Biotech Values

[biomaven0]

Digging up this old AKBA post because it was linked recently:

>>PS: i too was struck by the lack of dose response, but it probably has something to do w trial design such as ESA rescue, transfusion, and dose escalation after 8 weeks

So here is my big concern with AKBA drug:

Doses in $AKBA chart are 300mg QD, 450mg QD and 450 TIW. Suggests to me tachyphylaxis mechanism w/ daily dosing as $FGEN has claimed pic.twitter.com/DunX7OWQ93

— Peter Suzman (@Biomaven) April 25, 2017

So there we have three quite different doses all leading to the same efficacy. So there are two possible explanations for this that I see:

1. They've maxed-out efficacy and are at the flat part of their dose-response curve. I think this is really unlikely because of the TIW vs. QD dosing and also because FGEN drug shows basically linear dose response with absolutely no sign of being maxed out.

2. There is a countervailing negative feedback response to daily dosing, which is what FGEN has claimed.

Here's a quote from latest FGEN 10k:

>>Dose Frequency. In preclinical and Phase 1 studies, we observed that intermittent dosing yielded optimal responses to roxadustat. Our Phase 2 studies indicated that three times weekly, twice weekly and weekly dosing regimens achieved Hb maintenance. In our Phase 3 program we are dosing three times weekly for all studies except two (060 and 0608) which are dosing some patients twice per week and some patients once per week. We believe that intermittent dosing may help ensure a consistent and durable treatment effect for several reasons:

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Greater Hb Response While Minimizing Total Drug Exposure. Early preclinical studies in rodents with a HIF-PH inhibitor (that was not FG-4592) indicated that a greater Hb response could be achieved using a lower total weekly dose with intermittent dosing compared to daily dosing. In the studies shown below, rats were dosed with HIF-PH inhibitor using either a daily or twice weekly dosing regimen. Both a higher Hb response and a better dose response were observed in animals dosed with HIF-PH inhibitor twice weekly compared to animals that were dosed daily. Furthermore, the total weekly dose required to achieve this greater Hb response was lower than with daily dosing exposure.

In addition, our previous preclinical studies suggested that a wider therapeutic window was achieved with intermittent dosing compared with daily dosing. Preclinical observations such as these led us to conclude that intermittent dosing could enable a better Hb response with a lower overall drug exposure and offer a potentially wider therapeutic window.




o
Reduce the Risk of Changing the HIF Set Point. The HIF system has a built-in negative feedback mechanism. Genes for two of the prolyl hydroxylase domain (“PHD”) enzymes that are responsible for degrading HIF under normal oxygen conditions are actually HIF target genes. Thus, while these PHD enzymes are inhibited by hypoxia (or by a HIF-PH inhibitor), the resulting HIF activation leads to an increase in the very enzymes that are responsible for its degradation following the re-oxygenation (or potentially removal of the HIF-PH inhibitor). This negative feedback mechanism is important in enabling the HIF system to reset. However, under chronically hypoxic conditions, it has been shown that the elevation in PHD enzyme levels is maintained, leading to a change in the HIF set-point. Based on this knowledge of HIF biology, it is our belief that prolonged HIF activation by a HIF-PH inhibitor drug could similarly lead to a change in the HIF set-point, which we believe may then require an increased HIF-PH inhibitor dose to elicit the same HIF response. In an effort to avoid this potential risk, and to potentially prolong drug effectiveness, we have undertaken an intermittent dosing regimen.<<

AKBA is now also studying a TIW dose, but their main trials are still QD. So how will the FDA respond when they see daily dosing requires a much larger total dose than TIW? FDA always wants to see the minimum effective dose studied, and arguably AKBA has not yet done that. I could see it going either way if the drug is very safe, but it certainly adds some regulatory risk from my perspective.

Peter