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Cell and gene therapies hold great promise to improve the health of patients with severe or fatal conditions. However, there are challenges to finance and reimburse these regenerative medicines. In this Chapter, the various cell and gene regenerative therapies in clinical phases of development for the treatment of bleeding disorders and hemoglobinopathies will be discussed. The US healthcare system is facing challenges about the affordability and absorbing the treatment prices of these novel therapies and raised concerns from the public, US administration and payers. The different stakeholders recognize the fact that novel innovative payments arrangements for gene and cell therapies are needed. Value-based pricing combined with annuity-based payments is an attractive solution for payers and manufacturers to participate in this shared-risk financing model where continued reimbursement is linked to the long-term efficacy and safety of these potentially transformative and long-lasting therapies.

Hemophilia A arises from mutations in the F8 gene, affecting ~ 1/5000 males. Treatment options include frequent intravenous factor and subcutaneous non-factor therapies. While these approaches have been widely used, they have significant limitations, such as breakthrough bleeds and joint disease due to suboptimal adherence, non-ideal factor kinetics, inhibitor generation, (Weyand, Blood 2018) as well as risk of thrombotic events and coagulation test interference with newer non-factor therapies. (Peters, Nat Rev Drug Discov 2018) Alternative modalities such as cell therapies with genetically modified, ready-made human cells are being investigated. To avoid a cytotoxic immune response by the host, allogeneic cells either need to be physically shielded and/or the host immunosuppressed. Various biomaterials, e.g. hydrogels, could serve as the physical barrier that prevents host immune cells from accessing the allogeneic cells, avoiding the need for immunosuppression altogether. However, the host can still activate a foreign body response (FBR), targeting the biomaterial, which significantly limits cell survival and durability of cell therapies. (Anderson, Semin Immunol 2008) We have successfully identified a library of proprietary small molecules, which when conjugated to alginate used to create encapsulating spheres, limit the FBR (Bochenek, Nat Biomed Eng 2018). In addition, we further reduced the FBR using two-compartment design, 1.5 mm diameter spheres, in which the cells are encapsulated in an inner compartment surrounded by an outer, acellular compartment. Using this innovative technology, we aimed to create a novel product that will deliver long-term, sustained human coagulation factor VIII (hFVIII) in vivo. First, we selected a human epithelial cell line with optimal properties for encapsulation within the spheres; considerations included safety, contact inhibition and longevity. We genetically modified this cell line using a non-viral vector and an optimized the coding sequence for a B-domain deleted hFVIII to create a proprietary engineered cell line that constitutively expresses high levels of this protein. Second, we optimized the inner compartment matrix by modulating cell density/sphere and by the addition of a novel modified alginate; these changes maximized cell viability and protein production in vivo. Finally, we further optimized the acellular outer compartment with a proprietary mixture of small-molecule-modified and unmodified alginates. The resulting SIG-001 product candidate consists of two-compartment, 1.5 mm spheres encapsulating hFVIII-expressing human cells. The spheres are sufficiently porous to allow gasses, nutrients, and secreted proteins to freely diffuse, while limiting FBR and prohibiting cell contact with the host's tissues including immune cells. Our in vitro studies demonstrated similar secretion of hFVIII protein by non-encapsulated and encapsulated engineered cells, along with viability of the same cell line after encapsulation. Several doses of SIG-001 were administered intraperitoneally to mice. Stable hFVIII production and good cell viability was shown for spheres retrieved after long-term placement in immunocompromised mice (up to 6 months). Furthermore, our data showed dose-responsive hFVIII activity and efficacious correction of the bleeding phenotype in immunocompetent Hemophilia A mice (Carmona, ISTH 2019). In conclusion, SIG-001 can deliver sustained therapeutic plasma levels of hFVIII in vivo. Our technology could eliminate the need for regular factor injections, lowering the patient burden and providing consistent factor levels without the peaks and troughs observed with factor and non-factor therapies. It also has the potential for expanded use in pediatric patients, and allows for re-dosing if needed. Additionally, there is no concern about the pre-existing antibodies to viral capsids which limit eligibility for gene therapies. We aim to use our technology platform to develop a new category of medicines for severe chronic diseases including rare blood disorders such as Hemophilia A, and to advance their development into clinical testing. Disclosures Carmona: Sigilon Therapeutics: Employment. Barney:Sigilon Therapeutics: Employment. Sewell:Sigilon Therapeutics: Employment. Newman:Sigilon Therapeutics: Employment. Carroll:Sigilon Therapeutics: Employment. Beauregard:Sigilon Therapeutics: Employment. Huang:Sigilon Therapeutics: Employment. Heidebrecht:Sigilon Therapeutics: Employment. Corzo:Sigilon Therapeutics: Employment. Moller:Sigilon Therapeutics: Employment. Smith:Sigilon Therapeutics: Employment. Peritt:Sigilon Therapeutics: Employment. Vivaldi:Sigilon Therapeutics: Employment.