• ClinicalTrials.gov Identifier: NCT03734588 (Dose-finding Study of SPK-8016 Gene Therapy in Patients With Hemophilia A to Support Evaluation in Individuals With FVIII Inhibitors)
• SPK-8016 was in development for the treatment of pts. with inhibitors to FVIII
• Phase 1/2, open-label, non-randomized, dose-finding study:
  • Part 1 was to evaluate the safety, efficacy, and tolerability of SPK-8016 in adult males with clinically severe haemophilia A and no measurable inhibitor against FVIII.
  • Data obtained from Part 1 was to inform the study design and dose selection for Part 2 in patients with FVIII inhibitors

• Active, not recruiting ^2, *
• Last Update Posted: February 22, 2023 ^2, *

Data regarding the key inclusion inclusion were collected from here ^1-2 and summarized ass follows:

• Males ≥18 years old with FVIII:C ≤2%
• <1:5 neutralizing Ab to Spark AAV capsid
• >150 factor exposure days, with no history of clinically significant inhibitor
• Negative HIV viral load with CD4 ≥200/mm3
• Baseline treatment:
  • Prophylaxis –OR—
  • on demand with ABR >10
• Liver fibrosis ≤stage 2

No active HBV or HCV ^1-2

Hepatotropic bioengineered capsid; serotype not disclosed/manufacturing platform not disclosed ^1, 4

Codon-optimized B-domain– deleted FVIII cDNA ¹

Hepatotropic bioengineered capsid to package a codon-optimized B-domain-deleted FVIII cDNA, with expression driven by liver-specific promoter ¹
- No further information concerning the expression cassette was reported -

 1-hour outpatient intravenous infusion was reported as the method of vector delivery in the presentation given at the EAHAD 2021 meeting ¹

Co. 1: 5e11 (4) ¹  - 1/4 pts. (Subject 3, age 63) was HIV sero(+), HIV DNA(‐)

Follow-up times were reported in the abstract and in the presentation at the EAHAD 2021 meeting ¹ and on ClinicalTrials.gov ^2-3 as follows:

• NCT03734588 - Phase 1/2 study - 52 weeks follow up
• NCT03432520 - Long-term study has a follow up period of 9 years, ensuring 10 years of follow up post-infusion

Not reported

FVIII activity levels after vector infusion were reported in the abstract at the EAHAD 2021 meeting¹ as follows:

Based on a graph displaying the plotted FVIII activity over time in the presentation at the EAHAD 2021 meeting¹, the initial peaks of factor response occurred between day 30 to day 90 
 - These observations were not mentioned in the publication referred to above -

Efficacy data related to ABR were reported in the abstract and in the presentation at the EAHAD 2021 meeting ^1,a as follows:

• 85% reduction in ABR were reported as well in the presentation mentioned above

^a Data cut-off: October 26, 2020. Follow-up - Mean, 16.5 months (range: 15-18 months); 5.5 patient- years

Efficacy data related to AIR were reported in the abstract and in the presentation at the EAHAD 2021 meeting ^{1, a} as follows:

• 98% reduction in AIR were reported as well in the presentation mentioned above

^a Data cut-off: October 26, 2020. Follow-up - Mean, 16.5 months (range: 15-18 months); 5.5 patient- years

None ^1,a

^a Data cut-off: October 26, 2020. Follow-up - Mean, 16.5 months (range: 15-18 months); 5.5 patient- years

AEs related to SPK-8016 were reported in the presentation at the EAHAD 2021 meeting ^1,a as follows:

• 1 AE related to SPK-8016: 1 participant experienced a “warm feeling” on day 0 that resolved spontaneously
• No SAEs related to SPK-8016 was reported

^a Data cut-off: October 26, 2020. Follow-up - Mean, 16.5 months (range: 15-18 months); 5.5 patient- years

AEs related to immunomodulatory agents were reported in the presentation at the EAHAD 2021 meeting ^1,a as follows:

• 3/4 pts. experienced mild to moderate and nonserious steroid-associated AEs as follows:
  • Fatigue
  • Weight gain
  • Back pain
  • Skin infection
  • Hyperglycemia
  • 1 participant experienced “sore throat/thrush”
• 1 participant was reported to have azathioprine-induced hepatotoxicity:
  • Transient transaminitis
  • Abdominal discomfort
  • Nausea
  • Vomiting
  • The event resolved as expected in 10 days after azathioprine was discontinued

Safety data related to an increase in liver transaminases were reported in the abstract and presentation at the EAHAD 2021 meeting ^1, 5 as follows : 

• No participant demonstrated persistent ALT/AST elevations outside of the normal range, with the exception of the transaminitis associated
  with azathioprine toxicity in one participant that resolved as expected after azathioprine was discontinued
• Based on a graph displaying the plotted ALT levels over time in the EAHAD 2021 presentation ¹, P4 (1/4 pts.) had an ALT levels peak corresponding 
  to 2 times the ULN between day 330 and day 360, which might be related to the mentioned transaminitis associated with azathioprine toxicity
  - These observations were not mentioned in the publication referred to above -

See above the variable “ALT elevations (peak level, timing)”

Yes, for 3/4 pts. (P1, P2 and P4) laboratory evidence of cellular immunity against AAV capsid‐derived peptides was reported here ¹ 
- peak level and timing were not reported explicitly -

Safety data regarding immune responses and steroid treatment were reported in the abstract and presentation at the EAHAD 2021 meeting ^1,a as follows:

• Due to the observed laboratory evidence of unstable FVIII:C activity and cellular immunity against AAV capsid‐derived peptides in P1, P2 and P4:
  • Daily oral steroids at weeks 3‐7 resulting was initiated. These 3 pts. received courses of oral steroids for 43‐48 weeks
  • As steroid use exceeded 4-5 months, steroid-sparing immune-modulating co-therapy with azathioprine and/or tacrolimus 
    was added for P1 & P2 to limit total exposure to prednisone
    • P1: 31.6 weeks total
    • P2: 19.5 weeks total
  • Immune modulation had been discontinued for 2‐6 months in all subjects at the time of data cut‐off (October 26, 2020)
• P3 (FVIII:C 21.8%, HIV-seropositive) did not require immunosuppressive therapy

^a Data cut-off: October 26, 2020. Follow-up - Mean, 16.5 months (range: 15-18 months); 5.5 patient- years

None ^1,a
a Data cut-off: October 26, 2020. Follow-up - Mean, 16.5 months (range: 15-18 months); 5.5 patient- years

None ^1,a
a Data cut-off: October 26, 2020. Follow-up - Mean, 16.5 months (range: 15-18 months); 5.5 patient- years

AAV, Adeno-associated virus; AEs, Adverse events; ABR, Annualized bleeding rate; AEs: adverse events; AIR, Annualized FVIII/FIX infusion rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CH, Chromogenic Assay; Co., cohort; DOACs, Direct oral anticoagulants; D, days; EDs, exposure days; FIX, factor IX; FIX-Padua, gain of function FIX variant; FVIII, factor VIII; gc, genome copies; HEK cells, human embryonic kidney cells; IQR, interquartile range; IRR, Infusion-related reaction; NAbs, neutralizing antibodies; OS, One-stage clotting assay; Pop., population; pt., patient/participant; pts., patients/participants; P1, Participant 1; PI, phase I; PBGD, porphobilinogen deaminase; PBMC, peripheral blood mononuclear cells; SAEs, serious adverse events; SFU, spot-forming units; TAC, tacrolimus; ULN, upper limit of normal; VCN, vector copy number; vg, vector genomes; W, weeks; WT, wild type; Y, year