Biogen Inc (BIIB) 2015 Q2 法說會逐字稿

Good morning.

My name is Chris, and I'll be your conference operator today.

At this time, I would like to welcome everyone to the Biogen second-quarter 2015 earnings conference call.

(Operator Instructions)

Thank you.

Carlo Tanzi, Director of Investor Relations, you may begin your conference.

Thank you, and welcome to Biogen's second-quarter 2015 earnings conference call.

Before we begin, I encourage everyone to go through the investor section of Biogen.com to find the press release and related financial tables, including a reconciliation of the GAAP to non-GAAP financial measures that we'll discuss today.

Our GAAP financials are provided in tables 1 and 2.

Table 3 includes a reconciliation of our GAAP to non-GAAP financial results.

We believe non-GAAP financial results better represent the ongoing economics of our business, and reflect how we manage the business internally.

We've also posted slides on our website that follow the discussions related to this call.

I would like to point out that we will be making forward-looking statements, which are based on our current expectations and beliefs.

These statements are subject to certain risks and uncertainties, and our actual results may differ materially.

I encourage you to consult our SEC filings for additional detail.

On today's call I'm joined by our Chief Executive Officer, Dr. George Scangos; Dr. Doug Williams, EVP of Research and Development; Tony Kingsley, EVP of Global Commercial Operations; and our CFO, Paul Clancy.

We'll also be joined for the Q&A portion of the call by our Chief Medical Officer, Dr. Al Sandrock.

Now, I'll turn call over to George.

Thank you Carlo, and good morning everyone, and thanks for joining us today.

There are two set of data on which most of you have been focused, so let me lead with those issues.

First is the commercial trajectory.

So versus prior year, we achieved 7% revenue growth and 21% non-GAAP EPS growth.

Good numbers, but certainly lower than we had anticipated a few months ago.

We had expected to see a reacceleration of Tecfidera this quarter, but that did not happen to any appreciable extent.

Rather, Tecfidera experienced modest sequential patient growth, as we continued to work through the same commercial challenges experienced in the first quarter of the year.

We continue to believe that Tecfidera remains the preferred oral option in the MS market, based on its strong efficacy and favorable safety profile, and we're working hard across the organization to improve Tecfidera's trajectory.

With that said, our multiple sclerosis portfolio continues to add patients globally.

Tecfidera is the most-prescribed oral MS therapy globally, and has now been used to treat over 155,000 patients.

We believe that Plegridy is on its way to becoming the interferon of choice, as we continue to make it available in new markets around the world.

And Tysabri, which we believe is viewed as the preferred high-efficacy therapy, continued to add patients this quarter.

The second development was the recent announcement of a new data from aducanumab Phase I-b study at AAIC.

By now, you've all seen the data, which we take to be positive, in-line with, and supportive of the data that we reported earlier.

Doug will provide some additional details on this analysis later in the call.

We've initiated sites for two pivotal Phase III trials for aducanumab in early Alzheimer's disease, and are screening patients for enrollment.

With millions of people worldwide living with Alzheimer's disease and no disease-modifying treatment options, we believe that this important investment has the potential to be a significant future growth driver for Biogen.

Moving on to other areas, through our joint venture with Samsung Bioepis, we announced positive results across our anti-TNF biosimilar portfolio at the EULAR conference in June.

With these results, we believe that we're well-positioned to bring these widely used anti-TNF therapies to physicians, payers, and ultimately the patients who need them most next year.

Just this month, we announced our intent to build a new next-generation manufacturing facility in Solothurn, Switzerland, to support our emerging pipeline, a significant step towards ensuring a long term global supply of new world-class therapies for patients.

We expect to break ground on the facility early next year and start manufacturing activities in 2019.

So we had a busy second quarter with an important second half of the year ahead of us, in which we will focus on improving the trajectory of Tecfidera and ensuring that we execute important clinical trials to move our pipeline forward as quickly as possible.

Now, I'd like to turn the call over to Doug, who will update you all on our progress in R&D.

Thanks, George.

Earlier this week at the Alzheimer's Association International Conference, we presented additional interim results from the aducanumab Phase I-b study in subjects with prodromal and mild Alzheimer's disease.

To remind you, we previously presented results for the 1, 3, and 10 milligram per kilogram patient cohorts at six months and one year, and for the 6 milligram per kilogram cohort at six months.

The new results now include one-year data for 30 subjects treated with 6 milligrams per kilogram of aducanumab, and for an additional 10 subjects randomized to placebo.

The 6 milligram per kilogram one-year results demonstrated a statistically significant reduction on brain beta amyloid levels versus placebo, as assessed by PET imaging.

The results at six months and one year show very strong dose and time dependent reduction of brain beta amyloid, and extend our previously reported observations.

We observed a numeric improvement on the MMSE and CDR Sum of Box clinical measures compared to placebo, though the results did not achieve statistical significance.

The 6 milligram per kilogram dose at one year was intermediate, in effect to that seen with the 3 and 10 milligram per kilogram doses on the CDR score, which will be the primary end point for the Phase III program.

The safety results were consistent with previously-reported results.

Overall analysis of the 1, 3, 6, and 10 milligram per kilogram clinical results at one year demonstrated a statistically significant dose-dependent impact on MMSE and CDR sum of boxes compared to placebo.

Additional analyses demonstrated strong positive correlations between reduction in beta amyloid levels in both CDR and MMSE scores.

We believe that the totality of the aducanumab Phase I-b study results strongly support development and registrational studies.

Based on feedback from regulatory agencies, we've recently finalized the aducanumab Phase III study design.

The Phase III program includes two identically-designed placebo-controlled studies, referred to as ENGAGE and EMERGE.

Each study is expected to include 1,350 subjects with early Alzheimer's disease.

Study subjects will be screened by PET amyloid imaging to confirm elevated beta amyloid plaque levels in the brain.

The primary endpoint will be CDR sum of boxes, a clinical measure including both cognitive and functional components, measured at 18 months.

In each Phase III study, ApoE4 non-carriers will be randomized to receive 6 milligrams per kilogram, 10 milligrams per kilogram, or placebo, while ApoE4 carriers will receive 3 milligrams per kilogram, 6 milligrams per kilogram, or placebo.

Study dosing will include an up-titration period, in an effort to reduce ARIA and maximize aducanumab's benefit-risk profile.

The Phase III program will be conducted globally, and is planned to include more than 300 sites.

Good progress has been made in operationalizing the studies, and initial investigational clinical sites for ENGAGE and EMERGE are now active and screening patients.

Moving on to our other programs, I'm pleased to mention that the European Medicines Agency has accepted the marketing application of Alprolix for the treatment of hemophilia B, signifying the initiation of the review process.

Last week, our partner, Sobi, exercised its opt-in right for Alprolix to assume final development and commercialization in certain territories, including Europe.

Our collaborator, Isis Pharmaceuticals, recently presented additional results from the ongoing Phase II studies evaluating SMNRx in infants and children with spinal muscular atrophy.

We believe the available data are increasingly supportive of SMNRx having a therapeutic effect.

Two Phase III studies for SMNRx are active, with enrollment currently ongoing.

We recently obtained Phase II study results for Neublastin in moderate to severe sciatica.

The clinical results observed did not achieve our target product profile, and while we've made the decision to terminate this program, developing new therapies for pain remain an area of focus for Biogen.

We've made good progress advancing development plans of our Nav 1.7 inhibitor acquired from Convergence, and we expect to begin enrolling patients into a Phase III study in trigeminal neuralgia next year.

We've also obtained Phase II study results for Tysabri in acute ischemic stroke.

Study results did not demonstrate an impact on the change in infarct volume, the primary endpoint of the study.

However, secondary and exploratory endpoints, including the modified Rankin scale evaluating stroke recoveries suggest that Tysabri may have had a beneficial impact on the functional deficits experienced by stroke patients.

We believe that the benefit observed, if confirmed, would be clinically meaningful.

We're evaluating additional study designs to pursue development of Tysabri in stroke.

Earlier this month, we announced a collaboration with AGTC to develop gene therapies in ophthalmology.

The collaboration is focused on adeno-associated virus-based gene therapy, with the goal of developing one-time transformative treatments for XLRS and XLRP.

Expansion of our pipeline into these orphan ophthalmic indications represents a natural extension of Biogen's focus in neurology.

Furthermore, through this collaboration, we have further bolstered Biogen's capability to utilize gene therapy as a therapeutic approach.

Before I turn the call over to Tony, I want to say that as many of you know, this will be my last earnings call for Biogen.

I'll be leaving the Company at the end of next week to take on the role of CEO of a new start-up Company.

During the last 4.5 years at Biogen, I've had the opportunity to work with many extraordinary people, and the Company has been transformed in many ways.

We have strengthened the pipeline and put a strong emphasis on discovery science excellence, which will pay off over the coming years.

The R&D team is in very capable hands with Al and Spyros.

And the Company is performing extraordinary science in the labs, and in the clinic under their guidance.

I'd like to thank George and my colleagues at Biogen for giving me such a great opportunity, and I look forward to many more successes for the Company.

With that, I'll turn the call over to Tony.

Thanks, Doug.

Our basic strategy in MS remains the same, to position Tecfidera as the standard of care in the marketplace, to establish Plegridy as the interferon of choice, and to leverage Tysabri as the leading high-efficacy agent.

In light of continued headwinds affecting Tecfidera, we saw moderated patient growth for our MS portfolio as a whole this quarter.

Our 2015 business plan for Tecfidera made two important assumptions: First, that Tecfidera would continue to stimulate higher than historical market growth and switch rates, as it drives the market from injectables to orals.

And second, that Tecfidera, with what we believe is a strong all-in profile, would continue to capture a high rate of both new starts and switches.

Through the second quarter, both of these were weaker than planned, particularly in the more mature and larger markets in the US and Germany.

In the US, total market growth and switch rates remained lower than our original expectations, and appear to have returned to historical averages typically seen in the market before the launch of Tecfidera.

We believe the safety event reported in late 2014 has created greater caution on the part of both physicians and patients about switching to orals.

Our US market research indicates a moderation in physician intent to prescribe, though in Q2, Tecfidera continued to gain patients in the US.

We believe our promotional and educational efforts are strong and well-resourced.

In the US, we remained focused on emphasizing Tecfidera's strong efficacy profile, while ensuring physicians and patients are educated on proper monitoring requirements for lymphopenia, and we believe we are making progress.

We have recently increased our share of voice across print and digital media to increase patient awareness, and I've also ramped up Tecfidera sales calls by our field teams.

In more mature markets in Europe such as Germany, Tecfidera has faced similar dynamics as in the US.

On a patient basis, this has been offset by robust uptake in newly-launched markets such as the UK, Italy and Spain, where the launch curves to date have mimicked prior experience and very rapid uptake.

For example, in the UK, where full reimbursement funding really came into place around the turn of the year, we believe the uptake curve through June has actually exceeded what we saw in the US and Germany.

While patient growth for Europe as a whole was robust, total European Tecfidera revenue was dampened, both by the change of price and softer demand in Germany.

In Europe, our promotional strategy is similar to what I described in the US, maintaining high reach and frequency, and emphasizing the strong value proposition of the product.

However, in Europe, we have been more limited in our ability to educate physicians about any new monitoring requirements, as we are still waiting for an updated European label.

We continue to believe in Tecfidera's competitive profile, and believe the product can drive future patient growth, although at a more moderated rate.

Establishing Tecfidera as the standard of care in MS remains a primary focus, and we will be tireless in those efforts.

We believe that Avonex and Plegridy will continue to play an important role, and that we are gaining share among interferons.

Plegridy has seen steady early uptake, and has continued to source patients broadly.

Tysabri continues to set itself apart in a market with an increasing number of alternatives.

Tysabri demonstrated positive patient growth again this quarter, and we believe this strong performance is a testament to the high level of efficacy that Tysabri provides to patients.

Finally, in MS, we are gearing up for the potential launch of Zinbryta with our collaboration partner, AbbVie.

If approved, we believe Zinbryta could be an important new therapeutic option for relapsing MS patients.

Turning to our hemophilia business.

Alprolix and Eloctate continued to grow market share this quarter in the US.

We continue to broaden both breadth and depth of prescribing amongst physicians, and educate the community about the importance of maintaining protection from bleeding with less frequent infusions.

Recent market research suggests that the product awareness continues to increase, and the convenience of our products' dosing schedules is well-appreciated by patients.

Outside of the US, we have also seen strong initial uptake of Alprolix and Eloctate in Japan, which we believe is an attractive long-term growth opportunity.

I'll now pass the call to Paul.

Thanks, Tony.

Our GAAP diluted earnings per share were $3.93 in the second quarter.

Our non-GAAP diluted earnings per share were $4.22.

Total revenue for Q2 grew 7% year-over-year to approximately $2.6 billion.

Foreign exchange, offset by hedging, weakened total revenue by approximately $79 million year-over-year.

Global second-quarter Tecfidera revenue was $883 million, an increase of 26% versus second quarter of last year, and an increase of 7% versus the prior quarter.

This quarter's Tecfidera revenues consisted of $721 million in the United States, and $163 million outside the US.

US gross to net adjustments were lower this quarter than Q1 by approximately 400 basis points.

We estimate we ended the quarter with approximately 2.5 weeks of inventory in the US wholesale channel for Tecfidera, a similar level to last quarter.

In Germany, Tecfidera sales are being recorded at EUR12,800, as the free pricing period ended in mid-February.

Largely driven by this, ex-US Tecfidera sales decreased 8% versus prior quarter, despite unit growth of 14%.

Foreign exchange impact, offset by hedging, weakened Tecfidera revenue by approximately $10 million year-over-year.

Interferon revenues including both Avonex and Plegridy were $690 million during the second quarter, including $455 million in the US and $235 million in sales outside the US.

Compared to the first quarter of 2015, US interferon revenues decreased 12%.

We estimate that approximately $50 million of the decrease is due to an inventory draw down in the US wholesale channel.

We believe this was the result of rebalancing of inventories, subsequent to the launch of Plegridy.

Foreign exchange impact, offset by hedging, weakened Q2 interferon revenue by approximately $27 million year-over-year.

Tysabri worldwide revenue was $463 million in Q2.

These results were comprised of $269 million in the US and $195 million internationally.

As a reminder, Tysabri sales outside the US in the second quarter of 2014 included $54 million of previously-deferred revenue related to our EFA agreement.

Foreign exchange impact, offset by hedging, weakened Tysabri revenue by approximately $35 million year-over-year.

Moving to hemophilia, Alprolix revenue in Q2 was $54 million and Eloctate revenue was $74 million.

Our US profit share for Rituxan and Gazyva, as well as our profit-sharing royalties on sales of rituximab outside the US, were $338 million.

Turning to the expense lines on the non-GAAP P&L.

Q2 cost of goods sold were $286 million, or 11% of revenue.

Q2 R&D expense was $491 million, or 19% of revenue.

In Q2, SG&A expense was $492 million or 19% of revenue.

Our non-GAAP tax rate was approximately 24% for Q2, which benefited by approximately 50 basis points, related to a discrete item.

We ended the quarter with approximately $4.5 billion in cash and marketable securities, split approximately 50%/50% between the US and ex-US.

Our weighted average diluted shares at the end of the quarter were 236 million.

This brings us to our non-GAAP diluted earnings per share, which were $4.22 for the second quarter.

Let me turn to our updated full year 2015 guidance.

We now expect revenue growth between 6% and 8%.

This substantial decrease from our prior guidance is primarily driven by a change in our estimate for Tecfidera's trajectory.

Our balance of year forecast assumes limited patient growth for Tecfidera in the United States.

Additionally in Europe, overall reimbursement is below our original plan.

Our revenue estimates for the rest of our MS portfolio remained largely unchanged.

Moving to operating expenses, as a percentage of sales, OpEx is unchanged, as we've worked to contain costs for the balance of the year.

R&D expense is expected to be between 19% and 20% of revenue, unchanged from prior guidance.

Assuming deal closure, we'll book an approximately $40 million expense to R&D in the third quarter related to our collaboration with AGTC.

SG&A expense is expected to be approximately 20% to 21% of revenue, unchanged from prior guidance.

I'd like to point out that we'll owe Neurimmune a $60 million milestone payment upon dosing of the first patient in the Phase III trials for aducanumab.

This payment will be an expense, and presented within the non-controlling interest line in the P&L.

We anticipate non-GAAP earnings per share results between $15.50 and $15.95 and GAAP EPS to be between $14.25 and $14.70.

From a cash perspective, we now expect to pay approximately $850 million in CVR payments in 2015, related to the sales of Tecfidera, a reduction from prior guidance.

We anticipate capital expenditures of approximately $650 million to $700 million, an increase over 2014, as we continue to expand our manufacturing footprint.

Included in this forecast is the recently-announced agreement related to Eisai's Research Triangle Park campus.

Overall, we're very disappointed in the change of outlook for the year.

Nevertheless, we remain committed to working tirelessly to turn around the commercial performance, and we'll aggressively look for opportunities to reduce expenses while simultaneously ensuring we invest in the pipeline.

I'll turn the call over to George.

Okay, thanks, Paul.

Look, we obviously have a lot of work ahead of us as we strive to maximize the success of our commercial business, and execute on our operational goals.

Over the long term, we expect that the primary source of value creation will be from the introduction of new therapies so in closing, I'd like to highlight several pipeline programs that may be future value drivers for the Company.

Zinbryta is currently under regulatory review as a potential new therapeutic option for relapsing MS patients.

If approved, we believe that Zinbryta could be an interesting addition to our MS portfolio, and provide Biogen with an additional treatment option for patients.

Later this year, we anticipate Phase III results for Tysabri in secondary progressive MS, a form of the disease impacting approximately 30% of MS patients, and for which there are no proven effective therapies today.

We also recently obtained Phase II results suggesting that Tysabri may improve clinical outcomes in stroke patients.

And we're rapidly moving forward to better understand Tysabri's potential as a post-stroke therapy, with hopes to offer new potential therapeutic option for the millions of patients experiencing this debilitating condition.

The Phase III SMNRx program developed with our partners at Isis Pharmaceuticals represents another important opportunity for Biogen.

SMNRx is being developed with the goal of improving and extending the lives of patients with spinal muscular atrophy.

The available clinical results increasingly suggest that SMNRx may indeed be having this effect.

We look forward to obtaining Phase III data late next year or in early 2017.

We're eagerly awaiting the anti-LINGO Phase II MS results next year, and expect to provide an update on the AON data at ECTRIMS in the fall.

While available MS therapies slow the course of the disease, anti-LINGO has the potential to work in a fundamentally different way by acting as a restorative therapy.

And of course, Alzheimer's disease is an area of intense focus for Biogen, with several active clinical programs.

In addition to aducanumab, our lead program, we're working with our partner, Eisai, to develop BAN2401 and E2609, potential disease modifying therapies in Phase II.

BAN2401 is an anti-beta amyloid antibody, while E2609 is an oral base inhibitor that seeks the block of production of amyloid plaque.

Clinical results are expected for both product candidates next year, and we look forward to providing updates on the progress of our R&D efforts as we continue to advance the pipeline.

Before I end the call, I want to take a moment to acknowledge Doug Williams' contributions to Biogen.

Doug joined Biogen over four years ago, and since then has been a great friend and colleague, and has done an amazing job helping to invigorate Biogen's R&D.

I think that the progress that we've made should be obvious to everyone.

So as Doug prepares to leave the Company, I'm sad to see him go, but I'm happy for him that he has the opportunity to move to a new role that truly excites him.

I want to publicly thank Doug for all that he has done, and wish him all the best in his next endeavor.

Fortunately for us, Doug has helped build a deep team, including physicians and scientists who continue to advance Biogen's R&D efforts.

Leadership for the research and development organization will be assumed by Al Sandrock, our Chief Medical Officer; and Spyros Artavanis, our Chief Scientific Officer.

Both Spyros and Al are extremely talented and accomplished, and I'm confident in the continued success of our R&D organization.

Finally, as always, I want to thank the many Biogen employees who have contributed to our success.

Through good and challenging times, I'm always gratified to see the consistent dedication to patients and shareholders exhibited by our employees.

And I'm confident that we will all continue to work hard to accomplish our ambitious goals.

So with that, we'll end the call, and open it up for questions.

(Operator Instructions)

Your first question is from Geoffrey Porges with Sanford Bernstein.

Thanks very much, and I'm sure there will be lots of questions on the Tecfidera and rest of the MS portfolio outlook.

Paul, I wanted to ask you a question first about margins, and on a related basis, about capital allocation.

As you've had a chance now to look at this revised guidance and the outlook for the core business, and then the various clinical trials that you're planning, what confidence do you have that 48% to 49% operating margin that you have today can be maintained over the next two to three years?

And related to that, you have a very strong balance sheet.

You mentioned the $4.5 billion in cash and marketable securities, next to no debt.

Some of your competitors have used their balance sheet quite effectively, and we're wondering, are you contemplating that, would you take on leverage, if so how much, and what are your capital allocation priorities now?

Thanks.

Okay, thanks, Geoff.

Thanks for the question.

Pretty expansive, so let me try to tackle it.

On the margin front, certainly, I'd point to what the guidance now assumes.

I think from a multi-year perspective, we certainly would continue to still want to drive towards margin improvement.

The dynamics of our margin improvements, obviously over the next couple of years, are going to be a little bit different.

As the revenue growth has attenuated, we're going to have to work harder to control costs, and I think that we came into this year starting to do that with our SG&A.

We are certainly doing that with the balance of year forecast, maintaining the OpEx targets as a percentage of sales, that effectively assumes not an insignificant pullback in our spending.

We're coming off a period that we purposely, and as I've articulated, that we did not want to be penny wise and pound foolish.

We had an unprecedented number of product launches for a Company our size.

I think that was the appropriate, and I think we now need to pivot towards making sure any and all waste gets out of the organization.

That will be a very fine delicate balance, because we want to continue to invest in the pipeline, and we will absolutely make that an incredible priority.

So we'll navigate through that.

It will be a little bit of challenge, but there's no doubt that we're up to it.

With respect to capital allocation, the balance sheet and leverage, George and I will tag team this one, now.

Certainly, we have a pristine leverage profile, and a pristine capital structure.

I don't, as I said before, don't think that should be measured on a quarter in or quarter out basis, but I think this Company can, and we would love to have a capital structure that has more debt on it, but that will be driven by the opportunity to be able to do that, as opposed to falsely trying to do that.

As people noted, we have authorization from the Board for a $5 billion share repurchase program.

We have cautiously communicated that would be done within five years' time.

If the stock is under pressure, as it was in pre-market today, I suspect that we will look for opportunities to lower the share base, and capital allocation is much broader than that.

Obviously, we continue to look for M&A opportunities.

They've got to be the right thing.

They got to be the right value, and I'll let George kind of pick up on that as well.

Thanks, Paul, thanks, Geoff.

The question is, are we willing to use our balance sheet and our debt capacity for M&A, for acquisitions, for projects, products, compound acquisitions.

The answer is certainly yes, and we are constantly looking, and we will be aggressive when we find opportunities that we think are attractive and consistent with our strategy.

The next question is from Michael Yee with RBC Capital Markets.

I guess a question for Al or Doug, staying with Alzheimer's, which is maybe you could give more specific comments about your interpretation of the recent data, specifically the 6 milligrams, and how we should interpret the clinical meaningfulness of this.

I think people are looking at MMSE and then CDR and not confident on that clinical meaningfulness.

So maybe you can give more perspective on that data, and why you're confident, now that you've disclosed also the doses?

Thanks.

Michael, this is Doug.

I'll start, and Paul will jump in as well.

And look, I'll simply say that when Al and I looked at the data from 6 milligram cohort, I think we were both very happy to see that it lined up very nicely with our expectations for what we thought should have happened.

I think the fact that, for CDR, it slotted right in between the 3 and 10 milligrams per kilogram dose cohorts was, you couldn't ask for a better outcome frankly, in terms of how that data shook out.

That is, as I mentioned in the call earlier, that's the primary end point for the Phase 3 studies, so I think we're increasingly confident that the data is continuing to be very, very consistent across multiple parameters.

We believe that this data is increasingly strong, and we're very confident setting up and starting the Phase 3 study based on the results we've seen.

I will go back in history and say that the last time that I personally was associated with a study at this stage where the results were this consistent across multiple parameters was back in my Enbrel days.

So again, I believe that we have a really firm basis on which to go forward into Phase 3. The MMSE data, a little bit of wobble in that.

That's the only data point that I can think of across the entire spectrum that didn't just line up almost perfectly, so we're strong believers in this product, and feel very confident moving it forward.

I completely agree with Doug, and I have nothing to add.

The next question is from Mark Schoenebaum with Evercore ISI.

I apologize, I have the flu, if I sound a little down.

First, I'd just like to just say congratulations to Al, as you know, Wall Street loves him, as do I.

We do too.

In a friendly non-romantic type of way.

So I just wondered, just a couple points, Paul, I just want to be really clear.

You're basically telling us that from a volume perspective, Tecfidera is basically going to stay flat this year?

I just want to make sure -- that seems like a core -- there's all these numbers.

I want to make sure that is the message here, in the US, in the US.

And then I wanted to ask you, I wanted to push you a little bit on M&A.

Now, the unexpected slowing of the core business, and a very interesting pipeline, but several years before it's going to contribute to the P&L.

It would seem just obvious that plugging in some new products here like Celgene perhaps has been doing, could make a lot of sense.

You really haven't been very active in the M&A front.

I think the last thing you did was the Elan transaction, which is just sort of buying something you really knew.

So can you talk about that?

And I think the Street would love to see you get more aggressive.

Stocks go up every time acquirers buy a Company.

And I'll leave it at that, and get back in the queue.

Thanks a lot.

Yes, Mark, I'll take the first part is, your interpretation is exactly accurate.

I mean, there's some very modest patient growth, but essentially what we're assuming, and I know there will be kind of assessment of whether or not we're being conservative or not, but essentially what we're assuming is extremely limited patient growth on a sequential basis for the balance of the year in the United States.

Our aspirations are obviously, commercially, we're aspiring for much more than that, but that is the assumption that we have in the balance of your forecast.

Mark, on M&A, I think I want you to see your observation certainly is right.

Every time there's some M&A event, stocks go up.

We are certainly not engaging in M&A for any short-term stock performance, but we certainly are -- I would say increasingly aggressive about wanting to add additional compounds to our portfolio and to our pipeline, and we will be aggressive when we see good opportunities that are consistent with our strategy, so I think you can count on that.

The next question is from Ying Huang with Bank of America.

Thanks for taking the questions.

I want to probe you further on Tecfidera.

So we now have a second confirmed based PML, even though it's off label, and then we will see Ocrelizumab data in RMS in Phase 3. So if you take a longer term look at Tecfidera, what do you think those could affect the growth trajectory for Tecfidera?

And also second question I have on the SPMS trial.

I know you have a special product agreement with the FDA on the Phase 3 trial for Tysabri in SPMS.

Can you elaborate a little more?

What do you need to see in order to be able to file for approval here?

Thank you.

Thanks, Ying, it's Tony.

So on the second PML case, let me talk about that and then talk about Ocrelizumab.

I guess that it's still early days, but its certainly been several weeks and the information is out in the market, so we think the market has had some chance to absorb it.

Look, the first PML case was a pretty significant change statement for the profile of Tecfidera, given its very pristine safety profile at the time.

Our sense is that the second one is a much less significant change statement.

The case is within the expected profile, still exceptionally rare.

So in discussions that we had with physicians, with thought leaders, they seem to be -- the appearance is that they are processing that much more straightforwardly.

We've also monitored media pick up, social media pick up, other things like that, and to date have seen very significantly less reaction on that front.

So this feels like a significantly different and more muted reaction to date than the first case.

Ocrelizumab, look, I think, consistent with what we've said before, have seen increasing excitement in the market about Ocrelizumab, particularly among specialists.

We don't know the full data.

Looks like a product that will play in the high efficacy space.

It's likely to appeal to the kind of specialist, particularly, the Tysabri user, the Rituxan user.

That, we think, is more of an issue frankly, for Tysabri, as it competes in the high efficacy space and probably in a narrower customer, more specialized customer base over time.

So we think of that as probably less relevant to Tecfidera.

Look, in terms of Tecfidera's long term profile, which is where you'd asked that, I'll say this.

To date, we look at our market research, the indicators and the leading indicators of brand health, we believe continue to be pretty favorable.

Our market research says the benefit-risk profile has changed, but we believe it's still overall very positive.

It's the most requested product by patients, based on our research.

Physicians state that they intend to use more, again all from market research, and they see it as appropriate for a broad set of patient types.

So in the current environment, that's essentially why we're doubling down in what's been a slow market.

The market has been more cautious, and we think a lot of it is on the margin more cautious, but for a big brand like Tecfidera on the margin matters.

So region frequency, patient outreach and emphasizing the benefits of the product continue to be where we will put our efforts.

Ying, this is Al Sandrock.

I'm still blushing from Mark's comments, but I'll try to answer the question on SPMS.

As you point out, it was kind of important to get approval prior to starting, because this is the first time the drug would be approved using the new composite measure of disability progression, and so that's why it was important to get a SPA agreement.

And this composite measure, I think whether or not the drug gets approved is going to rest almost entirely on whether or not the drug is statistically significant on this measure, which by the way, this measure has the EDSS standard, EDSS one point change that we've been using for a long time in relapsing MS. But also in addition, has two other pieces, the 9-hole peg test, a certain percentage change in the 9-hole peg test as well as the timed 25-foot walk.

So we believe that increases the sensitivity to change, so we will see disability progression better, and therefore, increase the chances that Tysabri will show a treatment effect.

The next question is from Matt Roden with UBS.

Great, thanks very much for taking the question.

While I share the love for Al, and say congrats to your promotion, I also want to say congrats to Doug on a great run at Biogen, and good luck on your next venture.

Thank you.

The question is on the Alzheimer's program.

So the new information for us today is the dosing in the Phase 3 program, and if you look at the numbers you have on CDR, some of the boxes at 3 and 6 milligrams, would you get stat sig -- statistical significance, if the sample size were 1,350 patients which is what you are using in ENGAGE and EMERGE.

Related, just to better understand the strategy of using the multiple doses here, is it meant to enable patients in the real world to move up and down dose, or is it meant to just take people all the way up to 78 weeks in a particular dose and then reassess?

Just trying to understand whether or not the clinical trial is capturing what you mean to do in a real world.

Thanks.

Yes, well again, Al and I will tag team this.

I think the intent here, obviously we've analyzed the data very carefully, and it's a very small sample size coming out of the current Phase 1b study, but what we've seen in terms of consistency of response across the doses, I think, has allowed us to do some very nice statistical modeling, and make some assumptions about sample size that obviously, we think will allow us to achieve statistical significance.

With the sample size, with the increased duration of dosing, because as you'll recall from the previous look at the data, the longer you dose, the more amyloid you remove, and what we've shown in the most recent presentation is that there is a very nice correlation between amyloid removal and improvement in cognition.

So I think all of these factors have come into play to both size the study and to pick the dose, and I would say that what we're trying to do is to actually push the dose, and to push it as high and as hard as we can, to remove as much amyloid as possible, because we know that seems to be an important parameter for efficacy with our drug.

So all of this has been factored into the sample size, and I think we've designed a study now that allows us to take into account the fact that increasing doses work better.

Increasing duration seemed to work better and stratifying based on ApoE4 status is an important parameter for allowing us to both push the dose, but at the same time, try to minimize ARIA, and I think the up-titration is another element to the study that will improve our chances of maximizing the benefit-risk.

Yes, I think any time we go from Phase 2 to Phase 3, we do sort of a discounting, if you will.

We assume that the variability will increase.

We assume, and we look at sort of 95% confidence intervals of what the actual treatment effect is, and that's what Doug was saying about the modeling.

And so I think we're pretty confident using this sample size, that we will achieve statistical significance.

In terms of how we view this drug to be used once it's approved, I do think that people get genotyped, and the dose will be based on genotype, on whether or not they are ApoE4 carriers.

And then, we'll have to look at the data to see which dose is superior, in each of the subgroups, the carriers and non-carriers, and that will probably be the recommended dose.

And then the other complication is if there's some ARIA, whether or not people would dose reduce, because that's what was typically done in the Phase 1b trial.

People dose reduced and most people were able to continue dosing with the dose reduction, so that's how I see it playing out.

The next question is from Terence Flynn with Goldman Sachs.

Thanks for taking my question.

Maybe just two quick ones for me.

First is just, Tecfidera, as you think about the out year trajectory in the US, I know your outlook was flat, but just would help us think about the dynamics, in terms of what really drives a trajectory change there?

And then just on Alzheimer's, was wondering if you can remind us of any similarities or differences between O37 and the Eisai antibody, and endpoint they're using in that ongoing Phase 2 trial?

Thanks.

Yes, thanks, Terence.

It's Tony.

Just maybe some qualitative comments on the outlook.

We believe that the market continues to move to orals, and we continue to believe that we have the best oral.

So those are the two core things.

And as I said, based on what we see in the market today we continue to believe that we have a very good product profile.

We think that we can continue to add patients.

It's harder work at this point, given where it is in the product life cycle.

In terms of the band versus BIIB 37, the band trial is using a composite measure, that includes some of the measures that we looked at in the BIIB 37 study, so it's a different kind of measure that is rather unique, actually.

I think it was developed by the scientists and clinicians at Eisai.

In terms of the differences in the antibodies, band finds a different epitope than BIIB 37.

Band is a humanized mouse antibody, whereas BIIB 37 is a fully human antibody derived from human B cells.

And also, band tends to bind to protofibrils, and so exactly which species of a beta, in terms of the aggregation status, and fibrillar status, there are probably going to be some differences, although I would say that BIIB 37 also binds to the oligomers as well the fibrillary data, so those are the differences.

The next question is from Matthew Harrison with Morgan Stanley.

I want to ask, just on stroke, can you clarify exactly what you saw in those functional endpoints, how similar or different they might have been from TPA, and then when we should think about some sort of Phase 3 design or plan for that, and when we might see that data?

Thanks.

This is Al Sandrock.

So what we -- the primary endpoints was the volume of the stroke, basically based on MRI at day 5. And as Doug said, that was not statistically significant, so we missed on the primary end point.

What was surprising to us is then, when we looked at the other clinical outcome measures at day 30 and day 90, we saw some interesting trends, and in some cases at certain times with certain measures, there were statistical significance.

And the other measures that were looked at were the modified Rankin scale, the Barthel index, and the NIH stroke scale.

Those are the typical stroke scales, and in effect, people often combine them into a global scale.

When we look at those, we see some interesting trends, as I said.

With odds ratios -- so then the other way to look at it is the odds ratios are reaching a favorable outcome on these endpoints individually, and as a composite, sort of a global score.

And when you look at that, it's actually in the range of what we're seeing with TPA, which makes us interested in what we saw.

And so you mentioned going to Phase 3. I'm not sure we'll jump right into Phase 3, but we're still mulling over the data.

We're looking at it in every which way that we can.

We're discussing it with stroke experts, and we'll let you know what we're going to do next, but I think it bears further study.

The next question is from Eric Schmidt with Cowen and Company.

Thanks for the question.

Maybe Paul, I think we've touched on Tecfidera's growth trajectory but it sounds like your guidance for the second half of the year, essentially on the top line, implies no growth in revenue over the first half of the year, and I guess if there's no growth H2 over H1, maybe why should we be optimistic for growth in the future as well?

So perhaps you just talk about the overall top line growth trajectories you're expecting over the next 6 to 12 months?

Yes, I mean we got to still sort that out as we move into 2016, and I think that's what you're getting at, Eric.

The guidance assumes that Tecfidera patients in the United States are relatively limited growth, and that is clearly what we have to kind of get motoring along.

So that's the homework assignment.

Outside the United States, we are growing in terms of patients.

We had a hiccup this quarter versus Q1, as noted from the German pricing.

That's a dynamic that will now settle out, but certainly, we've got some work to do on the commercial front.

The next question is from Robyn Karnauskas of Deutsche Bank.

So just to take a step back and help me feel more comfortable around the rest of the year.

Two things.

Again, it's early, but have you seen any impact from generic Copaxone as like pushback on price or utilization.

Second, when you thought about Tecfidera and flat sales, how much -- to what extent do you think there will be people stopping drug versus just minimal growth?

And how are you thinking about that?

And then third, given the lack of growth in one of these core products, like you talked about share buybacks, but like -- I guess this is going to a point that was made earlier.

Has that changed your interest in bringing in something that will be a growth driver and M&A potential candidate that might help the Company grow during the time in which you're developing your pipeline, and you're facing such headwinds?

Thanks.

Robyn, it's Tony.

First on, Glatopa, generic Copaxone.

Absolutely to date, within our expectations, which I think we have talked about for awhile now, is we think that product largely has an impact within the Copaxone molecule category.

Last I looked, which was probably a couple weeks back to early July there were 400 or 500 Rxs, 90%-plus of them were switches.

97% of those switches were from Cop QD, so to date, absolutely where we expected it to be.

You've seen the WAC, which is 63,000, 64,000.

Don't have clarity on what their contracting strategy will be, but absolutely within the expectation that we had.

And then good point Robyn, what you're bringing up with respect to Tec.

Certainly one of the dynamics that we've seen, that we didn't expect was a modest but not trivial increase in discontinuations in Tec in the United States in particular.

That's probably, we think, traces back to the monitoring to some extent.

It traces back to efficacy breakthroughs, which is typical for most of the disease modifying or majority traces to is some of the GI.

So that is, both dynamics are actually happening.

We're hopeful that we can actually bring that back to a bit normal state, but TBD, as we move forward.

And this is George, Robyn.

Look on the M&A question, I think as we said before, we have a good balance sheet, we have debt capacity.

We will not be shy about using it when we see opportunities that are interesting, and consistent with what we want to do.

I don't think we're in any panic situations, to be desperate, but as we see good opportunities, we will be aggressive about bringing them in.

The next question is from Geoff Meacham with Barclays.

Thank you for taking the question.

One for Tony, and one for Doug or Al.

So for Tony, you have talked about Europe being as big as the US, in terms of peak potential for Tecfidera.

Just wondering if that was still the case, and how you think about how quickly you could reaccelerate growth O-US?

And then for Doug or Al on aducanumab, maybe help us with the criteria for elevation, beta amyloid elevations in PET scans?

I know you had a correlation between beta amyloid levels and cognition, but is there a threshold that you're looking for, that you feel like you'd have maximal efficacy or does it matter, over an 18 month period, do you feel like just clearance of the plaque, even a marginal clearance, would have some sort of effect on cognition?

Thank you.

Thanks, Jeff.

Tony.

On Europe, short answer is basically mathematically impossible for Europe to be as big as the US, given the differential in pricing, and therefore net revenue per patient across.

You have a big patient population in Europe.

As I said, more mature markets like Germany, we believe we've seen dynamics that are a little bit more like the US, but launch markets, we're seeing really nice uptake, and we believe it's very consistent with what we saw in the other launches.

So the total dynamic is, we have seen to date good patient growth in Europe.

We have had both net price and also FX working against us this year.

We are basically through all the major reimbursement decisions at this point, and when all the dust has settled, the net prices we were able to achieve there were certainly lower than our aspiration, and I think what our plan was.

We always cautioned that, given how broadly Tecfidera would be used, you'd have a gravitational pull down to the platform therapies.

The argument for us with the pricing authorities obviously was superior efficacy, better profile fit and the platform has been a very tough row to hoe.

It was made tougher by Aubagio, which went ahead of us and took what was a pretty low price strategy that increased the pressure over there.

So I think Paul referenced it and I talked a little in my comments, the net revenue per patient in Europe is just structurally substantially lower than the US, and for Tecfidera specifically, has come out lower than we would certainly have aspired to, given those market dynamics.

And on the question about the lowering of amyloid.

What we did there was to look to see whether there was a PK-PD relationship essentially, and it was sort of a scientific question.

Does the effect on cognition need to go through the effect on amyloid lowering?

And in a way, it's sort of asking is the amyloid hypothesis correct?

And what we saw was that it's consistent with the amyloid hypothesis being correct.

Your question goes to another thing which is, are we going to be using this as a biomarker in the clinic when it's approved, and will there be some threshold effect being used in the clinic, and I think it's far too early to speculate on that.

I think it might go to that part, but I would not say that this one standard deviation unit that we chose to look at would be that threshold.

I think there's a lot more work that has to be done before we get to that stage.

The final question is from Cory Kasimov with JPMorgan.

Thanks for squeezing me in.

I wanted to go back to aducanumab, and see if you could provide a little more clarity on the titration there.

I'm just not clear.

Can anyone go up to 10 if they're tolerating the drug, and what's the trigger to up-titrate?

And also how much was the plan titration schedule informed by the titration cohort you added to the Phase 1b trial?

Thanks.

We haven't actually released the specific details on how the up-titration is going to work, except to say that all of the patients will undergo that process as they get to their final dose in the study.

Again, I think we'll have more clarity on that once we actually begin enrolling patients, but for the moment, I think we'll simply say that is based on a variety of parameters.

Primarily that there are two things we know correlate with the incidence of ARIA.

One is obviously dose, so a lower dose has a lower incidence of ARIA, and the second is time.

Most of the ARIA occurs during the first five doses of administration, so the hypothesis that is being tested right now with this cohort you mentioned is whether or not at a lower dose for a period of time you can get through this period of risk, I'll call it, for developing ARIA, and end up with a lower overall incident on your way up to the final dose.

Okay, with that, we'll bring the call to an end.

Thank you all for calling in today.

Thanks for all of the questions, and we can all get back to work now.

Thank you.

Ladies and gentlemen, this concludes today's conference call.

You may now disconnect.