now seriously biotechworld, why on earth would I ask "myself" if Achillion gave us the percentage of phase 1 participants who were GT1a vs. GT1b, and then answer it with "No, I don't think so."? What kind of silly exercise in stupidity and futility would THAT be??? Trust me, Magnum is a separate person from me. Now you, however, might be binary....
Go to seekingalpha and read the article called "Gilead Sciences Gets Ambushed By The Patent Troll, AbbVie."
Gilead is not going to want ACHN to fall into ABBV's hands.
Mag or binary - has ACHN given us the number of 1a versus 1b genotypes in the phase 1? I hope it's at least 50-50%. The more 1b types in the trial, the greater the load reduction.
Here is what sofosbuvir accomplished back when it was code nqamed IDX21437 and Idenix was doing their 7 day viral load reduction in proof of concept: In GT 1 HCV-infected patients (n=8), the mean maximal viral load reduction was 4.2 log10 IU/mL in the 300 mg arm. I suspect 3422 will achieve this or close to it at a higher dose level without the aid of 3102. We'll see. It still appears to be a very potent nuc.
1) Is decreased dosage in the 3422/3102/sovaprevir combo the sole criterion for "best" full suppression, or are there other characteristics (e.g. side effect profile, rate of suppression, etc.) that lead to this designation?
It is both the decreased dosage and the synergistic/additive effects of the three drug combo, by my reading.
2) Given 3 and 4. above, 3102 appears to be the agent leading, in combination, to "best" suppression. What do the authors posit as the mechanism of action for this?
It's really the synergistic combo of 2102 with 3422., but by adding sovaprevir the doses decreased across the board. I didn't see them positing the mechanism of action for this other than two tables quantifying both the synergistic and the additive effects of the combinations. It seems that the most powerful cocktail to date is a nuc (that inhibits the NS5B protein in the viral genome that is responsible for replicating viral RNA) with an NS5A inhibitor - that protein being responsible for viral replication and viral assembly. That combo is exactly what Gilead's Harvoni is, which is also 3422 combined with 3102. NS3 protease inhibitors are important but seem to play a supporting role in HCV viral destruction, rather than the key role.
Magnum - feel free to chime in here please!
Here's what the scientific paper on pre-clinical analysis says about ability to suppress emergent resistant colonies in GT1-a using 3422, 3102, and sovaprevir:
1. No individual agent completely suppresses resistant colonies of HCV.
2. 3102 in combo with sovaprevir (without 3422) completely suppresses resistant colonies, but only at high doses.
3. Best full suppression of emergence of resistant colonies achievable with 3422 and 3102 combo instead of 3422 and sovaprevir.
4. 3422, 3102, and sovaprevir in combo achieved a superior effect to any other combo. Drug doses were much less than in other combos in order to achieve complete blockage of emergence of resistant colonies. The assays show that there may be different concentrations of 3422 and the combo drugs still possible to be equally effective to what is shown.
5. 3422 is pre-clinically superior to sofosbuvir in GT1-b and GT-3
yes it was very revealing, and docs are simply not going to put their neck on the line to risk a non-cure on a patient, when they could have prescribed 12 weeks and gotten the cure. So if somebody like ACHN comes along and get's that 97%-100% cure rate at 8 weeks (and really watch out, everyone, if they hit it at 6 weeks), then the 12 week cure is in play. And, back to the thesis, GILD simply can't afford to have an 8 week - let alone a 6 week - cure get into a competitor's hands, which is why I think they will be "forced" to acquire ACHN.
Well Apokerace, good luck with that. Here's my thinking: Based on your handle, you're a poker player of sorts. So you probably know that a good poker player either 1) has a good hand, 2) the makings of a good hand, or 3) is bluffing. Now with poker, unlike the market, you can bluff partially or completely. With the market, you can't really bluff anyone except yourself. So, let's look at the long they before you do this:
1. Patent apps are good and all entities for ACHN have or will be granted unchallengeable patents.
2. Based on pre-clinical data 3422 is looking very good. 3102, 2684, and sovaprevir are all looking stellar.
3. There are multiple players who are going to be interested in acquiring ACHN for $15-$20 WITHOUT 3422.
4. If 3422 turns out to be slightly inferior to Sovosbuvir in GT1, but superior in GT3, add another $10 to the valuation.
5. If 3422 turns out to be equal to or better than Sofo in all GT's, add $30-$40 to the price tag.
As you can see, the longs have graduated risk with very little downside and a whole lot of upside.
Now, let's look at the short position:
1. 3422 crashes and burns - low efficacy. (Really? after all the pre-clinical data and recent comments about "worthy of further investigation."?)
2. Patents don't hold up (very low chance of that happening - GILD is driving the bus against Merck on defending its NS5B uridine-analog nucleotide, and ACHN is structurally different than theirs!)
3. A short position has zero graduated risk - you either wake up one morning and ACHN is at $5-7 (temporarily), or it could be as high as $30-50. There isn't much in between on a short position of ACHN. So, you think a short's $5-7 gain on the upside is worth a $20-40 downside, when that latter scenario is looking pretty good?
From a poker standpoint, those look like bad odds to me!