TSLP

Upstream announces the first global Phase 2 asthma study of a biologic inhibiting TSLP signaling including a 24-week dosing regimen and the potential to achieve best-in-class efficacy based on highly differentiated potency in asthma patients. WALTHAM, Mass.--(BUSINESS WIRE)-- Upstream Bio, a clinical-stage biotech company advancing new therapies to treat inflammation, today announced the dosing of the first patients in its Phase 2 VALIANT clinical trial of verekitug (UPB-101) in patients with severe asthma. Verekitug is a recombinant fully human immunoglobulin G1 monoclonal antibody designed to block the thymic stromal lymphopoietin receptor (TLSPR) and thus inhibit TSLP-driven inflammation. Verekitug is currently under investigation in a Phase 2 study for patients with chronic rhinosinusitis with nasal polyps (CRSwNP). “We are thrilled to initiate the Phase 2 study in severe asthma after the findings from our multiple ascending dose (MAD) study in asthma patients demonstrated that verekitug produces a compelling reduction in disease-related biomarkers,” said Aaron Deykin, Head of R&D and Chief Medical Officer. “The 100 mg dose in the MAD study showed a 54% reduction from baseline in FeNo and EOS at week 12 that was sustained through week 32, which was 24 weeks after the last dose. These observations not only demonstrate the higher potency of verekitug compared to published data from tezepelumab, but also enable Upstream to study extended dosing regimens in Phase 2 including every 24 weeks.” The VALIANT study is a randomized, double-blind, placebo-controlled study evaluating verekitug in doses of 100 mg every 24 weeks (Q24W), 400 mg Q24W, 100 mg every 12 weeks (Q12W), or placebo administered subcutaneously in a single injection. The study will evaluate verekitug’s efficacy in the treatment of severe asthma as reflected by the registrational primary endpoint of the annual asthma exacerbation rate (AAER). “Verekitug has the potential to be a best-in-class inhibitor of TSLP signaling based on its swift, substantial and sustained effect on clinically relevant biomarkers that are known to correlate with impact on AAER,” said Sam Truex, Chief Executive Officer. “Our team is thrilled to carry our momentum from Phase 1b into our global Phase 2 studies where we intend to demonstrate how verekitug’s high potency translates to clinical outcomes that will benefit patients with many types of asthma.” About Verekitug (UPB-101) Verekitug is a novel recombinant fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to the human thymic stromal lymphopoietin (TSLP) receptor (TSLPR) to inhibit signaling. In preclinical studies, verekitug demonstrated inhibition of cytokine production from both CD4+ T cells and ILC2, suggesting that it may be effective against multiple types of inflammation. Data in three Phase 1 studies conducted to date demonstrate that verekitug is safe and well-tolerated. In a Phase 1b study, verekitug became the first TSLP signaling inhibitor to demonstrate sustained target engagement and maintain maximal inhibition of disease-related biomarkers in patients with asthma 24- weeks after the last study dose. Results of the Phase 1b study demonstrated that verekitug is a potent inhibitor of TSLP-driven biology. It is the most advanced TSLP signaling inhibitor in global development and is the only agent with clinical data out to 32 weeks from a completed study in asthmatic patients. The company’s lead indication is asthma, a chronic disease of the lungs that affects approximately 350 million people worldwide and is often underdiagnosed and under-treated.1 Of the more than 25 million people in the U.S. living with asthma2, about 5-10% suffer from severe asthma. CRSwNP is a chronic disease of the upper airway that obstructs the sinuses and nasal passages. CRSwNP is highly comorbid with asthma, in fact up to 65% of patients with CRSwNP suffer from asthma.3 About TSLP and TSLPR Blockade Thymic Stromal Lymphopoietin (TSLP) is a cytokine that is a key driver of the inflammatory response in major allergic and inflammatory diseases, such as asthma, where disruption of TSLP signaling has been clinically validated as an effective therapeutic strategy. TSLP signaling is one of the first events in the inflammatory cascade stimulated by allergens, viruses, and other triggers. TSLP signaling activates downstream targets such as IL-4, IL-5, IL-13, IL-17 and IgE. Because TSLP is a target upstream in the inflammatory cascade, there is an opportunity to address disease at its root, prior to the influence of other disease-related cytokines. Inhibiting TSLP signaling by blocking the TSLP receptor presents an opportunity for a single treatment to impact the drivers of multiple pathological inflammatory processes across a broad set of diseases. About Upstream Bio At Upstream Bio we strive to reach the source of inflammation and conquer it. Our lead program, verekitug (UPB101), is a clinical-stage monoclonal antibody that inhibits the TSLP receptor. TSLP is a validated target positioned upstream of multiple signaling cascades that affect a variety of immune cells pivotal to common and rare diseases. We have completed Phase 1b in asthma and have initiated Phase 2 studies in both CRSwNP (Chronic rhinosinusitis with nasal polyps) and asthma in Q1 2024. We are leveraging our diverse roots and the team’s substantial industry experience to develop verekitug to ease the burden of inflammatory and allergic diseases on patients and their loved ones. _________________________________________________________________ 1 EEACI Global Atlas of Asthma, April 2021 2 American Lung Association, website, 2023 3 Bachert C, Bhattacharyya N, Desrosiers M, Khan AH. Burden of Disease in Chronic Rhinosinusitis with Nasal Polyps. J Asthma Allergy. 2021 Feb 11;14:127-134. doi: 10.2147/JAA.S290424. PMID: 33603409; PMCID: PMC7886239

ROCKVILLE, Md. and SUZHOU, China, Feb. 29, 2024 /PRNewswire/ -- Innovent Biologics, Inc. (Innovent) (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, metabolic, autoimmune, ophthalmology and other major diseases, announces that the first participant has been dosed in Australia in a first-in-human (FIH) phase 1 clinical trial of IBI3002, a global first-in-class bispecific antibody targeting Interleukin 4 receptor α (IL-4Rα) and thymic stromal lymphopoietin (TSLP). This FIH study (NCT06213844) is a randomized, double-blind, placebo-controlled, single ascending dose (SAD) study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) (only in participants with asthma) of IBI3002 in healthy participants and participants with mild to moderate asthma, and to support further global clinical development of IBI3002. IBI3002 is a humanized bispecific antibody targeting cell surface IL-4Rα and the alarmin cytokine TSLP, discovered and developed by Innovent for the treatment of inflammatory diseases, including asthma. IL-4 receptors mediate the IL-4 signaling (both type 1 and type 2) and the IL-13 signaling (type 2). Both cytokine signaling pathways play key roles in the pathophysiology of type 2 (T2) inflammatory disorders1. TSLP is an epithelial cell-derived alarmin cytokine and triggers both T2 and non-T2 inflammation in asthma2. IBI3002 has high-efficient dual-blocking function on both IL-4Rα and TSLP. In-vitro assays have shown superiority over the marketed monoclonal antibodies to respective target. By targeting both IL-4Rα and TSLP, IBI3002 is hypothesized to have potential effect in suppressing T2 and non-T2 inflammation. The potential synergistic effect in suppressing T2 inflammation is believed to be the basis of its superior efficacy in the treatment of T2 inflammatory disorders. Dr. Lei Qian, Vice President of Clinical Development at Innovent, stated, "In the last few decades, knowledge about both pathophysiological mechanisms, clinical phenotypes and therapeutic options for asthma have significantly increased. In particular, the introduction of biologics for severe asthma paved the way to a true revolution in the field of asthma management, by potentially allowing a precision medicine approach. Targeting specific steps of the immune-inflammatory cascade through highly selective drugs represents a true revolution in the field of severe asthma management, and brings with it the potential of achieving optimal disease control in different severe asthma inflammatory phenotypes. We are looking forward to the development of this molecule in asthma and other inflammatory diseases." About Asthma Asthma is a heterogeneous disease driven by multiple immune cells, cytokines and inflammatory mediators, affecting all age groups. Characterized by variable symptoms of wheeze, shortness of breath, cough, and chest tightness, asthma is associated with chronic airway inflammation, reversible airflow limitation, and airway hyperresponsiveness3. According to the 2015 Global Burden of Disease (GBD) study, about 358 million people are suffering from asthma4. Asthma can be broadly classified as eosinophilic or non-eosinophilic on the basis of airway or peripheral blood cellular profiles. Eosinophilic inflammation is driven predominantly by T2 inflammation, including T-helper cells type 2 and group 2 innate lymphoid cells5. Compared with eosinophilic asthma, non-eosinophilic asthma is poorly understood6. Up to 10% of adults and 2.5% of children with asthma have severe asthma7. Patients with severe asthma have persistent symptoms or frequent exacerbations that require repetitive systemic glucocorticoid bursts or maintenance, despite adequate treatment with high-dose inhaled treatments8. In these patients, add-on treatment, which may include biologic therapies, is needed to reduce the disease burden2,3. About IBI3002 IBI3002 is a global first-in-class bispecific antibody targeting cell surface IL-4Rα and the alarmin cytokine TSLP. It has high-efficient dual-blocking function on both IL-4Rα and TSLP. In-vitro assays have shown superiority over the marketed monoclonal antibodies to respective targets. By simultaneously targeting IL-4Rα and TSLP, IBI3002 has the potential of treating several inflammatory disorders, including asthma. IL-4 is a central mediator of type 2 lymphocyte cell differentiation; it induces the production of type 2 associated cytokines such as IL-5, IL-9, IL-13, and/or type 2 related chemokines as thymus and activation-regulated chemokine (TARC/CCL17) and eotaxins-3. IL-4 involved in B cells regulated isotype class switching to produce serum IgE, and the eosinophils recruitment through IL-5 releasement. Although IL-13 displays some redundancies in these pro-inflammatory processes, it has additional roles in mediating goblet cell hyperplasia, mucus production, smooth muscle contractility, and airway hyperresponsiveness. Together, IL-4 and IL-13 play critical roles in T2 inflammation1. TSLP is an epithelial cell-derived alarmin cytokine that occupies an upstream position in the T2 inflammation induction and Th2 cells differentiation and maturation via IL-4, IL-5 and IL-13 production. TSLP is also believed to be a trigger of non-T2 inflammation in asthma 2. About Innovent Innovent is a leading biopharmaceutical company founded in 2011 with the mission to provide high-quality biologics that are affordable to all. The company discovers, develops, manufactures and commercializes innovative medicines that treat some of the most intractable illnesses. Its pioneering therapies to treat cancer, cardiovascular and metabolic, autoimmune and eye diseases. Innovent has 10 products in the market, 3 new drug applications under the NMPA review, 4 assets in Phase III or pivotal clinical trials and 20 more molecules in early clinical stage. Innovent partners with over 30 global healthcare leaders, including Eli Lilly, Roche, Sanofi, Adimab, Incyte and MD Anderson Cancer Center. Guided by the motto, "Start with Integrity, Succeed through Action," Innovent maintains the highest standard of industry practices and works collaboratively to advance the biopharmaceutical industry so that first-rate pharmaceutical drugs can become widely accessible. For more information, visit , or follow Innovent on Facebook and LinkedIn. Statement: Innovent does not recommend the use of any unapproved drug (s)/indication (s). Forward-looking statement This news release may contain certain forward-looking statements that are, by their nature, subject to significant risks and uncertainties. The words "anticipate", "believe", "estimate", "expect", "intend" and similar expressions, as they relate to Innovent Biologics ("Innovent"), are intended to identify certain of such forward-looking statements. The Company does not intend to update these forward-looking statements regularly. These forward-looking statements are based on the existing beliefs, assumptions, expectations, estimates, projections and understandings of the management of the Company with respect to future events at the time these statements are made. These statements are not a guarantee of future developments and are subject to risks, uncertainties and other factors, some of which are beyond the Company's control and are difficult to predict. Consequently, actual results may differ materially from information contained in the forward-looking statements as a result of future changes or developments in our business, the Company's competitive environment and political, economic, legal and social conditions. The Company, the Directors and the employees of the Company assume (a) no obligation to correct or update the forward-looking statements contained in this site; and (b) no liability in the event that any of the forward-looking statements does not materialise or turn out to be incorrect. References: 1. Zhu J. T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production[J]. Cytokine, 2015, 75(1): 14-24. 2. Brusselle G G, Koppelman G H. Biologic therapies for severe asthma[J]. New England Journal of Medicine, 2022, 386(2): 157-171. 3. Global Initiative for Asthma. 2023 GINA Report, Global Strategy for Asthma Management and Prevention. 2023. 4. GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015 [published correction appears in Lancet Respir Med. 2017 Oct;5(10 ):e30]. Lancet Respir Med. 2017;5(9):691-706. 5. Gans MD, Gavrilova T. Understanding the immunology of asthma: Pathophysiology, biomarkers, and treatments for asthma endotypes. Paediatr Respir Rev. 2020;36:118-127. 6. Israel E, Reddel H K. Severe and difficult-to-treat asthma in adults[J]. New England Journal of Medicine, 2017, 377(10): 965-976. 7. Settipane RA, Kreindler JL, Chung Y, Tkacz J. Evaluating direct costs and productivity losses of patients with asthma receiving GINA 4/5 therapy in the United States. Ann Allergy Asthma Immunol 2019; 123(6): 564-572.e3. 8. Caminati M, Vaia R, Furci F, Guarnieri G, Senna G. Uncontrolled Asthma: Unmet Needs in the Management of Patients. J Asthma Allergy. 2021;14:457-466. SOURCE Innovent Biologics

-- Novel approach to directly target local tissue complement dysregulation resulted in durable and efficacious complement blockade without systemic inhibition in preclinical studies -- -- Company is planning to evaluate ADX-097 in a Phase 2 clinical trial of complement-mediated renal diseases, with initial data expected by year-end 2024 and topline results in 2025, and a Phase 2 clinical trial in ANCA-Associated Vasculitis (AAV) -- WALTHAM, Mass., Feb. 21, 2024 /PRNewswire/ -- Q32 Bio Inc., a clinical stage biotechnology company developing biologic therapeutics to restore immune homeostasis, today announced the publication of preclinical data in Molecular Therapy that further validates the therapeutic potential of ADX-097, a tissue-targeted complement inhibitor. The paper, titled "C3d-Targeted factor H inhibits tissue complement in disease models and reduces glomerular injury without affecting circulating complement," was co-authored by Q32 Bio scientists Fei Liu, Ph.D., and Sarah Ryan, with Chief Scientific Officer Shelia Violette, Ph.D., and Stefan Wawersik, Ph.D., Vice President and Head of Research at Q32 Bio as senior authors. ADX-097 is Q32 Bio's lead program from its tissue-targeted complement inhibitor platform. Q32 Bio has completed a Phase 1 clinical trial of ADX-097 and expects to initiate an open-label Phase 2 renal basket clinical trial this year as well as a Phase 2 clinical trial in ANCA-Associated Vasculitis (AAV). Initial data from the renal basket trial is expected by year-end and topline results from both Phase 2 trials are expected in 2025. "These data described in the Molecular Therapy paper underscore the transformative potential which a tissue-targeting approach may provide, representing an exciting next generation evolution within the complement therapeutics field," said Michael Holers, M.D., University of Colorado Smyth Professor of Rheumatology and a co-founder of Q32 Bio. "Although systemic inhibitors can be leveraged to treat diseases of complement hyperactivity, complete and highly effective inhibition in tissues is very difficult to achieve due to high circulating concentrations and rapid turnover of complement components, and local complement factor production. Systemic treatments also increase infection risk because of complement's essential role in innate immunity." Q32 Bio explored the biodistribution and pharmacology of fusion proteins containing a C3d antibody and a fragment of the complement negative regulator factor H (fH) in various animal models. The findings supported C3d as an effective localization target to deliver a novel and potent tissue-targeted approach to complement inhibition as demonstrated in mouse, rat and non-human primate models of complement activation. Additionally, in the Passive Heymann Nephritis model of membranous nephropathy in rats, researchers found that local complement inhibition is sufficient to modulate disease progression in vivo. Notably, without requiring systemic complement inhibition, C3d-mAb-fH fusion proteins in this model reduced glomerular complement, as measured in kidney tissue via immunostaining, as well as urinary complement activation biomarkers including the soluble C5b-9 complex. The fusion proteins also inhibited progression of renal injury and preserved podocyte architecture, suggesting disease-modifying efficacy. "These preclinical data support Q32 Bio's novel approach to tissue-targeted regulation of the complement system and the potential of ADX-097 across multiple complement-mediated diseases," said Dr. Violette. "Together with the promising results from our Phase 1 clinical trial in healthy volunteers, which demonstrated a favorable tolerability and immunogenicity profile across all single and multiple dose cohorts, we are excited to advance ADX-097 into a Phase 2 basket clinical trial in multiple renal disease indications this year." "The data presented indicate that tissue C3d deposition is a feature of several autoimmune diseases affecting multiple organs, co-localizing with active complement, and that C3d-targeting could be a means of locally delivering a complement inhibitor for these indications," added Dr. Wawersik. "These results suggest C3d-directed targeting as a strategy for potent, localized complement inhibitors, demonstrating that targeting local tissue complement results in durable and efficacious complement blockade while avoiding systemic inhibition. This has long been a goal in treating patients with autoimmune and inflammatory disorders." About ADX-097 ADX-097 is based on a novel platform enabling tissue-targeted regulation of the complement system without long-term systemic blockade, a key differentiator from current complement therapeutics. Q32 Bio recently completed a first-in-human, Phase 1 ascending dose clinical study of ADX-097 in healthy volunteers. Results from the Phase 1 clinical trial demonstrated a favorable tolerability and immunogenicity profile across all single and multiple dose cohorts and weekly subcutaneous dosing met exposures for predicted complete complement inhibition in the tissue with no systemic inhibition. Q32 Bio expects to initiate an open-label Phase 2 basket clinical trial, with initial data expected by year-end 2024, and a Phase 2 clinical trial in ANCA-Associated Vasculitis (AAV), with topline results from the AAV and basket trials expected in the second half of 2025. About Q32 Bio Q32 Bio is a clinical stage biotechnology company developing biologic therapeutics targeting potent regulators of the innate and adaptive immune systems to re-balance immunity in autoimmune and inflammatory diseases. Q32 Bio's lead programs, focused on the IL-7 / TSLP receptor pathways and complement system, address immune dysregulation to help patients take back control of their lives. Q32 Bio's program for adaptive immunity, bempikibart (ADX-914), is a fully human anti-IL-7Rα antibody that re-regulates adaptive immune function for the treatment of autoimmune diseases. It is being evaluated in two Phase 2 trials for the treatment of atopic dermatitis and alopecia areata. The IL-7 and TSLP pathways have been genetically and biologically implicated in driving several T cell-mediated pathological processes in numerous autoimmune diseases. Q32 Bio's program for innate immunity, ADX-097, is based on a novel platform enabling tissue-targeted regulation of the complement system without long-term systemic blockade – a key differentiator versus current complement therapeutics. Q32 Bio has recently completed a first-in-human, Phase 1 ascending dose clinical study of ADX-097 in healthy volunteers. Cautionary Statement Regarding Forward-Looking Statements This communication contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995, including statements regarding the expectations surrounding the potential, safety, efficacy, and regulatory and clinical progress of Q32 Bio's product candidates, including ADX-097, and anticipated milestones and timing, among others. Forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as "may," "will," "should," "would," "expect," "anticipate," "plan," "likely," "believe," "estimate," "project," "intend," and other similar expressions among others. Statements that are not historical facts are forward-looking statements. Forward-looking statements are based on current beliefs and assumptions that are subject to risks and uncertainties and are not guarantees of future performance. Actual results could differ materially from those contained in any forward-looking statement as a result of various factors, including, without limitation: (i) potential unforeseen events during clinical trials could cause delays or other adverse consequences; (ii) risks relating to the regulatory approval process; (iii) interim, topline and preliminary data may change as more patient data become available, and are subject to audit and verification procedures that could result in material changes in the final data; (iv) Q32 Bio's product candidates may cause serious adverse side effects; (v) the potential for ADX-097 to provide therapeutic benefit in complement mediated diseases; (vi) the company's reliance on third parties, including for the manufacture of materials for our research programs, preclinical and clinical studies; (vii) failure to obtain U.S. or international marketing approval; (viii) ongoing regulatory obligations; effects of significant competition; (ix) unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives; (x) product liability lawsuits; (xi) securities class action litigation; (xii) the impact of the COVID-19 pandemic and general economic conditions on our business and operations, including the combined company's preclinical studies and clinical trials; (xiii) the possibility of system failures or security breaches; risks relating to intellectual property; Except as required by applicable law, Q32 Bio undertakes no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise. Important Information about the Merger and Where to Find It This communication relates to a proposed transaction between Homology Medicines and Q32 Bio. In connection with the proposed transaction, Homology Medicines has filed with the SEC a registration statement on Form S-4 that includes a proxy statement of Homology Medicines and that constitutes a prospectus with respect to shares of Homology Medicines' common stock to be issued in the proposed transaction (Proxy Statement/Prospectus). Homology Medicines may also file other documents with the SEC regarding the proposed transaction. This document is not a substitute for the Proxy Statement/Prospectus or any other document which Homology Medicines may file with the SEC. INVESTORS, Q32 BIO STOCKHOLDERS AND HOMOLOGY MEDICINES STOCKHOLDERS ARE URGED TO READ THE PROXY STATEMENT/PROSPECTUS AND ANY OTHER RELEVANT DOCUMENTS THAT ARE OR WILL BE FILED BY HOMOLOGY MEDICINES WITH THE SEC, AS WELL AS ANY AMENDMENTS OR SUPPLEMENTS TO THESE DOCUMENTS, CAREFULLY AND IN THEIR ENTIRETY BECAUSE THEY CONTAIN OR WILL CONTAIN IMPORTANT INFORMATION ABOUT THE PROPOSED TRANSACTION AND RELATED MATTERS. Investors, Q32 Bio stockholders and Homology Medicines stockholders will also be able to obtain free copies of the Proxy Statement/Prospectus and other documents containing important information about Homology Medicines, Q32 Bio and the proposed transaction that are or will be filed with the SEC by Homology Medicines through the website maintained by the SEC at . Copies of the documents filed with the SEC by Homology Medicines will also be available free of charge on Homology Medicines' website at or by contacting Homology Medicines' investor relations department by email at [email protected]. No Offer or Solicitation This communication is not intended to and shall not constitute an offer to buy or sell or the solicitation of an offer to buy or sell any securities, or a solicitation of any vote or approval, nor shall there be any sale of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction. No offer of securities shall be made, except by means of a prospectus meeting the requirements of Section 10 of the Securities Act. Participants in the Solicitation Homology Medicines and certain of its directors and executive officers may be deemed under SEC rules to be participants in the solicitation of proxies of Homology Medicines stockholders in connection with the proposed transaction. Information regarding the persons who may, under SEC rules, be deemed participants in the solicitation of proxies to Homology Medicines stockholders in connection with the proposed transaction are set forth in the Proxy Statement/Prospectus on Form S-4 for the proposed transaction, has been filed with the SEC by Homology Medicines. Investors and security holders of Q32 Bio and Homology Medicines are urged to read the Proxy Statement/Prospectus and other relevant documents that are or will be filed with the SEC by Homology Medicines carefully and in their entirety when they become available because they contain, or will contain, important information about the proposed transaction. Investors and security holders will be able to obtain free copies of the Proxy Statement/Prospectus and other documents containing important information about Q32 Bio and Homology Medicines through the website maintained by the SEC at . Copies of the documents filed with the SEC by Homology Medicines can be obtained free of charge by directing a written request to Homology Medicines, Inc., One Patriots Park, Bedford, MA 01730. Contacts: Investors: Brendan Burns Media: Sarah Sutton Argot Partners 212.600.1902 [email protected] SOURCE Q32 Bio