BMS-986001 Bone, Metabolic Data Compare Well to Tenofovir Through 48 Weeks
There's more than one nucleoside analog reverse transcriptase inhibitor (NRTI) working its way through the antiretroviral pipeline. Although most eyes have been focused on the progress of tenofovir alafenamide fumarate (TAF), the patient-friendlier prodrug of tenofovir (Viread), another thymidine analog is moving through development as well: BMS-986001.
Actually, the name of the drug is now technically OBP-601: It was initially being codeveloped by Oncolys BioPharma and Bristol-Myers Squibb (BMS), but BMS terminated the development agreement. It is up to Oncolys, a small biopharmaceutical company, to further develop the drug on its own or seek a new partnership.
While OBP-601's future remains in flux, data continue to flow forth from its previous incarnation as BMS-986001. ICAAC 2014 featured a pair of presentations exploring the safety and efficacy of the drug at 48 weeks in antiretroviral-naive patients. The overarching efficacy and safety data were presented in an oral abstract session by Samir K. Gupta, M.D., M.S., while a closer examination of bone and metabolic impact was presented in a poster by Grace McComsey, M.D., a professor of pediatrics and medicine at the Case Western Reserve University School of Medicine in Cleveland.
I spoke with McComsey at her poster to discuss the study results and other questions surrounding the development of BMS-986001/OBP-601.
What is BMS-986001?
That's a new NRTI that's a thymidine analogue. This [poster] is looking at the safety data. The reason is: Obviously, the thymidine analogues d4T and AZT had very bad metabolic data, which caused people not to use them. This [aims to be part of] the better, new generation of thymidine analogues. This poster is looking at safety data from bone, to lipids, to fat tissue -- both peripheral and visceral fat. In terms of bone: First, comparing three different doses of this NRTI, compared to tenofovir, I think the results were expected. Tenofovir, like with any other study, led to greater drop in hip BMD, as well as lumbar spine BMD, compared to the NRTI that we're testing [BMS-986001].
Like I said, this is not unusual; this is comparable to the data with TAF, compared to tenofovir.
You see some decrease in BMD, like you see with any other regimen, but it's not to the same extent that we're seeing with tenofovir.
Is this a reflection of the effect all antiretrovirals have on bone density, or is this just age-related bone decline that we're seeing?
We know, actually, [with] every antiretroviral regimen tested to date: When you first start it, the first 24 to 96 weeks, you'll see a decrease in BMD. Usually it's between 2% and 6%. Then it stabilizes after that. It doesn't recover; that's the bad thing. It stabilizes; it doesn't get back to normal. It's more accentuated than just age -- just spending a year of life. That's not going to drop the BMD that much. Mainly, most of these people are men, median age [between] 31 and 32. So you don't expect them to lose any significant bone mass during that time.
I know we've had studies suggest that reduction of BMD doesn't necessarily result in actual fracture risk increasing, or any kind of real demonstrable clinical impact.
Right. But actually there are a lot of other data -- including some cohorts -- showing that BMD, even in HIV patients, does relate to fractures. So people who had low BMD by DEXA ended up having fractures.
I think the reason the data is conflicted [is] because we don't have enough long-term follow-up yet. We're just starting to learn about bone. The first bone studies we did were probably in 2004 or 2005. That's nothing. Five years or 10 years of bone data is nothing. You need decades.
All right. Let's talk fat AND BMS-986001.
When you talk fat you always worry about two things: lipoatrophy, which is limb fat loss, as well as accumulation of fat.
So we looked at, by DEXA scan, limb fat versus trunk fat. And we looked by CT scan -- CT is better because it shows you visceral fat as well as subcutaneous fat. The data was consistent with both methods: We didn't see loss of fat. What we saw is gain of fat.
And the gain, with all the different arms, [was] mainly with the highest dose of 400 QD [of BMS-986001]: [It] seemed to be worse than tenofovir.
To what extent is this a reflection of people recovering fat from baseline, as opposed to actually having a fat problem?
Right. That's what I was telling people. Everybody's asking me, "Is this bad?" We don't know. What we know is ACTG-5224, which I had chaired, found exactly the same data when abacavir [Ziagen] was compared to tenofovir. We also saw that abacavir had more gain of fat compared to tenofovir.
So you can say maybe tenofovir somehow interferes with the normal return to health. Or maybe it's a pathological increase of fat. Nobody knows yet.
This fascinates me -- that we're still asking questions like this.
Yeah, but you know why? We don't know the BMI. We don't know anything about these patients before their HIV. So unless we have a cohort like the MACS, where people are followed before HIV and then after HIV [infection], and then after drugs [to treat HIV], we're not going to be able to answer that.
The data we have from other studies is showing that visceral fat seems to correlate with inflammation markers. So we're saying that, "Oh, that's bad, because that's probably a little bit too much. It's not just a return to health; it's pathological." But I don't think we know that yet. The other thing people were worried about is lipoatrophy. So even though overall people gained fat, was there a subset of people who lost fat and had lipoatrophy?
And the answer is no, not really. Because when we look at the very stringent [definition of] subclinical lipoatrophy, which is a loss of 20% from baseline, you see that the tenofovir arm had even more people who had those losses versus the BMS-986001 arm. So it's even looking better than tenofovir from that point of view. And we know that you rarely see [lipoatrophy] on tenofovir. So it looks good.
And then, lastly, because it's a thymidine analogue, mitochondria are a big thing. People were worried that you're going to see mitochondrial DNA depletion. So we did fat biopsies, looking at mitochondrial DNA numbers. And the bottom line is, in all the arms, the changes in mitochondrial DNA were within the limit of the tests, the variability of the tests. There were no significant changes in either of the arms.
So it's good. It seems benign from the mitochondrial point of view.
How about lipid values?
The lipids: We don't have P values for those. But we looked at the usual: total LDL, HDL and triglycerides. And, at least visually, numerically it looks like there may be some differences with tenofovir -- tenofovir leading to less changes. But if you look at the absolute differences, we're talking about 5 mg, 7 mg of cholesterol. So it's really not that much.
Is it enough to be a concern for patients who may be within the danger zone of very high cholesterol?
This is too [early], after one year. This is really minimal absolute differences between the two [drugs].
Thymidine analogues have been around for a long time. How is it that we're now seeing -- within a span of a couple of years -- two really significant thymidines suddenly come through the pipeline?
Oncolys, the company [now developing the drug], had it at least for three or four years. But they were doing Phase 1 studies to make sure mitochondria looks really clean. I think that's what delayed it.
It was just extra cautiousness?
I think so, because it's a thymidine. I mean, they want to be very careful because nobody wants to put money in to discover that you're going to see the same problems that d4T had.
Now that we've got the rise of integrase inhibitors, what is the place for a new-generation thymidine analogue?
For most regimens, we still need NRTIs. I think people are trying to shy away from tenofovir now: They worry a little bit about abacavir and cardiovascular. They want the perfect NRTI that's benign, that doesn't have the kidney and renal [toxicity], so they can add it to dolutegravir [Tivicay, DTG] or other drugs. For the next 5 to 10 years we are still going to see most people use NRTIs, in addition to integrase, probably, as first-line.
I think for patients it's good to have a lot of options. I mean, you can't have just TAF as one NRTI.
Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.
Follow Myles on Twitter: @MylesatTheBody.