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 administration of SIG-001 and be evaluated for at least 4 weeks prior to enrollment of subsequent pts. The next dose level will be initiated following safety review of all pts from the previous dose level(s). The study will include adult males (≥18), with severe or moderately-severe HA (≤2% FVIII activity) who have had ≥150 exposure days to FVIII product(s). The key exclusion criteria include pts with current or past history of FVIII inhibitors.
SIG-001 will be administered into the peritoneal cavity using a short laparoscopic procedure, and pts will be followed for 5 years after SIG-001 administration. Primary endpoint of the study is safety, including clinically significant changes in vital signs, clinical laboratory tests, and treatment emergent adverse events compared to baseline. Secondary endpoints include FVIII one-stage and chromogenic activity levels, FVIII inhibitor titers, annualized bleeding rate, and annualized FVIII concentrate use. Exploratory endpoints include QoL metrics, and joint health and physical activity assessments. Results will be analyzed using descriptive statistics. The study will be conducted at sites located in the UK, US and Germany.
In conclusion, Sigilon has developed an innovative, modular, scalable, cell-based platform of candidate products for the treatment of chronic diseases, including rare bleeding disorders. The platform was designed to overcome the significant challenges of allogeneic cell therapy, namely immune rejection and PFO. SIG-001 produces hFVIII with in vitro and in vivo functionality. SIG-001-121, first-in-human clinical trial of SIG-001 in HA, is targeted to open in 2020.
Shapiro:Agios: Research Funding; BioMarin: Research Funding; Bioverativ: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Catalyst BioSciences: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glover Blood Therapeutics: Research Funding; Kedrion Biopharma: Research Funding; Novartis: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; OPKO: Research Funding; Octapharma: Research Funding; Pfizer: Research Funding; ProMetic Bio Therapeutics: Consultancy, Research Funding; Sangamo: Research Funding; Sigilon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees. Konkle:Sigilon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BioMarin: Consultancy; Takeda: Research Funding; Spark: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; CSL Behring: Consultancy; Uniquire: Research Funding; Roche: Consultancy; Baxalta: Research Funding. Croteau:Bayer: Consultancy; Genentech: Consultancy; Pfizer: Consultancy; Novo Nordisk: Research Funding; CSL-Behring: Consultancy; Spark Therapeutics: Research Funding; ATHN: Research Funding; Sigilon Therapeutics: Consultancy; National Hemophilia Foundation: Honoraria; Hemophilia Federation of America: Honoraria. Miesbach:Ablynx: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aventis: Consultancy; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Consultancy, Membership on an entity's Board of Directors or advisory committees; Freeline: Consultancy, Membership on an entity's Board of Directors or advisory committees; LEO: Consultancy, Membership on an entity's Board of Directors or advisory committees; LFB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sigilon: Consultancy; UniQure: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees. Mihova:Sigilon Therapeutics: Current Employment. Rangarajan:Takeda: Other: Conference support, Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Reliance Life Sciences: Other: Conference support; Sangamo: Research Funding. Pasi:Roche: Honoraria, Other; Sobi: Consultancy, Honoraria, Other; Tremeau: Research Funding; Pfizer: Other; Octapharma: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia , Speakers Bureau; Novo Nordisk: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia ; Catalyst Biosciences: Consultancy, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Biotest: Consultancy, Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Alnylam (Sanofi): Other: Personal fees and nonfinancial support ; Takeda: Consultancy, Honoraria, Other: Personal fees; honoraria as member of scientific advisory boards and symposia ; ApcinteX: Consultancy, Other: Personal fees ; uniQure: Other: Grants and nonfinancial support , Research Funding; BioMarin: Consultancy, Honoraria, Other: Grants, personal fees, and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Sanofi: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia, Research Funding; Sigilon: Research Funding.
Author notes
Asterisk with author names denotes non-ASH members.
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