dirloctocogene samoparvovec (RG6357) / Roche - LARVOL DELTA

Preclinical evaluation of SPK-8011QQ, an adeno-associated virus gene therapy for people with hemophilia A leveraging the dirloctocogene samoparvovec platform encoding an activated Protein C-resistant B-domain deleted factor VIII (ASH 2025) - "Surrogate SPK-8011QQ, which leverages the previously clinically evaluated SPK-8011(dirloctocogene samoparvovec) platform to introduce FVIII-QQ, demonstrates markedly enhancedhemostatic potency under APC-sensitive conditions in ex vivo and in vivo mouse models. Furthering thelearnings from the safety and durability of the SPK-8011 platform, our preclinical data collected to datesupport the ongoing evaluation of SPK-8011QQ, which aims to optimize FVIII potency and hemostaticpotential."

Gene therapy • Preclinical • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

SPK-8011 vector genome maintains an active transcriptional state for up to 72 weeks in adult mice (ISTH 2025) - "ATAC-seq revealed similar chromatin accessibility of the AAV vector genome at weeks 5 and 72. Bisulfite sequencing found a low mean percentage (week 5: 13.75%; week 72: 13.04%) of methylation in the five CpG sites within the promoter region, and no significant difference (p=0.55, unpaired t-test) between weeks 5 and 72."

Preclinical • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Pharmacodynamics (PD) and pharmacokinetics (PK) of dirloctocogene samoparvovec in people with severe to moderately severe hemophilia A (HA) (EAHAD 2025) - No abstract available

PK/PD data • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

KEYSTONE 1: Study of a Gene Therapy Treatment for Hemophilia A (clinicaltrials.gov) - P3 | N=0 | Withdrawn | Sponsor: Spark Therapeutics, Inc. | N=85 ➔ 0 | Recruiting ➔ Withdrawn

Enrollment change • Gene therapy • Trial withdrawal • Viral vector • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Long-Term Follow-Up of Participants in the Phase I/II Trial of Dirloctocogene Samoparvovec (SPK-8011): Durable FVIII Expression and Clinically Meaningful Reduction of Bleeding (ISTH 2024) - P, P1/2 | "Aims: Describe long-term safety and efficacy of dirloctocogene samoparvovec and novel non-steroid immune prophylaxis (tocilizumab, mycophenolate mofetil) use in the Phase I/II trial. At cut-off (October 10, 2023), 25 participants were enrolled across dosing cohorts of 5×10^11 vg/kg (n=2), 1×10^12 vg/kg (n=3), 1.5×10^12 vg/kg (n=11), or 2×10^12 vg/kg (n=9). Median time since dosing was 220.6 weeks (range: 45.3–340.3). Sixty-six treatment-related adverse events occurred: 37 immunomodulation-related, 29 vector-related, including one serious Grade 2 alanine transaminase (ALT) elevation with elective hospitalization for intravenous corticosteroids."

Clinical • P1/2 data • Gene Therapies • Hematological Disorders • Hemophilia • Immunology • Rare Diseases

Engineering of a High-Activity FVIII-BDD Gene Therapy Vector with High AAV-Packaging Efficiency for Hemophilia A (ASGCT 2024) - "By combining the above optimized elements, we generated several AAV expression cassettes and packaged into AAV8 for validation in vivo, together with two FVIII-AAV benchmark controls, BMN-270 and SPK-8011. To address this, we have implemented measures such as inserting the lambda II filling sequence outside the ITR sequence, screening for the optimal RC and helper plasmid combination, and extensive optimization of the purification processes. We have successfully increased the packaging efficiency and virus yields and in addition, controlled the residual plasmid and Host Cell DNA (HCD) at very low levels, laying a solid foundation for advancing our FVIII gene therapy into clinical trials."

Gene therapy • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

KEYSTONE 1: Study of a Gene Therapy Treatment for Hemophilia A (clinicaltrials.gov) - P3 | N=85 | Recruiting | Sponsor: Spark Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Gene therapy • Viral vector • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

IMPROVED JOINT HEALTH AFTER GENE THERAPY WITH DIRLOCTOCOGENE SAMOPARVOVEC (SPK-8011) IN PEOPLE WITH HEMOPHILIA A (THSNA 2024) - P, P1/2 | "In a Phase I/II trial of HA gene therapy, clinically meaningful improvements in joint health, ongoing at Y3, were persistent in participants who received dirloctocogene samoparvovec, suggesting that this treatment has the potential to improve the pain and musculoskeletal impact of HA. Improvement in participants’ self-reported function and resolution of TJs supported these results. The small sample size limits interpretation."

Gene therapy • Gene Therapies • Hematological Disorders • Hemophilia • Musculoskeletal Diseases • Musculoskeletal Pain • Pain • Rare Diseases

Improved quality of life in people with hemophilia A following gene therapy with dirloctocogene samoparvovec (SPK-8011) (WFH 2024) - No abstract available

Gene therapy • HEOR • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

Improved joint health after gene therapy with Dirloctocogene Samoparvovec (SPK-8011) in people with hemophilia A (WFH 2024) - No abstract available

Gene therapy • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

Improved Joint Health After Gene Therapy with Dirloctocogene Samoparvovec (SPK-8011) in People with Hemophilia A (WFH 2024) - No abstract available

Gene therapy • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

KEYSTONE 1: Study of a Gene Therapy Treatment for Hemophilia A (clinicaltrials.gov) - P3 | N=80 | Not yet recruiting | Sponsor: Spark Therapeutics, Inc.

Gene therapy • New P3 trial • Viral vector • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

Long-Term Safety and Efficacy of Spark-Sponsored Gene Therapies in Males With Hemophilia A (clinicaltrials.gov) - P=N/A | N=29 | Active, not recruiting | Sponsor: Spark Therapeutics | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Gene therapy • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

One-Stage Assay Analysis Demonstrates that Gene Therapy-Derived Factor VIII (FVIII) from Dirloctocogene Samoparvovec Reduced Clot Times Compared with Endogenous FVIII at Comparable FVIII Levels (EAHAD 2024) - No abstract available

Gene therapy • Gene Therapies

Expression of the Human Factor VIII Transgene from Dirloctocogene Samoparvovec, a Liver-Specific Recombinant Adeno-Associated Virus Gene Therapy, for up to 72 Weeks in Adult Mice (EAHAD 2024) - No abstract available

Gene therapy • Preclinical • Gene Therapies

A Gene Transfer Study for Hemophilia A (clinicaltrials.gov) - P1/2 | N=25 | Completed | Sponsor: Spark Therapeutics | Active, not recruiting ➔ Completed | N=50 ➔ 25

Enrollment change • Trial completion • Viral vector • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

Long-Term fviii Expression with reduced bleeding following gene transfer for hemophilia a: follow-up on the dirlocogene samoparvovec phase i/ii trial (GTH 2024) - P=N/A, P1/2 | "Introduction Hemophilia A (HA) is managed with factor (F)VIII replacement, or non-factor replacement therapy such as emicizumab. Conclusion With up to 5 years of follow-up (range: 2–285 weeks), a dirloctocogene samoparvovec infusion in participants with HA resulted in sustained year-to-year FVIII expression and clinically meaningful ABR and AIR reductions. No major safety signals were reported, indicating dirloctocogene samoparvovec was well tolerated."

P1/2 data • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

Lead-in Study to Collect Prospective Efficacy and Safety Data of Current FVIII Prophylaxis Replacement Therapy in Adult Hemophilia A Participants (clinicaltrials.gov) - P=N/A | N=25 | Completed | Sponsor: Spark Therapeutics | Active, not recruiting ➔ Completed | N=55 ➔ 25 | Trial completion date: Dec 2023 ➔ May 2023

Enrollment change • Trial completion • Trial completion date • Genetic Disorders • Hematological Disorders • Hemophilia • Rare Diseases

Improved Joint Health After Gene Therapy with Dirloctocogene Samoparvovec (SPK-8011) in People with Hemophilia A (ISTH 2023) - P=N/A, P1/2 | "Participants with baseline and Year 1 data were included. Two participants who lost transgene expression were excluded. By data cut-off (Oct 4, 2022), mean total HJHS had improved at Years 1–3; change from baseline was clinically meaningful at Years 2 and 3 (Fig."

Gene therapy • Gene Therapies • Hematological Disorders • Hemophilia • Musculoskeletal Diseases • Musculoskeletal Pain • Pain • Rare Diseases

Improved Quality of Life in People with Hemophilia A Following Gene Therapy with Dirloctocogene Samoparvovec (SPK-8011) (ISTH 2023) - P=N/A, P1/2 | "At data cut-off (Oct 4, 2022), Haem-A-QoL Year 1–3 and EQ-VAS Year 1 were compared versus baseline. Haem-A-QoL total score (TS; Fig. 1) and domains (Table 1) trended towards improvement across time."

Gene therapy • HEOR • Gene Therapies • Hematological Disorders • Hemophilia • Pain • Rare Diseases

A Gene Transfer Study for Hemophilia A (clinicaltrials.gov) - P1/2 | N=50 | Active, not recruiting | Sponsor: Spark Therapeutics | Recruiting ➔ Active, not recruiting

Enrollment closed • Viral vector • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

The Effects of Immunomodulation with Corticosteroids to Manage an AAV Capsid Immune response in the Phase I/II Study of SPK-8011 (ASH 2022) - P=N/A, P1/2 | "Two of these 12 participants completely lost FVIII expression following a presumed capsid immune response (one initiated emicizumab; one resumed FVIII prophylaxis); FVIII expression was maintained in the remaining 10 participants. Overcoming the challenge of capsid immune responses to achieve long-term stable and predictable FVIII expression remains a goal of AAV gene transfer for HA. Reactive oral corticosteroids were well tolerated but did not prevent loss of FVIII expression in all participants. Early prophylactic corticosteroids did not consistently prevent presumed capsid immune responses and resulted in prolonged immunomodulatory courses with associated AEs."

P1/2 data • CNS Disorders • Gene Therapies • Hematological Disorders • Hemophilia • Immune Modulation • Immunology • Inflammation • Insomnia • Rare Diseases • Sleep Disorder • IFNG

Rapid Clearance of Vector Following AAV-Mediated FVIII Gene Transfer in the Phase I/II Trial of SPK-8011 in People with Hemophilia A (ASH 2022) - P=N/A, P1/2 | "Following a single infusion of SPK-8011, time to clearance was fastest in urine, saliva, semen, and serum, with vector genome concentration below the quantification limit for these matrices in all participants by 3 weeks, and by 12 weeks in PBMCs. Knowing the rate of clearance in saliva, semen, and urine allows boundaries to be set for the duration of sample collection and safety precautions such as barrier contraception, thereby reducing the patient burden in the clinical trial setting."

P1/2 data • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

Long-Term Durable FVIII Expression with Improvements in Bleeding Rates Following AAV-Mediated FVIII Gene Transfer for Hemophilia A: Multiyear Follow-up on the Phase I/II Trial of SPK-8011 (ASH 2022) - P=N/A, P1/2 | "HA is currently managed with intravenous (IV) infusions of replacement FVIII or non-factor replacement therapy such as emicizumab. With up to 5 years of follow-up, a single infusion of SPK-8011 resulted in durable year-to-year FVIII expression and clinically meaningful reductions in ABR and AIR. No major safety signals were reported, indicating SPK-8011 was well tolerated in this population of people with HA."

P1/2 data • Gene Therapies • Hematological Disorders • Hemophilia • Immune Modulation • Immunology • Inflammation • Rare Diseases • Rheumatology

A Gene Transfer Study for Hemophilia A (clinicaltrials.gov) - P1/2 | N=50 | Recruiting | Sponsor: Spark Therapeutics | Trial primary completion date: Dec 2022 ➔ Dec 2023

Trial primary completion date • Viral vector • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases