Finding Bristol's Next Wave Of Innovation: An Interview With Douglas Manion

With a focus on specialty drugs, Bristol wants to be known for more than immuno-oncology. To that end, specialty development head Douglas Manion is charged with leading innovation in immunology, virology and cardiovascular, genetically defined and fibrotic disease.

Bristol-Myers Squibb Co. has been pivoting away from primary care for several years now, making its biggest splash as one of the leaders in immuno-oncology with PD-1 inhibitor Opdivo (nivolumab). But the Princeton, N.J., pharma is aiming more broadly to be a leader in specialty care.

So, while it has de-emphasized discovery work in the previously fruitful areas of HIV and hepatitis, Head of Specialty Development Douglas Manion has been tasked with seeking out innovation in five non-cancer therapeutic areas, including virology, where a number of clinical development programs continue despite the end of discovery efforts. This includes new areas of focus for Bristol in genetically defined disease and fibrotic disease, as well as continuing efforts in cardiovascular and immunological medicine (Also see "Bristol’s Caforio Says Opdivo Is Just The Beginning" - Pink Sheet, 24 Jul, 2015.).

Manion last sat down with "The Pink Sheet" during the American Association for the Study of Liver Disease conference in 2013, when he detailed the pharma's plans in hepatitis C and hepatitis B (Also see "Bristol’s Virology Focus Turning To Hepatitis B? An Interview With Doug Manion" - Pink Sheet, 11 Nov, 2013.). Roughly two years later, with a reworked title that reflects a revised R&D focus, Manion overviewed what Bristol is doing and where it is trying to go in the broad areas under his purview. An edited version of that discussion appears below:

"The Pink Sheet": How has your role changed since Bristol reworked its R&D focus, including ending discovery in virology?

Douglas Manion: I'm in charge of all of specialty [indications], which means all of drug development outside of oncology. That includes five disease areas: cardiovascular, immunoscience and immunologic agents, virology, genetically defined diseases and fibrotic diseases. We call those specialty, but it often gets a little bit confusing because everything we do is focused on specialty medicines, which are medicines that have transformational impact, that are going to actually satiate an enduring medical need, and that are going to be prescribed by specialists, often hospital-based specialists.

But we're not in the primary care business anymore. We really are focusing all of our work toward transformational advances in therapeutics for specialists and even sub-specialists.

In each of those disease areas, we have areas of focus as well. The plan would be that amongst these five disease areas we’d have one or more that would be the source of the next big wave of innovation, and very clearly the current wave of new innovation for us is in the immuno-oncology space, and that is following on a previous wave of innovation that was in the delivery of Eliquis (apixaban) to the market, Orencia (abatacept) to the market, the hepatitis C assets to the market (Also see "Bristol-Myers Boosted By Opdivo Sales, Growth Prospects" - Pink Sheet, 27 Oct, 2015.).

My job basically is to help construct the wave after immuno-oncology, and maybe the wave after that wave. Obviously, there could be multiple additional waves of innovation in oncology, and what's going on both in terms of oncology specialty and non-oncology specialty is pretty amazing. So this is a pretty exciting time for our industry in terms of making differences for patients.

"The Pink Sheet": What are Bristol's plans and goals going forward in HCV?

Manion: We really want to go where the science is breaking in a way that we think will [bring about] the greatest reward for innovation. It is very clear that we – science, industry – have been very effective in terms of transformational advances in the treatment of HCV. Now, we have 95%-plus cure rates with finite therapy in many patient populations.

We believe that the final frontier for HCV is really going to be in those difficult-to-treat patient populations that we have been focusing on (Also see "U.S. HCV Competition Increases As Bristol, AbbVie Get Same-Day Approvals" - Pink Sheet, 24 Jul, 2015.). With Daklinza (daclatasvir) and sofosbuvir [Gilead Sciences Inc., Sovaldi], with or without ribavirin, this includes pre-liver transplant patients, HCV/HIV co-infected patients, tough-to-treat genotypes like genotype 3, and patients with more advanced cirrhosis, including decompensated cirrhosis.

Bristol's Head of Specialty Development

Douglas Manion

Manion is overseeing development in five specialty care areas central to Bristol's strategy outside of cancer.

Source: Bristol-Myers Squibb

A lot of our energy has been placed on that. The FOURward study actually was looking at another area, which I now think is coming to ground: what is the shortest amount of time which could reliably get high rates of cure. FOURward was studying a four-drug combination [nucleoside polymerase inhibitor sofosbuvir with the NS5A inhibitor daclatasvir, protease inhibitor asunaprevir and non-nucleoside polymerase inhibitor beclabuvir] for four weeks; those results will be coming out at AASLD. They’re not public yet.

We've been probing shorter durations of therapy and we're continuing to probe that in the ALLY 3+ [daclatasvir, sofosbuvir and ribavirin], looking at 12 and 16 weeks of therapy for genotype 3 [patients], down from 24 weeks, which is currently the standard of care with Sovaldi. But we think for us the future is going to less about shortening duration and more around increasing response rates with as short a therapy as possible for those tough-to-treat populations.

"The Pink Sheet": What is the status of the combination of your three proprietary drugs, daclatasvir, asunaprevir and beclabuvir? [Bristol stopped work on a daclatasvir/asunaprevir duo in the US for commercial reasons in 2014 (Also see "Asunaprevir NDA Withdrawal Likely To Mean Daclatasvir Delay" - Pink Sheet, 7 Oct, 2014.).]

Manion: That is called our trio. The trio actually has completed Phase III studies in a variety of different indications and we are constantly looking at the evolving competitive landscape to see where best to deploy it (Also see "Bristol Already Preparing Daclatasvir Supplemental Filings In HCV" - Pink Sheet, 27 Feb, 2015.). Currently, we're continuing to get either Daklinza alone or the Daclinza plus Sunvepra (asunaprevir) combinations approved around the world and now we're in the final stages of deciding where we want to file and commercialize the trio.

A big opportunity for us in HCV has been in Asia. We've had tremendous success with our dual Daklinza/Sunvepra combination there. It's the first oral combination therapy available in Japan, 50,000-plus patients have been treated with it and there we had over a year lead time against the competition (Also see "Japan Approves 22 Drugs Including First IFN-Free Hep C Therapy" - Scrip, 11 Jul, 2014.).

We would like to replicate that success in China. In fact, we already have initiated a Phase III study of our dual combination in China, the results of which are being shared at AASLD. Our thought is to try to replicate what we did in Japan in China as closely as possible. The regulatory realities in China are a bit more challenging than they are in Japan, but we intend to be the first to bring an oral therapeutic solution to HCV patients in China.

"The Pink Sheet": That sounds like a huge undertaking if Bristol can succeed.

Manion: We learned a lot from our work in Japan. A lot of our success has to do with very close collaborations with in-country thought leaders and obviously the regulatory agencies. In terms of Asia, all of this is building off the strength that was forged with the success of Baraclude (entecavir), which is the top anti-hepatitis B drug in the world. It's one of the top-selling drugs in China and we developed very close ties with in-country thought leaders and regulators due to hepatitis B and we leveraged that in HCV (Also see "BMS Makes Deeper Dent In Asia Hepatitis Market As Baraclude Moves Toward Blockbuster Status" - Scrip, 21 Feb, 2012.).

"The Pink Sheet": What other indications is Bristol still working on in the virology space?

Manion: Because we thought the opportunity for additional transformational advances in therapeutics for HCV just wasn't there, we made the decision several months ago to announce that we're turning off the spigot. We're stopping discovery work in HCV. That was announced I think in the fall of 2013. As of June of this year, we're doing the same thing in HIV, but that shouldn't be misconstrued as us lacking commitment to developing our very strong clinical pipeline for HIV (Also see "Bristol Drops Virology Discovery In Latest R&D Reshuffling" - Pink Sheet, 25 Jun, 2015.).

We have two assets, one in Phase III, an attachment inhibitor, and one in Phase II, a maturation inhibitor (Also see "Keeping Track: FDA Clears Big Batch Of Products; 'Breakthrough' For Bristol HIV Drug" - Pink Sheet, 27 Jul, 2015.). We are continuing to develop those and we think they are going to be significant advances but our belief is that the window for transformational impact for therapeutics in HIV using traditional direct-acting antivirals is closing. We will wait for the science to break before we pivot back into, for example, curative therapies in HIV. But it’s science that we're following very closely.

"The Pink Sheet": How did Bristol make the decision to stay in HCV to the degree it has, with a focus on tough-to-treat patients and Asian markets, rather than getting out entirely?

Manion: We want all of our investments to be fit for purpose. We want to be sure that we have the right level – not too little, not too much. And most importantly we really want to be focusing on our "north star," which is having transformational impact. So when we saw that the landscape in terms of treating the easier-to-treat genotype 1a patients looked like it was going to be a relatively simple nut for other companies to crack, although we already had datasets in that space, we immediately saw that we needed to go after the tougher-to-treat patients, which proved to be a very good choice made over 18 months ago (Also see "With Gilead’s Lock In Hepatitis C, What’s Next For The Field?" - Pink Sheet, 24 Nov, 2014.).

I think that's very emblematic of how we are as a company now, in that we want to make sure that we're going after the highest-yield clinical development of our drugs, be it in oncology or elsewhere. Us going into a space where we aren't going to be that transformational just goes against our belief system and it isn't where you're going to generate the most value for patients. And even though we have tremendous budget freed up in HIV and HCV, there are other areas in specialty [medicine] where we're up-investing.

"The Pink Sheet": What are some examples of that?

Manion: Well, for instance, in cardiovascular we announced [on Nov. 2] the intent to purchase Cardioxyl Pharmaceuticals Inc., which has a very interesting Phase II asset for congestive heart failure [See Deal]. This follows on the heels of an alliance that we struck with an interesting company in Europe named uniQure NV, which has a gene therapy [calcium-binding protein S100A1] targeted to another segment in the congestive heart failure space [See Deal].

We are pretty rapidly creating a reason to believe that we are going to be a big player in congestive heart failure, and that's adjunctive to the success that we have always had in terms of antithrombotics, first with Plavix (clopidogrel) in partnership with Sanofi and more recently with Eliquis in partnership with Pfizer Inc. We actually have a good pipeline of additional antithrombotics that begin to attack the more difficult, arterial side of the clot equation, so with this we could actually get into stroke, not just prevention but also treatment.

So in cardiovascular, we're very focused on expanding our leadership in thrombosis and becoming a leader in congestive heart failure.

"The Pink Sheet": What is Bristol's focus in immunology outside of immuno-oncology?

Manion: In immunoscience, we're a leader already with our unique mechanism-of-action drug Orencia, which has been approved in rheumatoid arthritis, juvenile RA and now we're pursuing other indications, for example in psoriatic arthritis and others even beyond that. So we want to build off of that strength.

Our approach to immunologic diseases is that we’re looking for transformational and not just disease-modifying but disease-reversing agents, so that we're not just stopping progression of joint erosion, for instance, but reversing it. And we're focusing on rheumatoid arthritis, inflammatory bowel disease, also colitis and Crohn's, and systemic lupus, with a focus on nephritis.

Now, because these are pluripotential agents, we're open to also going into other indications; many of the drugs that have action in this space become essentially a franchise in a bottle because they can be used in multiple different places.

"The Pink Sheet": What can you tell us about the new focus in genetically defined diseases?

Manion: Genetically defined diseases is a very novel place for us to be working. We have decided to begin discovery efforts in a small set of what we call monogenic diseases. These are diseases where a single dysfunctional actually identifies the patients and gives us an inkling of the mechanism of action of the disease. And the idea in genetically defined diseases would be for us to have significantly better targeted medicines to better identified patients.

And our belief is that's how we're going to get a better foothold in some diseases that have a subset of patients who fit that rubric. As an example, we purchased a company called iPierian Inc. that had a very interesting molecule that works against extracellular tau, which is also called eTau (Also see "Bristol Shifts Early R&D Focus With iPierian Purchase" - Pink Sheet, 29 Apr, 2014.). ETtau is causative for a bunch of diseases called tauopathies, where you get accumulation of this tau protein that causes a bunch of different disease patterns.

One rare form of a genetically defined disease is called progressive supranuclear palsy (PSP), so we have begun clinical research in that disease to show basically that our anti-eTau antibody actually works in a very select tauopathy, but then the idea would be to go to other tauopathies (Also see "Investors Find Opportunity In Tau-Targeting Biopharmas" - Scrip, 22 Oct, 2015.). The Holy Grail of tauopathies would be Alzheimer's disease. From a pathologic perspective, the kind of end-stage of Alzheimer's is accumulation of this tau protein in the brain. The idea would be to show activity in PSP and then pivot to other small tauopathies but also begin de-risking activities toward Alzheimer's disease.

That's the logic. We think that can also be applied to other diseases including Parkinson's disease, neuropathic pain, and muscular dystrophy including Duchenne muscular dystrophy, so we want to be very focused in terms of our internal efforts and we want to be very selective in terms of external activities.

"The Pink Sheet": What progress has Bristol made so far in fibrotic disease?

Manion: We bought a company a couple of years ago called Amira Pharmaceuticals Inc. that had a very interesting LPA1 molecule [AM152, a lysophosphatidic acid 1 antagonist now in Phase II] that we are developing for interstitial pulmonary fibrosis, which is kind of the thin edge of the wedge for us in fibrotic disease [See Deal].

We are focusing on basically four organs: the lung, with the sentinel disease being interstitial pulmonary fibrosis; liver, with the sentinel disease being non-alcoholic steatohepatitis (NASH); the kidney, with the sentinel disease being IgA nephropathy; and then congestive heart failure, where we're not looking primarily at fibrotic mechanisms for it. We're really looking at muscle-function approaches like Cardioxyl and uniQure, but clearly some of our antifibrotic drugs will have application for the fibrotic mechanisms that also exist in cardiac fibrosis and congestive heart failure.

The way we are doing this is obviously we have an internal discovery effort but we have very quickly through four separate business development transactions developed a very nice pipeline in fibrosis. I've mentioned Amira. The three others that we've secured are we have a clinical collaboration with a company called Calibr [California Institute for Biomedical Research], which is a very interesting approach to reversing fibrosis [See Deal], then we have another deal with a company called Galecto Biotech AB, which has an oral anti-galectin we've been working with in interstitial pulmonary fibrosis [See Deal], and then we recently announced an option deal with Promedior to eventually acquire [See Deal]. They have a drug called pentraxin [PRM151, a recombinant human form of pentraxin-2], which is being used for both myelofibrosis, which is a form of fibrosis in cancer, and for interstitial pulmonary fibrosis.

Here is a nice example of where there's actual synergy between our internal specialty group and our oncology group, because we're small enough that we talk to each other all the time and can actually find value that kind of crosses both areas. With Promedior, the myelofibrosis development program is already in Phase II, so we are active in the clinic in fibrosis currently.

"The Pink Sheet": In NASH, do you think there will be synergy with what Bristol has previously done in hepatitis?

Manion: Yes. We have been looking at NASH as an adjacency. We obviously have very good relationships with hepatologists around the world first because of our activity in hep B and more recently our work in HCV. We're also very active in terms of hepatocellular carcinoma in our oncology group, and although we haven't gotten into liver transplantation with our transplant drug Nulojix (belatacept), we could at some point. Clearly, we have had and will have a reason to be talking with hepatologists for quite some time.

NASH is kind of the new frontier for hepatologists, so AASLD is going to be dominated by NASH this year. People are starting to pivot away from HCV because of the advances that already have occurred. So we see a clear opportunity.

Internally for NASH, we are only working on what's called direct fibrotic mechanisms. In NASH, there's both a metabolic insult and the deposition of scar tissue, which is fibrosis. Our internal efforts are all looking at direct fibrotic mechanisms so that would impact NASH and all of the other fibrotic diseases, but we're also looking externally at mechanisms that are prefibrotic, although we are not going after purely metabolic agents since we decided to move away from diabetes in our divestiture to AstraZeneca PLC (Also see "AZ Doubles Down On Diabetes, Buys Out Bristol’s Share in Alliance" - Pink Sheet, 19 Dec, 2013.).

"The Pink Sheet": Intercept announced Oct. 28 that its Japanese development partner Sumitomo Dainippon Pharma Co. Ltd. had failed to meet the primary endpoint in a Phase II dose-ranging study testing obeticholic acid, an FXR agonist, in NASH. What are your thoughts on Intercept's Phase II failure?

Manion: NASH in general is a challenging space … [if you] contrast NASH with genetically defined diseases. You don't have as clearly identified patients suffering from NASH. There is a lot of heterogeneity in NASH, although there is a scoring system that helps to better define that.

There also is a lot of heterogeneity in terms of the cadence in which people have their NASH progress. By almost any way you slice it except in the most advanced patients, there is kind of spontaneous regression, where's there ebb and flow to scarring in the liver. Not reversal to normal, but instead of getting worse they either don't progress or they even appear to regress slightly. You have to prove an effect on top of that background, which is challenging, so all of the studies will be challenging to interpret for that reason.

The smaller the study, the greater the risk that you could get spurious results, so I know that the Japanese study you're referring to is smaller than the Phase III that Intercept Pharmaceuticals Inc. is doing globally (Also see "With Phase III NASH Endpoints In Place, Intercept May Reach Market By 2018" - Pink Sheet, 19 May, 2015.). I think the study in Japan is smaller than the Phase II FLINT study. But that is the dynamic in the NASH space and we're very attentive to that as we are moving into that space ourselves.

"The Pink Sheet": Outside of immuno-oncology, Bristol's immunoscience portfolio is dominated by Orencia (abatacept), which is possibly going to face biosimilar competition. What can you tell us about addressing a maturing immunoscience franchise?

Manion: Orencia is maturing as an in-line brand, so that will follow its natural course. We do have an extremely good pipeline in immunoscience and we have taken a broad approach in terms of mechanisms of action. We are clearly a world leader when it comes to T-cell immunotherapeutics, specifically T-cell immuno-agonism. Turning on T-cell immunity is the cornerstone of our immuno-oncology efforts. At the end of the day, Orencia and for that matter Nulojix are both T-cell immuno-antagonists, so they're both looking at turning off T-cell immunity or at least dampening T-cell immunity.

But we're also looking at innate immunity and B-cell immunity and we believe that combination of different approaches will actually work in complicated diseases like RA and systemic lupus, where it isn't really clear whether those diseases are T or B or innate immunity-specific. We are not the least bit averse to combining mechanisms. We think it makes sense to probably not combine within the T-cell, B-cell or innate classes, but to go across those classes.

And if you look at our pipeline in immunoscience, that's exactly what we have. We have anti-CD28 [lulizumab], which is currently being tested in lupus [Phase II], we have anti-CD40 and anti-CD40 ligand [both in Phase I], and we have others as well that basically cover the three categories of immunotherapeutics.

We're also doing some clever things in the early space to try to hone our thinking, because we don't want to be going after all three mechanisms in every disease or every subgroup of the disease. Like in lupus, there are a lot of subgroupings within the lupus disease family, so as we do in oncology, we want in Phase I to be able to test many drugs in combination relatively quickly and then basically play the winners and move away from the ones that are not looking as interesting.