A Phase 3, Single-arm, Open-label, Multicenter Study of the Safety and Efficacy of Dirloctocogene Samoparvovec (SPK 8011, Adeno-associated Viral Vector With B-domain Deleted Human Factor VIII Gene) in Adults With Severe or Moderately Severe Hemophilia A

The purpose of this study is to evaluate the efficacy of SPK-8011 in preventing bleed episodes compared with FVIII prophylaxis in participants with hemophilia A without FVIII inhibitors on routine FVIII prophylaxis.

Start Date13 Mar 2024

Sponsor / Collaborator

Spark Therapeutics, Inc.

NCT03432520 / Active, not recruitingNot Applicable

A Multi-Center Evaluation of the Long-Term Safety and Efficacy of Spark-sponsored Gene Therapies in Males With Hemophilia A

This long-term follow-up study will continue to evaluate the long-term safety and efficacy of SPK-8011 and SPK-8016 in males with hemophilia A, who have received a single intravenous administration of SPK-8011 or SPK-8016 in any Spark-sponsored SPK-8011 or SPK-8016 study.

Start Date14 Aug 2018

Sponsor / Collaborator

Spark Therapeutics, Inc.

NCT03003533 / CompletedPhase 1/2

Gene-transfer, Open-label, Dose-escalation Study of SPK-8011 [Adeno-associated Viral Vector With B-domain Deleted Human Factor VIII Gene] in Individuals With Hemophilia A

This clinical research study is being conducted by Spark Therapeutics, Inc. to determine the safety and efficacy of the factor VIII gene transfer treatment with SPK-8011 in individuals with hemophilia A.

Start Date26 Jan 2017

Sponsor / Collaborator

Spark Therapeutics, Inc.

100 Clinical Results associated with SPK-8011

100 Translational Medicine associated with SPK-8011

100 Patents (Medical) associated with SPK-8011

Literatures (Medical) associated with SPK-8011

01 Mar 2022·Molecular Therapy - Methods & Clinical DevelopmentQ2 · MEDICINE

Preclinical assessment of an optimized AAV-FVIII vector in mice and non-human primates for the treatment of hemophilia A

Q2 · MEDICINE

ArticleOA

Author: High, Katherine A ; Sabatino, Denise E ; Frick, Jennifer ; Armour, Sean M ; DiPietro, Marti ; Crosariol, Marco ; Davidson, Robert J ; Anguela, Xavier M ; Elkouby, Liron ; Wang, Chuansong ; Wang, Yuhuan ; Silverberg, Joseph ; Willet, Mallory ; Kutza, Stephanie ; Nguyen, Giang N ; Toso, Raffaella

Extensive clinical data from liver-mediated gene therapy trials have shown that dose-dependent immune responses against the vector capsid may impair or even preclude transgene expression if not managed successfully with prompt immune suppression. The goal of this preclinical study was to generate an adeno-associated viral (AAV) vector capable of expressing therapeutic levels of B-domain deleted factor VIII (FVIII) at the lowest possible vector dose to minimize the potential Risk of a capsid-mediated immune response in the clinical setting. Here, we describe the studies that identified the investigational agent SPK-8011, currently being evaluated in a phase 1/2 study (NCT03003533) in individuals with hemophilia A. In particular, the potency of our second-generation expression cassettes was evaluated in mice and in non-human primates using two different bioengineered capsids (AAV-Spark100 and AAV-Spark200). At 2 weeks after gene transfer, primates transduced with 2 × 10¹² vg/kg AAV-Spark100-FVIII or AAV-Spark200-FVIII expressed FVIII antigen levels of 13% ± 2% and 22% ± 6% of normal, respectively. Collectively, these preclinical results validate the feasibility of lowering the AAV capsid dose for a gene-based therapeutic approach for hemophilia A to a dose level orders of magnitude lower than the first-generation vectors in the clinic.

18 Nov 2021·New England Journal of MedicineQ1 · MEDICINE

Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A

Q1 · MEDICINE

Article

Author: Curran, Marla ; Jaworski, Kristen ; George, Lindsey A. ; Croteau, Stacy E. ; Samelson-Jones, Benjamin J. ; Mingozzi, Federico ; MacDougall, Amy ; Ragni, Margaret V. ; Eyster, M. Elaine ; Kuranda, Klaudia ; Recht, Michael ; Reape, Kathleen Z. ; High, Katherine A. ; Sullivan, Spencer K. ; Monahan, Paul E. ; Anguela, Xavier M. ; Noble, Robert ; Chang, Tiffany ; Rasko, John E.J.

BACKGROUNDThe goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose.METHODSIn this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5 × 10¹¹ vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 10¹² vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII.RESULTSThe median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration).CONCLUSIONSSustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.).

News (Medical) associated with SPK-8011

04 Jan 2024

·www.globenewswire.com

4DMT Highlights Recent Clinical Pipeline Progress, Near-Term Milestones and Organizational Updates

Poised for multiple meaningful catalysts in 2024 driven by strong clinical progress across large market programs in wet age-related macular degeneration (wet AMD), diabetic macular edema (DME) and cystic fibrosis (CF)Established next-generation AAV & CRISPR/Cas-based genetic medicines partnership for central nervous system (CNS) diseases with Arbor BiotechnologiesAnnounced organizational updates, including the appointment of UCSF Professor Noriyuki Kasahara (Nori), M.D., Ph.D. as Chief Scientific OfficerWell capitalized ending 2023 with $300 million in estimated cash, financial runway guidance unchanged and cash expected to be sufficient to fund operations into H1 2026 EMERYVILLE, Calif., Jan. 04, 2024 (GLOBE NEWSWIRE) -- 4D Molecular Therapeutics (Nasdaq: FDMT, 4DMT or the Company), a leading clinical-stage genetic medicines company focused on unlocking the full potential of genetic medicines to treat large market diseases, today announced clinical pipeline progress, updates to near-term milestones and organizational updates. “2023 was a landmark year for 4DMT, highlighted by rapid enrollment for 4D-150 in wet AMD and DME, strong CFTR protein expression data for 4D-710 in lungs of people with CF, multiple value-generating business development partnerships, and key additions to the Executive Team,” said David Kirn, M.D., Co-founder and Chief Executive Officer of 4DMT. “Looking forward to 2024, we plan to release multiple important datasets from our lead programs in wet AMD, DME and CF. We also plan to share guidance on the design and timing of Phase 3 clinical trials. In addition, we expect to initiate clinical development of 4D-175 in geographic atrophy by the second half of the year. By the end of 2024, we intend to progress clinical development in four large market diseases, positioning us well in our strategy to become a fully integrated large market genetic medicines company.” Large Market Ophthalmology Portfolio Recent Updates and Expected Upcoming Milestones 4D-150 for Wet AMD: Phase 2 PRISM Clinical Trial Randomized Dose Expansion arm (N=50) in advanced high treatment need patients: Initial interim 24 week landmark data to be presented at the Angiogenesis, Exudation, and Degeneration 2024 Conference on Saturday, February 3, 2024 followed by a corporate webcast with details to be announced at a future date Population Extension arm (N≤45) in broad population (non-advanced, standard treatment-need): Enrollment update expected in Q1 2024Initial interim 24 week landmark data analysis expected in H2 2024 Received both RMAT and PRIME in Q4 2023, enabling increased collaboration between the FDA and EMA on regulatory approval planning, in addition to the opportunity for expedited product developmentUpdate on Phase 3 trial plans expected in February 2024 along with the interim randomized Phase 2 PRISM trial data 4D-150 for DME: Phase 2 SPECTRA Clinical Trial: Part 1 – Dose Confirmation Stage Completed enrollment in Q4 2023Initial interim 24 week landmark data expected in H2 2024 4D-175 for Geographic Atrophy: IND filing expected in Q2 2024Phase 1 initiation expected in H2 2024 Pulmonology Portfolio Expected Upcoming Milestones 4D-710 for CF Lung Disease: Update on FDA feedback on development plan for monotherapy and approved CF modulator combination regimens expected in Q1 2024Interim data update from Phase 1/2 AEROW clinical trial expected in mid-2024 4D-725 for A1AT Deficiency Lung Disease: Program update and initiation of IND-enabling studies expected in 2024 Cardiology Franchise Expected Upcoming Milestones 4D-310 for Fabry Disease Cardiomyopathy: Interim data update including cardiac functional, imaging, quality-of-life and cardiac biopsy data for all 6 patients dosed to be presented in the late-breaking session at the WORLDSymposium™ 2024 in San Diego, California on Friday, February 9 (10:15 a.m. to 11:15 a.m. PT) titled “Phase 1/2 clinical trial evaluating 4D-310 in adults with Fabry disease cardiomyopathy: Interim analysis of cardiac and safety outcomes in patients with 12-33 months of follow-up”FDA submission of data from the non-human primate (NHP) study evaluating the safety and biodistribution of intravenous (IV) 4D-310 with the rituximab/sirolimus (R/S) immunosuppressive regimen compared to the prior prednisone regimen expected in Q2 2024 Rare Inherited Retinal Disorders Portfolio Expected Upcoming Milestones 4D-110 for Choroideremia and 4D-125 for X-Linked Retinitis Pigmentosa: The safety and tolerability profiles for both product candidates remain unchanged from prior data releases. All enrolled patients are expected to reach 24 months of follow-up in 2024, and we plan to assess the magnitude and durability of key imaging and functional endpoint changes in evaluable patients. We expect to provide program updates in 2024. Expanded CNS and Gene Editing Capabilities Through Partnership with Arbor Biotechnologies Partnership with a leader in next-generation genetic medicines to engineer, co-develop and co-commercialize (50:50 profit share) AAV-delivered CRISPR/Cas-based therapeutics for up to six product candidates in CNSInitial product candidate, led by Arbor, will be developed for a target in amyotrophic lateral sclerosis (ALS) with additional targets expected to be in diseases with high unmet need in both rare and large patient populationsMore information can be found in the press release issued on January 3, 2024 Corporate Governance Update: New Chief Scientific Officer (CSO) and Scientific Advisory Board (SAB) Appointment of Noriyuki (Nori) Kasahara, M.D., Ph.D. as CSO: Noriyuki Kasahara (Nori), M.D., Ph.D., was appointed as Chief Scientific Officer of 4DMT, effective January 2, 2024, and previously served as a member of 4DMT’s Board of Directors and chaired the Board’s Science & Technology Committee from September 2022 to December 2023. Dr. Kasahara was most recently Professor & Alvera L. Kan Endowed Chair of Neurological Surgery and Radiation Oncology at the University of California, San Francisco Medical School (UCSF). He brings more than 30 years of experience and has authored more than 150 peer-reviewed articles in the fields of gene therapy and genetic engineering. As an academic researcher, he previously established the first Vector Core & Shared Resource facilities for gene delivery vector research at both the University of Southern California and the University of California, Los Angeles. Most recently, in addition to his professorship and Endowed Chair, he served as a Principal Investigator in the UCSF Brain Tumor Center. Dr. Kasahara’s research has focused on optimizing the application of multiple and diverse viral vector delivery systems to achieve maximal therapeutic potential, as well as developing next-generation gene transfer technologies with greater therapeutic efficacy in vivo.In his new role as CSO, Nori will lead the creation and validation of new genetic medicine delivery and transgene payload platforms. Our Chief Development Officer An Song, Ph.D., will continue her role in leading nonclinical and clinical scientific development functions, including AAV product design and engineering, in vitro and in vivo pharmacology, toxicology, immunology, biomarkers and bioanalytical development, and further advancing the AAV-based Therapeutic Vector Evolution platform. Newly Formed SAB Combines the Expertise of Renowned Key Opinion Leaders in AAV Gene Therapy, Immunology and Core 4DMT Therapeutic Areas Ronald Crystal, M.D. is Professor and Chairman of the Department of Genetic Medicine at the Weill Medical College of Cornell University, where he is also the Bruce Webster Professor of Internal Medicine, Director of the Belfer Gene Therapy Core Facility and Attending Physician at the New York-Presbyterian Hospital/Weill Cornell Medical Center. Dr. Crystal is a pioneer in the field of gene therapy, where he was the first to use a recombinant virus as a vehicle for in vivo gene therapy and has carried out human trials of gene therapy for CF, cardiac ischemia, cancer and central nervous system disorders.Amit Gaggar, M.D., Ph.D. is the William C. Bailey Endowed Chair of Pulmonary Medicine and Professor of Medicine at University of Alabama at Birmingham (UAB), where he serves as Scientific Director of the UAB Lung Health Center. Dr. Gaggar is a physician-scientist with a long standing interest in protease biology and innate immune signaling in chronic lung disease such as chronic obstructive pulmonary disease (COPD) and CF.Douglas Hanahan, Ph.D. is Director Emeritus of the Swiss Institute for Experimental Cancer Research at École Polytechnique Fédérale de Lausanne (EFPL) and is a Distinguished Scholar at the Ludwig Institute for Cancer Research. Dr. Hanahan is a pioneer in angiogenesis, cancer research, and is a recipient of the AACR Lifetime Achievement Award in Cancer Research.Richard Moss, M.D. is Professor Emeritus at Stanford University School of Medicine in the Department of Pediatrics’ Center for Excellence in Pulmonary Biology. He is former Chief of the pediatric pulmonary and allergy-immunology divisions, and former allergy-immunology and pulmonary fellowship training programs Director at Stanford Children’s Health/Lucile Packard Children’s Hospital Stanford. He was Director of the Stanford Cystic Fibrosis Center from 1991 to 2009 and Principal Investigator for the CF Foundation’s Therapeutics Development Network, where he also served as the inaugural Chair of the TDN Protocol Review Committee. He has served on CFF’s Clinical Research Committee, Translational Advisory Group and Clinical Research Advisory Board.Amy Rosenberg, M.D., a physician-immunologist, trained in basic immunology in Al Singer’s lab in the Experimental Immunology Branch of the NCI, NIH, following medical residency and specialty training in Internal Medicine and Infectious Diseases. She then established a laboratory and performed regulatory duties at the FDA and there, for 33 years (14 as Director of the Division of Therapeutic Proteins then Division III in the Office of Biotechnology Products), regulated an array of biotechnology products including cellular and protein therapeutics and cell-device combination products. She is currently Senior Director of Immunology and Protein Therapeutics at EpiVax, Inc.Ramesh Shivdasani, M.D., Ph.D. is Professor of Medicine / Medical Oncology at Harvard Medical School, and serves as Deputy Director of the Dana-Farber Cancer Institute. He is a gastrointestinal disease expert, medical oncologist and laboratory investigator in the Gastrointestinal Cancer Center at Dana-Farber and Brigham and Women's Hospital, and is an internationally recognized expert in cellular and tissue development and oncology.Daniel Takefman, Ph.D. is Principal of Takefman Gene Therapy Advisors since March 2020. Dr. Takefman provides expert regulatory advice for the development and commercialization of cell and gene therapies, and assists in due diligence assessments of gene therapy assets for venture capital firms and is a member of multiple scientific advisory boards. Previously Dr. Takefman was SVP and Head of Regulatory Affairs at Spark Therapeutics for 5 years. At Spark, Dr. Takefman supervised the submission through to approval of the FDA and EMA Luxturna® marketing applications. Dr. Takefman also supervised the regulatory process for multiple AAV based investigation products including two additional Breakthrough Designation products: SPK-9001 for the treatment of Hemophilia B (marketing applications currently under review by FDA and EMA) and SPK-8011 for the treatment of Hemophilia A. Dr. Takefman held multiple positions during his 15-year career at FDA, ultimately becoming Chief of the Gene Therapy Branch.Paul J. (PJ) Utz, M.D. is Professor of Medicine at Stanford School of Medicine in the Department of Medicine, Division of Immunology, where he has directed a translational research lab for 24 years. He co-founded several companies including Bayhill Therapeutics, Tolerion and Yolo Immune, and has decades of experience as a consultant and SAB member for many biotechnology and pharmaceutical companies. Dr. Utz studies autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, scleroderma, myositis, Sjögren's disease, type I diabetes, vasculitis and multiple sclerosis.More details on our members can be found in the SAB section of our website About 4DMT 4DMT is a leading clinical-stage genetic medicines company focused on unlocking the full potential of genetic medicines to treat large market diseases in ophthalmology and pulmonology. 4DMT’s proprietary invention platform, Therapeutic Vector Evolution, combines the power of the Nobel Prize-winning technology, directed evolution, with approximately one billion synthetic AAV capsid-derived sequences to invent customized and evolved vectors for use in our wholly owned and partnered product candidates. Our product design, development, and manufacturing engine helps us efficiently create and advance our diverse product pipeline with the goal of revolutionizing medicine with potential curative therapies for millions of patients. Currently, 4DMT is advancing five clinical-stage and two preclinical product candidates, each tailored to address rare and large market diseases in ophthalmology, pulmonology, and cardiology. In addition, 4DMT is also advancing programs in CNS through a gene editing partnership. 4D Molecular Therapeutics™, 4DMT™, Therapeutic Vector Evolution™, and the 4DMT logo are trademarks of 4DMT. All of our product candidates are in clinical or preclinical development and have not yet been approved for marketing by the FDA or any other regulatory authority. No representation is made as to the safety or effectiveness of our product candidates for the therapeutic uses for which they are being studied. Learn more at www.4DMT.com and follow us on LinkedIn. Forward Looking Statements: This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding the therapeutic potential, and clinical benefits of 4DMT’s product candidates, as well as the plans, announcements and related timing for the clinical development of our clinical and preclinical product candidates, and statements regarding our estimated cash or anticipated cash runway. The words "may," “might,” "will," "could," "would," "should," "expect," "plan," "anticipate," "intend," "believe," “expect,” "estimate," “seek,” "predict," “future,” "project," "potential," "continue," "target" and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including risks and uncertainties that are described in greater detail in the section entitled "Risk Factors" in 4D Molecular Therapeutics’ most recent Quarterly Report on Form 10-Q as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent 4D Molecular Therapeutics' views only as of today and should not be relied upon as representing its views as of any subsequent date. 4D Molecular Therapeutics explicitly disclaims any obligation to update any forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward looking statements. Contacts: Media: Katherine SmithEvoke CanaleKatherine.Smith@evokegroup.com Investors: Julian PeiHead of Investor Relations and Corporate CommunicationsInvestor.Relations@4DMT.com267-644-5097

Executive ChangePhase 2Phase 3

27 Jul 2023

·www.fiercebiotech.com

Roche loses spark for gene therapy, axing hemophilia A candidate from pipeline

Roche disclosed the removal of RG6358 from its midstage pipeline alongside details of changes in phase 1 Roche’s gene therapy ambitions have taken another blow. Shortly after writing down (PDF) the value of one of Spark Therapeutics’ hemophilia A candidates, the Swiss drugmaker has removed a second therapy aimed at the disease from its midphase pipeline. Buying Spark for $4.3 billion in 2019 gave Roche control of hemophilia A gene therapies that could have posed a threat to its existing drug Hemlibra. Revised sales forecasts forced Roche to take a charge of 519 million Swiss francs ($606 million) related to one of the hemophilia gene therapies, SPK-8011, in its most recent annual results, but the value of the second candidate remained unchanged at that time. Now, Roche has removed (PDF) the second gene therapy candidate from its pipeline. Spark designed the other hemophilia A gene therapy, known as RG6358 or SPK-8016, for use in up to 30% of people with severe or moderately severe hemophilia A who have inhibitors to factor VIII (FVIII). The goal, as Spark co-founder Katherine High, M.D., told investors in 2018, “is to eradicate the inhibitor using a gene-based approach.” Spark shared preliminary data on four patients with no history of FVIII inhibitors in 2021 and kept going toward its targeted primary completion date, which slipped from April 2020 to March 2023 over the course of the study. Dropping RG6358 at the phase 1/2 stage leaves Roche’s hemophilia A gene therapy ambitions resting on SPK-8011, also known as dirloctogene samoparvovec. Roche listed the start of a pivotal phase 3 of the candidate among the second quarter achievements of its hemophilia A franchise, which continues to grow in the absence of gene therapies because of rising demand for Hemlibra. On an earnings call with journalists this morning, Roche Pharmaceuticals CEO Teresa Graham explained that RG6358 had been removed from the pipeline because it “simply wasn't having the impact that we thought that it was going to have.” “When you know that your treatment isn't going to be able to impact patients the way that you hoped, the responsible thing is to refocus your resources on something that you believe will,” Graham said. “Developing in the gene therapy space is exceptionally difficult,” she added. “And I think we've seen that in the industry, there's a lot of difficulty in making sure that you've got the right vector that you're directing at the right target and that you're creating a treatment that is actually going to be maximally impactful and durable over time.” Still, Graham explained that Roche has been “very pleased” with how Spark has integrated with its parent company and pointed to the pharma's continued efforts with SPK-8011. Roche disclosed the removal of RG6358 from its midstage pipeline alongside details of changes in phase 1. One of the culled phase 1 candidates was reportedly the first T-cell receptor-like bispecific antibody to enter a clinical trial. Roche began a phase 1 trial of the candidate, RG6007, in 2020 to start exploring if targeting the HLA-A2-WT1 complex on tumor cells and CD3 on T-cells treats acute myeloid leukemia. The Swiss drugmaker “put a temporary hold on recruitment until further notice” in April. RG6007 was followed out of the door by RG7637 and RG6392. Roche moved (PDF) RG7637 into phase 1 in 2020, listing it as a treatment for neurodevelopmental disorders. The candidate, now listed as being in development in psychiatric disorders, left the pipeline in the latest cull. RG6392, also called RO7497987, is a cancer candidate with a publicly unknown mechanism that Roche was testing in healthy volunteers.

Phase 1Gene TherapyPhase 3Financial Statement

27 Jul 2023

·www.biospace.com

Roche Drops Hemophilia A Candidate, Prepares for the Impacts of IRA

Pictured: Roche tower at its headquarters in Switzerland/iStock, olli0815 Roche is discontinuing the development of the mid-stage gene therapy candidate RG6358, or SPK-8016, which was previously being assessed as a treatment for hemophilia A patients with inhibitors to factor VIII, the company announced Thursday in its second-quarter earnings report. The decision to drop the Phase II program comes as the Swiss pharma is preparing for the potential effects of the Inflation Reduction Act (IRA), Roche CEO Thomas Schinecker said during a media call following the release of its financial results, as reported by Reuters. The IRA, which President Joe Biden signed into law in August 2022, includes a Drug Price Negotiation Program which will empower the Department of Health and Human Services to renegotiate prices for the most widely prescribed medicines. While it will not be as severely affected as other pharma companies, the pinch from the price negotiation program has pushed Roche to take a second look at its pipeline and business strategy, and also to focus its resources on the most financially viable programs and deals, Schinecker said during the media call. Aside from the investigational gene therapy for hemophilia A, Roche is also dropping four other early-stage candidates: RG6007 in acute myeloid leukemia, RG7637 in psychiatric disorders, RG6392 in cancer and a vaccine candidate for solid tumors that was being developed in partnership with Massachusetts-based SQZ Biotech. Despite these discontinuations, however, Roche is moving forward with another hemophilia A hopeful. The Swiss pharma revealed during Thursday’s second-quarter report that it had launched a pivotal Phase III trial for the investigational gene therapy SPK-8011, also dubbed dirloctogene samoparvovec. In a statement to Endpoints News, a Roche spokesperson said that the trial, called Keystone1, will assess SPK-8011 through a 66-week study period and then follow patients for 10 years to evaluate the candidate’s long-term safety and efficacy. SPK-8011, along with the discontinued SPK-8016, joined Roche’s portfolio in 2019, when the pharmaceutical giant bought gene therapy specialist Spark Therapeutics for $4.8 billion. At the time, Spark had already generated promising early data for SPK-8011, demonstrating a 97% response rate in hemophilia A patients following a one-time treatment. Even before the buyout, Spark was already eyeing a Phase III trial for the candidate. Roche is pushing through with these plans and is preparing to open enrollment into Keystone1 later this year. The Phase III study is also in line with the company’s plan to shore up its late-stage drug development pipeline following several clinical disappointments last year, according to Roche CFO Alan Hippe, who is quoted in a Reuters report. In November 2022, the company’s investigational antibody gantenerumab fell short of its primary efficacy endpoints in two Phase III Alzheimer’s disease trials. Earlier last year, in March 2022, another Roche antibody failed a late-stage trial, this time in small-cell lung cancer. Tristan Manalac is an independent science writer based in metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Phase 3AcquisitionPhase 2VaccineGene Therapy

100 Deals associated with SPK-8011

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Indication	Highest Phase	Country/Location	Organization	Date
Hemophilia A	Phase 3	US	Spark Therapeutics, Inc.	14 Feb 2019

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03432520 \| NCT03003533 (ISTH2023)	Phase 1/2	Hemophilia A FVIII activity	-	Dirloctocogene samoparvovec (SPK-8011)	eeqmiwsgon(hchwvxgexd) = Some HJHS components showed improvements, with proportions of participants with severe symptoms decreasing over time zaqibszuqx (hwjmpadjpi )	-	24 Jun 2023
NCT03432520 \| NCT03003533 (ASH2022) Manual	Phase 1/2	Hemophilia A	21	SPK-8011	(sshqippwrs) = in saliva, semen, serum, urine, and PBMCs was 2 (1-2) weeks, 2 (1-2) weeks, 2 (2-3) weeks, 2 (1-2) weeks, and 5 (4-6) weeks, respectively bizrisefum (fojkynhnnb )	Positive	12 Dec 2022
NCT03432520 \| NCT03003533 (ASH2022) Manual	Phase 1/2	Hemophilia A	23	SPK-8011	(qvesplmbxt) = emxzrawhva chulookjdo (drlqonhmux ) View more	Positive	15 Nov 2022
NCT03003533 (ISTH2021) Manual	Phase 1/2	Hemophilia A	17	SPK-8011	suaglrwlct(igqswqfcon) = qnsgtiffwy rgupoyqjst (jrvzaueigh ) View more	Positive	17 Jul 2021
ASH2018 Manual	Phase 1/2	Hemophilia A	12	SPK-8011	ktxyuhfncy(lwqkmuluiu) = ldvmqbottd tyjantkrep (tvwynwhyos )	Positive	29 Nov 2018
ASH2018 Manual	Phase 1/2	Hemophilia A	12	SPK-8011	ktxyuhfncy(lwqkmuluiu) = qjrldaxlue tyjantkrep (tvwynwhyos )	Positive	29 Nov 2018

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