Two interesting posts by PP on Prurisol. Plenty
Post# of 72447
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Posted On: 04/16/2018 1:26:46 PM
Two interesting posts by PP on Prurisol.
PlentyParanoid Monday, 04/16/18 12:08:12 PM
Re: loanranger post# 224383
Post # 224477 of 224506
Oh darn, I was afraid that my post might misfire. Loanranger, you are absolutely right about my post being obscure. I try to clarify.
How do PASI and sPGA scores relate to each other:
PASI50 score is roughly equivalent to sPGA score reduction by 1 point (often called sPGA shift 1)
PASI75 score is about equal to sPGA score 0/1 with at least 2 point reduction from baseline sPGA index
PASI90 does not have equivalent in sPGA world
PASI100 is about equal to sPGA 0 with at least 2 point reduction
In practise and only for subjects with moderate to (very) severe psoriasis
PASI75 score is about 1.15 +- 0.25 (st.dev) times sPGA0/1 score based on a sample of 200 value pairs. About 75 % of ratios were above 1.0.
PASI100 score is about 0.9 +- 0.20 (st.dev) times sPGA0 score based on a sample of 50 value pairs. About 75 % of ratios were below 1.0.
The drop in PASI/sPGA ratio reflects relative weakening of sPGA score definition from 0/1 to 0. Strict sPGA equivalent to PASI100 would be sPGA score 0 with at least 3 point reduction in sPGA score, not by 2 points as it is now.
What I was trying to demonstrate was
1. Quite a number of kill/continue decisions on psoriasis drugs have been based on trials with similar population sizes as in prurisol p2a trial.
2. All kill decisions in my sample were based on weaker efficacy numbers than those for prurisol.
3. Even the two go ahead decisions in my sample were based on weaker efficacy numbers than those for prurisol.
4. The one drug in my sample, CF101, that failed in p3 should not have been there in the first place. It got to p3 only because of an astoundingly flawed phase 2 data analysis.
5. If prurisol were a big pharma drug it probably would be in late p2 or p3 trial right now, which, strangely, is the case right now. What a flabbergasting coincidence.
Specifically about Otezla: decision to proceed with Otezla was based on trials with 20 mg BID dose and PASI75 scores 24.4 and 30 %. Afterwards, in dose ranging trials optimal dose was deemed to be 30 mg BID. For 30 mg dose Otezla trials have recorded PASI75 values in the range 28.7 to 40.9 % and sPGA 0/1 values in the range 20.4 to 33 %. About the same as for prurisol 200 mg in p2a (for Otezla PASI75 to sPGA 0/1 ratio is anywhere from 1.11 to 1.53, depending on a trial). Highest PASI100 or sPGA0 reported for Otezla is 3.4 %.
In conclusion
A. It looks like results from small psoriasis trials do indicate significant efficacy trends.
B. Irony is obviously lost in salad eating hop-alongs.
C. I am not saying that prurisol is a sure winner. Neither am I saying that PASI75 score for prurisol 300 mg dose will be above 50 %. I doubt that. What I am saying is that, so far, indication are pointing more into winning direction than into losing. What convinced me of this is prurisol's 10.5 % score for sPGA 0. sPGA0 scores above 2 % for placebo have NOT been reported as far as I know and, in general, sPGA0 above 10 % is reserved for biologicals.
Opposition case: the points TIAB should be making are:
Fine, prurisol shows some indications of efficacy. But:
1. We do not have any evidence that this efficacy will scale upward with dose. Both bell shaped (CF101) and quickly saturating efficacy/ dose curves have been reported.
2. There is no guarantee that the efficacy level shown in p2a will survive in larger trials. The size of p2a trial is too small to infer that; granularity in efficacy is of the order of 5 % per subject. Therefore, efficacy in larger trial could as well be 20 or 25 % percent measured by sPGA 0/1 ie. below or at the clear stop/go threshold. Prurisol is probably dead if sPGA 0/1 for prurisol in p2b turns out to be about 20 %.
We have a case of different opinions based on incomplete set of facts. I have as much evidence (well, probably bit more) to say that prurisol will succeed than TIAB has to say it will not. TIAB's problem is that sPGA 0 score for prurisol.
Sorry about the length of the post. My bad habit. I even lecture to audience of 2 (me and myself).
PlentyParanoid Sunday, 04/15/18 05:17:53 PM
Re: TheBunny post# 224372
Post # 224373 of 224508
Incomplete history of psoriasis treatment failures in phase 2
I took it to myself to provide some scientific support for TIAB’s position that prurisol 2a trial results don’t have any scientific or predictive value and hence are a gross insult to stuff that is mere useless.
Below are psoriasis p2 trials for some compounds that got terminated at phase 2 or went to die in phase 3.
Apo805K1 p2 with 12 subjects, scored PASI75 of 16.7 %. Promptly forgotten.
Lipitor p2 with 11 subjects, scored PASI 50 of 27.3 %. Instantly killed for psoriasis.
CF101 p2 with 17 subjects scored PASI50 of 35.3%, PASI 75 of 5.9%, sPGA 0/1 of 23.5 %. This one went to die in P3 with PASI75 score at 8.5% and equaling placebo. Turns out that the Co. had forgotten from sPGA 0/1 definition the part saying ‘and improvement of at least 2 sPGA points'. The real sPGA 0/1 in p2 was 5.9 %.
Doxercalciferol p2 with 25 subjects scored PASI50 of 20 %. Buried.
Navarixin p2 with 21 subjects scored sPGA 1 point shift of 38.1% (about the same or slightly worse in terms of PASI50). Swiftly nixed.
PF-04965842 p2 with 14 subjects scored PASI75 of 14.3 %. Terminated with prejudice.
SRT2104 p2 with 12 subjects scored sPGA 0/1 of 16.7 %. Mercifully removed from life support.
Talarozole p2 with 45 subjects scored PASI75 of 15.6 %. Dropped like dead pigeon.
For comparison, a succesful transition from p2 to market:
Apremilast (Otezla) p2 with 30 subjects and 20 mg dose scored PASI50 of 46.7 %, PASI75 of 30.0 and went thru successful P3 to generate over 1 B$ in yearly sales.
So, how does those numbers for prurisol look in this company
Prurisol p2 with 19 (sPGA=3) subjects and 200 mg dose scored sPGA0/1 of 31.6 % and sPGA 0 ( about equal to PASI 100) of 10.5 %. Even ignoramus can see that these number don’t show any sort positive trend. And if not an ignoramus then surely an educated man. And if not an educated man then unquestionably a pre-med student who paid for his chemistry and biology grades. And if not him then, well <que in the music>
Somebody (somebody)
ooh somebody (somebody)
Can anybody find me somebody ...
PlentyParanoid Monday, 04/16/18 12:08:12 PM
Re: loanranger post# 224383
Post # 224477 of 224506
Oh darn, I was afraid that my post might misfire. Loanranger, you are absolutely right about my post being obscure. I try to clarify.
How do PASI and sPGA scores relate to each other:
PASI50 score is roughly equivalent to sPGA score reduction by 1 point (often called sPGA shift 1)
PASI75 score is about equal to sPGA score 0/1 with at least 2 point reduction from baseline sPGA index
PASI90 does not have equivalent in sPGA world
PASI100 is about equal to sPGA 0 with at least 2 point reduction
In practise and only for subjects with moderate to (very) severe psoriasis
PASI75 score is about 1.15 +- 0.25 (st.dev) times sPGA0/1 score based on a sample of 200 value pairs. About 75 % of ratios were above 1.0.
PASI100 score is about 0.9 +- 0.20 (st.dev) times sPGA0 score based on a sample of 50 value pairs. About 75 % of ratios were below 1.0.
The drop in PASI/sPGA ratio reflects relative weakening of sPGA score definition from 0/1 to 0. Strict sPGA equivalent to PASI100 would be sPGA score 0 with at least 3 point reduction in sPGA score, not by 2 points as it is now.
What I was trying to demonstrate was
1. Quite a number of kill/continue decisions on psoriasis drugs have been based on trials with similar population sizes as in prurisol p2a trial.
2. All kill decisions in my sample were based on weaker efficacy numbers than those for prurisol.
3. Even the two go ahead decisions in my sample were based on weaker efficacy numbers than those for prurisol.
4. The one drug in my sample, CF101, that failed in p3 should not have been there in the first place. It got to p3 only because of an astoundingly flawed phase 2 data analysis.
5. If prurisol were a big pharma drug it probably would be in late p2 or p3 trial right now, which, strangely, is the case right now. What a flabbergasting coincidence.
Specifically about Otezla: decision to proceed with Otezla was based on trials with 20 mg BID dose and PASI75 scores 24.4 and 30 %. Afterwards, in dose ranging trials optimal dose was deemed to be 30 mg BID. For 30 mg dose Otezla trials have recorded PASI75 values in the range 28.7 to 40.9 % and sPGA 0/1 values in the range 20.4 to 33 %. About the same as for prurisol 200 mg in p2a (for Otezla PASI75 to sPGA 0/1 ratio is anywhere from 1.11 to 1.53, depending on a trial). Highest PASI100 or sPGA0 reported for Otezla is 3.4 %.
In conclusion
A. It looks like results from small psoriasis trials do indicate significant efficacy trends.
B. Irony is obviously lost in salad eating hop-alongs.
C. I am not saying that prurisol is a sure winner. Neither am I saying that PASI75 score for prurisol 300 mg dose will be above 50 %. I doubt that. What I am saying is that, so far, indication are pointing more into winning direction than into losing. What convinced me of this is prurisol's 10.5 % score for sPGA 0. sPGA0 scores above 2 % for placebo have NOT been reported as far as I know and, in general, sPGA0 above 10 % is reserved for biologicals.
Opposition case: the points TIAB should be making are:
Fine, prurisol shows some indications of efficacy. But:
1. We do not have any evidence that this efficacy will scale upward with dose. Both bell shaped (CF101) and quickly saturating efficacy/ dose curves have been reported.
2. There is no guarantee that the efficacy level shown in p2a will survive in larger trials. The size of p2a trial is too small to infer that; granularity in efficacy is of the order of 5 % per subject. Therefore, efficacy in larger trial could as well be 20 or 25 % percent measured by sPGA 0/1 ie. below or at the clear stop/go threshold. Prurisol is probably dead if sPGA 0/1 for prurisol in p2b turns out to be about 20 %.
We have a case of different opinions based on incomplete set of facts. I have as much evidence (well, probably bit more) to say that prurisol will succeed than TIAB has to say it will not. TIAB's problem is that sPGA 0 score for prurisol.
Sorry about the length of the post. My bad habit. I even lecture to audience of 2 (me and myself).
PlentyParanoid Sunday, 04/15/18 05:17:53 PM
Re: TheBunny post# 224372
Post # 224373 of 224508
Incomplete history of psoriasis treatment failures in phase 2
I took it to myself to provide some scientific support for TIAB’s position that prurisol 2a trial results don’t have any scientific or predictive value and hence are a gross insult to stuff that is mere useless.
Below are psoriasis p2 trials for some compounds that got terminated at phase 2 or went to die in phase 3.
Apo805K1 p2 with 12 subjects, scored PASI75 of 16.7 %. Promptly forgotten.
Lipitor p2 with 11 subjects, scored PASI 50 of 27.3 %. Instantly killed for psoriasis.
CF101 p2 with 17 subjects scored PASI50 of 35.3%, PASI 75 of 5.9%, sPGA 0/1 of 23.5 %. This one went to die in P3 with PASI75 score at 8.5% and equaling placebo. Turns out that the Co. had forgotten from sPGA 0/1 definition the part saying ‘and improvement of at least 2 sPGA points'. The real sPGA 0/1 in p2 was 5.9 %.
Doxercalciferol p2 with 25 subjects scored PASI50 of 20 %. Buried.
Navarixin p2 with 21 subjects scored sPGA 1 point shift of 38.1% (about the same or slightly worse in terms of PASI50). Swiftly nixed.
PF-04965842 p2 with 14 subjects scored PASI75 of 14.3 %. Terminated with prejudice.
SRT2104 p2 with 12 subjects scored sPGA 0/1 of 16.7 %. Mercifully removed from life support.
Talarozole p2 with 45 subjects scored PASI75 of 15.6 %. Dropped like dead pigeon.
For comparison, a succesful transition from p2 to market:
Apremilast (Otezla) p2 with 30 subjects and 20 mg dose scored PASI50 of 46.7 %, PASI75 of 30.0 and went thru successful P3 to generate over 1 B$ in yearly sales.
So, how does those numbers for prurisol look in this company
Prurisol p2 with 19 (sPGA=3) subjects and 200 mg dose scored sPGA0/1 of 31.6 % and sPGA 0 ( about equal to PASI 100) of 10.5 %. Even ignoramus can see that these number don’t show any sort positive trend. And if not an ignoramus then surely an educated man. And if not an educated man then unquestionably a pre-med student who paid for his chemistry and biology grades. And if not him then, well <que in the music>
Somebody (somebody)
ooh somebody (somebody)
Can anybody find me somebody ...
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