Thread by @victoriacyanide

NEW OBELDESIVIR (OBV; GS-5245) DATA! $GILD

Ph1 PK/PD from @GileadSciences' @ECCMID poster.

OBV = OBVIOUS! 🙊😂 #GS441524 #GS5245

Key points in thread 🧵 1/13
https://t.co/zOpymoJLicaskgileadmedical.com/conferences/co…

First, this was a healthy volunteer PK study. Impt to point this out bc it was strange that 25% of pts in PBO grp had grade 2 AE 🧐.

Also, note the dosing grps. They tested QD & BID regimens. The ph3 dose is 350 mg BID but this wasnt actually tested here...2/13

...350 mg BID likely decided bc of decreased creatinine clearance (grade 2) at >500 mg in some pts. 3/13

Now the interesting part: plasma PK of GS-441524!

~Cmax in µM
QD SAD:
100 mg: 2
300 mg: 6
900 mg: 20
1600 mg: 25

QD MAD:
900 mg D1: 21
900 mg D5: 18

BID:
500 mg D1: 13
500 mg D5: 16

For ref, in my FIW w PO GS-441524 TID, I got Cmax ~13 µM. 4/14 https://t.co/fZQDFPy9nWosf.io/am5s8/

The graph. The > 24h t1/2 we saw w GS-441524 after IV RDV can be seen here at ≥300 mg

Suggests intracellular accumulation of phosphorylated metabolites in tissue --> catabolism back to '524 --> bloodstream over time.

Will also happen at 350 mg BID ph3 dose (good!) 5/13

Aside: dose cohort selection is p interesting, esp if you compare w the molnupiravir FIH cohorts (50, 100, 200, 400, 600, 800, 1200, 1600 mg)

Big jumps in obeldesivir dose cohorts & starting at 100 mg in the SAD suggests Gilead rly doubted F% imo. 6/13
journals.asm.org/doi/epub/10.11…

FOOD EFFECT

Cmax in µM at 500 mg QD

fasted: 12.4
fed: 11.7

Comparable.

Slight delay in Tmax after fed but, as they point out, the extent of absorption is comparable.

Good! 7/13

They didnt show PBMC PD data, but summarized.

Accumulation of GS-441524 in plasma after repeat dosing TRACKS w accumulation of GS-443902 (active metabolite) in PBMCs.

What surprises me the most is that 350 mg BID gives [GS-443902] likely HIGHER than that produced by RDV! 8/13

Remarkable bc RDV is V GOOD at loading PBMCs w GS-443902.

I consistently contended the SAFETY PROFILE of GS-441524 >> RDV, that you could dose higher & get ⬆️ GS-443902 in target tissue

If this is true, we could've had a PO COVID drug > 2 y ago 😔 9/13
https://t.co/6JXs6TfqLhpubs.acs.org/doi/10.1021/ac…

🐘 in room: how does OBV stack up to #VV116, the tri-iBu GS-441524 deuterated prodrug from the WIV?

Cmax in µM for SAD:
25 mg: 0.6
200 mg: 3.8
400 mg: 6.5
800 mg: 9.6
1200 mg: 10.6

COMPARABLE!

Ph3 VV116 dose is 600 mg BID D1, 300 mg BID D2-5. 10/13
https://t.co/FyE2CExue7nature.com/articles/s4140…

So I'd say...

OBV ph3 @ 350 mg BID, ~ 7 mg Cmax

VV116 ph3 @ 600 mg BID D1 ~8 mg Cmax, 300 mg BID D2-5 ~5 mg Cmax

SUUUUPER comparable.

Always thought tacking on extra iBu = 🤡 move. Horrible tradeoff. Maybe even no benefit here.

Good job Gilead for not doing that! 11/13

So looks like VV116 may indeed be a bellweather for OBV. Interesting no creatinine issues reported w VV116.

Remember this VV116 vs. #paxlovid ph3 in @NEJM?

Well they're running VV116 vs PBO in vax'd pts now (NCT05582629). Looking fwd to results! 12/13
nejm.org/doi/full/10.10…

Finally: @GileadSciences should've jumped on GS-5245/GS-441524 3 YEARS AGO!

We pointed this out to their big wigs SEVERAL TIMES during 2020-2022 🤡

Excited for ph3 data. But this is WAAAYYYY overdue.

Smh. That comment section was also madness lol 13/13
statnews.com/2020/05/14/gil…