Replies to post #202530 on Biotech Values

[poorgradstudent]

It's also possible that once you have triggered cytokine release syndrome (or some variant) it might be too late to turn anything off because it becomes self-sustaining. Might be analogous to blowing out the lighted match that set a forest fire.

Agree. I'd say that argues for prophylaxis or dose adjustment upfront (as you point out) rather than in vivo activity adjustment via a secondary mechanism.

Not to say a rheostat might not be useful - it would at least allow you to slowly increase the dosage over time

This is a good point and I agree with it. I was actually going to wade in a similar direction in the previous post but worried about digressing too much.

As you mentioned, there are clear cases where having a ramp in dosing improves the efficacy / AE mix. In addition to brigatinib, INCY's ruxolitinib has also benefitted from this type of strategy.

But in a sense, these examples underscore the difficulties of the rheostat concept. I can only namely a handful of drugs with this type of ramp scheme. That may be due to a lack of interest / lack of trying or simply that it's only applicable to a small minority of drugs.

The other factor is these ramps in dosing are much easier for the small molecule crowd than the CAR-T crowd. Persistence and clearing of these CAR-Ts, even without adjusting the rheostat, is something people are trying to understand now, whereas small molecules are comparatively much simpler to predict via PK/PD.

All very interesting and all very exciting. But it's an area where I'm skeptical about those actors who claim next generation levels of fine tune and control when we're still dealing with first generation questions of if and how.

[dewophile]

I think it's worth noting that a lot of the SEs described to date w CAR-Ts come from experience targeting CD19. It could be that each new target has a somewhat unique set of SEs and a new learning curve to some degree for optimal use. I would guess many potential off target effects (e.g. skin w EGFR, cardiac w HER2, GI w CEA) would benefit from turning down T cell killing (i.e. not a situation like cytokine storm that is self sustaining, or severe cerebral edema where there may be no coming back). So while I agree w much of the skepticism by PGS and others regarding the ultimate utility of such switches, if i were investing in this area (and I am not at present), I think i would put some value in a platform that incorporates such technology as long as the company is not overstating its value. It may ultimately be worthless, but at this point we just don't know and i figure it can't hurt.
JMO