First-in-Human Phase 1/2 Clinical Trial of SIG-001, an Innovative Shielded Cell Therapy Platform, for Hemophilia Α

• Published in: Blood 2020-11, Vol.136 (Supplement 1), p.8-8
• Main Authors: Shapiro, Amy D, Konkle, Barbara A., Croteau, Stacy E., Miesbach, Wolfgang A., Hay, Charles Richard Morris, Kazmi, Rashid, Mihova, Marina, Rangarajan, Savita, Pasi, John
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2020-141381

Hemophilia A (HA) arises from pathogenic variants in the F8 gene, affecting ~ 1/5000 males. Current factor replacement therapies have limitations, including treatment burden, kinetics (peaks/troughs), morbidity and mortality from breakthrough bleeds, including chronic joint disease, inhibitor development, as well as risk of thrombotic events and coagulation test interference with novel non-factor therapies. Cell therapies with genetically modified human cells expressing hFVIII have been tested as a new potential therapeutic approach. To avoid host cytotoxic immune response, allogeneic cells either need to be physically shielded and/or the host immunosuppressed. Various biomaterials, which can provide a physical barrier from the host immune cells, activate a foreign body response, resulting in pericapsular fibrotic overgrowth (PFO) that significantly limits efficacy and durability of these cell-based therapies. Sigilon utilized a library of proprietary small molecules that avoid PFO when conjugated to alginate biomaterials (Bochenek Nat Biomed Eng 2018) to create a modular, cell-based platform with potential for utilization across a range of chronic diseases, including rare blood disorders. The platform consists of genetically modified allogeneic human cells engineered to produce the therapeutic protein of interest, encapsulated in a two-compartment sphere which supports the function of cells (inner compartment) and shields the cells from the host's immune system and PFO (outer layer) (Barney ASGCT 2020). SIG-001 is a buffered suspension of 1.5 mm alginate spheres encapsulating hFVIII-expressing human cells. SIG-001 can produce functionally active hFVIII in a dose-dependent manner, correct the bleeding phenotype in HA mice, and produce sustained long-lasting hFVIII levels in NSG mice sacrificed at 6 months (Carmona ASH 2019). In preparation for entry into the clinic, SIG-001 was evaluated in mice and non-human primates (NHP). The studies showed no concerning signals in the safety/toxicology profile of SIG-001 (Carmona ISTH 2020). The first-in-human phase 1/2 trial in HA (SIG-001-121, EudraCT 2019-004210-33) will assess the safety, tolerability and preliminary efficacy of SIG-001. This multi-center, open-label study with sequential, dose escalating cohorts, will enroll up to 18 participants (pts), including up to 3 initial pts per cohort and 3 additional pts if cohort expansion is warranted at any dose. A sentinel pt in each cohort will receive a single admi