Idenix CEO Ron Renaud Q&A April 11, 2012
Idenix has been the subject of considerable attention with EASL (The European Association for the Study of the Liver) approaching and embargoed abstracts flying around the web. The company’s shares have been battered, dropping nearly 50% from January highs as questions have arisen over the potency of lead compound IDX184. I spoke by phone today with Idenix CEO Ron Renaud:
Ron: I wish I could tell you what’s going on with our stock. All we can do focus on is focus on our data and focus on our pipeline. As you and I were talking last week we’ll be providing an update on our NS5a program and we’ll be talking to folks about 184 as well so we’re looking forward to the meeting next week and we think we’re on the right track with all of our programs.
Q: Will your update be broadcast from your website?
Ron: Yeah, we’ll have an update next week so I’d stay tuned on that. We’ll release data right around EASL. That probably means a press release some time next week.
Q: What makes a drug a backbone HCV treatment?
Ron: A backbone treatment is a mechanism that represents a common thread through however a disease is treated. So if you think about inflammation right- on the large molecule side, you’d say the backbone is probably the TNF inhibitors, for the small molecule it could be the COX-2 inhibitors. I think for cancer, a backbone therapy for breast cancer is anything that includes cyclophosphamide. I think in HCV or virology in general, we’ve taken pages out of the HIV and HBV book, and if you think about any patient that gets treated with HAART, with the combination therapy regimen, it’s a nucleoside-containing regimen. If you think about Hepatitis C, everybody gets a nucleoside. And the reason for that is nucleosides hit the most conserved area of the genome of the Hepatitis C virus. So protease inhibitors, they hit a shallow pocket, the non-nucs, they hit the allosteric binding sites around the virus, NS5a hits a very specific area on the virus; but it’s not the way that the nucleoside actually gets in there an chain-terminates. So because of that, it represents a very high barrier to resistance, it has the potential to be pan-genotypic, and my guess is it will probably go a long way with its high barrier to resistance to suppress the mutations that might crop up with the other lower barrier to resistance mechanisms like PIs, non-nucs, and NS5as. Those are all potent classes, but their barrier to resistance is very low. That’s why we believe and a lot of people believe, that nucs will be a backbone compound.
Q: 184 is often compared to 7977; how do you think it compares to INX189?
Ron: I think if you look at the active metabolite and active triphosphate that’s generated by 189, it’s the exact same triphosphate, active metabolite that gets generated by IDX184. So you could compare it to INX189 but we haven’t seen RVR data from 189, we haven’t seen EVR data from 189, so I’m only making comparisons to 7977 because it’s generated the most data that can draw direct comparisons to.
Q: Is 7977 also the same active metabolite?
Ron: No, so 7977- you know the difference between purines and pyrimidines right? So you have different bases, 7977 is a pyrimidine analog, you hit a different base- it comes from the uridine side, the pyrimidines. Both 184 and 189 are guanosine analogs. So the active metabolite for 7977 will be a uridine triphosphate. It’s that uridine triphosphate that will get into the hepatocyte and kill the virus. It’s gonna incorporate itself into the RNA and kill the virus. In the case of 184 and 189, it’s going to be a guanosine triphosphate that gets incorporated.
Q: What differentiates IDX184 and Bristol’s INX189?
Ron: Different pro-drug mechanisms. So the pro-drug mechanism for 189 is very different from what Idenix uses. I would say that represents the biggest difference between the two compounds.
Q: If it’s the same triphosphate, would you expect them to have similar activity?
Ron: It depends on what that pro-drug does. We’ve only done 3-day monotherapy studies because that’s all the FDA allowed us to do. There was a concern about resistance- we were the first ones out- with the next generation nucleosides. After us, both Pharmasset and Inhibitex were allowed to do seven day studies. From here on out we’ll be allowed to do seven-day studies. But back then we were only able to do three-day studies.
189, over seven days generated some pretty impressive viral load reduction, but I don’t remember exactly what they were at the top of my head. But they were more than what we saw with 184- but they were also seven-day datasets compared to our three-day datasets. And we do know that with these guanosines and our pro-drug approach, it takes us a little longer to get to steady-state. So it’s not an apples to apples comparison and that’s the best we can do and probably why you don’t hear us draw too many comparisons to 189 as much as we do with 7977.
Q: Why do you think companies would choose 184 as a partner?
Ron: Giving you a sense of the kind of discussions we have, if you think of really potent protease inhibitors, NS5a inhibitors, even non-nucs that are out there; the one thing that they all lack, they don’t lack potency, they lack barrier to resistance. And you can see resistance in some of the PIs and non-nucs, in some cases you can see them in a matter of hours. With the other target it takes a little bit longer, but these drugs by themselves- they need a barrier to resistance as part of an all-oral combination approach. When we talk about 184 with folks, they see an RVR of 73%, which is as potent as just about any antiviral we’ve seen out there, with the exception of 7977. And now we’ve generated EVR data that shows it’s just as potent as 7977 at 93%. So I think folks realize this could be a good backbone or a good part of an all-oral regimen. Because if you think about it, it’s not about any individual drug- folks have to go back and stop looking at individual drugs and focus on combinations like in HIV. If you look at historical data from HIV drug studies, different mechanisms of action and overlapping resistance pathways is where you get the best response rates. Atripla doesn’t have the three best antivirals in HIV, they just work really well together. So you have combinations that compensate for each other’s resistance profile, safety and tolerability, and if you look at all of these, nucs are part of the picture.
Q: Abbott showed a four drug combo that showed good activity. Some are suggesting you might not need a nuc. What do you think?
Ron: I look at the Abbott study and I see n’s of 19 in the first sub and 14 in the second sub, and 17 in the third arm, I say its still small patient numbers. Look at conclusions that have been drawn from drugs out there with small patient numbers and what happened when we’ve allowed that to become doctrine. I think you’ve got to wait and see what happens in large datasets before you can draw conclusions that you can cure 100% of patients or I think they got to 98-99% SVR. What we’re encouraged about that data is- if you follow the thesis that a regimen is only as good as its weakest component- if you look at the Abbott regimen, they have a non-nuc in there that generated a 50% RVR and had no barrier to resistance and is now part of a 90%+ regimen. How does anybody explain that? It’s back to getting to the right combo, and only empirical evidence is going to get us there, generating the data. Wall Street’s not going to be able to figure out what the right combination is just by looking at these datasets. It’s going to be a lot of mixing and matching and permutations of dose, potency, and resistance profile before we get this right. And when we get this right, my sense is we’ll have three or four different groups that get it right. And ultimately, I think the group that’s going to win- and I think there will be more than one- but the group that’s going to win, is going to be about the regimen, is going to be about the cure, is going to be about what’s convenient, all-oral, how easily it can be given, how potent is it, and how safe is it. And I think if you’re really lucky, you’ll have a regimen that’s pan-genotypic. And that’s really where Idenix thinks we can set ourselves apart from everybody else.
Q: How do you see the HCV market shaping up? Will one company lead as in HIV, or will it be fragmented?
Ron: From where I sit today- and this may change in six months- I don’t see one dominant regimen. I see three, four, maybe five different regimens that are all going to generate 80%+ SVRs and what you are going to compete on is how safe are they, how convenient are they. The only way to differentiate at that point is are they pan-genotypic, which then you can take one or two pills and give it to anyone who has HCV.
Q: Will you show combination data for your NS5a and 184 next week?
Ron: No. Quite frankly, we’ve looked at with replicon studies combinations with NS5a, PI. The greatest synergy is a three drug combination. When we did it pre-clinically we did it without ribavirin- I’m not ready to rule ribavirin out yet- but the most synergy in killing the virus is when you put a nuc, and NS5a, and a PI on top of it.
Q: Do you think that will be required going forward?
Ron: We don’t know. That’s exactly where we are. We don’t know if it’s two drugs plus riba, three drugs plus riba. I think if you want a 12-week or less regimen, you will need to have a delicate balance of potency and resistance and overlapping resistance mechanisms and that may require at least two drugs plus riba or three drugs plus riba. We don’t know.
Q: In the preclinical studies, does the 184+NS5a or 184+P1 show greater synergy?
Ron: It’s hard to tease that out. We’ve got to do this empirically. I think there’s still a lot of work the industry needs to do right now especially if we’re going to take peg-interferon out of the mix and cure the disease in less than 12 weeks.
Q: The Roche study showed some relapse in their combination study.
Ron: That was a ritonavir boosted protease inhibitor- that was the INFORM study- ritonavir boosted danoprevir plus mericitabine. Mericitabine is a first generation nuc, it is one-gram of nuc a day, it is not liver-targeted, it is not focused on liver, so it gets out systemically and you get a fraction of triphosphate that gets into the liver that actually kills the virus than you get with the next generation nucs. It is definitely a much less potent nuc and it is hard to say what that meant in combination.
Q: Who do you see as your top competitor?
Ron: We don’t really see competitors, we’d probably say Gilead because they have 7977 because they have a direct competitor as a nuc. But by and large, we see most of the rest of the HCV space as potential collaborators. We view 184 as very combinable with any of the protease inhibitors and we’ll combine with our own NS5a. We’re working to get that study underway by the end of this year. To the extent that anyone has an NS5a inhibitor they may be a competitor, but right now, we really view the field as potential collaborators, not really competitors.
Q: Would it be possible to collaborate with Gilead on 7977?
Ron: I think theoretically you could collaborate with their nuc because they’re different bases. Their drug PSI-938 was a guanasine analog, it was a drug that looked a lot like IDX184, and that was a part of their nuc-nuc strategy, so theoretically you could do it. Given those drugs are structurally very similar, we’d probably like to have more diversity in a real nuc-nuc strategy. If I want to put two nucs together, I’d not only want to have a different base, I’d want to have different sugars as well.
Q: Is there anything out there that fits that qualification?
Ron: We’re working on them ourselves. In the last 18 months, we have developed over 1,500 new nucleotide prodrugs in a very aggressive campaign to find the best qualities of a prodrug, the best qualities of the sugars, the best qualities of the base, how the drugs are metabolized. We’ve done an extensive, an absolutely one of the most robust medicinal chemistry efforts we’ve ever done to understand what makes a really good nucleotide prodrug, one we’re going to bring into the clinic in the middle of this year and probably another half dozen compounds we’re excited about and we’ll try to get as many of those into the clinic over the next 12 to 18 months as possible.
Q: How is the new compound, IDX19368 an improvement over 184?
Ron: So this is one of the compounds where we really looked at how do we improve on generating as much triphosphate as possible in a hepatocyte. And right now with 368, we think we have a compound that generates more triphosphate in a hepatocyte than anything we’ve seen in the clinic today. That would be the most significant difference. Other than that, we’re not going to talk about any of the other differences between it and 184 till we get to the clinic. It’s a program we’re quite excited about.
Q: Lots of people are working on NS5a- why do you think that has become such a hot target?
Ron: Because the second generation compounds that have come out, really led by Bristol Myers, have shown some very fantastic potency. When you’re seeing two or three log in one day, you know you’re having an impact on the virus. In fact we presented data back in February in genotype 1 patients in a small single rising study where we generated 3.7 logs of RNA reduction in one day. And we saw those patients continue to stay at low levels 48-72 hours after they were dosed.
Q: What data are you looking forward to seeing at EASL?
Ron: We’re at the tip of the iceberg in understanding what it takes to cure HCV. And I think we’re going to see a lot of data. A nuc with an NS5a, I think that’s going to be interesting to the extent we can get an update on 7977 and 052. That will be very instructive for Idenix. But also, looking at all these other combinations and trying to understand why these other combinations worked and certain ones don’t I think affords us the opportunity to avoid these pitfalls and put out compounds in combinations that give them the best chance to succeed. So we look forward to any nuc-containing regimen, good data and bad data.
Q: Does Idenix have plans to become a fully integrated biopharma?
Ron: We’ve been there before- in hepatitis B, we discovered, developed, and got approved a drug for hepatitis B. It is now sold by Novartis and generates over $100 million in sales. We had a commercial organization and we reorganized in 2007 and gave that drug back to Novartis in exchange for royalties and dismantled our sales organization. It’s not easy and that was in HBV where competition is somewhat limited. If we look out at HCV, HCV is going to be an absolute- I think- a sales and marketing battle going forward given the sheer number of players in the space. So, I think today, sitting here April 2012, is to really focus on giving our pipeling the best chance to succeed. By the time we get down to the pathway of registration trials, pivotal trials, we’ll want a partner aboard that’s helping us with that. We believe this is going to be a landscape that’s dominated by Big Pharma.
My Take:
I like the company. I believe nucs will be the backbone of HCV treatment and Idenix will be a player.
Disclosure: Long IDIX
