oncogenic pathway. Preclinical studies have shown the MALT1 inhibitor to be highly potent and selective, demonstrating antitumor activity both as a monotherapy and in combination with BTK and BCL-2 inhibitors.

The FDA's fast track program is designed to expedite the development and review of drug candidates that address serious conditions and fill an unmet medical need.² This designation offers several key benefits to the drug developer, including more frequent interactions with the FDA throughout the development process, potentially leading to earlier guidance on clinical trial design and regulatory strategy. Furthermore, products granted fast track designation may be eligible for accelerated approval, priority review, or rolling review, subject to meeting relevant criteria. These mechanisms aim to bring promising new therapies to patients more quickly.

Initial data from the ongoing phase 1 clinical studyof the MALT1 inhibitor in patients with relapsed/refractory B-cell malignancies, including WM, have shown a favorable safety profile and good tolerability.¹ These preliminary findings, recently presented at the European Hematology Association Annual Congress and International Conference on Malignant Lymphoma, also indicated encouraging signs of efficacy across multiple B-cell malignancy subtypes. Notably, responses were observed in patients with WM who had previously been treated with a BTK inhibitor, suggesting its potential utility in this challenging patient group.

Margaret Dugan, chief medical officer at Schrödinger, further emphasized the significance of the fast track designation. "This fast track designation in Waldenström macroglobulinemia, combined with our encouraging phase 1 data across a broad range of relapsed/refractory B-cell malignancies such as chronic lymphocytic leukemia, diffuse large B-cell lymphoma, and marginal zone lymphoma, reinforce the potential of the MALT1 inhibitor as a future therapeutic option for patients," she said in the press release. The company anticipates discussing the complete phase 1 study results and the recommended phase 2 dose with the FDA later this year.

Lymphomas: © immimagery - stock.adobe.com

The development of the MALT1 inhibitor leverages Schrödinger's computational platform, allowing for rapid and efficient molecular discovery. The drug was identified approximately 10 months after the initiation of the company's MALT1 program. In addition to the fast track designation for WM, the MALT1 inhibitor also received orphan drug designation from the FDA in August 2023 for mantle cell lymphoma, based on preclinical data.

The pursuit of novel targets like MALT1 is crucial in addressing the evolving landscape of resistance in WM and other B-cell malignancies. This fast track designation signifies a critical step forward in bringing a potentially impactful new therapy to patients who currently have limited treatment options. Ongoing clinical trials will further elucidate the full therapeutic potential of this MALT1 inhibitor in this vulnerable patient population.

REFERENCES:

1. Schrödinger receives fast track designation for SGR-1505 for the treatment of relapsed/refractory Waldenström macroglobulinemia. News release. Schrödinger Inc. June 27, 2025. Accessed June 30, 2025. https://tinyurl.com/ncbwt72v

2. Fast track. US FDA. Updated August 13, 2024. Accessed June 30, 2025. https://tinyurl.com/y748ywj9