Thread by @Brianhemophilia

20 Snippet thread from @wfhemophilia Novel products and Gene Therapy (GT) summit:
1. Work ongoing to develop capsids which transduce LSEC cells which would be better for FVIII GT
2. Regeneron working on drugs to prevent or suppress AAV ab to allow re-dosing or dosing those 1/13

who are AAV+. Includes blocking CD40 cells, or a bi specific antibody linvoseltamab or combinations
3. Liver fibrosis in mice leads to reduced vector uptake, alters vector clearance and biodistribution
4. Liver steatosis leads to increased vector uptake and faster loss 2/13

5. PWH with a higher BMI responded better to Hemgenix FIX GT. In the trial 58,% had a BMI of 25-30
6. The BMN-270-205 trial gave FVIII GT to 2 PWH with active inhibitors-1 was tolerised. Also to 7 with prior inhibitors - no recurrence of inhibitors 3/13

6. Protein S antibody VGA039 trialed in 35 healthy volunteers. Well tolerated with increased thrombin generation. No thrombosis. Potential to treat VWD and RBDs
7. Data on HMB-001 for Glanzmanns. Phase 1 data 7 with Glanzmanns-no SAEs,well tolerated, accumulation of FVIIa 4/13

and increased thrombin generation.
8. Camelid heavy chain nanobody increased VWF and FVIII for up to 14 days. Small, easily bioengineered low cost production
Could be promising tx for HMB in women
9. MiM8 stimulates proteolytic activity of FIXa more than 20, 000 fold 5/13

10. Inno8 oral mimetic candidate therapy has a similar effect as emicizumab at a 90 fold lower molar concentration. Half life 115 hours in dog model
11. NXT007 will increase fibrin formation v Emicizumab from 15% to 100% FVIII
12. 41/105 FIX variants looked at increased 6/13

clotting activity using emicizumab. Some also responded to MiM8
13. BE-101 edits FIX into B lymphocytes using FIX-Padua and CRISPR Cas9. BeCome9 trial open for enrolment. Could possibly result in stable expression, continious secretion,durable, titratable,redosable ,used 7/13

In children also.
14. Approach using LNP to deliver siRNA to hepatocytes targeting plasminogen. Good early results in mice and dogs. Promising for HMB and other types of bleeding
15. ET3 FVIII variant containing porcine FVIII sequences more efficiently secreted from cell 8/13

Higher specific activity, good correlation between OSA and chromogenic assays. Immunogenicity unknown.
16. Exciting work ongoing on FVIII variants to improve FVIII GT expression / durability. Human WT FVIII not optimised for clotting activity. Variants include FVIII QQ 9/13

which gives better clots at lower levels of expression, FVIII-K6 59 which increases FVIII 4 fold, hFVIII-delta3-Sp/DE which gives a 3-5 fold increase in FVIII, decreases ER stress and may improve durability. Some variants can be combined
17. First 2 PWH dosed in trial of 10/13

Platelet targeted Lenti -FVIII. First PWH ABR decreased from 9.6 to 0 and he had improved joint mobility after 1.5 years. Second PWH similar results at 3 months.
18. CD68-Et3-Lv CD34+ lentiviral GT trial in India on HSC cells. 5 PWH treated to date. FVIII 6 months post 11/13

on first 4 wete 8%,4%,45%,21%. Age range 22-34
19. Dual AAV vector GT for VWD challenging due to size of VWF. Long term expression of VWF from hepatocytes does not support clotting due to lack of mulltimers. Work ongoing
20. MASH related HCC will be a major population 12/13

Problem. Misfolded FVIII may predispose to HCC. Deletion of the ER protein ATF6 may decrease risk. 13/13