GlaxoSmithKline PLC has been a trendsetter in the pharmaceutical industry’s ongoing experiment to find the right size and configuration to overcome weak pipelines and waning income from blockbuster drugs gone generic. The company has twice reorganized its R&D and more recently began an initiative to pull global manufacturing and commercialization into the bench-to-bedside loop, the better to inform strategies, including how to sway both private and government payers.

After he took the helm of the U.K. pharma giant in 2008, Andrew Witty carried out a series of changes designed to reinvigorate GSK’s R&D enterprise, and important trials are starting to read out, with a consistent data flow expected into 2020 Also see "Glaxo Confident In Output From Its Revamped R&D Engine" - Pink Sheet, 3 December, 2012..

But while the pieces of the R&D puzzle were coming together, the commercialization environment was changing, and to meet that challenge Witty has again instituted transformational efforts, this time in marketing and manufacturing operations. The company has embraced a global franchise model that aligns the drug development and commercialization sides of the business early on in the life of a drug Also see "GSK Is Getting Ready For A Return To The ’90s" - Pink Sheet, 10 December, 2012..

Paolo Paoletti

For GSK’s oncology business, however, that sort of feedback loop has been business as usual since March 2011, when the company formed its first integrated R&D/commercial business unit under Paolo Paoletti, president of GSK oncology. In fact, oncology has been a GSK testing ground not only for combining R&D and commercialization but also for the organization of the R&D effort itself; the unit was the first in the company to fully integrate discovery and development and the first to embrace personalized medicine Also see "GSK’s New Oncology R&D Structure Reflects Personalized Medicine Emphasis" - Pink Sheet, 22 September, 2008..

Paoletti, whose remit includes all activities within GSK Oncology, from early discovery through clinical development and on to product positioning, launch and life cycle management, talked with “The Pink Sheet” about the advances in precision medicine, regulatory climate change, the need to provide value for payers and the company’s commitment to double cancer survival globally over the next 10 years.

GSK’s top oncology candidates are dabrafenib, a BRAF inhibitor, and trametinib, an inhibitor of MEK 1 and 2 – both proteins on the MAP kinase pathway. The company submitted initial filings for the two drugs to FDA in August 2012 seeking approval for monotherapy use to treat metastatic melanoma, but GSK has promising data on the two in combination and has moved quickly to try the combo in a Phase III trial against BRAF V600 mutation-positive metastatic melanoma Also see "GSK’s Oncology Expansion Heavily Dependent On Dabrafenib, Trametinib" - Pink Sheet, 3 August, 2012.. The two drugs, each of which is being investigated independently in other cancers, pretty much define GSK’s future as an oncology company.

“The Pink Sheet”: How are dabrafenib and trametinib helping to establish a new strategic direction for GSK oncology?

Paolo Paoletti: I want to highlight the excitement in this field but also how much it is moving fast. You may remember that two years ago our colleagues over at Roche were presenting the BRAF results [for first-in-class vemurafenib, approved in August 2011 as Zelboraf] ([A#100820d1]).

One year after, we were presenting the combination MEK and BRAF that appeared better than BRAF, so the standard of care basically will be changing in less than two years. The biology and understanding [of this mutation] is a driving force for melanoma.

In GSK we understood a key mechanism of resistance, that by blocking BRAF you were activating MEK – that is one of the main reasons you can have skin cancer. We had a very nice experiment done in animals where giving BRAF you have the skin lesion, then giving MEK and BRAF the skin lesion disappeared. So we translated this knowledge to the clinic, and we have clearly an advancement and enhancement on efficacy, and we have a significant reduction of the skin cancer.

Now we have filed MEK and BRAF [as monotherapy] and we have presented [data at scientific meetings], and there was a publication in the New England Journal of Medicine [in November] about the combination Also see "Glaxo’s Emerging BRAF/MEK Melanoma Combo Threatens Roche’s Zelboraf" - Pink Sheet, 1 November, 2012..

This highlights our commitment to understanding the science and developing the right drug and the combination of drugs. [It is also] the first time that a known combination, two targeted agents, were developed together before approval.

We want to be driven by the science and we want to translate the knowledge of basic science in the clinic and try to maximize the possibility of efficacy even in small groups of patients. And that is our key driver, which is consistent with our vision of trying to double cancer survival in the next 10 years.

“The Pink Sheet”: So, developing drugs for what we might call niche indications is really part of a broader strategy to look more closely at the heterogeneity of tumors and target them with the proper medicine.

Paoletti: Absolutely. The discovery process is something [where] you put your effort and your bet to identify new mechanisms by which, for example, cancer cells can develop and be resistant or persistent. But when your discovery process identifies a target, and we have the proof that it works, even if it is in 3%-4%-5% of patients with that cancer, we are committed to make it happen. In this way we can give the right drug to the right patient, and for society and payers, for everybody, there will be an advantage.

Chemotherapy like a nuclear bomb – give the drug to everybody and you have a response rate of 20% or 25%, and 75% of patients do not respond – it’s over. Don’t misunderstand me. Chemotherapy is still the backbone for many treatments, but, thank God, we are evolving.

When you look at lung cancer, for example, it is not only a histology disease, like it was in the past. It may be a series of lung cancers where some genetic mutations are the driving forces, and when you start to sub-segment in this way, it is becoming a series of, if you want, rare disease and specific unmet medical needs in a small segment of patients.

If you take the BRAF mutation that in melanoma is present in 50% of the patients, more or less, but in lung cancer, it is 3% of the patients, we are trying to develop [dabrafenib] for this 3% of the patients, but it requires, of course, a different way to develop the drug and a different regulatory mindset.

“The Pink Sheet”: What kind of regulatory mindset are you talking about?

Paoletti: I think one important component of this evolution of science is the evolution of the regulatory world.

To find three patients with the BRAF [V600] mutation, which occurs in three patients with a BRAF mutation out of 100, the effort to identify patients is big; the regulatory agents cannot require a 600-patient Phase III trial. Dr. Pazdur [director of FDA’s Office of Hematology and Oncology Products] and other regulators realize that, and there is a willingness to work together to identify a novel way. Indeed, the FDA has demonstrated recently with a series of accelerated approvals, including [Pfizer Inc.’s] ALK inhibitor [Xalkori (crizotinib)], where in a small Phase II trial you have important relevant responses.

But, the cost of development in such niche areas cannot be the cost of the development 10, 15 years ago when you were developing [Sanofi’s] Taxotere [docetaxel] or whatever in lung cancer and you needed 1,000 patients to have a 20% improvement. Here, it is a completely different model, and if we do the right things in terms of identifying the right patient with the mutation, having a development in a small group of patients, the approval and the cost of the development [will have] been less, and then hopefully the cost also of the drug will be proportional to the investment.

The model has been changing. I think that in the future you will see more niche busters and not blockbusters. And if you have four, five of these tailored drugs I think it is good for everybody. Hopefully [it will be] a more intelligent way of developing drugs.

“The Pink Sheet”: If we’re talking about precision medicine and “niche busters” we have to talk about the importance of companion diagnostics.

Paoletti: Yes. I foresee a future where the mutation or biomarker for cancer should be used like we are using today cholesterol LDL or HDL. Society is facing a big turning point. We are in an interesting moment because in the United States, the payers, but outside the United States, maybe the government, needs to equip themselves to be sure this diagnostic is available.

And from a pharmaceutical company point of view … when we understand that there is a target and for that target we may have a medicine and that target is present in a certain cancer and you need to identify the patients that have this biomarker or genetic mutation … we will be working with a diagnostic company to optimize a test.

I want to give you an excellent example of France, where the government has implemented 70 sites all around the country. Wherever you live in France you can send to the closest site the biopsy and they will do the testing for the key driving mutations that are well-known today.

I travel all around the world and I can tell you that we are not yet there. In the United States, frankly, of course if you go to Memorial-Sloan Kettering or MD Anderson, you have this testing, but if you are going to a cancer center in the Dakotas that is not happening.

“The Pink Sheet”: Has the regulatory environment for diagnostics caught up with the need to harmonize with drug development?

Paoletti: We can [no longer] develop drugs like we would develop anthracycline plus taxane versus anthracycline alone. We are now in the era of selecting the patient. Then we need to find the best way to speed up the process of validating the diagnostic test.

To have the perfect diagnostic test at the moment of approval is almost impossible, so [regulators] need to accept [that], and they are working. The leadership of the FDA took a strong position to drive toward an important simplified approach and change, so I am very optimistic.

Are we there today? No. Is the journey started in the right way? The answer is yes. I have never seen in all these years, and I have now white hair in development of oncology, such a positive attitude to work together based on the excitement that the science is giving to all of us, to the regulators, to the oncologist, to the patient, so we now say, ok, the world is changing.

What is interesting is while this is happening if you take the BRAF testing, Roche was developing their own test. We were developing our own test. The entire scientific community is developing independently their own test, which they are using independently of what Roche and we are doing, and appropriately so because the science is so strong that we needed to know if a patient has a BRAF mutation. They didn’t want to wait for the approved test. And, by the way, the non-approved tests worked pretty well.

“The Pink Sheet”: Are combinations like dabrafenib/trametinib the future of cancer drug development?

Paoletti: My personal opinion is yes. Unfortunately cancer cells are very smart, and one weapon, with few exceptions, is not effective. And it is not the combination of signal transduction kinase inhibitors, but … the combination of possible different mechanistic components. I foresee the possibility of combining medicines that are acting directly on a key driving force, for example, the mutation, but also associating immunomodulation that is enhancing, boosting, the immunological response of the host, of the patient, and together they may achieve a better result.

If the area of cancer metabolism is successful, you will be able to give a drug in parallel that interferes with the cancer metabolism together with a well-known signal transduction inhibitor. And, last but not least, is epigenetics, which is a new area that we are very committed to at GSK.

“The Pink Sheet”: Your pipeline shows quite a commitment to immunotherapeutics. Can you talk a little bit about that?

Paoletti: GSK has a strong tradition in vaccines generally speaking. That was our history, and then a group of people started to study immunotherapeutics. And within immunotherapeutics there was an important antigen that is on the surface of lung cancer and melanoma, which is MAGE-3, as well as other antigens they are studying.

Again, this is precision medicine. Only patients that have [non-small cell] lung cancer or melanoma with MAGE-3 overexpression are being enrolled [in the Phase III trials].

Usually vaccines are studied in late-stage disease when the disease is already metastatic. For an immunological response to fight the spread of the disease [at that point] is extremely difficult. So what we did is study the vaccine in the adjuvant setting, which is when you remove the disease in a surgical way, and then hopefully the immunological response can kill or can react on the minor cancer eventually that is remaining in the body.

In the adjuvant setting you need a large number, and I think that we have done the largest ever conducted lung cancer study because we screened more than 10,000 patients to identify 2,500 patients that have the MAGE-3 overexpression. The trial has been completed and we are waiting for the events and we will read out in the next year. If this works it will be a transformational event.

“The Pink Sheet”: What about epigenetics?

Paoletti: It is very, very early stage, but we do have epigenetic drugs in development. One is a BET inhibitor that [is in Phase I] for a very rare kind of cancer.

[GSK525762 is an inhibitor of the BET (bromodomain and extra-terminal) protein family, transcription regulators important to cell cycle and growth. A Phase I/II trial launched in April to test the compound against NUT Midline Carcinoma, a rare, aggressive epithelial cancer, and other cancers.]

“The Pink Sheet”: During the Dec. 3 R&D day, Andrew Witty talked about a transformation in manufacturing and commercial operations. From your job description, it would appear that’s the way the oncology business has been working for a while now. Are you the model for the rest of the company?

Paoletti: Exactly. We have been the role model of what the other therapeutic areas will be doing. It has been a very successful experience engaging with the local operating companies all around the world and basically working as a unified team.

For oncology I must say it has been a little bit easier because we have a highly specialized business and it was a natural way to establish our self as an oncology company. In 2006-2007, when I arrived here, it was the moment of the patent loss for [antiemetic] Zofran [ondansetron], and everybody was doubtful we would be able to get to where we are today. When I arrived here there were only three oncologists; today we have over 35 oncologists working in the R&D center plus an additional 35 around the world.

Now we are the first company developing two non-approved drugs based on science, translating the knowledge to the clinic, going back to the laboratory – understand that I am summarizing what happened in seven years basically – but that focus on science, on unmet medical need was attracting top talent and now we have a very strong R&D organization, and our model integrating R&D and the commercial organization has been extremely successful.

And when I say commercial organization, I’m saying commercial organization that is very close to the development team to try to understand what will be the profile of the drug. We are working together on the early phase commercially, and when the drug is moving to the market we are working very close to the commercial policy organization on the market. We have created what I call a global community that is connected by our vision, which is doubling cancer survival, being the fastest growing company in terms of business, delivering products of value to society and being the most respected and trusted company by society.

“The Pink Sheet”: Does the continuous loop right through commercialization under one unit president make it easier to deal with payer questions, come up with something they will pay for and give a return on your investment?

Paoletti: I would like to quote what Andrew has said many times. We want to price in a responsible way but based on the value that our medicines are giving to society. The key element is generating the value that we are giving in comparison to standard of care that is meaningful. Now, what is of value also varies disease by disease. And cancer has been in evolution through the years by increment.

In pancreatic cancer today, 95% of the patients die probably in two years, and the median survival is six months. If I have a new drug that is bringing the median survival from six to eight months, it is huge in this disease. That’s what I’m trying to say. You need to look at the value in the context of the different cancers and in the context of the different stage of the cancer, where eventually a small increment may be very relevant and in another disease the same increment may be not significant.

The trick in this moment is that I don’t want to kill an increment that may be relevant, though the payer and society may not like a small increment. This is a dilemma that as a doctor but also working for a pharmaceutical company I have. However, precision medicine may be a way to have a good increment because we are not diluting the effect.

“The Pink Sheet”: Within your R&D organization, how much is virtual?

Paoletti: It is a combination. The model of the discovery performance unit – this little biotech company that we have many of within GSK – the CEO, if you want, is allowed to do his or her three-year plan in theory by having five people and externalizing all the rest if he or she wants. So we have DPUs that are very virtual and we have DPUs that are more focused internally Also see "Putting The Pieces Together Again: GSK Creates End-To-End Business Units " - In Vivo, 1 January, 2011..

It’s extremely important for us to be connected with the top of the science in discovery. We have a partnership with the top institutions. We [recently] announced the collaboration with MD Anderson for an interesting target in immunomodulation ([A#14121207004]).

“The Pink Sheet”: Can you talk a little about GSK’s efforts to repurpose existing untargeted drugs for unmet needs that might involve small populations of patients?

Paoletti: We do have that commitment to unmet medical need and we do have a strong history there starting with nelarabine in children, Votrient with the sarcomas and Promacta in ITP, as well now as hepatitis C and aplastic anemia.

[GSK’s oral thrombocytopenia drug Promacta (eltrombopag) was approved in November for use as supportive care to enable hepatitis C patients with low platelet levels to use interferon-based therapy Also see "GSK’s Promacta Cleared For Use With Interferon In Hep C Patients" - Pink Sheet, 19 November, 2012.. Arranon (nelarabine) won accelerated approval in 2006 to treat relapsed T-cell lymphoblastic leukemia, a population estimated at 500/year, 200 of whom are children ([A#00670450007]).]

When we were developing Votrient [pazopanib] in Phase I, our medicine development leader, who was a fantastic person, very passionate, observed some responses in sarcoma. I was just taking the job here at GSK, and I remember she came to me and showed me the results, which were astonishing. It was driven by a signal [that we] wanted to confirm in a Phase II trial, [which] was very innovative because we were selecting – sarcoma is more than 100 different histologies – we were stratifying patients by liposarcoma, [lamellar] sarcoma, androsarcoma, etc., and we have over three of these histologies [showing] positive results. So we launched after that the Phase III selecting the patients with these histologies, and the results were positive and here is where we are Also see "FDA Opts For Full, Rather Than Accelerated, Approval Of GSK’s Votrient In Sarcoma" - Pink Sheet, 27 April, 2012..

I’m very proud to work in a company that allows an investment in such a rare disease and will continue to invest. Votrient in sarcoma is approved after chemotherapy. Now we are showing some activity in combination with chemo and we want to go in the first line. That’s the story of sarcoma. It was the right thing to do, with a certain degree of risk, if you want, but at the end of the game it paid out.

And with MEK and BRAF, melanoma is a rare disease. We advanced the field with the combination but we are exploring with BRAF mutated patients in lung cancer, in cholangiocarcinoma, etc., where there is a mutation, so it is part of our plan.

Promacta in aplastic anemia is a very nice story as well. Aplastic anemia is a very rare disease. There are not more than 400 patients per year in the United States. Basically all the bone marrow does not work so the patient needs transfusion of red cells, platelets, they don’t have white cells, and after seven, 10 years they die. One investigator at NIH came to us and asked to try Promacta in this disease, and of course we gave the drug to him. He had experience with other growth factors and these drugs did not work in aplastic anemia, so he said let me try to show that also platelet growth factor does not work in this disease.

Guess what? It does work, and it works not only with platelets but also with all the three lines, with neutrophils and the red cells. And indeed we have this beautiful publication in the New England Journal of Medicine, and we’re speaking to the regulators. There is such an unmet medical need and we are going there.

“The Pink Sheet”: So serendipity plays a part in this program?

Paoletti: It is a program identifying the unmet medical needs where our drug can make a contribution, and sometimes, frankly, you need a little bit of serendipity, because I would be lying to you if I was thinking that this drug was going to work in aplastic anemia.

To be completely honest the commitment was there, the serendipity was that we found activity beyond platelets. I was hoping to have activity with platelets because it made a lot of sense, it’s a thrombopoieten factor, but the fact that it did work also in the other lines has been fantastic and we are now trying to understand why.

Precision Medicine And The Advent Of The “Niche Buster”: An Interview With GSK’s Paolo Paoletti

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