NB,
<<We just have to figure out what the right strategy is.>.
Exactly. But, should this right strategy path be in pass! That was my point in: Message 19380286
Were they full of itself with 100X more potent Trap than Kineret? Or CRP level reduction from baseline, observed in PI, was (for them) clear surrogate indicator that they have right dose? Going beyond 100 mg dose was not feasible at PII start, because they had problem (too low drug concentration in injectable formulation)?
What about IL-1 level? Is there surge in IL-1 after dosing started? Surge in other cytokines? IL-15? IL-6? What percentage of the Trap is bound to plasma proteins and what is free and available for IL-1? Synovial membrane penetration? Level of the circulating IL-1 neutralization? Level at inflamed site IL-1 neutralization? Is CRP, SER, RF,... true surrogate measurements that indicate drug biologic activity? What about other components of the CRA score?
I can continue with those ??? for months...., but is there any answer?
Well, Kineret direct injection to OA knee seams may be OK:
From RA conference, next week (thanks Stafan).
Tuesday, 11:00 a.m. - 11:15 a.m.
Presentation #1822: Safety and Efficacy of Intra-articular Injection of IL-1ra
(IL-1 Receptor Antagonist) in Patients with Painful Osteoarthritis of the
Knee: a Multicenter, Double Blind Study – This was a prospective, multicenter,
double-blind trial. Six doses were considered a priori: from a placebo-like dose (0.01
mg) up to 150 mg of IL-1ra. Fourteen patients were included (results are presented
until day 30 of follow-up) and this number was sufficient to define the maximum
tolerated dose (MTD). One patient received the placebo-like dose and 13 patients
received an i.a injection of 150 mg of IL-1ra. No episode of toxicity occurred and the
150 mg dose was considered as the MTD amongst the doses chosen for this study.
Baseline visual acuity score (VAS) of pain and WOMAC were respectively 50+/-12 and
44.0+/-13.3. Compared with baseline level in the 13 patients who received 150 mg,
there was a significant improvement in VAS of pain at day 4 (-27+/-18; p<0.001;
n=13), day 11 (-26+/-21; p=0.002; n=13) and day 30 (-25+/-23; p=0.014; n=11).
Normalised WOMAC global scores when compared with baseline improved
dramatically: day 4 (-22.6+/-15.0; p=0.001; n=13), day 11 (-24.2+/-14.6; p<0.001;
n=13) and day 30 (-23.5+/-18.9; p=0.003; n=11). Conclusion: Intra-articular injection
of IL-1ra in patients with knee OA shows an excellent safety profile and a dramatic
therapeutic response is still observed at month 1. This study opens a new promising
therapeutic perspective for patient with OA.
Bottom line, we do not know how close to anti-TNF regime (IF at all) will anti-IL-1 approach come, or will be commercially interested product. Worse, we do not know will Trap work at all at the approvable level?
We are back to ground zero. No side effects at current regime does not translate into safety at higher drug doses or more frequent dosing. All this will be answered one day, I hope. Or Novartis can shake BMS hands! <grrr>
Miljenko |
