Turtlepower, >> PYMX << - There is a more complete set of slides from the April 23 conf call, with additional slides showing efficacy by both the new FDA guidelines and by the previous 'per study analysis plan' guidelines -- see link at PYMX's website (link below), and the audio of the conf call is also available.
The April presentation also has 6 slides showing all the confidence intervals from each patient population group for the various time periods following treatment, and also 3 slides with time to clinical response graphs for each patient population (per protocol, mITT, and ITT), and a slide with the number of patients in each population broken down by dosing arm -
Also note that in these slide presentations, the PDF slide number is not the same as the actual slide number due to the corporate logo slide in the beginning (so PDF slide 12 is actually slide 13).
>>> Specifically the clinical response in ITT population doesn't seem to show a dose response (slide 14). <<<
In the Q+As, they explained that the drop off in the mid-dose group was due to a combination of the small size of that arm (35 patients in per protocol population vrs 39 and 40 in the high and low arms) and that there were several patients in the mid-dose arm who responded to treatment but who didn't return for the later evaluation (most sites were in Russia and Ukraine). Since they didn't return, they had to be considered treatment failures and this skewed the mid dose figures lower than the high and low dose arms.
The close similarity between the high and low dose efficacy suggests that all dosing levels were likely higher than needed for good efficacy, and this jives with the PK/PD data from the Phase 1 and from preclinical animal efficacy data. The next trial will include arms using a lower dose, and also shorter dosing periods - 1 day (single dose) and 3 days (rather than the 5 days of dosing used in this Phase 2).
PMX-30063 has a very long halflife of 23 hours in humans, and the time it remains in tissue is also very long at 17 hours. The CEO explained that all their animal studies have shown that efficacy for PMX-30063 depends primarily upon C-Max rather than the length of time of dosing. With the defensin mimetic mechanism and the very long halflife of PMX-30063, all that is required for complete efficacy is getting the blood and tissue concentration of the drug to a high level once. So unlike other antibiotics which must enter the bacterial cell and disrupt biochemical pathways to be effective, a long period of dosing isn't required with defensin mimetics - the drug quickly binds to the outer cell wall, creating pores which allow water into the bacterial cell which then bursts. It's a quick process requiring only a single exposure to the drug.
Side effect-wise, there were 2 patients who discontinued treatment due to high blood pressure, one in the high dose arm and one in the mid-dose (the trial had 215 patients), and these were patients with some existing hypertension. In the conf call they said the elevation of blood pressure occured over time, so the proposed shorter dosing regimen (1 day and 3 days, rather than the 5 days in this trial) should minimize any side effects. The main side effect for PYM-30063 has been transient paresthesia (tingling, numbness) which didn't cause any treatment discontinuations, and was mild and resolved after the study.
The sustained clinical response data for the per protocol population (days 10 and 28) looked very good (mid-dose skewed a bit due to the factors noted above). For antibiotics you need to show non-inferiority, and other factors are also considered such as the lack of bacterial resistance developing, much shorter dosing required (only 3 days, or perhaps just 1 day), etc -
Day 10 -
Low Dose --- 92.3 %
Mid Dose --- 93.8 %
High Dose -- 100 %
Daptomycin - 97.7 %
Day 28 -
Low Dose --- 97.2 %
Mid Dose --- 87.5 %
High Dose -- 100 %
Daptomycin - 97.8 %