Biogen Inc (BIIB) 2017 Q3 法說會逐字稿

Good morning.

My name is Dan, and I will be your conference operator today.

At this time, I would like to welcome everyone to the Biogen Third Quarter 2017 Financial Results and Business Update.

(Operator Instructions)

I would now like to turn the conference over to Mr. Matt Calistri, Vice President, Investor Relations.

You may begin your conference.

Thanks, Dan.

Thank you, and welcome to Biogen's Third Quarter 2017 Earnings Conference Call.

Before we begin, I encourage everyone to go to the Investors 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 the risk factors discussed in our SEC filings for additional detail.

On today's call, I'm joined by our Chief Executive Officer, Michel Vounatsos; and Dr. Michael Ehlers, EVP of Research and Development.

We will also be joined for the Q&A portion of the call by our Chief Medical Officer, Dr. Al Sandrock; and Dr. Paul McKenzie, EVP of Pharmaceutical, Operations and Technology.

Before I conclude, I would also like to note that starting with the Q1 2018 earnings call, Biogen intends to cease publishing press releases related to future earnings calls, earnings releases and investor events via newswire services.

We will post these materials on the Investors section of Biogen's website, www.biogen.com, and issue a statement on Twitter when they become available.

Our Twitter handle is @biogen.

Now I will turn the call over to Michel.

Good morning, everyone, and thank you for joining us.

For the third quarter of 2017, Biogen generated revenues of $3.1 billion.

On an apples-to-apples basis, excluding hemophilia, revenues grew 13% from the same period a year ago.

Revenues grew 4% when we include hemophilia revenues in the prior period.

We enjoyed a record earnings this quarter with GAAP net income of $1.2 billion and non-GAAP net income of $1.3 billion.

Our GAAP EPS was $5.79, and non-GAAP EPS was $6.31, both at a record level.

In July, we communicated our strategy to become the leader in neuroscience by developing transformational therapies to address what we believe are becoming the world's most significant unmet medical needs.

In pursuit of becoming this leader, we are focusing our R&D efforts mostly on 4 core growth areas.

We also highlighted 5 priorities, and the execution of those is important to successfully implement our strategy.

This strategy requires us, first, to fortify our core business while also ensuring that we create new sources of value.

Today, we are sharing exciting developments with each priority in turn.

Overall, we are making encouraging progress on our core, meaning maximizing the resilience of our MS business, accelerating performance in SMA and creating a leaner and simpler operating model.

All are important to generating significant cash flow.

We are putting this cash flow to work in the form of the final 2 priorities: reprioritizing capital allocation efforts and developing and expanding our neuroscience portfolio.

We believe we have the ability to be the leader in neuroscience, and we are committed to building out our pipeline through both our internal R&D efforts and prudent but high-impact business development and strategy collaborations.

We believe this strategy will maximize long-term shareholder returns.

With that context, I am very pleased to discuss our Q3 performance.

First, in the third quarter, our MS core business held up to our expectations.

We continued the strong launch momentum on SPINRAZA as we have meaningfully grown the number of patients treated in the U.S. and globally.

We made progress advancing our neuroscience pipeline.

We improved our collaboration arrangements with Eisai and Neurimmune.

And we made progress streamlining our operations as we evolve towards a leaner and simpler operating model.

We are eager to build on this momentum as we close 2017 and progress into 2018 and beyond.

Let me start with our first strategic priority, maximizing the resilience of our MS core business.

Our MS business is expected to be the driver of near and midterm performance for Biogen and a significant source of cash generation.

MS revenues, including $65 million of OCREVUS royalties, were $2.3 billion, close to the all-time high we had in Q2.

We continued to add patients globally with a 3% increase versus the prior year and a relatively stable patient count versus Q2.

This core franchise helped drive $1.1 billion in free cash flow this quarter, which is key to fueling our investment for future growth.

We have also improved our overall position on U.S. formularies for 2018.

We are very pleased with this progress.

We have seen a trend of 5 major national plans that have recently embraced an open access strategy.

And just last month, Aetna placed TECFIDERA, AVONEX and PLEGRIDY on their preferred list.

I give a lot of credit to our team in the U.S. They have really executed on building trust and demonstrating the value of our portfolio to payers.

Now the performance of our core MS products.

TECFIDERA maintained its global market share and remains the leading MS therapy -- overall MS therapy.

Global revenues were a strong $1.1 billion this quarter, a 3% increase versus the prior year as we saw 9% increase in total TECFIDERA patients over the same period.

U.S. TECFIDERA revenues declined 4% to $836 million in the third quarter compared to a record high in Q2, primarily due to a slight decline in patient demand.

As a reminder, in Q3 2016, TECFIDERA benefited by approximately $40 million to $50 million due to an inventory build, which impacts the year-over-year comparison.

In Q3, inventory levels for TECFIDERA were flat relative to Q2.

In Europe, TECFIDERA patients grew approximately 16% year-over-year and 4% quarter-over-quarter.

While in Japan, TECFIDERA has rapidly grown to over 10% market share.

TYSABRI remains the leading high-efficacy MS therapy with global revenues of $469 million.

U.S. TYSABRI revenues were $267 million, an 8% decline from the prior quarter and an 11% decline year-over-year.

We have seen an uptick in discontinuation, particularly amongst JCV+ patients as OCREVUS continues its launch in the U.S.

Outside of the U.S., TYSABRI revenues were $203 million.

In Europe, TYSABRI patients grew by 2% versus last quarter as it benefited from updated label, providing improved clarity on restratification and patient management.

While our MS business has shown signs of resilience, we are not stopping here.

We are continuing to evolve our operating model in MS, including the recent rollout of the new regional structure in the U.S., which we believe will increase accountability and bring us closer to the customer.

Next, I would like to talk about our second strategic priority, accelerating SMA.

We see SPINRAZA as a key current and future growth driver for Biogen.

We are very pleased with the growth being delivered by the global launch of SPINRAZA as we generated $271 million in revenues in the third quarter, including $198 million in the U.S.

We saw a 75% increase in the number of patients on therapy in the U.S. as compared to the end of Q2.

As a reminder, Q2 revenues in the U.S. included approximately $30 million of inventory build while inventory levels remain flat in Q3.

Approximately 10% of U.S. SPINRAZA revenues in the third quarter were attributed to maintenance dose as a large number of patients who completed the 4 dose-loading regimen in prior quarters did not receive a dose in Q3 due to the once every 4 months maintenance dosing.

Additionally, over 65% of patients currently on therapy are type 2 and 3s, and a growing 20% are over the age of 15 years old, suggesting that the most severe patients are treated first and also significant opportunity remains in the other patient population.

Infrastructure in the U.S. continue to improve.

As of the end of the third quarter, over 180 sites have administered SPINRAZA, an increase from 145 sites last quarter.

And we now have over 250 sites that have submitted start forms.

Importantly, we have received hundreds of start forms from patients that are not yet on therapy, a great indicator for demand.

We are diligently trying to help these patients start on SPINRAZA while also working to reach the thousand of older SMA patients who are either not aware of SPINRAZA or have not yet indicated an intent to start treatment.

To help reach this broader population, we're expanding the size of our U.S. SMA team.

Outside the U.S., SPINRAZA revenues were $73 million in Q3.

Revenues and volume from ex-U.

S. launch this quarter surpassed what we saw in Q1 of the U.S. launch.

We have now launched in 11 European countries as well as in Japan, and we recorded revenues from named patient sales from multiple countries across the Middle East and Latin America.

So far, we have submitted 20 pricing and reimbursement dossiers in Europe.

This quarter, SPINRAZA was approved in Brazil and Switzerland, and we filed in Argentina.

Over time, we aim to make this therapy widely available across the globe.

For our strategic priority to create a leaner and simpler operating model, we intend to streamline our operations and relocate resources with the goal of redirecting up to $400 million by the end of 2020 to be reinvested in prioritized research and development and commercial value-creation opportunities.

To achieve this, we expect to make total expenditure of up to $170 million, primarily in 2018, through a restructuring program across a number of strategic operational and organizational initiatives.

Moving to our biosimilar business.

Revenues grew 12% to $101 million, and the European Commission granted the marketing authorization for our Adalimumab biosimilar, IMRALDI.

Biogen is now the first company with approved biosimilars in Europe for the 3 most prescribed anti-TNF biologic treatments.

So it was an exciting quarter with healthy progress in our core business.

We saw resilience in our MS franchise.

We accelerated our achievements in SMA with several strong country launches, and we continued to grow our biosimilar business.

We believe this foundation gives us an even greater ability to create more value for patients and shareholders in the future.

We are incredibly excited about the work that is underway to both develop and expand our existing portfolio as well as to invest in building our pipeline.

And now I would like to transition to our plan to create new sources of value.

The team has been working tirelessly to ensure that we have the right capabilities and pipeline to win in this area, including: optimizing partnership to better position us for new growth; advancing R&D candidates; actively looking for pipeline assets; enhancing our BD capabilities; and further building our senior management team.

Before I turn it over to Mike, a few highlights.

First, we renegotiated our agreement with our partner, Eisai.

Biogen will now receive 55% of profits in the U.S., 68.5% of the profits in Europe and 20% of the profits in Japan.

This leverages Biogen's strong presence in the U.S. and Europe and Eisai's distinct advantage in Asian markets.

Eisai also exercised its option to jointly develop and commercialize aducanumab.

We are pleased by this demonstration of Eisai's confidence for our lead Phase III Alzheimer's asset.

We also agreed to decrease our royalty obligations to Neurimmune.

We believe both of this new agreements will improve the long-term economics of aducanumab.

Second, we announced new data for the long-term extension of our ongoing Phase Ib study on aducanumab.

We are encouraged by these results as they are consistent with our previous reported data and support the design of our ongoing Phase III studies.

We will present detailed data from this analysis at the CTAD conference next week, and Mike will provide more details shortly.

Third, we advanced multiple assets in our pipeline.

We completed enrollment for natalizumab in stroke and BIIB054 in Parkinson's disease.

We initiated trials for natalizumab in epilepsy for our tau ASO in Alzheimer's disease in collaboration with Ionis and for opicinumab in MS. And we had a positive readout of STX-100 in idiopathic pulmonary fibrosis.

Finally, we continue to build our new senior management team, which we believe is critical to maintaining this momentum.

We could not become the leader in neuroscience without our class -- world-class talents.

Camille Lee has joined Biogen as Senior Vice President, Alzheimer's Therapeutic Area.

Dr. Sanjay Jariwala has joined as Senior Vice President, Worldwide Medical.

Anabella Villalobos has joined as Senior Vice President, Biotherapeutic Medicinal Science.

In addition, we are progressing well in our search for a new CFO and hope to make an announcement in the near future.

I will now turn the call over to Mike for an update on our recent progress in R&D.

Thank you, Michel, and good morning, everyone.

Last quarter, we provided additional clarity on Biogen's R&D strategy, which highlighted our vision to be the leader in neuroscience.

We continue to believe that no other area of medicine represents as much patient need, global economic burden and scientific opportunity as neuroscience.

We are enacting an R&D investment strategy aimed at definitive leadership in neuroscience.

I would now like to spend some time highlighting the significant progress we had made this quarter within our core and emerging growth areas.

Starting with MS and neuroimmunology.

We are committed to investing in R&D for MS to address key unmet needs.

This week, Biogen is releasing new data through more than 80 oral and poster presentations at the 7th Joint ECTRIMS and ACTRIMS meeting, including comparative effectiveness data for TECFIDERA and TYSABRI as well as an update on several real-world initiatives we are advancing to improve the diagnosis and monitoring of disease progression.

One of the key highlights for Biogen at the meeting will be the presentation of a post hoc analysis of data obtained in the Phase II SYNERGY trial, which we believe identifies a patient subset exhibiting sustained clinical improvement upon treatment with opicinumab, a first-in-class human monoclonal antibody directed against LINGO-1.

At the 10-milligram per kilogram dose, we found that opicinumab was associated with a greater and more durable treatment response in patients who had been diagnosed with MS within the last 20 years and in those whose brain MRI suggested lesions with lower myelin content as measured by magnetization transfer ratio, but preserved relative tissue integrity as measured by diffusion tensor imaging radio diffusivity.

These characteristics provide a biologically and clinically plausible hypothesis that we will test in our Phase IIb AFFINITY trial.

Specifically, AFFINITY, a multicenter, randomized, double-blind, placebo-controlled Phase IIb study that aims to enroll 240 patients with relapsing MS was initiated earlier this year.

The trial is designed to evaluate the potential for opicinumab to improve pre-existing disability in relapsing MS patients through remyelination.

A fixed dose of opicinumab that closely replicates the 10-milligram per kilogram dose from SYNERGY will be studied as an add-on therapy in patients who are adequately controlled on their anti-inflammatory disease-modifying therapy versus the DMT alone and who exhibit characteristics consistent with the potential SYNERGY responder population.

The primary endpoint of the study, overall response score, is an integrated measure of both the improvement and worsening of disability over time.

During the quarter, Lancet published new data investigating the correlation between PML risk for natalizumab and JC virus antibody index values through large observational studies.

The estimates suggests that PML risk remains low at JC virus antibody index less than or equal to 0.9 and increases at index levels greater than 1.5.

Specifically, over 6 years of natalizumab treatment, the cumulative risk of PML was lowest in patients with index less than 0.9 at 0.2%, which increased to 2.8% for patients with an index value greater than 1.5.

Our hope is that these data can provide physicians and patients additional information when making individualized benefit-risk assessments with TYSABRI.

These data are currently largely reflected in the EU label, and we are currently discussing these data with the FDA.

We also had exciting new developments within Alzheimer's disease and dementia, which, we believe, we have one of the most robust AD portfolios in the industry.

We recently conducted an additional interim analysis of the long-term extension of the ongoing Phase Ib study of aducanumab called PRIME, as Michel referred to.

The updated analyses include data from the placebo-controlled period and long-term extension for patients treated with aducanumab up to 24 months in the titration cohort and up to 36 months in the fixed-dose cohorts.

In patients treated up to 24 months in the titration cohort, amyloid plaque reduction was consistent with the dose and time-dependent results observed in the fixed-dose cohorts.

In patients treated up to 36 months, amyloid plaque continued to decrease in a dose and time-dependent manner with amyloid plaque levels in the 10-milligram per kilogram fixed-dose cohort reaching and remaining at a level considered below the quantitative cut point that discriminates between a positive and negative scan.

At both 24 and 36 months, analyses of CDR sum of boxes and the MMSE suggest a continued benefit of the treatment of aducanumab on the rate of clinical decline during the treatment.

In the Phase Ib long-term extension, the most commonly reported adverse events were headache, fall and amyloid-related imaging abnormalities or ARIA.

We look forward to presenting these data in detail next week at the Clinical Trials on Alzheimer's Disease conference in Boston.

Our collaboration partner, Ionis Pharmaceuticals, recently initiated a Phase I/IIa study with BIIB080 or IONIS-MAPTRx in patients with mild Alzheimer's disease and dosed the first patient earlier this month.

BIIB080 is an intrathecally administered antisense therapy designed to selectively reduce the production of the microtubule-associated protein tau in the brain.

Pathological accumulation of tau protein is a hallmark feature of Alzheimer's disease that correlates strongly with clinical status.

Reducing levels of tau via an antisense oligonucleotide, or ASO, represents a unique and independent approach to tau lowering relative to monoclonal antibodies.

Within neuromuscular disorders, we presented significant data for SPINRAZA at the 22nd International Congress of the World Muscle Society in Saint-Malo, France.

Key data highlights include a new analysis from the Phase III ENDEAR study, as measured by the Hammersmith Infant Neurological Examination, significant differences in motor milestone responders were observed in patients with disease duration at baseline less than or equal to 12 weeks as 75% of infants treated with SPINRAZA responded compared to none of the untreated patients.

For those with disease duration greater than 12 weeks of baseline, 32% of the treated patients responded while none of the untreated infants responded in this cohort.

There was also a statistically significant benefit in event-free survival in infants treated with SPINRAZA with disease duration less than or equal to 12 weeks.

Data from EMBRACE, a Phase II, multicenter, randomized, double-blind, sham procedure-controlled, 14-month study of SPINRAZA in infants and children not eligible to participate in ENDEAR was also presented.

The EMBRACE interim analysis showed a larger proportion of infants and children treated with SPINRAZA for Hammersmith Infant Neurological Examination motor milestone responders compared to those who are untreated.

In the ENDEAR and EMBRACE studies, SPINRAZA demonstrated a favorable benefit-risk profile.

And overall, the data presented contribute to a growing body of evidence that demonstrates SPINRAZA can make a meaningful difference in the lives of patients with SMA regardless of their age or stage of the disease.

Beyond SPINRAZA, we continue to be excited about the potential of our gene therapy program in SMA, and we expect to advance into the clinic in mid-2018.

Moving on to our progress in movement disorders.

BIIB054, our anti-alpha synuclein antibody targeting the core pathology of Parkinson's disease with the goal of slowing disease progression, has completed enrollment in the Phase I trial, and we anticipate sharing data from the Parkinson's cohort of this study next year.

We are also planning to initiate a Phase II study of this asset by the end of the year.

Moving on to other updates.

We are committed to enhancing and advancing our pipeline in, not just our core growth areas but also our emerging growth areas.

Specifically, we see significant potential in acute neurology, pain, neuropsychiatry and ophthalmology.

Within acute neurology, we are currently conducting a Phase IIb trial with natalizumab in acute ischemic stroke, with the aim of improving functional outcomes by limiting brain inflammation in the post-stroke period.

The study is fully enrolled, and we expect data early next year.

Natalizumab is targeting acute ischemic stroke patients with mild to moderate severity with a therapeutic time window of up to 24 hours after stroke onset.

This program complements BIIB093, our first-in-class IV glibenclamide therapeutic targeting brain edema in severe large hemispheric infarcts with a planned Phase III start next year.

During the quarter, we also initiated OPUS, a Phase II study for natalizumab, which we believe has the potential to be a first-in-class anti-inflammatory therapy for patients with drug-resistant focal epilepsy.

With over 750,000 target patients in the U.S. and EU5 alone, we see significant opportunity.

Specifically, the study will be a 70-patient, 6-month, randomized, double-blind, placebo-controlled study to assess the efficacy, safety and tolerability of natalizumab as adjunctive therapy.

Patients are expected to continue into a 6-month open-label phase after completion of the double-blind phase.

The primary efficacy objective of this study is to determine if adjunctive therapy of natalizumab reduces the frequency of seizures in adult participants.

Mechanistically, with multiple lines of preclinical and clinical research providing the rationale for a potential benefit, we believe blocking alpha-4 integrin with natalizumab may help to reduce leukocyte vascular interactions and stabilize blood-brain barrier integrity, which may ultimately help to reduce the frequency and severity of seizures.

Moving on to our emerging growth area of neuropathic pain.

Our Phase IIb study of BIIB074 in painful lumbosacral radiculopathy is currently enrolling with data expected next year.

Also next year, we anticipate initiating a Phase III program for trigeminal neuralgia as well as a Phase II study in small fiber neuropathy.

Outside of our core and emerging growth areas, we recently achieved proof of biology for BG00011 or STX-100 in a Phase IIa trial in idiopathic pulmonary fibrosis or IPF.

For assets like BG00011 that are not within our neuroscience focus, we intend to continue development as long as the science remains compelling and we see potential to add value.

The results from the 41-patient Phase IIa trial demonstrated substantial downregulation of the TGF beta pathway in IPF patients treated with BG00011 as measured by up to 70% inhibition from baseline of phosphorylated SMAD in alveolar macrophages isolated by bronchoalveolar lavage from IPF subjects.

Phosphorylated SMAD mediates the transcriptional activity at TGF beta signaling an increased level have been correlated with fibrosis in multiple preclinical models.

In addition, BG00011 was shown to impact multiple prespecified genes associated with TGF-beta signaling.

Through this study, we have identified a dose with an appropriate safety profile and anticipated level of efficacy to support advancement into a Phase IIb study next year.

As a reminder, our key strategic priorities within R&D are to build out our translational machine in neuroscience, invest in assets and capabilities in our prioritized core and emerging growth areas and to augment our pipeline.

We have made strong progress this year in increasing the probability of success for transitioning from the lab all the way to the market.

In 2017, we have transitioned 5 programs from research to development within our core and emerging growth areas, putting us on track to nearly double historical productivity and highlighting our focus on bringing novel drug candidates into the clinic.

We aim for a similar or greater level of R&D productivity next year, and a key component of our R&D strategy is to leverage antisense oligonucleotides, which offer a promising platform to get to and through the clinic faster than other modalities.

To that end, we recently opened an ASO manufacturing facility in North Carolina to support our growing ASO pipeline.

We have also been building our R&D leadership team, which Michel discussed, to help maximize future R&D productivity.

While we continue to make important progress advancing our portfolio, we recognize that accelerating our long-term growth will require further enhancement.

Internal productivity is already showing promise.

But in addition, we are highly focused on expanding our neuroscience portfolio through external opportunities and look forward to highlighting the progress we make here in the coming months.

In summary, across our portfolio, we see continued leadership in MS, including remyelination; a growing body of clinical data within SMA; an industry-leading Alzheimer's disease portfolio; a compelling program in neuropathic pain; a unique clinical portfolio in stroke; defining new mechanisms of biology in IPF; advancing assets in Parkinson's disease, epilepsy and ALS; and a growing number of high-quality drug candidates reaching the clinic.

I will now pass the call back to Michel.

Thank you, Mike.

Now let me share with you how we are thinking about the rest of 2017.

We expect that SPINRAZA continues on a strong trajectory in terms of patients uptake in the U.S. and internationally.

However, due to the impact of the dosing scheduling, we anticipate SPINRAZA revenue growth in Q4 will be mostly driven by ex-U.

S. markets.

We expect OCREVUS will have a modest net negative impact on our MS portfolio, and we expect the typical seasonality for MS in Q4.

And for expenses, we expect OpEx in Q4 to increase versus Q3 as we invest behind our strategic priorities.

In conclusion, I believe we have a clear direction.

Our actions are aligned to our strategic imperatives, and everything we do is linked to maximizing shareholder value over the long term.

Our market-leading MS business remains resilient.

We continued an impressive SPINRAZA launch.

We advanced assets in our neuroscience portfolio.

We increased our biosimilars revenues in Europe.

And very importantly, we enhanced our collaboration arrangements with Eisai and Neurimmune.

We intend to continue this momentum, especially with a focus on completing more business development to further expand our neuroscience portfolio so that we can achieve our mission to be the leader in neuroscience.

Looking forward within the next 12 to 18 months, we expect several meaningful readouts across our neuroscience pipeline, including: BAN2401 in Alzheimer's disease, natalizumab in stroke, BIIB067 for ALS, BIIB074 for painful lumbosacral radiculopathy, BIIB054 in Parkinson's and our gene therapy program for XLRS.

Before we go into Q&A, I would like to thank our employees around the world who are dedicated to making a positive impact on patients' life and all of the physicians, caregivers and participants in our clinical development programs, the past and future achievements could not be realized without their passion and commitment.

With that, we'll open the call for questions.

(Operator Instructions) Your first question comes from the line of Umer Raffat with Evercore.

I'll leave out SPINRAZA patient count stuff for the rest of the call.

But Michel, I actually wanted to focus on aducanumab for a minute.

And 2 parts to that.

First, I just wanted to think through what the $150 million payment to Neurimmune on the royalty reduction implies for the valuation of aducanumab?

And the reason I ask is because the implied valuation for aducanumab based on this $150 million payment is very different than what the market implies.

So I was just curious and just wanted to understand the context of this negotiation a bit better.

And then also on aducanumab, I was just curious, how much of your R&D spend is going towards aducanumab right now?

And I ask because of the amount of payments Eisai is going to have to make starting 2019, whether that's appropriately reflected in Street expectations for your R&D spend in 2019 onwards or not.

So thank you for the good questions.

We are very pleased with these new agreements.

We believe the potential opportunity with aducanumab, and therefore, we act in alignment with this belief.

And this took a lot of work, and it's probably the most important alliance or BD agreement that we reached in 2017 so far.

So I think this is very important.

For the $150 million, we are working on our long-term -- long-range operating plan, and we remain with the right assumptions, very bullish on the opportunity that we have with this product.

With Neurimmune, we have a long-term collaboration, and there are many things in play in the past, in the present and in the future.

And I would say, it's logical that working together we achieved this agreement between the 2 companies.

So I will not go much further in terms of the speculation of the potential link.

But I think it's very positive for the overall future profitability of aducanumab if we are able to succeed.

So we are pleased with this outcome.

Concerning the clinical spend, the only thing I can tell you is that, as per the time Eisai starts to contribute meaningfully to the clinical spend in 2019, a large portion of the overall spend will need to be -- to occur in '19 and beyond.

Somebody wants to add something?

Okay.

Your next question comes from the line of Geoff Meacham with Barclays.

I want to get some context for SPINRAZA just for the U.S. Obviously, it's flattish in Q3.

And you're also saying that, Michel, for Q4.

Are you guys seeing discontinuations or difficulties in getting reimbursement?

Or is this just your kind of wave 2 in the U.S. is more difficult than putting on wave 1, which would be the worst patients, the most severe patients?

Thanks for the question.

We are very pleased with the momentum in the U.S. And having 75% patient growth is not a simple achievement.

So I compliment the team.

As expected and also as difficult to model as it can be, based on the dosing regimen, it's -- the impact of the patients we got in Q1 and on the early access program was fully reflected in the Q3 because of the dosing regimen.

Over time, this will normalize, and that's why we are prudent, the way we have been prudent since the beginning of the year, if you recall well.

So we expect that the dynamic will normalize as the maintenance dose become majority of the revenue.

So this is basically the momentum we see.

We enlarge the reach.

We see a larger proportion of the patients above the age of 15, meeting with scientific leaders.

They are getting more experience on complicated spine in order to dose the patients.

And they are investigating potential routes of administration and procedure for patients more complicated, other one with the fusion.

And those ones are the more complicated.

And it is anticipated.

Just to come back, because I know that everybody has that in their mind, so yes, we said 60% of the patient have a complicated spine or mostly the patients with a type 2 and 3. And mostly the 2. But out of this proportion, it's actually between 10% and 20% of those patients who have a fusion that are the more complex.

The others are easier.

And apparently, according to scientific leaders, the proportion of fusion ex-U.

S. is much lower, just to give some context.

So we remain optimistic on the potential of SPINRAZA in the U.S. and ex-U.

S., and our peak sales objective did not change.

Your next question comes from the line of Eric Schmidt with Cowen and Company.

Yes, I guess I'm just having the same problem squaring the circle here on SPINRAZA.

It sounds like you did very well with new patient adds, 75% increase in number of patients on therapy from end of Q2 to end of Q3.

And a variety of large -- majority of those patients had to receive multiple doses.

So I guess maybe not to ask the same question a different way, Michel, but how is it that you can't get growth with that many new patients being added here?

There must be some change to gross to net or free drug or something of that sort.

The free drug elements, if I don't mistake, was 20%.

This is correct.

So there was a slight increase, but not a major impact.

Again, it's the 75% patient growth that was dosed.

In 75% of patient growth that were dosed with the initial dosing regimen and very little of patients with a maintenance dose.

This is the dynamic that we see.

It is clear that, for the later onset of disease and more complicated patients, it takes a bit more time to get dosed.

That's why we have hundreds of platforms that are not yet for patients who are not yet dosed.

So this is another dynamic that is not new.

But again, as I said, the infrastructure and the system is adjusting.

Do you expect growth in Q1?

I will not comment yet on Q1.

And the last element that we saw was an inventory play between Q2 and Q3.

Thanks, Eric.

Your next question comes from the line of Ying Huang with Bank of America Merrill Lynch.

Maybe, Michel, you talked about the formulary access for MS products.

Can you talk on a high level what your expectation is for 2018 net pricing for TECFIDERA and also the other products?

And then maybe another question is, with Eisai just opting in for aducanumab, and we know that the BAN2401 program is coming to an end, did Eisai have any clarity on the analysis of the result from the 12-month follow-up before they opted in?

So I would get started on the market access for '18, and that is now almost under contract.

And as communicated, we are very pleased with the progress for the U.S. And the growth to net impact is similar to prior years and the typical contracting arrangement for which our leadership position is helping, as you can imagine.

So we didn't see a dramatic erosion in order to maintain or enhance.

We saw a very limited one, actually.

So we are pleased with the momentum, including open formularies and including the win with some major payers like Aetna.

So this is an important achievement.

This is Al Sandrock.

In terms of what Eisai saw, they saw the same things we've seen so far, which include data from the Phase Ib trial that Mike talked about that we'll be presenting next week, which is the 36-month follow-up in the fixed-dose cohorts and the 24-month follow-up in the titration cohorts.

Your next question comes from the line of Cory Kasimov with JPMorgan.

Are you surprised by the relative strength of SPINRAZA overseas?

I guess is there anything noticeably different relative to the U.S. launch that you've seen over there in these early days?

Thanks for the question.

The -- we are very pleased.

And as communicated previously, we did anticipate that, unlike MS, we see that for SPINRAZA, mostly driven by the prevalence of the disease.

We see a higher proportion of opportunities in terms of top line revenue ex-U.

S. and U.S. So we are pleased with the early launch countries, Germany, couple of Nordics countries, Japan since a few weeks.

But this was mostly driven by Germany and some named patient sales in the Middle East, in Turkey and in Latin America.

Germany is doing -- is going very strong.

We got the [Journal Official] in Italy, and you recall that we had more than 100 -- close to 120 patients on early access program.

And overall, maybe one element that is helping also the momentum in Europe, ex-U.

S., was the very large number of early access program patients that were already identified just waiting to gain reimbursement in order to be shifted to commercial goods.

So obviously now, the question is, "Are we anticipating the same trends that basically many of you have anticipated and not just a linear growth on a country basis ex-U.

S.?" We believe that based on the sequence of access reimbursement and un -- and locking opportunities in different countries that is not at the same time that this trend will not be the same as in the U.S. I think that this would be a smoother trend in the right direction.

And again, overall, it's a very nice momentum, and we are trending above what we thought was our internal targets.

Cory, just to put some numbers on it, we had more than 500 patients in the early access program across 18 countries in Europe.

That compares to about 60 patients we had in the U.S. probably due to the timing a little bit between when we saw the data and when the drug was approved.

So a lot more interest in the EAP in Europe.

Your next question comes from the line of Geoffrey Porges with Leerink.

A quick clarification for Al, if I could, and then a question, Michel, for you.

Al, on the intrathecal ASO for Alzheimer's, could you just talk about the dosing frequency and the access there in terms of being able to deliver the treatment?

And then Michel, could you talk about your policy on pricing?

(inaudible) pricing has been a significant driver to the MS category overall in prior years, and then you -- the company changed the policy this year, and you've taken single-digit price increases on a once basis -- onetime basis this year.

Is that what we should be modeling going forward?

And I apologize for the double question.

Yes, Geoff.

This is Mike.

I'll take a stab at the first one.

We're -- I think it was about intrathecal access for this.

It turns out that we don't anticipate any more significant problems in terms of intrathecal delivery in this program than in the SPINRAZA program at all.

And the initial studies are really that their safety dose ranging findings in Alzheimer's subjects.

So we're trying to get an idea of exactly that kind of the right dose range.

And then from a technical standpoint, we don't see or anticipate any more significant challenge than what we've seen with SPINRAZA.

So concerning the second question.

Let me start by saying that we are very pleased with the resilience of our MS portfolio.

That is so important in terms of cash flow generation, and we intend actually to continue this momentum.

We organized a meeting in a few days with all the Biogen leaders where we are going to recommit (technical difficulty) so that we can defend, as much as we can, the market share while we speak is holding at 38%.

It was 38.3% before.

I don't know when exactly.

And as expected, in OCREVUS launch, we'll erode the share.

And if I look at the performance of the last 2 quarters, including OCREVUS that was still a minimum contribution, it is the last best 2 quarters ever for Biogen.

So it's not a cliff.

And we'll continue to drive the activity to generate demand and volume, and we will not comment on the price policy.

Your next question comes from the line of Carter Gould with UBS.

Just to come back to aducanumab.

On the updates with Eisai and Neurimmune, how should we think about these?

Were these proactive moves on your end?

Or more opportunistic moves after overtures from those companies?

So I will not enter into the details of the first move.

These are contracts that were signed a few years back.

We see data coming in the Phase I/Ib, and we are relatively pleased with this data.

We'll hear more at CTAD.

And I thought it would be an opportunity to see how we could improve the operation or give the best chance for the operation and the co-promotion the day we have potentially the product.

And therefore, playing out, "Who's the best where?" And obviously, I have the agenda to increase the profitability for Biogen.

And I think that with the 2 deals, this is what we are achieving.

But it's a win-win, and the partners at Eisai gets also the opportunity to co-promote the MS portfolio, which is important.

So we are very pleased with these 2 upgraded, I would say, agreements.

Your next question comes from the line of Matthew Harrison with Morgan Stanley.

Great.

I'd like to just go back to SPINRAZA one more time.

Sorry for starting to beat this too much.

Can you just help us?

Because the numbers don't square, and I'm just trying to figure out where -- what piece we may be missing.

So if you back out the inventory from the second quarter, you had 32% sequential revenue growth, but you had 75% growth in new patients.

And I thought at the beginning, you said that 10% of patients had a maintenance dose.

So it seems like you almost doubled -- well, I mean, a little less, but you had substantial hundreds of new patients add-on and some patients taking maintenance doses.

And so it seems like the price per patient has come down by 40%.

So is that right?

I mean, or what else are we missing in those numbers?

Matthew, this is Matt.

Let me try to help clarify.

So first of all, when we say 75% patient growth, what we're looking at is the end of second quarter to the end of third quarter.

If you look at the number of patients on therapy at the end of the second quarter versus at the end of the third quarter, we had 75% more patients.

Now how many of those patients at the end of the third quarter received 1, 2, 3 doses is -- we haven't revealed that, right?

So that's probably part of the reason you're -- it's a little more difficult for you to kind of square that math.

And the other thing we talked about was 10% of the revenues came from patients who had been on a loading dose in prior quarters.

So there's a lot of dynamics here, and the nature of loading dose versus maintenance doses I know makes it a little bit complicated, but that's kind of how the math plays out.

So I don't think it's a function of gross to net impacting.

And as you saw it, we believe it's 20% of patients on free.

It's more a function of just the timing of doses.

And as we said, we expect this is something that normalizes over time.

I think the other thing you're all trying to solve for is a commentary we said about Q4.

We said majority of growth is expected to come outside of the U.S. I don't think the message is that there's no growth in the U.S. I think the message is that there would be growth in the U.S., but the majority of growth would come from outside of the U.S. So I don't think we're trying to send a message that you're not seeing growth in SPINRAZA in the U.S. We're just comparing it to the -- of the dynamics in the rest of the world.

Does that help?

Yes.

No, I think it does.

So then -- and I think you've commented on the ex-U.

S. trajectory, but I mean, should we consider -- I guess maybe you could just give us some guidepost on what's going to grow ex-U.

S. trajectory.

Is it new country launches or additional patients in existing countries?

You can say new country launches would make -- we believe new country launches will be one of the drivers there that could lead.

And if you just look at the comments we've made, Germany, and Turkey made up a majority of the Rest of the World sales.

But as you look at the countries that have already approved and some of the kind of traction we're making, you're going to see more diversity across other countries.

That's our belief.

But Germany still has a long way to go, so you can actually expect both.

But in the first phase, obviously, the new product launches in new countries like Italy, while we speak, will add momentum -- should add momentum.

Your next question comes from the line of Terence Flynn with Goldman Sachs.

Maybe one for Michel or Mike.

You both referred to business development looking externally, neuro focus.

Maybe just give us your latest thoughts on early stage, later stage, how you're thinking about business development and maybe the cadence of the deal or deals?

So I will get started and Mike can add more color.

So first, we have strong cash flow generation, and we expect that this cash flow will grow mostly after 2019 when we have less royalties to pay on TEC.

So we'll make sure that the allocation of this capital will secure the maximization of the shareholder return, and we have communicated that unlike in the past, where we did the majority to the dollar back to shareholders in terms of share repurchase, we will also do the share and prioritize, as per now, the capital allocation efforts towards building neuroscience pipeline.

And in addition, we may continue to repurchase share on an opportunistic manner based on the price of the share and other elements.

So we are looking at different opportunities.

The Eisai and Neurimmune took a lot of time, and there are opportunities, and the sweet spot of Biogen remains at the early stage.

And we'll be very careful if we go beyond the early stage of the valuation of those assets or companies.

Mike?

Yes.

I'd add just a little bit to that.

We're quite committed to a couple of things within the R&D portfolio.

Number one was increasing productivity of our existing pipeline.

And number two was to be able to add important new assets to the pipeline.

So we're quite committed to portfolio growth.

Michel mentioned, which -- our sweet spot, we believe, is in early-phase clinical assets because of our ability to really derisk those and advance those to proof of concept well.

But of course, we look within that sweet spot and beyond.

We've got a number of active discussions ongoing.

We're augmenting our external innovation capabilities.

We've been bringing online more search and evaluation.

And we've -- we're really retuning a lot of the entire R&D organization and beyond to be more externally oriented.

So I think that you will see over time both an increase in the productivity of the existing portfolio and a number of assets coming into the portfolio.

Your next question comes from the line of Ronny Gal with Bernstein.

Question about the gene therapy platform.

Good to hear that you think you'll be starting now your trials in the mid-2018.

I guess my question is on the manufacturing here.

Is there an opportunity here to leapfrog in terms of your both capacity and cost?

Folks have been talking about how difficult it is to get enough material to be able to treat an entire patient population as opposed to just the type 1 SMA.

Cost per therapy suggesting hundred thousands of dollars per patient.

Have you been able to move away from triple transaction to something more stable?

Are you able to address the cost structure?

If you could just give us some kind of like landmarks around that?

Sure, Ronny, this is Paul McKenzie.

Thanks for the question, and thanks for your great recent gene therapy seminar that you gave.

A lot of people really benefited from that in the industry.

You bring up a great question around our ability and beliefs around our development and manufacturing capability.

As I shared with you before, that we have doubled down on our development capability.

We believe that will allow us to drive to a gene therapy platform that's industry-leading.

We also have invested in manufacturing partnerships and platforms that allow us to do these activities both development and manufacturing excellence in parallel.

We're very excited around our progress, around our clinical supplies, for the second half of 2018 dosing.

And we continue to make great strides on our PCL development for the future commercial process.

So more to come in the upcoming months, but we believe we're well positioned to continue to drive our agenda in gene therapy across the portfolio as a real platform play.

And Ronny, this is Mike.

Just following up on Paul's comment, so manufacturing is certainly one area where we believe there's an opportunity for real competitive advantage and a platform approach that could be attractive for SMA and beyond.

Within SMA, in particular, there are a number of things that we are quite focused on, which is, Are the right patient subtypes?

We certainly have gained a lot of experience with patient subtypes within SMA with our SPINRAZA experience.

And I think along with that are going to be important things that we're looking at, which are: delivery route; timing of dosing administration; potential combinations with SPINRAZA; and of course, front and center in our mind is how all that ties in with clinical safety.

And I think that a lot of this still has to play out.

So between manufacturing, patients subtype, delivery route, safety profile, those are key elements of our gene therapy strategy.

And your final question comes from the line of Michael Yee with Jefferies.

Given the update on the Eisai opt in, can you just remind us with the BAN2401 data coming, how to interpret that from the standpoint of a high hurdle given aducanumab's advancement in Phase III and so far ahead, how you would think about whether there would be 2 Phase III programs?

Or just the fact that there's a high hurdle for this program given that they've now opted in?

Mike, this is Al.

Well, first of all, it's prespecified in the agreement what the hurdles actually would be.

And so there's that.

The way I look at that data is: first, I want to see is there plaque reduction with BAN2401.

If there isn't, then I don't know how to interpret the rest of the data.

If there is plaque reduction, then the next thing you want to see is, is there at least a trend or a favorable effect on the composite measure of which includes things like CDR sum of boxes, which would allow us to sort of compare the effect of aducanumab with BAN2401.

And then finally, of course, we need to look at the safety, what are the relative -- what are the rates of the key adverse events, such as ARIA.

And then with that, we'll make a decision.

But as I said, the contract prespecifies what the efficacy hurdles sort of are.

So thank you all, and have a great day.

Bye for now.

Thank you to everyone for attending today.

This will conclude today's call, and you may now disconnect.