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GlaxoSmithKline plc (GSK) Q4 2018 Earnings Conference Call Transcript

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GSK earnings call for the period ending December 31, 2018.

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GlaxoSmithKline PLC (GSK 0.89%)
Q4 2018 Earnings Conference Call
Feb. 6, 2019, 9:00 a.m. ET


Prepared Remarks:


Analyst call for the GSK Fourth Quarter 2018 results. During the presentation, your lines will remain on listen-only. If you require assistance at any time, just key "*0" on your telephone and a coordinator will be happy to assist you.

I will now hand you over to Sarah Elton-Farr, Head of Investor Relations, who will introduce today's session.

Sarah Elton-Farr -- Head of Investor Relations

Thank you. Good morning and good afternoon. Thank you for joining us for our full year 2018 results which were issued earlier today. You should have received our press release and can view the presentation on GSK's website. For those not able to view the webcast, slides that accompany today's call are located on the Investor section of the GSK website.

Before we begin, please refer to Slide 2 of our presentation for our cautionary statements.

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Our speakers today are Chief Executive Officer, Emma Walmsley; Simon Dingemans, Chief Financial Officer; and Dr. Hal Barron, Chief Scientific Officer and President of R&D. We have a broader team available for Q&A.

We request that you ask only a maximum of two questions so that everyone has a chance to participate. Our presentation will last for approximately 45 minutes, slightly longer than usual, to give Hal time to update you on our R&D progress.

And with that, I will hand the call over to Emma.

Emma Walmsley -- Chief Executive Officer

Thank you, Sarah. Before we take you through our 2018 achievements, as this is the last quarter that Simon is going to be representing GSK, I'd really like to take the opportunity to reiterate my sincere thanks and appreciation to him for all he has done for the company over the last eight years. Our CFO-designate, Ian Mackay, is also on the call today, just in listening mode this time, and he will be on roll in April so you'll hear more from him on our Q1 call in May. I'm absolutely delighted to welcome him to our team.

In 2018, we have made good progress across the group, with improvements in sales, the group operating margin, earnings per share, and cash flow. Group sales growth of 5% in CER terms reflected an increase in sales in all three of our global businesses, with a particularly strong performance in vaccines. The Pharma business continues to shift its portfolio shape with excellent new launch growth. And although Consumer had a slower quarter, we remain confident and excited about the outlook for this business.

Group operating margins this year were up 50 basis points on a CER basis. On a total basis, earnings per share more than doubled to 73.7p and adjusted earnings per share were up 12% CER.

Our free cash flow position continues to improve and we are particularly pleased with the underlying improvement in our cash flow. For the year, free cash flow was almost £5.7 billion, up 63% in actual terms versus last year. Today, we declared a dividend in respect to the fourth quarter of 23 pence, resulting in a total dividend for 2018 of 80 pence.

When I became CEO of GSK in 2017, I laid out my three long-term priorities for the company: innovation, performance, and trust, all to be powered by a necessary change in culture. In 2018, we made significant progress on accelerating these priorities, have improved our operating performance, and reshaped the group's portfolio, including development of the pipeline. We've put in place new leadership who are already driving shifts in our culture.

We've put a clear focus on launch execution and have had considerable success, notably with Shingrix but also with Trelegy in Respiratory and the first of our two-drug regimens in HIV. Our clear priority is to improve Pharma performance and pipeline. Luke Miels, President of Commercial Pharma, has been restructuring to focus our commercial operations alongside a reduced manufacturing footprint. And last July, Hal, our Chief Scientific Officer, laid out our new R&D approach, with a focus on science related to the immune system, the use of genetics, and advanced technologies, and he'll update you more on our good progress since then later.

We've also made significant progress in reshaping the portfolio. Our first focus was R&D program prioritization and here we've terminated or divested around 80 programs since 2017, including seven within the last few months, to invest more behind the potential medicines we see bringing greater value to patients and strong growth for GSK. Of particular note is the expansion in oncology, from eight drugs in the clinic in July last year to now 16, with three pivotal study read-outs by year end.

We stepped up business development, be it in our partnership with 23andme, the recently closed transaction with Tesaro, or the global alliance we announced just yesterday with Merck KGaA, Darmstadt, Germany.

We've made non-core divestments, such as the announced divestment of Horlicks to Unilever, we've successfully bought out the Novartis stake in consumer healthcare, and at the end of the year, we made our most transformational announcement to date with a plan to create a new joint venture with Pfizer.

Looking now briefly at the new product launches, we've seen a very strong start to Shingrix in 2018, with sales of £784 million in its first full year. We've now administered more than 9 million doses globally since launch. And as we said last quarter, we're working hard to build capacity and meet long-term global demand and we've made good progress on this.

Moving to Respiratory, Trelegy has achieved sales of £156 million in its first full year. Labels in both the U.S. and Europe have been updated with data from the landmark IMPACT study, showing benefits over jewel therapies, and the international rollout continues. We expect the recently approved generic Advair to have minimal impact on this highly differentiated product, the first approved once-daily single inhaler triple therapy for COPD, and we look forward, too, to the CAPTAIN study for Trelegy in asthma, which is expected to report in the spring.

We continue to see strong performance also from our injectable asthma therapy, Nucala, despite the introduction of two new biologics during 2018. With additional investment, new patient growth in the U.S. has improved and in other key markets where competition has also launched, including Germany and Japan, Nucala continues to lead both the total market and in new patients.

In 2019, we do expect the competition to intensify and near-term growth will be lower but we believe the market opportunity is still significant, with less than 25% of suitable patients receiving therapy today, and we're excited about the opportunity to provide the convenience of home administration and have filed for U.S. and EU approval of an auto injector.

2019 is another important year for our HIV business and two-drug regimens. In 2018, the dolutegravir portfolio grew at 16%, benefiting from the launch of Juluca, with its first full year of sales of £133 million, demonstrating an encouraging indication of uptake for our two-drug regimens. We're maintaining our U.S. market share at 27% in a competitive marketplace. We anticipate U.S. approval for our dolutegravir and lamivudine combination in Q2 and we're also progressing our long-acting injectable two-drug regimen, cabotegravir and rilpivirine, and we'll be presenting data from the pivotal ATLAS and FLAIR studies at a conference shortly. Regulatory filings are planned for later this year, as well as for our therapy for heavily pretreated patients, fostemsavir. These two-drug regimens will help drive our long-term growth while bringing more treatment options to patients to help them manage their HIV with less impact on their lives.

So, in summary, we have seen good progress in 2018 in operational performance, in reshaping the portfolio, and in strengthening the pipeline, and we'll be building on this progress in 2019. In innovation, we will be focused on strengthening the pipeline further, particularly our growing portfolio of assets in oncology. And, of course, we will stay very focused on the execution of our recent and upcoming launches. In performance, we will continue to drive growth in operating performance across the group and will be working hard to plan for the integration with Pfizer's consumer business, which we expect to close in the second half of the year. And on trust, we want GSK to continue to lead with a broader contribution to society. Our first priority here is to innovate and we'll give you regular and transparent updates on our pipeline progress. So, you'll hear again from Hal at Q2. For trust building, we also remain very committed to our global health agenda, focused for impact on infectious diseases in the developing world. And because everything and anything we achieve comes from the talent, energy, and engagement of our people, we aim to be a modern employer to attract and retain the very best.

So, after a year of progress in 2018, we are ambitious again this year. We believe we have the right teams in place to make it happen and we've laid out a clear pathway over the next few years to the creation of two exceptional businesses. We will have a new, focused Global Pharma and Vaccines company and we will create a new, world-leading Consumer Healthcare company.

And so, with that, I will hand you over to Simon.

Simon Dingemans -- Chief Financial Officer

Thank you, Emma. I'm delighted to be presenting to you such a strong set of results, my last as CFO after 32 quarters. I'm sure you all have saved some particularly challenging questions to round everything off so I'm looking forward to answering those later on.

Overall, the group's results for the year are ahead of the top end of our guidance and demonstrate continued operational execution of our key strategic objectives, with strong performance in all three businesses. Our earnings release provides an extensive amount of information so I'll focus on major points, our expectations for 2019, and important comparatives to note for your models.

As usual, my comments today will be on a constant currency basis, except where I specify otherwise, and I'll cover both total and adjusted results.

Starting with the headline results, group sales were up 5% to £30.8 billion, total EPS more than doubled to 73.7p, and adjusted EPS were up 12% to 119.4p. Total operating profit was £5.5 billion, up 43%, and showed strong progression on 2017. Higher charges for the revaluation of acquisition-related liabilities, principally the VECCL, were more than offset by a stronger operating performance, lower restructuring costs, lower asset impairment charges, and a favorable comparison with the charges taken in 2017 related to U.S. tax reform £0.7 billion.

Adjusted operating profit grew at 6%, with operating margin up 50 basis points, driven by margin growth in Vaccines and Consumer Healthcare. Pharmaceuticals operating profit was flat, with operating margin impacted by continued investments in our new products and a weaker gross margin in the face of ongoing pricing pressures.

Free cash flow delivery was significantly stronger at £5.7 billion, up £2.2 billion, reflecting continued focus on cash conversion throughout the group, with particular progress this year on working capital management. We have delivered on the dividend expectations we laid out, with 80 pence declared for 2018. We also expect 80 pence for 2019.

Net debt ended the year at £21.6 billion, the increase from last year primarily driven by the £9.3 billion buy-in of Novartis' consumer stake and an adverse FX translation impact of £0.8 billion, partly offset by the improvement in free cash flow that was significantly ahead of the dividend. On currency, a slightly stronger sterling compared with 2017, particularly against the U.S. dollar, resulted in a headwind of 3% on sales and 5% to adjusted EPS.

The next slide summarizes the reconciliation of our total to adjusted results for the year and the rest of my comments will be on our adjusted results.

Turning to the top line, sales up 5%, driven by momentum in all three businesses. Sales within the Pharma business were up 2%, driven by HIV, which grew 11% for the year, as well as the new Respiratory products. Within HIV, our dolutegravir portfolio continued to grow strongly, up 16%. Q4 saw good growth in international, offset by a slower quarter in the U.S., which was adversely impacted by year-on-year stocking patterns which roughly halved the U.S. reported growth rate of 3%. We continue to expect HIV will be a meaningful growth driver, including in 2019, as we build on the successful launch of Juluca and expand our two-drug regimens.

Respiratory sales grew 1%, with growth from the Ellipta portfolio, particularly Trelegy and Nucala, more than offsetting lower sales of Seretide/Advair. U.S. Advair sales in 2018 were £1.1 billion, a decline of 30%. And with the recent approval of a generic, we factored into our guidance a significant decline in Advair in 2019. In the short-term, you should also expect particular volatility across Q1 and Q2 as the market adjusts inventory levels and responds to the supply available.

Relvar/Breo sales were up 10% for the year, driven by momentum in Europe and international, which offset a slight decline in the U.S. Given the expected impact on the ICS/LABA class of generic Advair, we expect Breo will see a sharper decline in the U.S. in 2019, resulting in a slight global decline for Relvar/Breo despite continued good growth expectations outside of the U.S.

We continue to focus on driving value and cash generation in our Established Pharmaceuticals portfolio, which declined by 4% for the year, at the better end of our expectations. Q4 benefited from around £80 million of additional sales resulting from post-divestment contract manufacturing sales and the first installment of a newly won Relenza tender. From Q1 2019, we will report the older Respiratory products, including Advair/Seretide, within the Established Pharmaceuticals and we'll give you restatement information ahead of Q1 so that you can update your models.

With the approval of a generic competitor to Advair, we expect the Pharmaceutical business overall to see a slight sales decline in 2019 before returning to growth in 2020, driven by our new products. This includes the expected top line contribution from Zejula now that we have closed the Tesaro acquisition. Zejula sales for 2018 were $230 million, impacted by some adverse mix and some destocking in Q4, but overall share at the end of the year was very much as we expected. Our focus in 2019 will be on building the penetration of the class, but the PRIMA read-out later this year will be key in expanding the market and our share.

Moving to Vaccines, sales up 16%, driven primarily by Shingrix, a strong performance in hepatitis, and good flu vaccines sales, as well as market and share growth for Bexsero, offset by some declines in Menveo and a number of other established vaccines.

Shingrix sales were slightly ahead of our 2018 guidance, as we made further progress in accelerating our production plans. More than 9 million doses have been administered since launch a little over a year ago and we continue to target high-teens millions of doses over the next two or three years. Importantly, we now have in place the detailed capacity plans necessary to deliver the meaningful increase in doses this target implies. Those plans include a significant step-up in doses for 2019 so that we can maintain the momentum that was established through the second half of last year behind this important vaccine and ensure patients can complete their two-dose course.

Flu sales up 10%, as we increased share, delivering 43 million doses in the U.S. Across the year, we saw some pricing pressure, which we expect to continue into 2019, with increasing competition in this category.

Meningitis franchise overall was more mixed. Bexsero up 9%, with demand and share gains in the U.S., but more widely, momentum was dragged by the completion of cohort catch-up vaccination programs in Europe and Bexsero growth was also largely offset by Menveo, which was impacted by supply constraints and unfavorable CDC stockpile movements. We expect to return to stronger growth for the Meningitis portfolio in 2019.

The momentum in the vaccines business continues to give us confidence in the mid- to high-single digit outlook for sales, compound annual growth, out to 2020.

Turning to Consumer, sales grew 2% for the year despite a drag of around one percentage point from the combined impact of the divestment of non-strategic brands and the final quarter's impact of GST in India. Oral Health and Wellness continued to deliver broadly based growth and the Consumer business gained share overall across the full year. Reported growth was impacted, though, by a weaker performance in Europe, particularly in the second half, when we saw a much tougher competitive environment. We have responded but these plans will take though Q1 to make a full impact.

In 2019, we expect reported growth also to be impacted by the loss of around £100 million of revenue from the smaller divestments completed at the end of last year and the phasing out of low-margin contract manufacturing as we restructure the Consumer supply chain. Given this drag, we now expect 2019 reported revenue growth for Consumer in the low single digits, assuming we keep the India nutrition sales for the full year. We remain confident in the prospects for the business and are on track with our margin objectives after another strong improvement in 2018.

Turning to operating profit, our adjusted margin of 28.4% was flat at actual rates, up 50 basis points in constant currency. COGS as a percentage of sales was 40 basis points higher at constant currency, primarily due to the continued adverse Respiratory pricing pressures we are seeing within Pharma, as well as the decline in Advair, and some input cost increases and some specific fourth quarter mix issues. These more than offset significant improvements in Vaccines and Consumer Healthcare.

SG&A increased by 4% in the year, as we invested in our recent launches in Vaccines, Respiratory, and HIV, partly offsetting tight control of non-promotional spending across all three businesses. R&D costs were down 2%, reflecting the comparison with the charge for the PRV in 2017, as well as savings from recent portfolio prioritization decisions. Investment in oncology accelerated in the second half and we continue to expect overall R&D spending to pick up significantly in 2019. With the Tesaro acquisition now closed and consolidating the costs fully, you should expect about half of the operating costs to be for R&D and the rest for commercial, medical, and other SG&A.

Royalties were £299 million for the year, down 17%, primarily reflecting the patent expiry of Cialis, and I'd expect 2019 royalties to be at broadly similar levels to 2018.

Moving to the bottom half of the P&L, net financing costs for the year were £698 million, reflecting higher debt following the acquisition from Novartis of their stake in the Consumer joint venture. This was slightly better than original expectations, benefiting from strong execution on our funding strategy. For 2019, as we finance Tesaro but continue to optimize our funding mix, we expect net financing costs of around £900 million to £950 million. This includes the expected impact of IFRS 16. We'll give you more detail on that before the first quarter results.

On tax, the adjusted rate was at the lower end of our expectations at 19% for the year and we expect the 2019 rate to also be around 19%.

The charge for NCIs was £674 million, down £119 million from 2017 as a result of the Novartis buy-in. We'll update you on the impact on minority interest of the Pfizer joint venture once we have more specificity on the timing of closing. Keep in mind, overall, we expect the deal to be broadly neutral to adjusted EPS in 2019 and accretive to adjusted EPS in the first full year post-closing.

Turning to cash flow, with a focus on driving greater cash discipline, the group made further significant progress this year, resulting in generation of £5.7 billion of free cash flow for 2018. The increase of £2.2 billion was particularly driven by progress on working capital despite the growth in the business, especially in inventory control and stronger collections. Reductions in CapEx, lower legal costs, higher proceeds from intangible divestments also contributed. There were some phasing benefits but only in the order of £200 million to £300 million.

The focus on cash conversion will continue into 2019 but, as in previous years, you should expect cash flows to be weighted to the second half. 2019 cash flows will see a step-down as the Advair generic flows through, we pay out the rebate payments on pre-generic sales of Advair. This will likely take a few quarters to unwind. Given the improvements in cash conversion and free cash flow generation across the business over the last couple of years, we remain comfortable that the balance sheet can support our future investment requirements.

In 2019, we now expect adjusted EPS to decline in the range of minus 5% to minus 9% at constant exchange rates. This guidance reflects the expected impact of the recently announced transactions, as well as the approval of a substitutable generic competitor to Advair. On top of the constant exchange rate performance, if exchange rates remain at January 31st closing rates for the rest of the year, we would expect a positive impact on sales growth of less than 1% and around a 1% positive impact to adjusted EPS growth.

When we announced the acquisition of Tesaro, we said that we still expected to deliver on our 2020 outlooks. Nothing has changed our post-Tesaro view and we continue to expect to deliver a percentage CAGR in adjusted EPS over the five-year period 2020 at 2015 exchange rates, at the bottom end of the range we previously indicated of mid- to high-single digits.

So, to conclude, a strong year of operational performance in 2018 with good progress from our new products and better operating margins. I'm particularly pleased with the improved free cash flow delivery after significant focus on this across the company. We're well prepared for generic Advair. The business is showing good momentum and with the important strategic moves we have made recently now in place, we're confident in the outlook for GSK.

And, with that, I'll hand you to Hal.

Hal Barron -- Chief Scientific Officer

Thank you, Simon. At Q2, I set out our new R&D approach based on science times technology times culture. We made a commitment at that time to being much more transparent with you about the decisions we are taking and the progress we are making through regular updates. This is the first of those updates and I'm very pleased with the advances we've made to the portfolio in the last six months. I believe our pipeline is now more focused on our most promising assets, allowing us to accelerate them while terminating those which have less potential. Eight assets have made encouraging progress, which I will describe in a moment.

Overall, we have significantly strengthened our oncology portfolio. Since Q2, we have added three new, internally generated assets to the portfolio, and through business development, added five -- four from Tesaro acquisition and one from the strategic alliance with Merck to jointly develop and commercialize M7824 -- resulting in a doubling of the size of our oncology clinical stage portfolio from eight to 16.

On culture, I've made a number of key leadership appointments, most recently with Chris Corsico joining us from Boehringer Ingelheim to head up our newly created development organization, as well as introducing a new, more robust governance model, which as of October 1st, is up and running and, I think, going very well. In addition, we're in the process of redesigning the discovery performance units and will establish a much smaller number of research units aligned with our focus on immunology and genetically validated targets. This is all helping us to create a culture of smart decision making, single point of accountability, and, importantly, focus.

Given the limited amount of time I have today, I'm going to focus on our pipeline and defer talking about the progress we've made on technology until the next Q2 update. But I could come back to this in the Q&A if you have any questions.

At Q2, I showed you this slide of our portfolio. At the time, we had 43 potential medicines in the clinic, 27 of which were immuno modulators. I would now like to talk you through the progress we have made in the last six months.

We've been focused on accelerating and strengthen our pipeline through disciplined decision making and taking smart risks. At Q2, I signaled that there were some programs I was optimistic about and others I had less confidence in. Based on data, particularly interim analyses, we have been rigorous in terminating investments of the less promising candidates and have now stopped seven programs since Q2. These terminations have freed up resources to reinvest elsewhere in the pipeline where we see more potential for developing transformational medicines. As I said, eight assets have made encouraging progress and I'd like to go over them now. I'd just like to mention that four of the assets, which are highlighted here with blue boxes, I have slides in subsequent minutes while I'll go into more detail on.

First, tafenoquine was approved and its two positive Phase 3 studies, DETECTIVE and GATHER, were recently published in The New England Journal of Medicine. Dolutegravir plus lamivudine, our second two-drug regimen for HIV patients, was subsequently filed for approval and we expect to receive that in the first half of 2019. With regards to cabotegravir plus rilpivirine, our long-acting injectable therapy for HIV patients, we have announced positive headline data for both the FLAIR and ATLAS studies and expect to present this data, as well, in the first half of 2019.

We also made one of the few major advances in TB vaccine development in nearly 100 years. A preliminary read-out from our ongoing Phase 2 trial was published in September in The New England Journal of Medicine showing the vaccine demonstrated a 54% reduction in the risk that TB-infected adults would develop active disease.

I'm pleased to report that our antibody to GM-CSF is progressing well and we're moving into Phase 3 and I'll expand on this, as I had mentioned, a little bit later.

Our BCMA program has advanced significantly. And at the Q2 call six months ago, we had mentioned that we had initiated the pivotal study. I'm pleased to report that we actually have completed that study ahead of schedule.

We continue to be excited about our ICOS agonist. We have encouraging data in-house, in combination with Keytruda, and expect to share this at a conference probably second half of this year. We have also started two new clinical studies, one in combination with CTLA4 in solid tumors, as well as a platform study in lung cancer.

Lastly, but equally important, is NYESO cell therapy. Cell therapies are an important part of our strategy and we are making good progress accelerating our first program in solid tumors. We hope to start a pivotal study for NYESO in synovial sarcoma next year, moving up our anticipated launch date by almost a year. We are also evaluating activity in other tumor types, including non-small cell lung cancer, with a more sensitive assay, our RT-PCR assay, as well as in multiple myeloma patients. We anticipate treating our first patient early this year.

I also talked at Q2 about how we would leverage business development to optimize our portfolio. And as you know, we have made a lot of progress here. The Tesaro acquisition has added four new clinical immuno modulatory medicines to our portfolio and significantly strengthened our position in oncology. Also, yesterday, we announced the strategic alliance with Merck to jointly develop the TGF-β trap, anti-PD-1 bifunctional protein, called M7824, for various tumor types. In addition, since Q2, we have also had four internal molecules advance into Phase 1, three of which were in oncology.

So, in summary, here's the portfolio as it currently stands. You can see we have increased the number of new molecular entities in development to 46 from 43, now 33 of which target the immune system. And, more importantly, we believe that the quality of the portfolio is much improved.

This is a view of our oncology portfolio, which is clearly much more robust, with twice the number of assets in the clinic than we had back in July. We now also have a number of molecules with diverse mechanisms of action, providing an opportunity for many innovative combination studies. And, importantly, we are expecting to see three pivotal read-outs this year, potentially resulting in new approvals in 2020. Those are the anti-BCMA ADC for fourth-line multiple myeloma; TSR-042, the anti-PD-1 in endometrial cancer; and the PRIMA study for Zejula in the front-line maintenance setting for patients with ovarian cancer.

I'm going to take a few minutes now to talk about the strategic alliance we announced yesterday with Merck to co-develop their first-in-class bifunctional fusion protein. Despite recent advances with checkpoint inhibition, many patients still do not respond to the anti-PD-1, anti-PD-L1 class of therapeutics. TGF-β is believed to create a suppressive tumor microenvironment and has been implicated as a resistance mechanism to the treatment of PD-L1 or PD-1 blockade. M7824 is the first-in-class bifunctional fusion protein designed to simultaneously block the PD-L1 and the TGF-β pathways. It's a fully humanized IgG1 monoclonal antibody against human PD-L1, fused to the extracellular domain of the human TGF-β receptor II, which functions as a cytokine trap for the three against TGF-β I through III. Preclinical data have demonstrated superior efficacy of this molecule versus PDL1 monotherapy, as well as a benefit with chemotherapy and particularly with radiation therapy, in multiple in vivo mirroring tumor models.

M7824 has been tested in 14 Phase 1B signal-seeking studies across more than 700 patients and has shown clinical activity across multiple hard-to-treat cancers, including non-small cell lung cancer, HPV-associated cancers, biliary tract cancer, and gastric cancer. Together with Merck, we will explore the potential of this novel asset alone and in various combinations with the four immuno-oncology clinical development studies ongoing or expected to commence in 2019. Importantly, we have seen encouraging clinical data in second-line non-small cell lung cancer patients and, based on this, a randomized, controlled Phase 2 trial was recently initiated to investigate M7824 compared with pembrolizumab as a first-line treatment specifically in patients with high PD-L1 expression, where the data to-date is most compelling.

Not only does this strengthen our immuno-oncology portfolio, but I'm excited by the potential synergy with our existing assets, including our ICOS agonist, the TLR4 molecule, and many of the recently acquired molecules from Tesaro. We believe that the M7824's unique design, supported by an alliance between two very complementary companies, will further accelerate our oncology strategy. I'm truly excited by the potential impact this first-in-class immunotherapy could have on the lives of many cancer patients.

Moving to Tesaro, the Tesaro acquisition, which we announced back in December and completed a few weeks ago, is really a significant step forward for both our oncology pipeline and our commercial capabilities. I've personally been working very closely with Mary Lynn Hedley, the President and CEO of Tesaro, and have met with her team and I'm even more convinced than ever that this is a great company with great science, great people, and a great culture.

While Tesaro brings more than just one asset, I want to spend some time reiterating the opportunity that we see for Zejula, which was the first PARP inhibitor to achieve a broad label for non-gBRCA ovarian cancer patients. PARP inhibitors have really transformed the course of disease for women with ovarian cancer. And as we dig deeper into the science, I remain convinced that the PARP class is underappreciated and our commitment to functional genomics and other technologies will enable us to use Zejula to help patients beyond those who have the gBRCA mutation, particularly those patients who have a defect in the genetic repair mechanisms called homologous recombination or so-called HRD-positive patients, which might represent, as you can see on the right side of this slide, as many as 50% of all ovarian cancer patients.

The reason we're so optimistic that patients with this so-called "wild type" or normal gBRCA is shown here. Tesaro's NOVA study explored three types of patients in a stratified manner: patients with the gBRCA mutation; those patients who were wild-type for gBRCA -- that is they had the normal gBRCA gene -- but who had evidence of homologous recombination deficiencies as measured by the myriad tests, the so-called HRD-positive patients; and the third group, who were gBRCA wild-type and who did not test positive for having HRD.

As you can see in these four Kaplan-Meier curves here, the benefit in the wild-type but HRD-positive patients was almost as impressive as the benefit in those patients with the gBRCA mutation. These data give us optimism for seeing a benefit of Zejula in patients who do not that the gBRCA mutation but are HRD-positive in the front-line setting.

The PRIMA study, which is expected to read-out at the end of this year, will definitively answer this question for us and could result in Zejula being approved as the first monotherapy beyond the women who simply have the gBRCA mutation.

Now, turning to GSK '916, or our BCMA ADC, this is a great example of how we're putting into action what we committed to at the Q2 call. When I spoke to you in July, we had just started the fourth-line pivotal study, DREAMM-2. Remarkably, we were able to fully enroll the study within about three months, ahead of plan, and we expect to get the data in the second half of this year to support a file by the end of 2019.

Very importantly, we now also have seen updated PFS data from the DREAMM-1 fourth-line monotherapy study. We had initially estimated a PFS of 7.9 months and presented that data at ASH in 2017. Now, with further follow-up, our updated PFS has increased to 12 months. We expect this data to be published in a leading journal very soon. Of course, this is based on a very small number of patients but, nonetheless, very encouraging information.

Also since our last update, we initiated DREAMM-6, which is a combination Phase 1-2 study that will enable the second-line pivotal study, DREAMM-7, to start this year. All together now, we have more than tripled the number of patients treated since July, reaching almost 300 patients by the end of this past January.

In addition, by taking this more focused approach to development and prioritizing our investments and resources behind BCMA, this year, we will start four pivotal studies: DREAMM-3, -7, -8, and -9, in the fourth-line, second-line, and front-line settings. We know multiple myeloma is a competitive space but it is also an area with significant unmet need remaining and where speed to market really matters to patients who are in need of new therapies. We continue to expect to be the first BCMA targeting agent to reach the market due to our accelerated development plan.

Moving to GSK '165, a human monoclonal antibody antagonist of GM-CSF, a pro-inflammatory cytokine that is increasingly recognized to play a role in the mediation of pain in a number of diseases, including rheumatoid arthritis. There remains significant unmet need for patients with rheumatoid arthritis to obtain better responses and, particularly, better control of the pain. We have seen encouraging results with '165 in RA, showing clinical responses, particularly in improving pain. These were presented at the ACR last year and we hosted a call at that time and included an external expert for his thoughts.

Following meetings with regulators, we have nearly finalized an innovative Phase 3 program that we expect we can start in the second half of this year to support, hopefully, a filing in 2023. The clinical program includes patients who have failed methotrexate and targeted therapies and compares GSK '165 against both the JAK inhibitor, as well as an anti-IL-6. We believe that this study design, the primary endpoint chosen on it of ACR-20 at 12 weeks compared to placebo, and the optimized dosing regimen will result in a successful program and potentially an even further increase in efficacy.

So, in summary, while there's still much more to be done, we've made a lot of progress over the past six months. Having completed the acquisition of Tesaro in January, we will continue to invest behind Zejula. We look forward to getting the PRIMA data in the front-line maintenance setting at the end of 2019. We'll also be looking at how we can optimize TSR-042, the PD-1 inhibitor we acquired from Tesaro, which we expect to get pivotal data on in patients with endometrial cancer to support a filling in the second half of this year. I look forward to discussing and focusing on this important asset at our next update. We will aggressively develop our BCMA ADC, as well as our other oncology pipeline molecules, including the TGF-β trap with our newest collaborator, Merck.

In 2019, we will continue to focus on optimizing the pipeline by investing in other promising areas of medicine, including the anticipated approval for dolutegravir plus lamivudine in HIV and filings for our long-acting HIV therapy and fostemsavir for highly treatment-experienced patients.

We will continue to focus on technologies that will enable the pipeline to deliver transformative medicines and, of course, we will continue to drive the culture change that is necessary to improve our R&D productivity. We are going to be generating a lot of data this year. There's a full list of all of that data in the appendix but on the right-hand side of this slide, you can see the key read-outs that I think you should focus on.

Thank you for your attention and I look forward to updating you again at our 2Q results and answering any questions you might have in the Q&A. And, with that, I'll hand it back to Emma.

Emma Walmsley -- Chief Executive Officer

Thank you very much, Hal. So, in summary, 2018 has been a year of significant progress, in terms of operational performance, reshaping of the portfolio, and development of the pipeline. In 2019, we will be building on this with continued execution of our priorities of innovation, performance, and trust, with an ongoing focus on the pipeline to provide a clear pathway to the creation of two exceptional businesses. And across GSK worldwide, we are all very committed to this tremendous opportunity to create substantial value for shareholders, patients, and consumers.

So, with that, Operator, I think a bit ahead of our 45-minute promise, the team is ready to take questions now.

Questions and Answers:


Thank you. Your first question comes from Richard Park from Deutsche Bank. Please go ahead.

Richard Park -- Deutsche Bank -- Analyst

Hi. Thanks for taking my questions. The first one is just for Hal on the M7824 deal. Obviously, since the disappoint with IDO, it feels like the industry has moved away from, or trying to move away from, making big decisions based on signals in single trials with the next-generation IO agents. Obviously, with M8724, it looks like Glaxo is not necessarily following that trend, given that that's being advanced into pivotal studies. I just wondered if you could help us understand. You've obviously seen a lot more data. What makes you confident to do that or is this just a calculated risk?

The second question is on the outlook for HIV. When I look at NBRx volumes in the U.S., it looks like they've declined on an absolute basis by 20% to 30% since the launch of Biktarvy. Obviously, the drug is only just launching now in Europe. I wondered if you could help us understand whether we should expect more or less impact to European new patient share as Biktarvy launches. Thank you.

Emma Walmsley -- Chief Executive Officer

Thanks so much, Richard. So, we'll come to Hal first and then to David. And just to say, aside from the scientific commentary that Hal will add, just a reminder that the construction of this deal is very heavily stage-gated for GSK but will be based on data. But, Hal, perhaps you'd like to comment on the question first?

Hal Barron -- Chief Scientific Officer

Yeah. Thank you, Richard. Well, let me walk you through why we're pretty convinced this is a smart risk to take. When you look at what advances have been made in cancer therapeutics by inhibiting PD-1 and PD-L1, it's really been very transformational. But it's important to remember that the vast majority -- actually, about 75% of the patients -- either don't benefit or will relapse after therapy. And so there's a clear need to find new agents, either given in combination with or that can compete with these agents, to provide patients with greater options.

When you look at this asset, it's very unique. It not only combines the IgG backbone of a PD-L1 inhibitor, but has this other component that allows it to be, basically, a receptor trap to bind the three isoforms of the TGF-β ligands. And the pre-clinical data is pretty compelling here, in terms of TGF-β playing a role in tumor progression and, particularly, PD-1/PD-L1 resistance at the tumor level because of the suppressive effects that TGF-β has been seen in the tumor microenvironment. And so we think this very unique, first-in-class, sort of novel mechanism agent was very, very interesting.

Now, you combine that with a very unique situation, which is that they had for us to review almost 700 patients treated in various Phase 1 settings for signal seeking. And, in fact, in that finding, four different diseases that I mentioned earlier, where there's clear evidence of activity. So, based on that pre-clinical biology and the data generated in those four diseases and, particularly, the data generated in the second-line lung setting, where the response rates really did appear to be superior to those historically seen with PD-1 in similar PD-1 inhibition in similar settings.

So, you're right that we don't have randomized controlled trials but it's that data that was exciting enough to initiate the Phase 2 randomized controlled trial against pembro. And as Emma said, the deal is structured in a way that gives us confidence that this was a smart risk to take. And hopefully for patients, this will wind up being a superior therapy.

Emma Walmsley -- Chief Executive Officer

Thanks very much, Hal. And so, David, specific questions around the dynamics of NBRx. I mean, I'd just also like to repeat that we do expect our ViiV business, our HIV business, to continue to be a key growth driver for GSK, primarily because of the bet that we're making on two-drug regimens, and we're very excited about all the, hopefully, both approvals and further data that's going to come through this year. But, David, over to you.

David Redfern -- Chief Strategy Officer

Yes. Thanks, Richard. Yeah, as Emma and Simon said, we do expect ViiV to be a meaningful growth driver in 2019 and going forward, although the dynamics of that growth, I think, will vary a little bit across the world.

So, in the U.S., the Tiviqay and Triumeq business is basically flat over the last few months. We are getting some penetration with Tiviqay, particularly into new patients, but there is some switching of both products. So, overall, we're broadly flat at around 35,000-36,000 prescriptions a week and our share is roughly just over 27% or around 27% of the core market. And NBRx is also pretty flat.

So, going forward in the U.S., the growth will come from ongoing momentum of Juluca and we've actually seen a pretty decent pickup in Juluca in the last quarter, in part, I think, driven by quite a favorable reaction to the two-year sort data that was presented. So, Juluca beginning to build quite strong momentum. And, of course, the launch, once we get approval, of dolutegravir and lamivudine, which we see as the key growth driver going forward.

I think, away from the U.S., in the European and international businesses, we expect the growth to actually be more broad-based across the whole dolutegravir portfolio, really building on the momentum we've seen this year. So, European business, dolutegravir was up 17% and growing very nicely. And international business, up 35%, very strong performances in places like Brazil, Japan, and so forth. And also just remember that this year, 2018, we had a reasonable drag, predominantly from the genericization, ongoing genericization, of Kivexa/Epzicom. It was about £150 million. And that will be less going forward.

Emma Walmsley -- Chief Executive Officer

Thanks, David. So, next question, please.


Your next question comes from the line of Tim Anderson from Wolfe. Please go ahead.

Tim Anderson -- Wolfe Research -- Analyst

Thank you. If I could go back to the M7824, just a couple of questions. When do you expect you'll have the first registrational data with that compound? I'm assuming that the Phase 2 study that you've referenced that's randomized is not registrational. And also can you talk about dose-limiting toxicities with the compound?

And then second question, on dolutegravir, I think in March, we're supposed to get the updated results from the TSEPAMO study looking at the possible side effect of neural tube defects. I'm wondering if you can tell us any update on what you think that may show or if there's anything new to share on that? Thank you.

Emma Walmsley -- Chief Executive Officer

David, briefly, on neural tube updates and then we'll go back to Hal.

David Redfern -- Chief Strategy Officer

Yes. So, as you say, Tim, that study is being run on trying to get to the bottom of this issue. We'll obviously need to wait and see when that data comes out. It's a study not run by us but actually run by the NIH. All I can say at this point, as time has gone on, we have seen, I think, no new cases of neural tube defects and, obviously, more babies being born. So, it looks less and less of a meaningful signal but, obviously, we need to see the definitive data when it comes out.

Emma Walmsley -- Chief Executive Officer

Thanks. Hal?

Hal Barron -- Chief Scientific Officer

Yeah. Thanks, Tim. First, we're not really giving timelines on when we will have data that can be submitted for registration. That said, let me be clear that registrational studies in oncology can sometimes take different forms and, depending on the efficacy observed, there's always opportunities to think through novel strategies.

Simon Dingemans -- Chief Financial Officer

Yeah. And I would just add, Tim, if you take a step back and look at the scale of the opportunity, I mean, pembro reported £7 billion, Opdivo was close to £7 billion, I think, in the high sixes. So, in terms of a relatively modest down payment, this gives us an opportunity potentially to disrupt this market.

Emma Walmsley -- Chief Executive Officer

Thanks. Next question. Oh, do you want to add another part now?

Hal Barron -- Chief Scientific Officer

I'm sorry, Tim. I just didn't get a chance to answer the dose-limiting tox part of the question.

Emma Walmsley -- Chief Executive Officer

Go ahead.

Hal Barron -- Chief Scientific Officer

I think the profile, from an immuno-oncology perspective, we don't see any new immune-related side effects. There is the skin findings with acanthosis, some skin disorders that we think are very manageable. But, overall, we don't see that being a limiting force in the development program.

Emma Walmsley -- Chief Executive Officer

Thanks. Thanks, Tim. Next question, please.


Thank you. Your next question is from the line of Emmanuel Papadakis of Barclays. Please go ahead.

Emmanuel Papadakis -- Barclays -- Analyst

Thank you. It's Emmanuel Papadakis from Barclays. Maybe one on Shingrix. Simon, you were kind enough to provide a little more clarity on, I think, a "significant" volume expansion in 2019. You'd previously alluded to some uncertainty as to the pace of step-up to that mid-high teens target. And I think you also now specified it will be high-teens. If you could perhaps give us a little bit of further clarity on what kind of volume expansion we should expect in 2019, that should be very well-received. Also, any comment on implication for margins? It looks like you're already at that mid-30s target. Any thoughts on that.

And then maybe just a quick one on Respiratory. You'd previously alluded to potential spillover, so to speak, of Advair generic pricing impact in the broader space, particularly for Breo. Could you just let us know what's embedded in your current guidance, in terms of broader pricing risk for the Ellipta franchise? Many thanks.

Emma Walmsley -- Chief Executive Officer

Yeah, so I'll come to Simon in a minute. I'll just make a few comments on guidance. There's no new update to the Shingrix margins. And, obviously, the guidance range at the moment is about the impact of an Advair generic across our ICS, which we've always flagged, and we still need to know the pricing and the supply rate there. But Simon can make some more comment on those.

And just to add on Shingrix capacity build, first, we're obviously absolutely delighted with the launch trajectory of this vaccine and see it as being a meaningful contributor to growth for, hopefully, years ahead as we pursue not only fully serving the markets we're in but also, eventually, geographic expansion. We're also very pleased to mobilize very effectively across our supply chain, both in Europe and the U.S., to increase supply through the second half of last year. And so our kind of confirming high-teens over the next two to three years. And you'll have heard Simon mention, so I shall reiterate, we're looking to continue the momentum that we were able to establish in the second half but we're not going to guide specifically for the number for '19. Obviously, we'll update you more as the year goes on.

Simon, do you want to add?

Simon Dingemans -- Chief Financial Officer

Yeah, I think on the Respiratory side, my remarks focused on Breo because the ICS/LABA category is where we see the main pressure points. And I know you've asked us a number of times on the impact on some of the other products. Clearly, there is a broader pricing dynamic that the respiratory sector is dealing with but I think the particular Advair -- knock on wood -- just will be largely restricted to ICS/LABA.

Emma Walmsley -- Chief Executive Officer

Next question, please.


Thank you. Your next question is from Graham Parry of Bank of America. Please go ahead.

Graham Parry -- Bank of America Merrill Lynch -- Analyst

Hi. Thanks for taking my questions and say well to Simon and thanks for working with you and also welcome to Ian. And then first question on guidance. So, could you just help us understand the assumptions baked into guidance for the rate of Advair generic decline? I think consensus is running at about 60% at the moment. Is that broadly in line with your internal planning guidance?

And also the timing of the Pfizer consumer deal is assumed in the guidance. I think you said second half '19. Are you assuming a full second half of that deal being in action and some dilution from it?

And then, secondly, if you could help us to understand your views on the HHS rebate/safe harbor rule proposal that came out last week, GSK's potential exposure to this, and what comments GSK would be submitting back to the administration, either individually or via pharma. Thanks.

Emma Walmsley -- Chief Executive Officer

Thanks very much. So, I'll come to Simon in a moment on the guidance questions and assumptions. I mean, broadly speaking, in terms of what was said about safe harbor, we support the administration's approach, which is about bringing more transparency to the kind of pricing value chain and continue to encourage, thereby, responsible pricing and, most importantly, passing on the discounts that manufacturers provide to patients so that out-of-pocket can be impacted. Obviously, we're digesting what's come through and we're looking to collaborate, as ever, with the administration on participating in next steps. But we're broadly supportive.

So, Simon, do you want to comment on the guidance question?

Simon Dingemans -- Chief Financial Officer

Yeah. So, clearly, at this point, there's a pretty wide range of outcomes. But if you look at the various analogs, then you would expect to see most of the decline to the endpoint we previously indicated during the course of 2019, given we're sitting at the beginning of February. And I think as we've also said before, I think unlike a sort of conventional tablet-type generic, which would normally lose about 80% in the first year, you would probably expect less than that. But it depends very heavily on what supply they've got and we don't know that yet and we don't know, really, until they start to signal. But I'll just remind you, we said back in 2015, we would expect to end 2020 with £200 million to £300 million of sales of Advair. And if you assume most of it goes in 2019, hopefully that gives you a reasonable range.

Around consumer, I think you should assume later in the second half rather than earlier in the second half and that's why we're expecting a broadly neutral impact in '19 but we gear up to the first full year being 2020 and where you'll see the impact from the synergies beginning to kick in. So, we don't know precisely yet. It's quite a complex regulatory process to go through. But it'll be toward the end of the year.

Emma Walmsley -- Chief Executive Officer

We'll update you more as we go. Thanks, Simon. Thanks, Graham. Next question, please.


Your next question comes from the line of Keyur Parekh from Goldman Sachs. Please go ahead.

Keyur Parekh -- Goldman Sachs -- Analyst

Can I have two questions, please? First, on HIV, Emma, I think you said you continue seeing this being a long-term growth driver for the company. More specifically, as you've thought about 2019 guidance, does it incorporate any HIV growth for 2019 and, if so, can you give us a flavor for what you expect that growth to be?

And then, secondly, for Hal, on the ICOS compound, your appendix slide shows that you kind of got the data for the pembro combination in-house for the combination therapy. Can you give us a flavor for what the data is? I'm surprised you haven't -- if it's positive, why it hasn't been moved to Phase 3 as yet. And when do we actually see the data from that? Thank you.

Emma Walmsley -- Chief Executive Officer

Hi, Keyur, and thanks. So, we'll come to Hal in a second. Just to reiterate, we do think that HIV is a growth driver for the company. You've seen a lot of activity from us in terms of two-drug regimens and a lot more to happen this year. That is where we expect the growth to come from, also to reiterate David's comments. And we do expect to see growth in '19. Obviously, that's going to be at a slower rate because the business is bigger and it's got a lot more competitive near-term. But we're looking forward to that 3TC, we hope, approval and building that portfolio of two-drug regimens looking forward. Hal?

Hal Barron -- Chief Scientific Officer

Yeah. Thanks, Keyur. So, as you heard me say, I think we have encouraging clinical data and we'll be presenting that at a meeting, likely in the second half of this year. We continue to enroll patients in the study at a nice clip and we'll be learning more about which indications we think are most appropriate to pursue and who to combine it with pembro and potentially other agents to optimize the impact it has on patients.

Emma Walmsley -- Chief Executive Officer

Thank you. Next question, please.


Thank you. Our next question is from James Gordon of J.P. Morgan. Please go ahead.

James Gordon -- J.P. Morgan -- Analyst

Hello. Thanks for taking the question. The question on M7824 is just where is the company or where is Hal most excited about the prospects of the product? So, is it in patients where PD-1 therapies have really worked well and this is going to work even better? So, a synergy angle. In that case, you are bullish about the head-to-head with Keytruda in PD-L1 high patients. Or is the excitement about using it in a broader population where PD-1 monotherapy is less successful and this could sensitize? And is that why the £500 million milestone, you're not yet committed to paying that because you're seeing lots of risk around actually showing you're better in high PD-L1 patients and the opportunity is really about going forward, although not necessarily being better?

Emma Walmsley -- Chief Executive Officer

Thanks, James. Hal?

Hal Barron -- Chief Scientific Officer

Yeah. Thanks, James. Well, I think that with these kinds of molecules, you have to really let the data tell you how to develop it. And the data to date suggests that the response rates in the second-line lung cancer setting were better than historically seen with pembro. And that gives us -- and particularly in the PD-L1 high. So, the design of the program is, as you say, the latter example, where we're looking to go head-to-head in the PD-L1 high, because we believe that the mechanism is that for -- because this molecule, and it's important to remember this, the molecule has the PD-L1 backbone so it can work like a PD-1 inhibitor. But at the same time, the PD-L1 -- because PD-L1 is expressed on tumor cells -- this actually enables the combined trap PD-L1 construct to be targeted to the cancer cell.

So, when the cells become resistant through TGF-β, we think that this will prevent that by inhibiting the TGF-β locally. So, we will work where the, potentially, PD-1/PD-L1 work but be more effective by both having the TGF-β there, as well as preventing the resistance. Now, of course, that's all pre-clinical and hypotheses but that's what the data to date would suggest, that we can actually work where PD-L1 inhibitors or PD-1 inhibitors work but better because of avoiding the resistance mechanism that appears to emerge.

Maybe, as we get more data, we'll find that it can expand even further beyond that and that may be what we see in some of the other indications where the activity does seem to be in places where PD-1 inhibition or PD-L1 inhibition hasn't previously been very robust. So, it's possible that both opportunities are pursued but the lung cancer opportunity is one, as I described.

Emma Walmsley -- Chief Executive Officer

Thank you. And thanks, James. Next question, please.


Thank you. Our next question is from Mark Purcell from Morgan Stanley. Please go ahead.

Mark Purcell -- Morgan Stanley -- Analyst

Thanks very much for taking my questions. On HIV, there's a lot of focus on NBRx but that's a market that's only about 7% of total prescriptions. So, I'd be interested in any comments you can give in terms of how to make that population more dynamic, expand the amount of switching that's going on in the marketplace with your dual strategy, where you could ultimately get much more significant market share gains going forward. That's the first question.

And then, secondly, on the '165 assay, GM-CSF. When you spoke last, Hal, you discussed a bit of uncertainty around the dosing of that assay and how it's optimally dosed at. It sounds like there's been some resolution or there'll be work over the next few months to resolve those questions. So, I'd be very interested to understand how you're dosing it in pivotals and the discussions you've had with regulators around dose, whether you can give us some clarity there.

And then just linking a very quick one, on the Merck relationship, on TGF-β, I'm just wondering how broad that can become going forward, giving that the ATM/ATR assets would fit very nicely with your park strategy and moving, ultimately, into earlier stages of cancer. Thanks very much.

Emma Walmsley -- Chief Executive Officer

Thanks very much, Mark. We'll let Hal pick up your two-and-three-quarter questions. But, first, over to David, with the sort of slight caveat from me that there's only so much we're going to declare on our competitive approach to driving switch. But, David?

David Redfern -- Chief Strategy Officer

Yes. Thanks, Mark. Well, as we said, and we've said this many times, we see the major part of our growth coming from two-drug regimens. And I think, in particular, hopefully starting this year, dolutegravir and lamivudine, which is absolutely an opportunity in naïve patients and that's where the GEMINI data was studied. But I think, also, in switch patients as well.

So, let me just make a few comments on that. I mean, I don't need to go through the 48-week GEMINI data. You've seen that. I think, following the presentation at IAS, we've actually had a pretty strong reaction from HGPs in the U.S. and around the world. In general, it exceeded their expectations and I think, particularly, in two areas. The fact that the efficacy was maintained and was so strong at the higher viral loads has definitely been important. And the fact that we saw no resistance at all at 48 weeks has also resonated. And so there's a pretty active debate going on with HGPs, thinking about exactly which patients they should prescribe it in.

I think there's an important point here, which is the 48-week is really just the start of the dolutegravir/lamivudine story. We run the GEMINI studies on through two years and then three years and we've seen, from the Juluca update, the two-year data is important. So, that data in the middle of the year, I think, will be important. And we are also investing now very heavily in switch studies, as demonstrated on the slide, the TANGO study and the SALSA study, and in a whole range of further studies around overall patient quality of life and a whole lot of technicalities around DNA archiving and getting really to the bottom of resistance. So, there's a lot going on there and while this is a conservative market and it will take time to build this story, we are ever more confident in the potential of two-drug regimes, in particular, dolutegravir/lamivudine.

Emma Walmsley -- Chief Executive Officer

Thanks, David. Hal?

Hal Barron -- Chief Scientific Officer

Thank you, Mark, for two thoughtful questions. First, we're not going to really disclose discussions we have with regulators but, in the spirit of transparency, I wanted to show you what the design will likely evolve to and that we've made the commitment to move to Phase 3. As you rightly point out, we highlighted one or two aspects of the Phase 2 program that we thought could be optimized. The first was to make sure that our primary endpoint in the study is ACR 20 and that that's done in the setting of compared to placebo. So, that's the new design. It's kind of harder to see. It's a little smaller on the slide but that's the primary endpoint.

We also have, on the left side, that the 180mg every other week dose that was used in the Phase 2 study appeared between Weeks 12-24 to be suboptimal. And what we were hoping to do is design a study that would use something close to that but on a weekly basis rather than an every other week basis. And as you can see in the design now, we have 150mg weekly being given beyond the 12 weeks. So, that actually will give us an increased exposure and a higher dose in that period of time when we, in the previous study, in Phase 2, kind of saw a flattening off, and maybe even a diminution, of the treatment effect over that time period. So, that's the increased exposure that we were alluding to hoping to get and, in fact, have designed into it. So, that, I think, hopefully answers your question about why we're optimistic about both the design and the dose there.

We've had limited, virtually no, discussions with Merck regarding their DDR programs, the ATM and ATR, as you mentioned. But let's just say we find the opportunity to look at medicines that could be synergistic with PARPs in a very interesting way and there are many that are emerging and just stay tuned to see how we're going to be approaching that for the future.

Emma Walmsley -- Chief Executive Officer

Thanks, Hal. Next question, please.


Thank you. Our next question is from Kerry Holford of Exane BNP Paribas. Please go ahead.

Kerry Holford -- Exane BNP Paribas -- Analyst

Hi. Yes, two questions from me, please. Firstly, on COGS, you talked about the increased price pressure in Respiratory and now also established vaccines. Is the latter there, is that a new issue from the end of this year? And can you talk more about these highlights. Just trying to understand whether that weaker gross margin in Q4 is something that we should expect to continue into 2019 and beyond.

And then, secondly, on M&A and in licensing, clearly, we've seen a flurry of recent deals so I just want to understand your flexibility and your appetite to do more from here. And in the context of some cash constraints here, what is your appetite to do more potential divestments of non-core Pharma assets. Within your Pharma business, we've seen you quite active in Consumer. I wonder if there's more you could do now on the Pharma side.

Emma Walmsley -- Chief Executive Officer

Thanks, Kerry. So, I'll take the second question and then I'll ask Simon to comment on the gross margin and COGS dynamics. So, first of all, as you've noticed, we were reasonably busy through the last quarter, in terms of our business development. And our No. 1 focus is to make sure we deliver the value from those deals beyond the Consumer side or, indeed, the Pharma side.

That said, I was extremely clear in July 2017 that our No. 1 priority is the strengthening of the pipeline. I'm pleased with the progress but BD will continue to be a key part of that. And I think the Merck alliance that we announced yesterday is exactly the kind of thing that we want to continue to do, whether it be on assets or technology platforms, and there will be cases of us looking for creative business development. There will probably also be examples of us looking to out-license things in the portfolio as well, a bit to your secondary comment, which is will we continue to review the portfolio and making sure we're allocating our capital as intelligently as we possibly can. And, yes, we will. But our No. 1 priority is to up the value from the various deals that we've done. So, with that, Simon?

Simon Dingemans -- Chief Financial Officer

Yeah. Kerry, on COGS, I think as we've talked about for some time, we are seeing some pressure at the gross margin, given the pricing environment, particularly in the Pharma business, and we're now seeing some more of that in the established and older part of the vaccines portfolio, which have a higher degree of exposure to some of the tender business and GABI type contracts. And that one's a bit more visible in the back half of last year. But I think those trends will continue. It's one of the reasons why we're putting a lot of focus and effort into restructuring the supply chain to deliver some efficiencies to offset those pressures.

I think Q4, specifically, you shouldn't read straight into 2019 because it had a number of specifics in there, particularly, the Relenza tender and some one-off sales of products that we've already sold, so we're contract manufacturing for third parties, which is a pretty low margin business but we delivered quite a heavy load of around that total of £80 million that I referred to. So, it was a particular factor in why there was such a sharp step-up in Q4.

Emma Walmsley -- Chief Executive Officer

Thanks, Simon. So, I think we have one last question. I really hope it's the last question for Simon. So, with that, please, over to the last question.


Thank you. That question comes from Steve McGarry of HSBC. Please go ahead.

Stephen McGarry -- HSBC -- Analyst

Hi, thanks for taking the question. Unfortunately, Simon, it's not a financial one.

Simon Dingemans -- Chief Financial Officer

You're not upsetting me at all.

Stephen McGarry -- HSBC -- Analyst

Just on M7824 and head-to-heads in non-small cell lung cancer versus Keytruda, what would encourage you to develop that drug more broadly? Does it have to be better than Keytruda or is not inferior or equivalent enough? And then following on from that, if you look elsewhere in the industry, you've got Keytruda in trials and 900 studies, Opdivo with 900 studies, and they consume the majority of R&D at those companies. Although it would be a great problem to have if M7824 was superior to Keytruda, how big could the clinical program and the R&D spend become at that point in time? Thanks.

Emma Walmsley -- Chief Executive Officer

Thanks very much, Steve. So, I'll hand that on to Hal. I think the main point to underline is your "good problem to have" point. One of the things that Hal has brought in with tremendous discipline -- he referred to it when he talked about new governance -- is really looking at the efficiency frontier across our R&D spend and the assets that we want to bet on and where we can get the biggest kind of returns. And so we are particularly disciplined about that. But you'll also remember that Simon said in his outlook for '19 that we do expect a meaningful uptick in our R&D spend. Whether that be the continuing bet on our internal assets that we've accelerated, like BCMA, or, indeed, backing the Tesaro teams and assets too. But the key is to make sure we are also dropping off and cancelling things that we don't think come high enough up that efficiency curve. So, Hal laid out his "what's in, what's out, what's accelerating, what's adding" chart today and that's something that we will, each six months, make sure we update you on to see what the progress is. So, Hal, do you want to come back on the M7824 question?

Hal Barron -- Chief Scientific Officer

Yeah. Thanks, Steve. I think I'll turn it over to Simon.

Simon Dingemans -- Chief Financial Officer

It would be a short answer.

Hal Barron -- Chief Scientific Officer

Okay. So, let me try to tackle the first one and then sort of reflect on the second one. I think the study is designed as a superiority trial, just to be clear, in Phase 2. Maybe your point is if we don't achieve superiority, would there be an opportunity to move forward with something that had similar effects. I'd say two things. First, one thing you have to be careful about in these Phase 2 studies is they're usually powered and the primary endpoints are usually on response rate, which doesn't always track to PFS and OS and we've seen that with IO agents in the past for a number of reasons. So, I think that one has to both consider the effect on response rates but also look at the data as it relates to PFS and OS, although it will be very underpowered.

But I want to point out that the philosophy, the sort of vision for our immuno-oncology group, is to really develop transformational medicine. So, I think that our focus is going to be on having benefit beyond Keytruda. It's a wonderful drug. It's done transformative things for patients and we think we can do better and this is one of what we believe are many smart bets we are taking to see if we can have superior therapies for patients with lung cancers and others.

How big is big and how big to go? It really is all dependent on the data. And I really think that we have a number of programs where you could ask the same questions. Should the data read out in a very profoundly positive way, they could result in lots of opportunities for us to do development in patients to benefit. But these are, as was mentioned, high-risk, high-reward. And that's why we're doing a number of these. We think it's a smart bet and I really hope this is the problem we have to face. So, more as we can unravel data soon.

Emma Walmsley -- Chief Executive Officer

Thanks very much, Hal. So, with that, I will reiterate my last public thanks to Simon. Thank you all for joining and we look forward to updating you through the year, a year that we hope will build on the good momentum of '18, be very focused on delivering operational performance, and planning for the delivery of value against our various deals, and, particularly, a highly effective integration under Brian's leadership at the Pfizer joint venture, and, most of all, updating you on our progress on R&D. Thank you very much.


This presentation has now ended.

Duration: 75 minutes

Call participants:

Sarah Elton-Farr -- Head of Investor Relations

Emma Walmsley -- Chief Executive Officer

Simon Dingemans -- Chief Financial Officer

Hal Barron -- Chief Scientific Officer

David Redfern -- Chief Strategy Officer

Richard Park -- Deutsche Bank -- Analyst

Tim Anderson -- Wolfe Research -- Analyst

Emmanuel Papadakis -- Barclays -- Analyst

Graham Parry -- Bank of America Merrill Lynch -- Analyst

Keyur Parekh -- Goldman Sachs -- Analyst

James Gordon -- J.P. Morgan -- Analyst

Mark Purcell -- Morgan Stanley -- Analyst

Kerry Holford -- Exane BNP Paribas -- Analyst

Stephen McGarry -- HSBC -- Analyst

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