322.

DISORDERS OF COAGULATION OR FIBRINOLYSIS | NOVEMBER 5, 2020

First-in-Human Phase 1/2 Clinical Trial of SIG-001, an

Innovative Shielded Cell Therapy Platform, for Hemophilia Α
1 2,3 4 *,5
Amy D Shapiro, MD, Barbara A. Konkle, MD, Stacy E. Croteau, MD, Wolfgang A. Miesbach, MD,
6 *,7 *,8
Charles Richard Morris Hay, MDFRCP,FRCPath, Rashid Kazmi, MBBS, Marina Mihova,
9 10
Savita Rangarajan, MD MBBS, John Pasi, MB, ChB, PhD FRCP, FRCPath, FRCPCH
1
Indiana Hemophilia & Thrombosis Center, Indianapolis, IN
2
University of Washington, Seattle, WA
3
University of Washington, Washington Center for Bleeding Disorders, Seattle, WA
4
Boston Children's Hospital, Boston, MA
5
Hemophilia Centre, University Hospital Frankfurt, Frankfurt, Germany
6
Manchester Royal Infirmary, Manchester, United Kingdom
7
University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
8
Sigilon Therapeutics, Cambridge, MA
9
University Hospital Southampton NHS Foundation Trust,
Southampton, United Kingdom, Southampton, United Kingdom
10
Barts and the London School of Medicine and Dentistry, London, United Kingdom

Blood (2020) 136 (Supplement 1) : 8.

http://doi.org/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 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.

Disclosures
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.

© 2020 by the American Society of Hematology