Enanta Pharmaceuticals Inc (ENTA)

[willyw]

Thoughts on 2nd Gen ABT-493 & ABT-530

Here is a little info on the ENTA/Abbvie phase 2 trial for genotype 2 & 3

This may have errors, omissions, incorrect opinion. It was all done in virtually one sitting so it may not be the final word on the trial, but it contains some information, resource and reasoning.


Here is some background in vitro preclinical testing of both compounds;
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=98363182

First consider that the two drugs ABT-493 and ABT-530 were tested in phase 2a trials, individually in several doses and perhaps durations (of the 3-D treatment) on genotype 1's.
in this trial.
A Study to Evaluate the Safety and Antiviral Effect of Multiple Doses of ABT-493 and ABT-530 in Adults With Genotype 1 Hepatitis C Virus (HCV)
http://clinicaltrials.gov/ct2/show/NCT01995071?term=ABT-493&rank=3

This trial of about 96 participants and 12 cohorts would provide about 8 participants per cohort.
The cohorts were 50/50; half were 493 in 6 dose strengths and the same with 530 in 6 distinct doses. The dosing for the trial compounds was only for 3 days of monotherapy followed by 12 or 24 weeks of the 3D abbvie regimen /w ribavirin. Presumably most participants treated for 12 weeks, but slower responders may have treated for longer (24 week duration of 3D). Since riba dosing reduction has been used successfully in various treatments it is also possible that some participants had their riba dosing reduced.

I wish that they would have had a trailing trial arm with the two compounds jointly administered, say 6-8 weeks following the start of the other cohorts to check on synergistic effect, but that didn't happen.

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Several months later this happened;
http://clinicaltrials.gov/ct2/show/NCT02068222?term=abt-530&rank=4
A Study to Evaluate the Safety and Antiviral Effect of ABT-450/Ritonavir and ABT-530 Co-administered With and Without Ribavirin in Adults With Genotype 3 Hepatitis C (HCV) Infection
This had two cohorts; one with and one without riba. 20 participants, so probably about 10 participants per cohort and treatment for 12 weeks each cohort.
Commentary; since this trial followed the 493/530 trial, it is presumed that the dosing was worked out on the 530; note, no third cohort w/ a higher or lower 530 dose. Also note they are trying it without 493. Why, I do not know.
But they could learn a few things from this trial. For instance what all participants (or high percentage) were cured just on the basis of the stronger 2nd generation 530? This might suggest that a lower 530 dose might work with the 493 when they were administered together.

Abbvie/ENTA would also have a decent idea of viral kinetics. They may have seen some people become clear/below quant in the first week.
I think this is possible since boosted 450 (in the area of a 4 log drop/3 day monotherapy) may provide a comparable viral reduction to Sovaldi (also 4 or just above 4.0 log drop if I recall correctly), and 530 should be significantly better than Ledipasvir, and the 2 second gen Abbvie drugs are matched well to cover a wider spectrum or resistant subspecies, so there *may* be comparable or even better synergistic response rates than Sovaldi and Ledipasvir. (and at minimum there should be with the 2 second generation drugs, IF the compounds are to proceed well in trials; there is little point in going forward with inferior compounds)

On the other hand, what if there was partial response, slower response? Then it may suggest a 3rd compound would be needed, or riba may be needed. Keep in mind that the trial sizes are small and it would skew the numbers.
Also keep in mind that these were naives without cirrhosis, so in theory they should be easier to treat and cure.
Any failures would also point towards the types of resistant sub species that 450 and 530 (and w/ or w/o riba) would spin off from the treatment.
Of these sub groups Abbvie/Enta should have a good idea if ABT-493 would eliminate them.
IF..... there was a high success rate it would seem that when 493 was added it would be significantly better, possibly meaning a shorter period needing to be treated, or lower dosing of 530 might be possible.
So by now they would have the initial viral responses, additional safety/tolerability information on 530, and possibly SVR-4 or maybe even SVR-8 data from this trial.

Simplistically they are testing the result of the existing 3D program, when the new drug ABT-530 is used to replace ABT-333 and ABT-267. They are testing it with and without ribavirin, as has been used in the 3D program.

Now; why test this with only 530?
At the time I wondered if they were testing to see if they could bypass using (and paying a royalty) ABT-493, or that they needed more information on the spectrum of coverage of 530. Dosing did not seem to be the issue.

Using the drug with and without riba just gives a more clear assessment of the efficacy; not imparts a suggestion that riba will be needed as part of the regimen. (or so I look at it that way- riba generally is less powerful than a DAA added instead of RBV. But part of this could be indeed to test the role of riba in g-3's
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Which brings us up to date; the present.
In mid- late September 2014 they started enrolling/dosing this phase 2B trial;
http://clinicaltrials.gov/ct2/show/NCT02243293?term=abt-493%2C+ABT-530&rank=1

A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Co-Administration of ABT-493 and ABT-530 With and Without RBV in Subjects With Chronic Hepatitis C Virus (HCV) Genotype 2 or Genotype 3 Infection

The enrollment is 175 participants and there are 7 cohorts; 3 cohorts for genotype 2 and & 4 cohorts for genotype 3
ALL of the trials are for 12 weeks; none longer or shorter. Two trial cohorts have ribavirin; one each for G-2 and G-3.
It appears to me that for genotype 2's, ABT 530 has a fixed dose, but they are evaluating the 493 dose.

For the tougher to treat genotype 3 there are 4 cohorts.
To me it looks like they have possibly chosen their dosing; 3 cohorts have the same dose of 493, and 3 out of 4 also have the fixed dose of 530.

Comparing the dosing between the 2 genotypes (2 or 3) the preponderance of cohort dosing seems to favor "Dose A" of ABT-530 for 6 of 7 trial cohorts (3/3 for G-2 and 3/4 for G-3)
For the drug compound ABT-493 dose B seems to be the favored appearing 5 out of 7 cohorts. Dose A appears once in each genotype trial cohort.

It is difficult to assess what the dosing differences are, but I would assume that they may be slight, and possibly to explain the either increased efficacy due to synergism, or that lack or synergism, suggesting they need more potency. I'm assuming the former, but my point is that these *may* be ultra fine tuning tests. It may also be that the size of the dose may become important if a 3rd compound were to be added into one(?) pill in the future. (would it be a deal breaker if it were 2 pills once/day for a cure/comparable efficacy?)

The fact that there is ribavirin in the trial means very little to me. Many of the other trials held in the past have had ribavirin. It is possible this was added at the request of the FDA merely to provide a base line for comparison/differentation. It has long been a virtually required drug with the DAA's and may be present for a period of time in trials. I have not yet begun to look, but it seems to me that RBV has and is still present in trials; even trials which will ultimately produce a RBV free treatment (or not, for some indications). Fair?

Abbvie ENTA in announcing the start of phase 2-B trials felt that the treatments would be IFN and RBV free, once a day, un-boosted, etc.
There is not much in this trial that looks that different to me from other past trials.

It is worth mentioning the composition of trial applicants in this trial. These are all either naive to treatment, or they are null responders to IFN/RBV (SOC) treatment. There are not cirrhotics in this trial, nor are there past protease inhibitor/DAA failures in this first 2B trial.

I personally do not see this as a big deal. From the standpoint of a patient/participant, Abbvie seems to be working their way into treatments and seems to be intent upon curing patients which they enroll, not merely exposing participants to non-viable dosings or durations. As these proceed and succeed, I would imagine that durations may get tested as well as raising the bar on harder to treat patient groups.

The fact that DAA failures are not being tested in this trial does not mean they won't soon be tested, Frankly, since most DAA failures revert back to wild type populations over 1-2 years, I question if it is *that* important at this point anyway to have this data from the onset.

I wrote this last week and thought; it's pretty long and contains some speculation. In the face of very little discussion about the combo I thought I would put this out there as a point of reference, a place to agree/ disagree/ correct me in my facts/assumptions or place to offer yours.
As mentioned, it was written pretty much in one sitting, and generally no errors have jumped out at me in re-reading it after what may be nearly a week, maybe after I post it. : )
~W