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Bristol-Myers R&D leaders Brian Gavin and Sean Connolly offered insight into the company's immunology focus for autoimmune diseases, which increasingly is driven by a search for biomarkers that point to the best use of the big pharma's drugs.



Hunting For Biomarkers


These days Bristol-Myers Squibb Co.'s immunology expertise is most often associated with its immuno-oncology blockbusters, but the company is also focused on expanding its position in autoimmune diseases, which is anchored by Orencia (abatacept).




In fact, Orencia – a selective T-cell co-stimulation modulator targeting CD80 and CD86 – won its initial US FDA approval in 2005, so it's been on the market far longer than the breakthrough immuno-oncology therapies Yervoy (ipilimumab) and Opdivo (nivolumab). And while Bristol continues to pursue new indications for the first-of-its-kind drug, the company also has a pipeline of early-stage drugs autoimmune diseases, including the Bruton's tyrosine kinase (BTK) inhibitor BMS-986195.




Bristol presented preclinical and Phase I results in healthy volunteers for BMS-986195 at the recent American College of Rheumatology (ACR)/Association of Rheumatology Health Professionals (ARHP) annual meeting, as well as multiple data sets for Orencia in its three approved indications – rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in adults, and juvenile idiopathic arthritis (JIA). Orencia generated $2.3bn in 2016 revenue and 2017 sales totaled $1.8bn through the third quarter.




Scrip spoke with Vice President and Orencia Development Lead Brian Gavin and Non-Registrational Data Lead Sean Connolly about the company's biomarker-driven immunology drug development strategy during the ACR/ARHP meeting in San Diego.




Scrip: Can you give an overview of what the goal was with the data that you presented here at this meeting?

Brian Gavin: I think the breadth of data that we presented this year, across both Orencia and the pipeline, really demonstrate our commitment and our leadership in the area of modulating the body’s immune system to treat disease.

We had 34 abstracts here at ACR, 32 of which were focused on various aspects of the Orencia program. [There were] a number in the RA space, looking at and expanding data that we’ve generated, looking at how you can use biomarkers to identify patients – what we term, "early, rapidly progressing patients." So these are patients who have been recently diagnosed, but have markers of poor prognosis such as anti-citrullinated protein (CCP) antibodies or erosions at baseline.



We also have data from our PsA program. We just got indications approved in Europe and the US in the middle of this year based on our Phase II and Phase III PsA data. (Also see "Pipeline Watch: Phase III Starts With Mogamulizumab, AR101 And Vilaprisan" - Scrip, 7 Jul, 2017.)



We’ve had sub-analyses here that looked, again, at how we could use biomarkers that select particular groups of patients that have particular benefit for Orencia or for treatment with Orencia. This is something that we’ve done very successfully in the RA space.


We also have data from our JIA program. We’ve had an indication for JIA since 2008 for our I.V. formulation, but we just expanded that to include our subcutaneous formulation in the US and also expanded the age range of the patients that we can treat down to 2 years old. Our I.V. indication is only 6 to 17. And then, finally, we have a couple abstracts from our pipeline on one of our BTK inhibitors. We had some very strong data in preclinical models showing very strong efficacy with the compound and then Phase I data, which showed really good pharmacokinetics and pharmacodynamics.




Scrip: And what is the status of the BTK program?

Gavin: So BTK is in Phase I, and we’re continuing to move it forward. The data that we presented here is very promising in terms of its safety and tolerability in people [and] really nice data in terms of the preclinical efficacy models.

That’s really just one of a large number of assets we have in our pipeline, all focused around how can we modulate the immune system to better treat patients with autoimmune diseases.



Really, we’re very much focused on those diseases where there are still unmet medical needs. Some people could say, "OK, we've got a lot of things to treat RA. Why are you still going after RA?" Well, we feel it’s important, because there’s still a fair amount of unmet medical need in RA. People are not getting to remission at the levels that they should; there are still questions around what happens if you want to remove therapy. But we’re also very much focused on lupus, where there’s a huge unmet medical need, and also irritable bowel disease (IBD).


Scrip: It's surprising that you get questions about RA, because many patients have failed everything that's available – it works for a time, and then it stops working. Rheumatologists must be used to the idea of needing new therapies, because they have patients that have failed all available treatments.

Gavin: Well, one of the things that we feel is very important – and we really feel that we’re helping to lead the way – is to move more towards personalized medicine in the RA space. It’s really about the right treatment for the right patient at the right time.

One of the things that we’ve shown with our Orencia program in the early, rapidly-progressing patients – these are patients recently diagnosed, but with those markers of poor prognosis – we’ve been able to show that there appears to be a differential benefit in that subset of patients compared to [tumor necrosis factor (TNF)] inhibitors. That, we believe, can give rheumatologists the confidence to go and treat those patients more aggressively earlier in their disease.



Because the question is always, when you look at a patient, is this going to be an indolent process? Is it going to take a while, and can I be more gradual in increasing therapies? Or is there that subset that you know is going to be in trouble real quickly, and maybe I should be more aggressive. And really, I think that’s the promise of getting to a personalized medicine approach.




Scrip: In the real world, is it easy or difficult to get doctors to go ahead and do that testing and try and speed up the treatment process for certain patients, if they can?
Sean Connolly: It’s a typical question of how clinically applicable are some of these biomarkers that we’re looking at, so we always keep that in mind, and we want to make sure that anything that we do discover and that we talk about is relevant to the practicing physician. And we’re very fortunate that these relevant biomarkers – these anti-CCP antibodies and erosions and high-disease activity, which makes up these poor prognostic patients – these rapidly-progressing patients are easily identifiable by all physicians.


Scrip: Then are the earlier-stage compounds, like the BTK inhibitor, all going after that personalized, biomarker-driven approach?
Gavin: Yeah, that’s something that we want to go in and incorporate into our development programs early on. Clearly, that is where medicine in general is progressing, but I think it’s going to be something that is going to be very important for autoimmune disease as we move forward.

And BMS as a company has a long history in modulating the immune system to treat disease. It actually started about 20 years ago with the development of Orencia. And even before that, Orencia is an engineered fusion molecule, which blocks the CTLA4-CD80/86 interaction. It was two BMS scientists that actually discovered that access – Peter Linsley and Jeffrey Ledbetter out in Seattle – more than 25 years ago. So that’s really where the history comes from, and as we look at how we can develop the pipeline we’re really focused on where is the science going to lead us.



And one of the nice things we have is, with a compound like Orencia, which has a well-characterized safety and efficacy profile, as we follow the science with Orencia and explore – not only in RA, but in broader autoimmune diseases – whether T-cells may play a role, we can actually use those studies and then build in investigational biomarker protocols or novel clinical endpoints, which we can then take into our development of compounds and help inform how we’re going to develop some of those molecules that are in the pipeline.


Scrip: In addition to making sure the right patient gets the right drug, do you think it gives you a competitive advantage too when you’re in a market with growing competition from new agents? Orencia has a lot of competitors it didn’t have a few years ago.

Gavin: Well, it does, but interestingly, Orencia is the only molecule in its class. We’re not a TNF where there’s multiple TNFs; we’re not an IL-6. Orencia is unique in that sense, and the only T-cell co-stimulation modulator that exists for the treatment of autoimmune diseases. So, yes, I would say with Orencia we do have an advantage. That, together with the scientific knowledge that we’ve built up over the years.


Scrip: How much of your discovery and early development in this area is in-house?

Gavin: Well, we’ve got a very rich preclinical pipeline. I can’t really discuss that. We have a number of molecules that are in clinical development at this point.

I mentioned the BTK inhibitor. We also have a TYK2 compound that’s coming forward. We also have programs in S1P1 [in Phase I for an undisclosed indication] and IP-10 [BMS-936557 in Phase II for ulcerative colitis and Crohn's disease] that are ongoing.



So we’ve got a number of different molecules, and we’re really looking at how we can affect those different components of the immune system, and really think about the immune system as something, not necessarily to inhibit, but to modulate. You want to be able to adjust how it responds, depending on what disease state you’re talking about.




Scrip: How much of what you are doing in immunology, in autoimmune diseases, crosses over with your oncology group? Because obviously immunology’s become more and more important on the oncology side of the business and there have been some panels at ACR talking about immuno-oncology as it relates to this area, too.

Gavin: Correct. As it relates to rheumatology, certainly. Actually one of the first immune-oncology agents to come out, ipilimumab, is anti-CTLA4, so it is related to Orencia in that sense that it modulates the CTLA4-CD80/86 pathway. Certainly, a number of the other immuno-oncology agents that are out there, both for ourselves and other competitors, also are looking at the inhibition of, or the modulation of, T-cell co-stimulation.

It does come back to the point that I made before, that what we’re talking about is immunomodulation. In some senses, you want to turn the immune system up, and in other senses, you want to turn it down. n the case of autoimmune disease, the immune system is over-reactive. In the case of cancer, in many cases, given how the cancer cells have evolved, you can say that the immune system is under-reactive, and you need to modulate it up.



Connolly: I think the thing that we might want to highlight between the two therapeutic areas is the need for biomarkers and personalized medicine. I think as we understand the heterogeneity of many of these diseases – both autoimmune as well as oncology – we really need to find that patient that will give the best response to the targeted therapeutics.



Scrip: It seems like, on the autoimmune disease side, targets have been very difficult to find. So is the hunt for good biomarkers difficult as well, because there’s still so much unknown about what’s driving a lot of these diseases?

Connolly: I absolutely agree. I think that, as the science advances, we’re paying very close attention to what our academic colleagues are doing, so hopefully we can learn from their experiences more about the nature of the disease.

And from there, we can understand how our drugs modulate certain disease pathways that we could therefore look for potential predictive biomarkers or prognostic biomarkers or pharmacodynamic biomarkers, so we’re always willing to continue to look for more opportunities to really tailor our medicines.



Gavin: I think this comes back to the point that I raised before that we’re in a unique competitive position, because we can leverage our ongoing trials and our ongoing research with Orencia to help inform how we develop some of the compounds within the pipeline. And I think it’s important to highlight too, that even though Orencia is a product that’s been on the market for more than 10 years, we’re continuing to actively invest in clinical development there.



And this is really, I think, true to one of the things that I would say is very important. I don’t know that I could say that it is unique about BMS, but certainly in this area, we’ve always followed the science with Orencia. So if there is science to tell us that T-cells may play a role in a particular autoimmune disease, we will follow that science.



And I think there are some good examples out there. We recently initiated a Phase III program in Sjogren’s disease with Orencia, because we had some very promising proof-of-concept data there. We also have an ongoing Phase III program – one that we just initiated – in idiopathic immune myositis, an orphan disease state where, through collaborating with external investigators, we got some very promising proof-of-concept data, which then led us to consider whether or not we should pursue this as an indication.

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