slc, thank you again.
A few notes and thoughts about that particular Phase 2 Otezla/ apremilast trial. This study is a good comparison study as the patients were dosed for 12 weeks and PASI 75 was monitored for 16 weeks which is the same as Prurisol 2b. Note the tail of the 20 mg bid group after discontinuation of apremilast at week 12. Prurisol Phase 2b is similarly structured and I'm sure the company is looking for (1) rapid onset of therapeutic effect and (2) more gradual decline or maintenance of therapeutic effect after discontinuation of drug.
Also, two doses of apremilast were studied, 20 mg qd which was comparable to placebo and 20 mg bid which yielded the 24.4/10.3 results that you cited. For the larger Phase 3 ESTEEM 1 and 2 trials, dosing was further increased to 30 mg bid. GI side effects and headache are common at this dose.
Clearly, apremilast 20 mg qd was ineffective while 20 mg bid yielded a clear result. From Prurisol Phase 2a we see that 50mg qd and 50 mg bid are ineffective whereas 100 mg bid is showing signs of benefit. We can not pretend to know the dose response relationship but it is reasonable to expect that Prurisol 150 mg bid/200 mg bid will be more effective than 100 mg bid. Is it possible that 100 mg bid is the maximum effect and further increases in dosage yields no further benefit. Of course it's possible but I believe this is unlikely. The bigger question for me is how these higher Prurisol doses will be tolerated. I'm expecting headache as a common side effect (like apremilast) and am unsure about liver function tests (LFTs) and if the effect is a) unrelated to dosage and/or b) is clinically limiting. Obviously, we are hoping for a comparable result with two arms of Prurisol dosed higher than the 100 mg bid that yielded an encouraging trend. Prurisol IS NOT Ziagen and is almost certainly metabolized differently. Though abacavir is the primary metabolite which allowed for 505(b)2 there are other downstream entities at play here which may impact dosing and side effect profile. IF Prurisol is well tolerated and there is a clear dose-response relationship then the company or partner might explore even higher dosing.
Though the Primary Outcome Measures are PASI-75 and Treatment Emergent Adverse Events, there's so much more to this trial. As I've stated before, an unimpressive PASI-75 with more limited PASI improvement but a marked reduction in pruritus (itching), a well tolerated drug, and a high level of satisfaction in the quality of life surveys should not be minimized. Pruritus can be absolute torture and there are few therapeutic options. Celgene addresses this in noting the rapid relief of pruritus with apremilast (as early as 2 weeks if I recall correctly).
There has also been little attention to the 505(b)2 designation for Prurisol which is based on crossover studies demonstrating adequate levels of abacavir after Prurisol dosing as compared to Ziagen. Eventual approval with 505(b)2 is extremely high and it is usually faster and less expensive than the usual 505(b)1 for new drugs.
My approach to Prurisol is not based on any one number or any one data point but the body of evidence and the relative consistency of each little piece of information within the big picture. Are the pre-clinical models reliable? Does the drug appear well tolerated and non-toxic? Are the early non-powered clinical results consistent with pre-clinical work and suggestive of efficacy? Has the dose response relationship been explored and optimized?
IMO, the pieces fit together in a way that I believe there is a high likelihood of success.Of course, I'm hoping it's clear-cut, no doubt about it great PASI-75 with a dose that's well tolerated but it might not be as there are no slam-dunks when it comes to speculating on the outcome of clinical trials.
The science hasn't changed. My tune has not changed over the past couple of years. I don't have a need to repeat the same comments on a daily basis or engage in circular arguments. Feel free to disagree. We'll know soon enough.
Looking forward to results.
biodoc
