In the second and final part of this interview, conducted at Takeda Pharmaceutical Co. Ltd.’s Tokyo headquarters during one of his regular visits to Japan, Dr. Andrew Plump assesses the company’s current pipeline and highlights some of what he sees as the major mid-term assets and their advantages.
For Part 1 see (Also see "Interview: Setting The Course For Takeda’s R&D Future" - Scrip, 30 Jun, 2017.)
As part of the general restructuring last year, some of the core functions are being retained in-house. What was the thinking behind what you retain internally and what you outsource?
There were three “buckets”: what we have and decided to keep in-house; what we have and decided to externalize; and then what we need but don’t even have. There were skill sets and capabilities within our therapeutic areas that we needed to enrich, and some skill sets that we didn’t have. But most of those we don’t have in house, we are partnering around. We made the decision that anything that was a capability that was scalable, or had a competitive nature, or had a variable capacity, we would put that outside.
One of the tendencies in a large company is if you have capacity, you use it – so what you end up doing is lowering the bar. Internally, you want your capacity to be below what your minimum need is, and then have the ability to source it. We have retained a nucleus of historical small molecule expertise internally.
Geographically, where is the split? Are you building up new capabilities in different places?
It’s a bit of both. We’ve tried to rationalize our fragmented geography. We’ve declared Japan and the US as our core bases. We’re a global organization in terms of development and medical, we had global teams all over. Today that’s limited, most of our global base is in the US, some in Japan, everything else is regional. We’ve narrowed regional responsibilities now and have said “know your market and go really, really deep.”
Turning to the current pipeline, do see it as strong and balanced enough, and are there any particular gaps at the moment?
It’s not strong or balanced enough right now. We’re expending a huge amount of resource around optimizing our internationally marketed products, somewhere around 75% of our external spend. We are doing some extra work around
Entyvio [vedolizumab], and with
Alunbrig [brigantinib] we got to market on Phase II so we are doing Phase III work. There is a lot of great science and value in these programs.
Ninlaro [ixazomib] is in a systemic amyloidosis study, where there are no treatments, so it’s a great opportunity to extend and grow.
In late development, our pipeline is quite depleted. We have the dengue vaccine, and two others: CX-601 is a Phase III stem cell product [with TiGenix NV for Crohn’s patients with complex perianal fissures. The pivotal study is small but it looks like there is quite a significant benefit. It’s a nice indication and a great way to get ourselves into regenerative medicine. Then our Tom40 Alzheimer’s study, from which we’ll have an interim analysis later this year, but it’s a low probability program [in Phase II].
[The late-stage situation] is not unexpected, and Christophe and I agreed we’d rather have nothing and use our resources in other ways, rather than just have a Phase III pipeline for the sake of it. The early pipeline is interesting. In the clinic, we have an interesting oncology pipeline, two programs, and a really interesting set of CNS programs.
Our next Phase III program will be pevonedistat in myelodysplastic syndromes. It is now in Phase II and we are very excited about this. In early research, we have brought seven molecules into our pipeline over the past year. It will start to pivot towards these [external] partnerships. For many of them, the intent is transformative benefit and even cure.
So in the meantime is true to say you feel comfortable with some of those gaps in the late-stage pipeline, and you’d rather focus on innovation?
Comfortable’s not the right word! We feel that we’re doing the right thing, we’re not panicking or rushing or making bad decisions just to fill the gap. The way we’re trying to solve this is making things happen, accelerating interesting programs. for our early pipeline we’re going after segments and strong translational plans. Then in terms of rebuilding our research organization, we’re pursuing partnerships.
I just wanted to focus on the reasons for divesting the CNS research group in the UK Cerevance Inc. , which seemed to go against Takeda’s strategic focus on the CNS area.
We made the decision that we were just too fragmented, and needed to focus; and secondly the decision to focus on Japan and the US. It wasn’t a divestiture per se, it was more of a value creation. We have a huge interest in Cerevance and a large equity stake, and we have rights or options, or right of first negotiation, to many of the key programs. We look at them as our partner in CNS. Another part of the program I like is the diversity of a different, more agile team, and set of processes. We don’t want to tie them down and want them to develop independently.
So turning to the acquisition of Ariad Pharmaceuticals Inc., it would be interesting to hear from you what the big attraction was?
Alunbrig. It won’t be the only source of opportunity but of the three programs at Ariad, brigatinib
has the greatest potential. Its preclinical and clinical profiles look like the best ALK inhibitor profile. The first-line study [in NSCLC] is enrolling very rapidly and we expect to see the first data next year. So far it has the best data.
Iclusig [ponatinib] is something of a niche product, but ongoing dose-ranging studies are optimising dosing to reduce toxicity and cardiovascular risk, and lastly EGFR exon20 mutation-targeting drug TAK-788 [AP32788], the question is to hit those mutants and not the wild type, as if you hit these, you have safety issues. In 12-18 months we should know if we are moving forward or not with this.
Going back to brigatinib, what are your comments on positioning versus other ALKs, and the competitive advantages?
We’re looking at relatively low numbers of patients, but if I had to distil it I would say safety is similar to alectinib, and efficacies will be significantly better than crizotinib, which I think will become a very niche product. There are indicators brigatinib has best-in-class potential, such as hitting every known resistance mutation preclinically, cross-study 2L PFS is better than some others, although you have to be very careful when making these cross-comparisons.
First-line readout will be next year, can you be more specific?
Not at this stage, it’s an event-driven trial, we expect to fully enroll this year, and then it depends on how good it is. Another piece to the market picture, is that even if we are not better, the market is growing for two reasons: one is more diagnostics and sequencing to identify ALK-positive patients; and secondly patients are living longer, there are more patients and more duration of therapy.
In terms of other differentiation, how important do you see the other data coming out for brain metastases for brigatinib?
Very important. It’s very difficult to tell where it will land as we have studied so few patients, but in the second-line study in 18 patients there were definitive conclusions with prespecified criteria, we saw an objective response in two thirds of those patients. But we need more patients to determine if that is differentiated enough.
You mentioned the broad activity against mutant types, are there plans to develop brigatinib in new populations?
It has a fairly narrow profile of activity against kinases, the other one it hits is ROS1, and ROS1-driven NSCLC is quite niche, only 1-2%, so 5% of the ALK population. Crizotinib is pretty good on ROS1 but not on other resistance mutations, so they complement each other. So we’re planning a study in ROS1-positive patients, so I suspect there’s a reasonable chance we’ll be effective.
Are there other pipeline assets that you would highlight?
It’s fun to talk about all of them, and it’s a bit dangerous to talk about early stage molecules, but I’ll give you an example of innovation in CNS. That is TAK-041, which we haven’t discussed very much and targets an orphan GCPR called GPR139, which it highly expressed only in the brain in a small number of neurons. It came out of the Envoy platform we purchased several years ago, and it's an agonist, it is well tolerated, gets into the brain, has a good half life.
It’s interesting that no one has really pursued this pathway, as it’s involved in many part of human behaviour such as fight/flight and reward and animal models suggest some activity. So, the hard part is figuring how where it will work, It is completely novel and a chance to test a hypotheses – if you look at CNS research it’s mainly been on serotonin. Potential indications include negative symptoms in schizophrenia and also looking at doing a crowd sourcing contest to try to ask “what would you do, what do you do to show efficacy.”
You can get some incredible ideas through this approach, as it’s a new way of doing things and opening ourselves up to the outside world. I think we’ll find ideas coming out of the woodwork.
Any other topics or highlights you’d like to mention?
This past year has been incredibly difficult for this organization. It’s also been incredibly exciting, we’ve put 50 partnerships in place, moving people around and training them. That we have not had any internal programs getting into humans this year shows how disruptive the changes have been, we’re kind of at that point where we’re starting to bounce back and it’s going be an interesting couple of years to see the organization re-energize and the partnerships start to come through.
I’m always optimistic by nature but I think we’re putting together something special and creating something unique.
From the editors of PharmAsia News.
