β-globin

SOMERVILLE, Mass.--(BUSINESS WIRE)-- bluebird bio, Inc. (NASDAQ: BLUE) (“bluebird bio”) today announced it has signed its first Medicaid outcomes-based agreement for LYFGENIA™ (lovotibeglogene autotemcel, also known as lovo-cel) with the state of Michigan. LYFGENIA is a one-time gene therapy approved for the treatment of patients 12 years of age and older with sickle cell disease and a history of vaso-occlusive events (VOEs). Approximately 50 percent of individuals living with sickle cell disease in the U.S. are insured by Medicaid. “Our commercial approach is built on the principle that people with sickle cell disease insured through Medicaid deserve the same timely access to gene therapy as patients with other forms of insurance,” said Tom Klima, chief commercial & operating officer, bluebird bio. “We are extremely pleased to have reached this agreement with Michigan Medicaid and with the momentum behind our reimbursement negotiations across the board just months following approval, which underscores payers’ shared commitment to equitable access and understanding of the value that LYFGENIA can bring to people living with sickle cell disease, their caregivers, and the healthcare system.” bluebird is an established leader in developing and implementing innovative, value-based contracting approaches. The Company has designed outcomes-based contract options unique to LYFGENIA that offer payers meaningful risk sharing tied to VOE-related hospitalizations—a claims-based metric that is directly correlated with clinical benefit and aligned with study endpoints in the LYFGENIA clinical development program—with patients followed for three years. bluebird’s outcomes-based contract offering for State Medicaid Agencies was designed with direct input from government payers to specifically address the challenges they face in adapting to provide access to one-time, transformative treatments, and reflects the Company’s unmatched experience delivering gene therapies in the commercial setting. bluebird is in ongoing discussions with more than 15 Medicaid agencies representing 80 percent of Medicaid-insured individuals in the U.S. Additionally, bluebird has signed multiple outcomes-based agreements for LYFGENIA with national commercial payer organizations representing dozens of downstream plans and covering approximately 200 million U.S. lives. bluebird is also engaged with the Center for Medicare and Medicaid Innovation (CMMI) on its Cell and Gene Therapy Access Demonstration Model, which is anticipated to start in 2025. About LYFGENIA™ (lovotibeglogene autotemcel) or lovo-cel LYFGENIA is a one-time ex-vivo lentiviral vector gene therapy approved for the treatment of patients 12 years of age or older with sickle cell disease and a history of vaso-occlusive events (VOEs). LYFGENIA works by adding a functional β-globin gene to patients’ own hematopoietic (blood) stem cells (HSCs). Durable production of adult hemoglobin with anti-sickling properties (HbAT87Q) is possible following successful engraftment. HbAT87Q has a similar oxygen-binding affinity to wild-type HbA, limits sickling of red blood cells and has the potential to reduce and VOEs. The Phase 1/2 HGB-206 study of LYFGENIA is complete and the Phase 3 HGB-210 study evaluating LYFGENIA is ongoing. bluebird bio is also conducting a long-term safety and efficacy follow-up study (LTF-307) for patients with sickle cell disease who have been treated with LYFGENIA in bluebird bio-sponsored clinical studies. Indication LYFGENIA is indicated for the treatment of patients 12 years of age or older with sickle cell disease and a history of vaso-occlusive events (VOEs). Limitations of Use Following treatment with LYFGENIA, patients with α-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions. LYFGENIA has not been studied in patients with more than two α-globin gene deletions. Important Safety Information Boxed WARNING: HEMATOLOGIC MALIGNANCY Hematologic malignancy has occurred in patients treated with LYFGENIA. Monitor patients closely for evidence of malignancy through complete blood counts at least every 6 months and through integration site analysis at Months 6, 12, and as warranted. Hematologic Malignancy Hematologic malignancy has occurred in patients treated with LYFGENIA (Study 1, Group A). At the time of initial product approval, two patients treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A) developed acute myeloid leukemia (AML). One patient with α-thalassemia trait (Study 1, Group C) has been diagnosed with myelodysplastic syndrome (MDS). The additional hematopoietic stress associated with mobilization, conditioning, and infusion of LYFGENIA, including the need to regenerate the hematopoietic system, may increase the risk of a hematologic malignancy. Patients with sickle cell disease have an increased risk of hematologic malignancy as compared to the general population. Patients treated with LYFGENIA may develop hematologic malignancies and should have lifelong monitoring. Monitor for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment with LYFGENIA, and integration site analysis at Months 6, 12, and as warranted. In the event that a malignancy occurs, contact bluebird bio at 1-833-999-6378 for reporting and to obtain instructions on collection of samples for testing. Post-Marketing Long Term Follow-Up Study: Patients who intend to receive treatment with LYFGENIA are encouraged to enroll in the study, as available, to assess the long-term safety of LYFGENIA and the risk of malignancies occurring after treatment with LYFGENIA by calling bluebird bio at 1-833-999-6378. The study includes monitoring (at pre-specified intervals) for clonal expansion. Delayed Platelet Engraftment Delayed platelet engraftment has been observed with LYFGENIA. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia. Two patients (4%) required more than 100 days post treatment with LYFGENIA to achieve platelet engraftment. Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise. Neutrophil Engraftment Failure There is a potential risk of neutrophil engraftment failure after treatment with LYFGENIA. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 0.5 × 109 cells/L obtained on different days by Day 43 after infusion of LYFGENIA. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with LYFGENIA, provide rescue treatment with the back-up collection of CD34+ cells. Insertional Oncogenesis There is a potential risk of lentiviral vector-mediated insertional oncogenesis after treatment with LYFGENIA. Hypersensitivity Reactions Allergic reactions may occur with the infusion of LYFGENIA. The dimethyl sulfoxide (DMSO) or dextran 40 in LYFGENIA may cause hypersensitivity reactions, including anaphylaxis. Anti-retroviral Use Patients should not take prophylactic HIV anti-retroviral medications for at least one month prior to mobilization and until all cycles of apheresis are completed. There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication. If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells. Hydroxyurea Use Patients should not take hydroxyurea for at least 2 months prior to mobilization and until all cycles of apheresis are completed. If hydroxyurea is administered between mobilization and conditioning, discontinue 2 days prior to initiation of conditioning. Iron Chelation Drug-drug interactions between iron chelators and the mobilization process and myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of mobilization or conditioning. Do not administer myelosuppressive iron chelators (e.g., deferiprone) for 6 months post-treatment with LYFGENIA. Non-myelosuppressive iron chelation should be restarted no sooner than 3 months after LYFGENIA infusion. Phlebotomy can be used in lieu of iron chelation, when appropriate. Interference with PCR-based Testing Patients who have received LYFGENIA are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a possible false-positive PCR assay test result for HIV. Therefore, patients who have received LYFGENIA should not be screened for HIV infection using a PCR-based assay. Adverse Reactions The most common adverse reactions ≥ Grade 3 (incidence ≥ 20%) were stomatitis, thrombocytopenia, neutropenia, febrile neutropenia, anemia, and leukopenia. Three patients died during LYFGENIA clinical trials; one from sudden cardiac death due to underlying disease and two from acute myeloid leukemia who were treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A). Pregnancy/Lactation Advise patients of the risks associated with myeloablative conditioning agents, including on pregnancy and fertility. LYFGENIA should not be administered to women who are pregnant, and pregnancy after LYFGENIA infusion should be discussed with the treating physician. LYFGENIA is not recommended for women who are breastfeeding, and breastfeeding after LYFGENIA infusion should be discussed with the treating physician. Females and Males of Reproductive Potential A negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before LYFGENIA administration. Women of childbearing potential and men capable of fathering a child should use an effective method of contraception (intra-uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of LYFGENIA. Advise patients of the options for fertility preservation. Please see full Prescribing Information for LYFGENIA including Boxed WARNING and Medication Guide. About bluebird bio, Inc. bluebird bio is pursuing curative gene therapies to give patients and their families more bluebird days. Founded in 2010, bluebird has been setting the standard for gene therapy for more than a decade—first as a scientific pioneer and now as a commercial leader. bluebird has an unrivaled track record in bringing the promise of gene therapy out of clinical studies and into the real-world setting, having secured FDA approvals for three therapies in under two years. Today, we are proving and scaling the commercial model for gene therapy and delivering innovative solutions for access to patients, providers, and payers. With a dedicated focus on severe genetic diseases, bluebird has the largest and deepest ex-vivo gene therapy data set in the field, with industry-leading programs for sickle cell disease, β-thalassemia and cerebral adrenoleukodystrophy. We custom design each of our therapies to address the underlying cause of disease and have developed in-depth and effective analytical methods to understand the safety of our lentiviral vector technologies and drive the field of gene therapy forward. bluebird continues to forge new paths as a standalone commercial gene therapy company, combining our real-world experience with a deep commitment to patient communities and a people-centric culture that attracts and grows a diverse flock of dedicated birds. bluebird bio and LYFGENIA are registered trademarks of bluebird bio, Inc. All rights reserved. Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements, such as statements regarding the momentum around the Company’s launch of LYFGENIA and its ability to successfully partner with payers and CMMI. Such forward-looking statements are based on historical performance and current expectations and projections about bluebird’s future goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond bluebird’s control and could cause bluebird’s future goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect bluebird bio’s business, particularly those identified in the risk factors discussion in bluebird bio’s Annual Report on Form 10-K for the year ended December 31, 2022, as updated by its subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. These risks and uncertainties include, but are not limited to: delays and challenges in bluebird’s commercialization and manufacturing of its products; the risk that the efficacy and safety results from bluebird’s prior and ongoing clinical trials will not continue or be seen in the commercial context; the risk that there is not sufficient patient demand or payer reimbursement to support continued commercialization of LYFGENIA; the risk of insertional oncogenic or other safety events associated with lentiviral vector, drug product, or myeloablation, including the risk of hematologic malignancy; and the risk that bluebird’s products, including LYFGENIA, will not be successfully commercialized. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, bluebird bio undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise

― On track to report topline data for Phase 3 REACH trial of losmapimod in facioscapulohumeral muscular dystrophy (FSHD) in the fourth quarter of 2024 ― ― Restart of the Phase 1b PIONEER trial of pociredir in sickle cell disease (SCD) underway ― ― Conference call and webcast scheduled for 8:00 a.m. ET today ― CAMBRIDGE, Mass., Feb. 27, 2024 (GLOBE NEWSWIRE) -- Fulcrum Therapeutics, Inc.® (“Fulcrum”) (Nasdaq: FULC), a clinical-stage biopharmaceutical company focused on developing small molecules to improve the lives of patients with genetically defined rare diseases, today reported financial results for the fourth quarter and full year of 2023 as well as an update to the business. “In 2023, we took important steps to advance our two key clinical programs which included completing enrollment for the Phase 3 REACH trial of losmapimod in FSHD and resolving the clinical hold for our Phase 1b PIONEER trial of pociredir in SCD,” said Alex C. Sapir, Fulcrum’s president and chief executive officer. “We are on track to report topline data for REACH in the fourth quarter of 2024, which could position losmapimod as the first approved treatment for patients with FSHD. The clinical data generated to date demonstrates losmapimod has the potential to slow progression and address the debilitating effects of this disease. Additionally, for PIONEER, we are encouraged by the level of physician engagement, and we are working diligently to activate additional trial sites and resume enrollment. We believe pociredir has the potential to shift the current standard of care and offer a differentiated, oral treatment option for patients with SCD.” Recent Business Highlights REACH, the Phase 3 clinical trial evaluating losmapimod in patients with FSHD continues to progress, and Fulcrum expects to report topline data in the fourth quarter of 2024. The trial enrolled 260 patients across sites in the United States, Canada, and Europe. There are currently no approved treatments for FSHD.Clinical trial sites have been activated for the Phase 1b trial evaluating pociredir in patients with SCD. Cohort 3 of the Phase 1b trial will evaluate pociredir at the 12 mg once daily dose, followed by Cohort 4 at the 20 mg once daily dose. Each cohort is expected to enroll approximately 10 patients. Fourth Quarter and Full Year 2023 Financial Results Cash Position: As of December 31, 2023, cash, cash equivalents, and marketable securities were $236.2 million, as compared to $202.9 million as of December 31, 2022. The increase in our cash position is primarily due to net proceeds from our equity offering completed in January 2023 of $117.3 million, partially offset by our net cash used in operating activities in 2023.Collaboration Revenue: Collaboration revenue was $0.9 million for the fourth quarter of 2023 as compared to $0.7 million for the fourth quarter of 2022. The increase of $0.2 million was attributable to an increase in revenues under our collaboration agreement with MyoKardia as we completed our research services during the fourth quarter of 2023.Collaboration revenue was $2.8 million for the year ended December 31, 2023, as compared to $6.3 million for the year ended December 31, 2022. The decrease of $3.5 million was attributable to the completion of activities under our collaboration agreement with Acceleron, which terminated in October 2022, and due to a decrease in revenues under our collaboration agreement with MyoKardia as we completed our research services during the fourth quarter of 2023. R&D Expenses: Research and development expenses were $19.0 million for the fourth quarter of 2023 as compared to $18.6 million for the fourth quarter of 2022. The increase of $0.4 million was primarily due to increased personnel costs.Research and development expenses were $71.8 million for the year ended December 31, 2023 as compared to $76.8 million for the year ended December 31, 2022. The decrease of $5.0 million was primarily due to a $5.0 million obligation to GSK incurred in the second quarter of 2022 upon initiation of the REACH clinical trial. G&A Expenses: General and administrative expenses were $9.9 million for the fourth quarter of 2023 as compared to $10.1 million for the fourth quarter of 2022. The decrease of $0.2 million was primarily due to decreased professional services costs.General and administrative expenses were $41.7 million for each of the years ended December 31, 2023 and 2022. Net Loss: Net loss was $24.8 million for the fourth quarter of 2023 as compared to $26.1 million for the fourth quarter of 2022. Net loss was $97.3 million for the year ended December 31, 2023 as compared to $109.9 million for the year ended December 31, 2022. Cash Runway GuidanceFulcrum continues to expect that its existing cash, cash equivalents, and marketable securities will be sufficient to fund its operating requirements into 2026. Conference Call and WebcastFulcrum Therapeutics, Inc. will host a conference call and webcast today at 8:00 a.m. ET to review the fourth quarter and full year 2023 recent business highlights and financial results. Individuals may register for the conference call by clicking the link here. Once registered participants will receive dial-in details and a unique pin which will allow them to access the call. The webcast will be accessible through the Investor Relations section of Fulcrum’s website at www.fulcrumtx.com or by clicking here. Following the live webcast, an archived replay will also be available for 90 days. About Fulcrum TherapeuticsFulcrum Therapeutics is a clinical-stage biopharmaceutical company focused on developing small molecules to improve the lives of patients with genetically defined rare diseases in areas of high unmet medical need. Fulcrum’s two lead programs in clinical development are losmapimod, a small molecule in development for the treatment of facioscapulohumeral muscular dystrophy (FSHD), and pociredir (formerly known as FTX-6058), a small molecule designed to increase expression of fetal hemoglobin and in development for the treatment of sickle cell disease (SCD). Fulcrum uses proprietary technology to identify drug targets that can modulate gene expression to treat the known root cause of gene mis-expression. For more information, visit www.fulcrumtx.com and follow us on Twitter/X (@FulcrumTx) and LinkedIn. About LosmapimodLosmapimod is a selective p38α/β mitogen activated protein kinase (MAPK) inhibitor. Fulcrum exclusively in-licensed losmapimod from GSK following Fulcrum’s discovery of the role of p38α/β inhibitors in the reduction of DUX4 expression and an extensive review of known compounds. Results reported from the Phase 2b ReDUX4 trial demonstrated slower disease progression and improved function, including positive impacts on upper extremity strength and functional measures supporting losmapimod’s potential to be a transformative therapy for the treatment of FSHD. Although losmapimod had never previously been explored in muscular dystrophies, it had been evaluated in more than 3,600 subjects in clinical trials across multiple other indications with no safety signals attributed to losmapimod. Losmapimod has been granted U.S. Food and Drug Administration (FDA) Fast Track designation and Orphan Drug Designation for the treatment of FSHD. Losmapimod is currently being evaluated in a Phase 3 multi-center randomized, double-blind, placebo-controlled, 48-week parallel-group study in people with FSHD (NCT05397470). About FSHDFSHD is a serious, rare, progressive, and debilitating disease for which there are no approved treatments. It is characterized by fat infiltration of skeletal muscle leading to muscular atrophy involving primarily the face, scapula and shoulders, upper arms, and abdomen. Impact on patients includes relentless and accumulating muscle and functional loss impacting their ability to perform activities of daily living, loss of upper limb function, loss of mobility and independence, and chronic pain. FSHD is one of the most common forms of muscular dystrophy and has an estimated patient population of 16,000 to 38,000 in the United States alone. About PociredirPociredir is an investigational oral small-molecule inhibitor of Embryonic Ectoderm Development (EED) that was discovered using Fulcrum’s proprietary discovery technology. Inhibition of EED leads to potent downregulation of key fetal globin repressors, including BCL11A, thereby causing an increase in fetal hemoglobin (HbF). Pociredir is being developed for the treatment of SCD. Initial data in SCD demonstrated proof-of-concept and achieved absolute levels of HbF increases associated with potential overall patient benefit. In clinical trials conducted prior to the clinical hold, which was lifted by the FDA in August 2023, pociredir was generally well-tolerated in people with SCD with up to three months of exposure, with no serious treatment-related adverse events reported. Pociredir has been granted U.S. FDA Fast Track designation and Orphan Drug Designation for the treatment of SCD. To learn more about these trials please visit ClinicalTrials.gov. About Sickle Cell DiseaseSickle cell disease (SCD) is a genetic disorder of the red blood cells caused by a mutation in the HBB gene. This gene encodes a protein that is a key component of hemoglobin, a protein complex whose function is to transport oxygen in the body. The result of the mutation is less efficient oxygen transport and the formation of red blood cells that have a sickle shape. These sickle shaped cells are much less flexible than healthy cells and can block blood vessels or rupture cells. People with SCD typically suffer from serious clinical consequences, which may include anemia, pain, infections, stroke, heart disease, pulmonary hypertension, kidney failure, liver disease, and reduced life expectancy. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this press release are forward-looking statements, including express or implied statements regarding Fulcrum’s clinical trials, including timing of topline data for the Phase 3 REACH trial of losmapimod; reinitiation of the Phase 1b trial of pociredir and enrollees in each cohort; Fulcrum’s ability to deliver an FDA-approved therapy for FSHD patients; the potential for pociredir to shift the standard of care; and Fulcrum’s cash runway; among others. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, risks associated with Fulcrum’s ability to continue to advance its product candidates in clinical trials; initiating and enrolling clinical trials on the timeline expected or at all; obtaining and maintaining necessary approvals from the FDA and other regulatory authorities; replicating in clinical trials positive results found in preclinical studies and/or earlier-stage clinical trials of losmapimod, pociredir and any other product candidates; obtaining, maintaining or protecting intellectual property rights related to its product candidates; managing expenses; managing executive and employee turnover, including integrating a new CEO and CFO; and raising the substantial additional capital needed to achieve its business objectives, among others. For a discussion of other risks and uncertainties, and other important factors, any of which could cause Fulcrum’s actual results to differ from those contained in the forward-looking statements, see the “Risk Factors” section, as well as discussions of potential risks, uncertainties, and other important factors, in Fulcrum’s most recent filings with the Securities and Exchange Commission. In addition, the forward-looking statements included in this press release represent Fulcrum’s views as of the date hereof and should not be relied upon as representing Fulcrum’s views as of any date subsequent to the date hereof. Fulcrum anticipates that subsequent events and developments will cause Fulcrum’s views to change. However, while Fulcrum may elect to update these forward-looking statements at some point in the future, Fulcrum specifically disclaims any obligation to do so. Fulcrum Therapeutics, Inc.Selected Consolidated Balance Sheet Data(In thousands)(Unaudited) December 31,2023 December 31,2022 Cash, cash equivalents, and marketable securities$236,221 $202,921 Working capital(1) 228,524 190,794 Total assets 257,694 226,685 Total stockholders’ equity 235,193 198,942 (1) Fulcrum defines working capital as current assets minus current liabilities. Fulcrum Therapeutics, Inc.Consolidated Statements of Operations(In thousands, except per share data)(Unaudited) Three Months EndedDecember 31, Year EndedDecember 31, 2023 2022 2023 2022 Collaboration revenue$871 $685 $2,805 $6,342 Operating expenses: Research and development 18,999 18,566 71,801 76,782 General and administrative 9,864 10,130 41,668 41,694 Restructuring expenses — (38) — 427 Total operating expenses 28,863 28,658 113,469 118,903 Loss from operations (27,992) (27,973) (110,664) (112,561)Other income, net 3,236 1,838 13,329 2,690 Net loss$(24,756) $(26,135) $(97,335) $(109,871)Net loss per share, basic and diluted$(0.40) $(0.50) $(1.59) $(2.44)Weighted-average common shares outstanding, basic and diluted 61,871 52,077 61,310 44,991 Contact: Chris CalabreseLifeSci Advisors, LLCccalabrese@lifesciadvisors.com917-680-5608

CorrectSequence Therapeutics' CS-101 Successfully Cures One Patient of Transfusion-Dependent β-Thalassemia SHANGHAI, Jan. 8, 2024 /PRNewswire/ -- On January 8, 2024, Shanghai,China, CorrectSequence Therapeutics Co., Ltd. (Correctseq), using innovative transformer Base Editing (tBE) technology to help people with severe diseases, announced positive results of its base editing therapy for transfusion-dependent β-thalassemia, CS-101. As a collaboration with the First Affiliated Hospital of Guangxi Medical University, the Investigator-Initiated Trial (IIT) of CS-101 has successfully cured the first treated patient with transfusion-dependent β-thalassemia, resulting in sustained transfusion-free for more than two months. Eight weeks after CS-101 treatment, the patient's fetal hemoglobin (HbF) level has increased to ~95 g/L, accounting for ~81% of total hemoglobin. The percentage of HbF-expressing cells (F-cells) has increased to ~80%. Up to the reporting date, the patient's hemoglobin level has been maintained at or above 130 g/L, and the patient has resumed normal life. Notably, to the best of our knowledge, this is the world's first report of successful clinical cure of hemoglobinopathy with base editing therapy. Continue Reading The world's first β-thalassemia patient who received base editing therapy (Correctseq's CS-101) has been two months free from transfusion and has resumed normal life. Encompassing β-thalassemia and sickle cell diseases (SCD), hemoglobinopathies are the most common group of monogenic diseases in the world, with about 7% of the global population carrying the mutant gene. About 400,000 newborns are with hemoglobinopathies every year worldwide. β-thalassemia is a genetic disease caused by mutations in the β-globin gene, resulting in defective hemoglobin production. Correctseq's CS-101 is a personalized treatment that begins with the collection of autologous hematopoietic stem cells from β-thalassemia patients. The transformer Base Editor (tBE) technology (Wang et al., Nat Cell Biol, 2021), developed by scientists at ShanghaiTech University, is then used to precisely edit the DNA sequence of the promoter region of the gene encoding γ-globin (HBG1/2) to mimic the naturally occurring single-nucleotide variant in the population with hereditary persistence of fetal hemoglobin, thereby reactivating the γ-globin expression to produce functional HbF. Finally, the edited stem cells are infused back into the patient, enabling the patient to continuously produce blood cells with intact hemoglobin and eliminating the need for frequent blood transfusions. While several gene editing strategies have been explored to restore normal hemoglobin levels in β-thalassemia patients, it has been shown that base editing of the BCL11A binding site at the HBG1/2 promoter by tBE – as in the CS-101 treatment – exhibited the highest level of γ-globin reactivation both in vitro and in vivo (Han et al., Cell Stem Cell, 2023). In Correctseq's CS-101 IIT study, the first patient who suffered from transfusion-dependent β-thalassemia (β0/β+ type) received the tBE-based gene editing therapy in October 2023. This patient began receiving blood transfusions at the age of two and had been receiving 4 units of red blood cells (RBC) every two weeks before beginning CS-101 treatment. After receiving CS-101 treatment, the patient successfully achieved hematopoietic reconstruction, with neutrophil engraftment occurring within 16 days, and stopped receiving blood transfusions at day 14 post-transplantation. Four weeks after treatment, the patient's HbF concentration was ~16 g/L, representing ~21% of total hemoglobin, and the F-cell ratio was ~23%. Eight weeks after treatment, the patient's HbF concentration increased to ~95 g/L, representing ~81% of total hemoglobin, and the F-cell ratio was ~80%. Up to the reporting date, the patient's hemoglobin level has been maintained at or above 130 g/L, and no adverse effects related to CS-101 have been observed. Compared with other CRISPR-based β-thalassemia gene editing therapies, CS-101 using tBE technology shows effective hematopoietic reconstruction, earlier recovery to the normal range of hemoglobin level, and shorter time to achieve transfusion independence. Importantly, CS-101 does not harbor safety risks such as large DNA fragment deletions, chromosomal rearrangements, or off-target mutations, owing to the innovative tBE technology. As a result, Correctseq's CS-101 has the potential to become the best-in-class gene editing therapy and first-in-class base editing therapy for β-hemoglobinopathies. The success of Correctseq's CS-101 IIT study offers great hope towards a cure for patients with β-hemoglobinopathies. In addition to this first adolescent patient who was successfully cured, one adult patient has been free from transfusion for more than one month after receiving CS-101 treatment. The ongoing IIT study is expected to yield further promising results. CS-101 is now entering IND stage, which will enable treatment of additional patients and further assessment of safety and efficacy. An investigational study using CS-101 to treat patients with SCD is also under active preparation. Correctseq is determined to efficiently promote the clinical translation of innovative gene editing technologies, bringing hope for "one-time treatment, life-time cure" to patients with severe diseases worldwide. Acknowledgement: The First Affiliated Hospital of Guangxi Medical University, ShanghaiTech University, Shanghai Clinical Research and Trial Center. About CorrectSequence Therapeutics CorrectSequence TherapeuticsTM (CorrectseqTM), incubated from ShanghaiTech University, aims to use our innovative gene editing technology to help people with severe diseases. We have developed multiple state-of-the-art base editing systems, which offer significant advantages in controlling off-target effects and improving in vivo editing efficiency. Our goal is to discover, develop, manufacture, and commercialize curative genetic medicines for various diseases. Multiple pipelines for genetic diseases, cancer immunotherapy, metabolic diseases, and infectious diseases are well underway. For more information about the transformer Base Editor technology and its therapeutics applications, visit: or contact: BD@correctsequence.com. SOURCE CorrectSequence Therapeutics