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Item 2.02 Results of Operations and Financial Condition.
On March 14, 2022, Sigilon Therapeutics, Inc. (the “Company”) issued a press release announcing the Company’s financial results for the quarter and fiscal year ended December 31, 2021. A copy of this press release is furnished as Exhibit 99.1 and is incorporated herein by reference.
The information in this Form 8-K (including Exhibit 99.1 attached hereto) is being furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference into any filing by the Company, under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filling.
Item 7.01 Regulation FD Disclosure.
On March 14, 2022 the Company updated its corporate presentation, attached as Exhibit 99.2 to this Current Report on Form 8-K. The corporate presentation will also be available in the investor relations section of the Company’s website at https://ir.sigilon.com/news-and-events/events-and-presentations. Representatives of the Company will use the presentation in various meetings with investors, analysts and other parties from time to time. The Company plans to use its website to disseminate future updates to the presentation and may not necessarily file or furnish a Current Report on Form 8-K alerting investors if the presentation is updated.
The information in this Form 8-K (including Exhibit 99.2 attached hereto) is being furnished and shall not be deemed “filed” for purposes of Section 18 of the Exchange Act, or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference into any filing by the Company, under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filling.
Item 9.01 Financial Statements and Exhibits.
Cover Page Interactive Data File (embedded within the Inline XBRL document)
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
SIGILON THERAPEUTICS, INC.
/s/ Rogerio Vivaldi Coelho, M.D.
Rogerio Vivaldi Coelho, M.D.
President and Chief Executive Officer
Date: March 14, 2022
SIGILON THERAPEUTICS REPORTS FOURTH QUARTER AND FULL YEAR 2021 FINANCIAL RESULTS AND RECENT BUSINESS HIGHLIGHTS
Announced strategic reprioritization, with plans to advance mucopolysaccharidosis type I (MPS-1) and diabetes as lead indications as well as continued platform optimization
Strengthened leadership team with appointment of new Chief Technical Operations Officer and other key leadership changes
Current cash position expected to fund operating plans into 2024
Cambridge, MA—March 14, 2022—Sigilon Therapeutics, Inc. (NASDAQ: SGTX), a biotechnology company that seeks to develop functional cures for chronic diseases through its Shielded Living Therapeutics™ platform, today reported financial results for the fourth quarter and full year ended December 31, 2021 as well as certain other business highlights.
“In 2021, we made important adjustments to our overall corporate and clinical strategy as well as our leadership team to best position us for sustained future growth and success,” said Rogerio Vivaldi, M.D., President and CEO of Sigilon. “Based on key learnings from our first-in-human trial in hemophilia A, we have shifted our clinical focus and plan to prioritize MPS-1, in addition to our diabetes program in partnership with Eli Lilly, as we continue to optimize our novel platform. Looking ahead, we remain dedicated to taking the necessary steps to advance our differentiated, non-viral engineered cell-based therapies with the goal of delivering functional cures to patients with a broad range of chronic diseases.”
Recent Program Highlights
|●||In December 2021, Sigilon announced a strategic reprioritization to enable the Company to focus on MPS-1 and diabetes as well as platform optimization. Sigilon expects the significant reduction in expenses associated with the strategic reprioritization to extend the Company’s cash runway into 2024.|
|●||The Brazilian Health Surveillance Agency, ANVISA, has cleared the Company’s Clinical Trial Application (CTA) for SIG-005 in MPS-1. In addition, Sigilon plans to submit an Investigational New Drug (IND) Application to the U.S. Food and Drug Administration for SIG-005.|
|●||In October 2021, the European Commission granted orphan drug designation to SIG-005 for the treatment of MPS-1.|
|●||Last month, Sigilon presented preclinical data on the rare lysosomal diseases MPS-1 and MPS-6 at the 18th Annual WORLDSymposium™, held February 7-11th in San Diego.|
|●||In March 2022, Sarah Yuan, Ph.D., joined the Company as Chief Technical Operations Officer (CTOO). Dr. Yuan brings more than 20 years of experience in process development, manufacturing sciences and CMC strategies from a broad range of leading biopharmaceutical companies. Prior to joining Sigilon, she held a number of leadership roles, most recently as Vice President of Process and Analytical Development at 2seventy bio, the oncology spinoff of bluebird bio.|
|●||Josias Pontes, M.B.A., was promoted from VP, Head of Finance to SVP, acting Chief Financial Officer. Mr. Pontes brings over 30 years of finance and accounting experience.|
|●||Olivia G. Kelly, Ph.D., was promoted from VP, Head of Diabetes Research to SVP, Head of Diabetes Research. Dr. Kelly has over 16 years of experience developing cell therapies for a range of disorders – including type 1 diabetes – in the biotechnology industry.|
Strategic Priorities and Anticipated Milestones
The Company is focusing its development efforts in three strategic areas:
MPS-1: SIG-005 is the Company’s product candidate that contains a cell line genetically modified with a non-viral vector to express human α L iduronidase, or IDUA, encapsulated within Sigilon’s spheres. SIG-005 is being developed to treat the non-neurological manifestations of mucopolysaccharidosis type 1, or MPS-1, in patients with the disease. The Company believes its product candidates for lysosomal diseases can leverage the well understood mechanism of enzyme replacement therapies, or ERTs, by using engineered cells to express functional human enzyme or other protein that more closely resemble normal physiology in a continuous manner. Sigilon is also working to develop next-generation product candidates to address the neurological manifestations of lysosomal diseases, starting with MPS-1, using transporter molecules designed to penetrate the blood brain barrier and molecules designed to extend plasma half-life.
Diabetes: SIG-002 is the Company’s product candidate designed to replace islet cells for the treatment of type 1 diabetes, or T1D. In T1D, the immune system attacks and destroys the insulin-producing beta cells within the endocrine islets of the pancreas. Insulin deficiency results in dysregulation of glucose metabolism. In April 2018, the Company partnered with Eli Lilly and Company, a global leader in diabetes, to develop cell therapies for the treatment of T1D, including SIG-002. Under the terms of the partnership, Sigilon is leading execution of the program through an IND and Lilly will develop and commercialize the program worldwide.
Platform optimization: Sigilon is continuing to optimize its Shielded Living Therapeutics, or SLTx, platform, which combines advanced cell engineering with cutting-edge innovations in biocompatible materials to pioneer a new class of therapeutics. In November 2021, the Company reported that spheres covered with pericapsular fibrotic overgrowth, or PFO, were observed during a retrieval procedure in its Phase 1/2 study of SIG-001 in severe or moderately severe hemophilia A. With the modularity of the SLTx platform, the Company is evaluating changes designed to further modulate or otherwise reduce the potential for a patient’s immune response to its product candidates.
In these prioritized areas, Sigilon expects to achieve the following milestones:
|●||In the second half of 2022, the Company expects to:|
|o||Present results of preclinical studies designed to evaluate PFO and mitigation strategies in humanized mice and non-human primates; and|
|o||Submit amendments to the Company’s CTAs for SIG-005 for MPS-1 in the United Kingdom and Brazil.|
|●||In 2023, the Company expects to:|
|o||Initiate a Phase 1/2 trial of SIG-005 for MPS-1 in the United Kingdom and/or Brazil;|
|o||Submit an IND application for MPS-1 in the United States; and|
|o||Conduct IND-enabling studies for SIG-002 in diabetes.|
|●||Cash Position: Cash, cash equivalents and marketable securities were $123.4 million as of December 31, 2021 compared to $202.2 million as of December 31, 2020.|
|●||R&D Expenses: Research and development expenses were $14.7 million for the fourth quarter of 2021 compared to $14.3 million for the fourth quarter of 2020. Research and development expenses were $65.1 million for the year ended December 31, 2021 compared to $53.5 million for the year ended December 31, 2020. The increase in research development for the fourth quarter of 2021 of $0.4 million was primarily the result of an increase in personnel expenses associated with the Company’s restructuring activities in December 2021, which were partially offset by a decrease in expenses for Sigilon’s SIG-002 program and a reduction in activities associated with its core research and platform development activities. The increase in research and development expenses for the year end December 31, 2021 was primarily related to ongoing platform, pipeline, and development activities related to Sigilon’s SIG-005 and SIG-007 programs, which received orphan drug designation in December 2020 and March 2021, respectively. The expenses increased for SIG-005 as the Company submitted a CTA to the MHRA in the United Kingdom and the ANVISA in Brazil. Personnel expenses for the year ended December 31, 2021 increased by $3.6 million primarily as a result of the increase in headcount in Sigilon’s research and development function, severance associated with the Company’s previously announced December 2021 restructuring and increases in stock-based compensation. These increases were partially offset by a reduction of $3.7 million associated with Sigilon’s SIG-002 program. The decrease in SIG-002 related expenses was due to timing of preclinical activities.|
|●||G&A Expenses: General and administrative expenses were $4.6 million for the fourth quarter of 2021 compared to $3.5 million for the fourth quarter of 2020. General and administrative expenses were $20.2 million for the year ended December 31, 2021 compared to $12.5 million for the year ended 2020. The increase in general and administrative expenses for the fourth quarter of 2021 was primarily attributed to a $0.7 million increase in the expansion of internal infrastructure to support the Company’s operations as a public company and a $0.3 million increase in employee related expenses associated with the Company’s restructuring activities in December 2021. The increase in general and administrative expenses for the year ended December 31, 2021 was driven by a $3.7 million increase in personnel expenses, which was primarily the result of an increase in headcount and an increase in stock-based compensation. Stock-based compensation expense increased to $3.9 million from $1.8 million for the year|
|ended December 31, 2020. In addition, the increase in general and administrative expenses for the year ended December 31, 2021 was driven by a $3.3 million increase in the expansion of internal infrastructure to support the Company’s operations as a public company.|
|●||Net Loss: Net loss was $17.7 million for the fourth quarter of 2021 compared to $14.1 million for the fourth quarter of 2020. Net loss was $77.3 million for the year ended December 31, 2021 compared to $54.6 million for the year ended December 31, 2020.|
About Sigilon Therapeutics
Sigilon Therapeutics seeks to develop functional cures for patients with a broad range of chronic diseases by harnessing the power of the human cell through its Shielded Living Therapeutics™ platform. Sigilon’s product candidates are non-viral engineered cell-based therapies designed to produce the crucial proteins, enzymes or other therapeutic molecules needed by patients living with chronic diseases such as lysosomal diseases and diabetes. The engineered cells are encapsulated by Sigilon’s Afibromer™ biomaterials matrix, which is designed to shield them from immune rejection. Sigilon was founded by Flagship Pioneering in conjunction with Daniel Anderson, Ph.D., and Robert Langer, Sc.D., of the Massachusetts Institute of Technology.
This press release includes forward-looking statements. These forward-looking statements generally can be identified by the use of words such as “anticipate,” “expect,” “plan,” “could,” “may,” “will,” “believe,” “estimate,” “forecast,” “goal,” “project,” and other words of similar meaning. These forward-looking statements address various matters, including the timing and results of our preclinical studies and clinical development of our current product candidates and next generation product candidates, our ability to evaluate PFO and mitigation strategies related thereto, the timing of our IND submission and CTA amendments for SIG-005, the timing for the initiation of our Phase 1/2 clinical trial of SIG-005 in MPS-1, the initiation and timing of IND-enabling studies for SIG-002, and our expected cash runway. Each forward-looking statement contained in this press release is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statement. Applicable risks and uncertainties include, among others, that if we fail to achieve the expected financial and operational benefits of our corporate restructuring, our business and financial results may be harmed; the results of our investigation of the preliminary results of our Phase 1/2 clinical trial of SIG-001 in Hemophilia A or failure of SIG-005 in clinical development could adversely affect our business and may require us to discontinue or delay development of other product candidates, which are all based on the same SLTx platform; the SLTx platform consists of novel technologies that are not yet clinically validated for human therapeutic use and the approaches we are taking to discover and develop novel therapeutics are unproven; we may not be successful in our efforts to identify and develop product candidates; if clinical trials of our current and future product candidates fail to demonstrate safety and efficacy to the satisfaction of regulatory authorities or do not otherwise produce positive results, we may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of such product candidates; if we are unable to obtain and maintain patent and other intellectual property protection our product candidates, our SLTx platform may be adversely affected; and the risks identified under the heading “Risk Factors” in our Quarterly Report on Form 10-Q for the quarterly period ended September 30, 2021, and filed with the Securities and Exchange Commission (the “SEC”), as well as the other information we file with the SEC.
We caution investors not to place considerable reliance on the forward-looking statements contained in this press release. You are encouraged to read our filings with the SEC, available at www.sec.gov, for a discussion of these and other risks and uncertainties. The forward-looking statements in this press
release speak only as of the date of this document, and we undertake no obligation to update or revise any of these statements, except as required by law. Our business is subject to substantial risks and uncertainties, including those referenced above. Investors, potential investors, and others should give careful consideration to these risks and uncertainties.
SIGILON THERAPEUTICS, INC.
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Common stock, par value $0.001 per share; 175,000,000 shares authorized at December 31, 2021 and 2020; 32,359,895 and 31,464,989 shares issued and outstanding at December 31, 2021 and 2020, respectively
Preferred stock, par value $0.001 per share; 25,000,000 shares authorized at December 31, 2021 and 2020; no shares issued and outstanding at December 31, 2021 and 2020
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SIGILON THERAPEUTICS, INC.
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SOURCE: Sigilon Therapeutics, Inc.
Robert Windsor, Jr., J.D.
VP, Head of Investor Relations
Pioneering a New Class of Allogeneic Cell Therapy ©2022 Sigilon Therapeutics, Inc. March 2022
Disclaimer This presentation has been prepared by Sigilon Therapeutics, Inc. (“we,” “us,” “our,” “Sigilon” or the “Company”) and is made fo r informational purposes only and not for any other purpose. Certain information contained in this presentation and statements made orally during this presentation relate to or are based on studies, publications, surveys and other data obtained from third - party sources and the Company’s own internal estimates and research. The Company has not inde pendently verified, and Sigilon makes no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third - party sources. The Company’s internal research has not been verified by any independent source. This presentation contains forward - looking statements. All statements other than statements of historical facts contained in thi s presentation are forward - looking statements. In some cases, you can identify forward - looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipa te,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “potential” or “continue” or the negative of these terms or other similar ex pre ssions, although not all forward - looking statements contain these words. Forward - looking statements include, but are not limited to, statements concerning: our current c ash runway; the initiation, timing, progress and results of our research and development programs, preclinical studies and clinical trials, including the timing of our cl ini cal trial for SIG - 005 and the submission of INDs or CTAs for SIG - 005 and our other product candidates; our ability to advance any product candidates that we may develop and success fully complete any clinical studies, including the manufacture of any such product candidates; our ability to leverage our initial programs to develop additional product ca ndi dates using our SLTx platform; and our ability to successfully scale our manufacturing capabilities. Any forward - looking statements represent the Company’s views only as of to day and should not be relied upon as representing its views as of any subsequent date. The Company explicitly disclaims any obligation to update any forward - looking statements, except as required by law. The Company’s business is subject to substantial risks and uncertainties that could cause these statements to be inaccurate. Appl ica ble risks and uncertainties include, among others, that we have incurred significant losses since inception and our need for additional funding; if we fail to achieve t he expected financial and operational benefits of our corporate restructuring, the results of our investigation of the preliminary results of our Phase 1/2 clinical trial of SIG - 001 in Hemophilia A or failure of SIG - 005 in clinical development could adversely effect our business and may require us to discontinue or delay development of other product candi dat es, which are all based on the same SLTx platform; there may be SAEs in addition to the SAE reported in our Phase 1/2 clinical trial of SIG - 001 in Hemophilia A, other un desirable side effects related to our product candidates or clinical studies, or limited efficacy of product candidates arising from our SLTx platform; the SLTx platform consists of novel technologies that are not yet clinically validated for human therapeutic use; that we do not have any results from the testing of any of our product candidates in cli nic al trials other than SIG - 001 and any favorable preclinical results are not predictive of results that may be observed in clinical trials; we may be unable to obtain and mai nta in patent protection and other intellectual property rights for SIG - 005 or any other product candidates and for our SLTx platform, or the scope of the patent and other intellectual property protection obtained may not be sufficiently broad; the FDA or other regulators may request additional preclinical studies or clinical trials beyond those th at we currently anticipate for SIG - 005 or other product candidates, that manufacturing changes may not have the desired effect; and other risks and uncertainties identified und er the heading “Risk Factors” and in our Annual Report on Form 10 - K for the year ended December 31, 2021 and in any subsequent filings with the Securities and Exchange C ommission. 1 Non - Confidential
2 MISSION: Harnessing the power of the human cell, we aim to deliver functional cures to patients with a broad range of chronic diseases
Modular SLTx Product Platform Manufacturing Placement Cells + Sphere 3 Spheres delivered to peritoneal space through interventional r adiology under local anesthesia Growing Intellectual Property Portfolio – 27 patent families; >96 pending applications in major markets
4 Shielded Living Therapeutics ( SLTx ), a Non - Viral Engineered Cell - Based Therapy Host genome unaltered 1 Shielded allogeneic cells 2 Redosable , retrievable and t itratable 3 Multiple tissue applicability 4 Established GMP manufacturing 5 Potential Attributes
Strong Foundation to Support Sustained Growth 5 2018 – 2019 Applying lessons learned to next programs Seminal work at MIT by Langer & Anderson with the discovery of Afibromer ™ Sigilon created by Flagship Pioneering (2016) Developed our modular platform IPO $145M (Dec 2020) Lilly partnership for T1D $75M upfront + up to $415M (2018) Ongoing manufacturing platform optimization Seasoned team executing pipeline strategy Anticipated Cash runway into 2024 First time Hem A patients ever dosed with an encapsulated, allogeneic cell therapy (2020 – 2021)
Clinical & Pipeline Update Phase 1/2 Hemophilia A Trial Update: • Three patients dosed (UK & U.S.) • Dose range: 300 million to 1 billion cells • One patient experienced SAE (inhibitor development) and spheres with PFO (pericapsular fibrotic overgrowth) • Established GMP manufacturing and logistics • No direct causal relationship between SIG - 001 and i nhibitor development established • Activity levels in highest dose cohort confounded by the presence of inhibitors 6 MPS - 1 Lead Indications: • Different cell line (iPSC) • Since 2018, partnership with Eli Lilly through IND Pipeline Reprioritization • Different immunological risk profile (engineered cell expressing hIDUA , disease & treatment) • Preclinical studies demonstrate potentially better outcome than enzyme replacement therapy (ERT) • Introduced cryopreserved drug substance • Implantation through interventional radiology (IR) under local anesthesia • Developing BBB - IDUA next gen product candidates Type 1 Diabetes Investigations to date
Non - Confidential 7 Industry Leaders with a Proven Track Record of Driving Value Rogerio Vivaldi, MD, MBA President, Chief Executive Officer Olivia Kelly, PhD S VP, Head of Diabetes Research Matthew Kowalsky , JD Chief Legal and Administrative Officer Rogerio Vivaldi, MD, MBA S i g i l o n T h e r ap e u t i c s Doug C ole , MD Chairman , F l a gs h i p P i on ee r i n g Robert Ruffolo , Jr., PhD Former Head of R&D, W y e t h Pha r ma c e u t i c a l s Eric Sh a ff , MB A Seres Therapeutics Stephen Oesterle MD Former CTO, M e d t r on i c PLC Kavita P a t el MD T he B r ook i n g s Institution Board of Directors: Josias Pontes, MBA SVP, Acting Chief Financial Officer Philip Ashton - Rickardt , PhD Chief Scientific Officer Brooke Story, MBA BD Integrated D i a g nos t i c Solutions May Orfali, MD, MBA Chief Medical Officer Sarah Yuan, PhD Chief Technical Operations Officer John Cox Repertoire Ajay R ai SVP, Head of Business Development
Preclinical Program Overview ✓ 28 - day NHP PK (SIG - 001 & SIG - 005) study confirmed bioavailability in plasma with relevant levels ✓ Multiple rodent studies in Hem A and MPS - 1, provided evidence on bioavailability in plasma and target organs BIOAVAILABILITY FROM IP → PLASMA ✓ Product delivery method evaluated in mice, pigs, NHP and human cadavers ✓ Hem A, MPS - 1, Fabry, FVII Def & Hem B dose/response in animal models ✓ Efficacy demonstrated by substrate reduction for MPS - I and Fabry ✓ 1000+ mice studied in multiple safety & tox studies over 3 programs ✓ 70+ NHP evaluated in safety & tox studies ✓ Full biocompatibility ✓ 12 - month rat Islet in STZ mouse model ✓ 6 & 12 - month NHP (empty spheres) ✓ 6 - month in NSG mice (SIG - 001, SIG - 005, SIG - 007) ✓ 6 - month efficacy MPS1 - H mice (SIG - 005) ✓ 4 - month NHP islets NONCLINICAL SAFETY DOSING, CONTROL, & REDOSING DURABILITY OF SLTX PLATFORM 8
Addressing a Broad Range of Chronic Diseases 9 PRIORITIZED AREAS OF DEVELOPMENT PROGRAM CELL PRODUCT RESEARCH & DISCOVERY LEAD OPTIMIZATION PRECLINICAL DEVELOPMENT PHASE 1/2 PHASE 3 SIG - 005: MPS - 1 Human IDUA SIG - 002: T1 Diabetes Human Insulin EXPANSION AREAS OF DEVELOPMENT PROGRAM CELL PRODUCT RESEARCH & DISCOVERY LEAD OPTIMIZATION PRECLINICAL DEVELOPMENT PHASE 1/2 PHASE 3 SIG - XXX: MPS - 1 + CNS Human IDUA + BBB SIG - 007: Fabry Human GLA SIG - 018: MPS - 2 + CNS Human IDS + BBB SIG - 020: MPS - 6 Human ARSB SIG - XXX: Liver Disease Undisclosed SIG - 001: Hemophilia A* BDD - FVIII Notes: IDUA = alpha - L - iduronidase ; GLA= alpha - galactosidase A ; IDS= iduronate sulfatase; ARSB= Arylsulfatase b ; BBB= Blood brain Barrier penetrants * Phase 1/2 clinical trial currently on hold – continuing to follow first three patients
SLTx Potential to Treat Lysosomal Diseases • SOC (enzyme replacement therapy) requires life - long weekly administration and can be hampered by a short enzyme half - life • Our SLTx platform offers the potential for sustained substrate reduction (vs. peaks and troughs) • Preclinically demonstrated enzyme transported to target tissues, even the hard - to - reach tissues like bone, heart and lungs • Received Orphan Drug designation for SIG - 005 (MPS - 1) and SIG - 007 (Fabry) in 2021 10 Lysosomal Diseases Therapeutic efficacy Sub - therapeutic efficacy No therapeutic efficacy 0 50 100 150 200 Plasma Enzyme Level Time (hours) Traditional Therapies Pulsatile protein delivery (ERT) SLTx product Modular platform to be applied across range of lysosomal diseases
11 MPS - 1 Overview MPS - 1: a rare genetic disease caused by a deficiency of IDUA enzyme that results in the accumulation of GAGs within cells affects many body systems and leads to organ damage ~1 in 100,000 live births enzyme replacement therapy (ERT) and bone marrow transplantation (BMT) for Hurler - Scheie SOC includes suboptimal long - term efficacy and treatment burden Unmet medical need includes ~ 500 patients eligible for SIG - 005 Lysosomal Diseases
12 SIG - 005 Produced Active hIDUA Both In Vitro and In Vivo for at Least 6 Months 0 4 8 12 16 20 24 0 2 4 6 Weeks, in vitro U/sphere/hour SIG - 005: Consistent levels of hIDUA produced from spheres for 6 - months in vitro SIG - 005: Low levels of HS in plasma 6 - months post - administration in MPSI - H mice* -4 0 4 8 12 16 20 24 0 2 4 6 8 Weeks, in vivo g HS/mL plasma MPS-1 Untreated MPS-1 SIG-005 Laronidase Pre-Dosing Washout Administration SIG-005 **** **** ** Laronidase 0.58mg/kg, qw MPS - 1: mucopolysaccharidosis type I; HS: heparan sulfate; U : nmol 4MU per hour Error bars indicate SEM; U ntreated , n=25; SIG - 005 , n=9; Laronidase , n=17; unpaired t - test vs untreated **** p<0.001; *** p<0.001; ** p<0.01; * p<0.05; n.s .. p>0.05 * MPS - 1H animals were treated with anti - mouse monoclonal antibody which modulates CD4 antigen (Qin et al. , 1990; Waldmann , 1989) in order to prevent the xenogeneic response to human cells in SIG - 005. Lysosomal Diseases
Reduction of Substrate in Tissues of MPSI - H Mice 6 Months After SIG - 005c 13 Untreated MPSI - H SIG - 005 * * * * * * * * * * * * 10x 10x 10x 10x 10x 10x 10x 10x 40x 40x 40x 40x 40x 40x 40x 40x MPS - 1: mucopolysaccharidosis type I; Images taken by NanoZoomer S60 with 20x Representative images taken from single untreated male mouse & single SIG - 005 treated male mouse Heart Lung Liver Kidney Zeiss 20x; Alcian blue; Black arrow indicates substrate ( Untx : G7 - 1; Tx: G3 - 1); * Glomerulus; * Bronchiole Lysosomal Diseases
14 MPS-1 Untreated SIG-005 HET 0 1 2 3 Zygomatic TV (mm3) ✱✱✱✱ Total Bone Volume (Zygomatic Arch) Bone Length (Femur) MPS-1 Untreated SIG-005 HET 13 14 15 16 17 Femur length (mm) ✱✱ Cortical Thickness (Femur Midshaft) Trabecular Bone Volume (Distal Femur) MPS-1 Untreated SIG-005 HET 0.10 0.15 0.20 0.25 0.30 Ct.Th (mm) ✱✱ MPS-1 Untreated SIG-005 HET 0 10 20 30 Tb.BV/TV (%) ✱✱✱✱ MPS - 1: mucopolysaccharidosis type I; HET heterozygous Error bars indicate min to max; U ntreated , n=23; SIG - 005 , n=9; HET: n=10 unpaired t - test vs untreated **** p<0.001; *** p<0.001; ** p<0.01; * p<0.05; n.s .. p>0.05 Lysosomal Diseases SIG - 005: Corrected Bone Phenotype in MPS - 1H Mice 6 Months After Administration
15 SIG - 005: Phenotypic Correction in Bone After 6 Months of Treatment in Mice With MPS - 1 Distal Femur – Sagittal View of Trabecular Areas Untreated MPS - 1H SIG - 005 Treated M F M F Untreated MPS - 1H SIG - 005 - treated Laronidase - treated F M F M F M Laronidase Treated M F Zygomatic Arch – Total Bone Volume Lysosomal Diseases
Non - Confidential 16 Cryopreserved Drug Substance Expected to Decrease Manufacturing Lead Times for SIG - 005 by 80% Thaw Drug Substance Encapsulation Cell Expansion & Cryopreservation ~4 Weeks Up to 300mL Pooled SIG - 005 Final Filled DP SIG - 005 QC Release Testing Bulk Drug Product (DP) ~1 week for Manufacture & Initial Release Fully Released Drug Substanc e Manufacture Any Time Initiate 1 week prior to patient administration Pooled Fresh Drug Substance Encapsulation Cell Expansion ~4 weeks Up to 150mL Pooled SIG - 001 Final Filled DP SIG - 001 QC Release Testing Bulk Drug Substance Bulk Drug Product ~1 week for Manufacture & Initial Release Initiate Manufacturing 5 weeks prior to patient administration SIG - 001 (Fresh DS) Thaw Drug Substance Encapsulation Cell Expansion & Cryopreservation ~4 Weeks Up to 300mL Pooled SIG - 005 Final Filled DP SIG - 005 QC Release Testing Bulk Drug Product (DP) ~1 week for Manufacture & Initial Release Fully Released Drug Substanc e Manufacture Any Time Initiate 1 week prior to patient administration Manufacturing Any Time Cell expansion & cryopreservation ~4 weeks SIG - 005 ( Cryo DS) Initiate 1 week prior to patient administration SIG - 005 MPS - I Program Heparan Sulfate Level in Liver Sham Fresh DS Cryo DS 0 200 400 600 800 1000 10000 15000 20000 25000 ng HS/mg total protein ns Equivalent substrate reduction for fresh and cryopreserved drug substance in SIG - 005 spheres Lysosomal Diseases
17 Developed Interventional Radiology (IR) Guided Sphere Delivery • No insufflation • Under local anesthesia only • Single incision • Closed delivery system from product bag • Insufflation • Under general anesthesia • 2 port incision Laparoscopic Surgery Interventional Radiology Guided Placement Lysosomal Diseases
SIG - 005: Clinical Development in MPS - 1 Non - Confidential Lysosomal Diseases Clinical Trial Preparation Submit CTA (UK & Brazil) amendment submission for SIG - 005 in MPS - 1 in 2H 2022 Serial Imaging Inflammatory biomarkers Inclusion/Exclusion Criteria PK measurements PFO Mitigation regimen 1 2 3 4 5 Clinical Trial Design Last ERT infusion 1 week prior to SIG - 005 At least 3 plasma enzyme + biomarker pre - ERT infusions. At least 2 clinical assessments (6MWT+FVC +ROM) Observation • Age 18+ • Open - label, dose ranging • N = 18 adult patients • Attenuated MPS - 1 only ✓ CTA cleared in the UK ✓ CTA cleared in Brazil • Next steps expected to include CTA amendments and IND filing in the U.S. 4 - 8 Weeks 4 - 8 Weeks IR Guided insertion of SIG - 005 Safety Review 3 Year Follow Up Trial Overview: Regulatory Overview: Expect to initiate Phase 1/2 trial in 2023 18
19 Type 1 Diabetes Overview T1D: ~1.6 M patients in the U.S. treatment focuses on managing blood sugar levels with exogenous insulin, diet and lifestyle to prevent complications SOC includes Unmet medical need includes Non - Confidential impaired awareness of hypoglycemia (IAH) even with CGM suboptimal long - term efficacy treatment burden Endocrine Diseases an autoimmune disease where the immune system attacks the insulin - producing beta cells in the pancreatic islets, which is where insulin is produced
Non - Confidential 20 Lilly Collaboration to Develop a Potential Functional Cure for Type 1 Diabetes • Discover, develop and commercialize encapsulated cell therapy for T1D • Sigilon will create proprietary products and develop through IND • Eli Lilly responsible for clinical development and commercialization • $75 million up front • $415 million in milestones • Tiered single - to - low double - digit sales - based royalties Our Strategic Partner Partnership Overview Lilly’s Financial Commitment Endocrine Diseases
21 Non - Confidential Functional Cure for Type 1 Diabetes Insulin Independence Without Immunosuppression Sneddon et al 2018 Cell Stem Cell 22:810 - 823 Iworima et al 2021 Stem Cells Transl. Med. 1 - 11 SIG - 002: Sigilon Spheres with iPSC - Islets Islet Cell Therapy Directed Differentiation of iPSC to Islets Endocrine Diseases
22 Sigilon Technology Demonstrates Durable Glucose Control in Preclinical Models Review Article by Langer R; Molecular Frontiers Journal (2017) Encapsulated Rat Donor Islets in Diabetic Mice Encapsulated Cadaveric Human Islets in Diabetic Mice 60 0 50 0 40 0 30 0 Time (Days) 600 500 400 300 200 100 0 330 300 270 24 0 210 18 0 150 120 90 60 30 0 Blood Glucose (mg/dL) 0 10 20 30 40 50 60 70 80 90 100 0 100 200 300 400 500 600 700 800 900 Time (Days) Blood Glucose (mg/dL) Encapsulated Hu Islets (n=5), ~3K IEQ Diabetic Control (n=6) Non-Diabetic Control (n=6) Endocrine Diseases
Expansion Areas Of Development Crossing The Brain Barrier - BBB - hIDUA BBB - penetrant Camelid HCAb BBB V H H Cargo Protein Half - life V H H Half - life extending Camelid HCAb VH + - 32% Technology Details Expansion Good systemic tissue penetration and functional activity towards target substrate Total Heparan sulfate reduction in systemic tissues 23 Liver Spleen Kidney Lung Heart 0 50 100 150 200 Total Heparan sulfate reduction in systemic tissues Percent of Untreated BBB-hIDUA Untreated ✱✱ ✱✱✱✱ ✱✱✱✱ ✱✱✱✱ ✱✱✱ Brain Heparan Sulfate Reduction BBB-hIDUA Untreated 0 50 100 Brain heparan sulfate reduction Percent of Untreated ✱✱✱✱ Liver Spleen Kidney Lung Heart 0 50 100 150 200 Total Heparan sulfate reduction in systemic tissues Percent of Untreated BBB-hIDUA Untreated ✱✱ ✱✱✱✱ ✱✱✱✱ ✱✱✱✱ ✱✱✱
Saline ConA 3T3 mIL-10 + ConA 0 2 4 6 Liver Score 24 Expansion Areas Of Development Developing Products for Liver Diseases Liver Necrosis Saline Concanavalin A ( ConA ) mIL - 22 spheres + ConA SLTx - IL - 10 SLTx - IL - 22 Saline Concanavalin A (ConA) mIL - 10 spheres + ConA Hepatocyte Necrosis Saline ConA 3T3 mIL-22 + ConA 0 2 4 6 Liver Score Protection from liver damage Expansion Proof - of - concept for inflammatory diseases Autoimmune hepatitis • Hepatocyte destruction by pro - inflammatory cytokines • Pathology shared with common liver diseases IL - 10 • Cytokine that resolves inflammation IL - 22 • Cytokine that regenerates the liver
25 Multiple Milestones Targeted within 18 months H2 22 • Results of preclinical studies designed to evaluate PFO and mitigation strategies in humanized mice and non - human primates • CTA (UK & Brazil) amendment submission for SIG - 005 in MPS - 1 2023 • Phase 1/2 Initiation: SIG - 005 in MPS - 1 • IND filing for SIG - 005 in MPS - 1 in the U.S. • IND enabling studies initiation: SIG - 002/ iPSC - derived islet cells
Strong Foundation to Support Sustained Growth 26 2018 – 2019 Applying lessons learned to next programs Seminal work at MIT by Langer & Anderson with the discovery of Afibromer ™ Sigilon created by Flagship Pioneering (2016) Developed our modular platform IPO $145M (Dec 2020) Ongoing manufacturing platform optimization Seasoned team executing pipeline strategy Anticipated cash runway into 2024 First time Hem A patients ever dosed with an encapsulated, allogeneic cell therapy (2020 – 2021) Lilly partnership for T1D $75M upfront + up to $415M (2018)
Thank You Contact Us: Robert Windsor, Jr., J.D. VP, Head of Investor Relations, Sigilon Therapeutics Robert.email@example.com 617.586.3837