雷傑納榮製藥 (REGN) 2017 Q3 法說會逐字稿

Welcome to the Regeneron Pharmaceuticals Q3 2017 Earnings Conference Call.

My name is Paulette, and I will be your operator for today's call.

(Operator Instructions) Please note that this conference is being recorded.

I will now turn the call over to Manisha Narasimhan, Head of Regeneron's Investor Relations.

You may begin.

Thank you, Paulette.

Good morning, and welcome to Regeneron Pharmaceuticals' Third Quarter 2017 Conference Call.

An archive of this webcast will be available on our website under events for 30 days.

Joining me on the call today are Dr. Leonard Schleifer, Founder, President and CEO; Dr. George Yancopoulos, Founding Scientist, President and Chief Scientific Officer; Bob Terifay, Executive Vice President, Commercial; and Bob Landry, Chief Financial Officer.

After prepared remarks, we will open the call for Q&A.

I would also like to remind you that remarks made on this call today include forward-looking statements about Regeneron.

Such statements may include, but are not limited to those related to Regeneron and its products and business, sales and expense forecasts, financial forecasts, development programs and related anticipated milestones, collaborations, finances, regulatory matters, intellectual property, pending litigation and competition.

Each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in that statement.

A more complete description of these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission, or SEC, including its Form 10-Q for the quarter ended September 30, 2017, which was filed with the SEC this morning.

Regeneron does not undertake any obligation to update publicly any forward-looking statement, whether as a result of new information, future events or otherwise.

In addition, please note that GAAP and non-GAAP measures will be discussed on today's call.

Information regarding our use of non-GAAP financial measures and a reconciliation of those measures to GAAP is available in our financial results press release, which can be accessed on our website at www.regeneron.com.

Once our call concludes, Bob Landry and the IR team will be available to answer further questions.

With that, let me turn the call over to our President and Chief Executive Officer, Dr. Len Schleifer.

Thank you, Manisha, and a very good morning to everyone who has joined us on the call and webcast today.

In my remarks, I'd like to focus on to EYLEA and Dupixent, which are 2 important near-term drivers of our business and also cover some of our late-stage pipeline progress.

EYLEA is a very important franchise to Regeneron and has continued to perform strongly in the third quarter, with 12% year-over-year growth in the U.S. and 20% year-over-year growth outside the United States.

We are committed to maintaining our leadership in retinal diseases.

Today, I want to talk specifically about our long-term strategy to drive EYLEA growth.

Our EYLEA sales are primarily derived from 2 large and distinct vision-threatening retinal diseases, age-related macular degeneration also known as wet AMD and diabetic macular edema, or DME.

Wet AMD represents approximately 70% of our U.S. EYLEA net sales and continues to grow as the population ages.

There are approximately 1 million patients with wet AMD in the United States and about 60% of them received anti-VEGF therapy.

Our goal in wet AMD is to ensure that patients are optimally treated to achieve the best visual outcomes and as importantly, maintain these vision gains over the long term using regular treatment in accordance with the labeled indication.

Our DME business represents approximately 25% of our U.S. EYLEA net sales and has been growing steadily.

We expect it to be an important driver of future growth.

EYLEA is currently the branded anti-VEGF market leader in diabetic macular edema.

This position was strengthened by data from Protocol T, which was an NIH-sponsored comparative effectiveness study in which diabetic macular edema that demonstrate -- and demonstrated that EYLEA treatment resulted in significantly greater gains in visual acuity than both Lucentis and Avastin treatment as well as significantly greater control of the edema itself.

The current treatment rates in diabetic eye diseases remain low.

In DME, the majority of patients are either untreated or received laser therapy, which in our pivotal trials was shown to be substantially inferior to treatment with EYLEA.

From a market penetration perspective, it's estimated that only about 10% of patients with DME in the United States are currently treated with an anti-VEGF agent.

Thus, DME represents a significant growth opportunity for EYLEA.

From a competitive perspective, we are not aware of any near-term, late-stage competitive threats on the horizon in DME.

It is important to remember that DME represents only a part of the overall diabetic eye disease opportunity for anti-VEGF therapy, which includes both proliferative and non-proliferative diabetic retinopathy without diabetic macular edema.

Recent data from a third-party study comparing EYLEA with pan-retinal laser photocoagulation in patients with proliferative diabetic retinopathy demonstrated that with EYLEA -- the resulted improvement in visual outcomes at -- EYLEA resulted in improved visual outcomes at the end of one year.

These data from the clarity study were published in Lancet in May of this year.

George will review these important results in greater detail.

As a reminder, EYLEA is approved in diabetic retinopathy for patients with DME.

It's estimated that there are approximately 500,000 patients in the United States with proliferative diabetic retinopathy and a vast majority are currently treated with laser therapy because of perceived medical urgency.

Data from the clarity study could potentially support the use of EYLEA in this setting.

In the U.S, there are approximately 1.8 million patients with vision-threatening diabetic retinopathy, including DME, proliferative diabetic retinopathy and severe non-proliferative diabetic retinopathy.

Currently, fewer than 30% of these patients are treated with anti-VEGF agents, representing a substantial potential market opportunity for EYLEA in diabetic eye diseases.

We have completed enrollment in our Phase III PANORAMA study of EYLEA compared to sham therapy in patients with non-proliferative diabetic retinopathy without DME and expect top line data in the first half of 2018.

George will review the strong data available that bode well for the PANORAMA study.

We are actively pursuing the indication of diabetic retinopathy and plan to submit a supplemental BLA in the second half of 2018 for this indication based on the PANORAMA study, should it be positive.

In addition to our PANORAMA study, the diabetic retinopathy clinical research network is conducting an government-sponsored Phase III study of EYLEA known as Protocol-W in diabetic retinopathy.

Let's turn now to Dupixent.

The launch in atopic dermatitis is underway and progressing very well.

Right from the early stages of the launch and continuing to the present, we have had a steady stream of about 500 prescriptions filled weekly for patients who are new to the brand.

Our patient and physician satisfaction rates are high, with over 90% of patients refilling their Dupixent prescription.

We have completed our Phase III program of dupilumab in asthma, and we and Sanofi are working toward a planned supplemental BLA submission to the FDA by the end of this year.

We recognized it will be a very competitive area and are confident that the efficacy and safety profile of dupilumab will place it in a very strong position if approved in asthma.

The dupilumab pivotal asthma program was the first with a biologic to enroll a broad population of uncontrolled asthma patients and demonstrate large and significant reductions in exacerbations and clinically significant improvements in lung function.

In terms of our broad strategy, we believe that dupilumab has the potential to improve the lives of patients with other allergic diseases because it targets a common central driver of type 2 inflammation.

In addition to atopic dermatitis and asthma, we have completed enrollment in 2 Phase III studies in nasal polyps and recently reported Phase II data in eosinophilic esophagitis, a disease with no FDA-approved treatment.

We believe this broad activity across these multiple allergic diseases is unique among the biologic therapy.

George will update you further on dupilumab data and clinical progress, and Bob Terifay will update you on our commercial activity.

With regard to our PCSK9 antibody Praluent, we believe that there is substantial opportunity yet to be realized.

We await data from our ODYSSEY OUTCOMES study in the first quarter of next year, and we continue to work on access, which is slowly starting to improve for this class of therapy.

We are pleased with the recent appellate court decision in our ongoing litigation concerning Praluent, which vacated the injunction and referred the case back for retrial in the District Court.

The appellate court ruled that the law requires a written description of the invention.

In this case, the antibodies, not the antigen or epitope they bind to.

Moreover, they instructed the district court to admit important new evidence that was improperly excluded from the first trial.

Finally, our immuno-oncology program with cemiplimab, our PD-1 antibody, continues to advance.

We are moving forward with the first planned regulatory submission in advanced cutaneous squamous cell carcinoma, a difficult to treat skin cancer as well as expanding the development program in first and second-line lung cancer, basal cell carcinoma and cervical cancer in addition to studies in combination with other antibodies and bispecifics.

Our pipeline continues to be robust with 16 product candidates in clinical development, all of which were discovered in our own labs and serve as a testament to the fact that our innovation engine continues to be exceedingly strong and productive.

With that, I'd like to turn the call over to George.

Thank you, Len, and a very good morning to everyone who has joined us on the call.

As Len mentioned, EYLEA continues to be a leader in the retinal disease space with a number of important near-term opportunities.

First, we expect to have our supplemental BLA for every 12-week dosing of EYLEA in wet AMD filed by the end of this year.

Echoing Len's thoughts, let me also update you on the potential opportunity for EYLEA in diabetic eye disease.

In our original pivotal studies in DME, we demonstrated superiority of EYLEA to laser in terms of visual acuity and other outcomes.

In the government-sponsored Protocol-T study, EYLEA was demonstrated to be superior in terms of visual acuity to the other commonly used anti-VEGF agents at the 1-year primary endpoint.

In these studies, in addition to these endpoints, EYLEA demonstrated a 2 or more step improvement in the diabetic retinopathy severity score, or DRSS, suggesting activity in both proliferative and non-proliferative diabetic retinopathy.

Consistent with this, as Len mentioned, positive data from the third-party clarity study in patients with proliferative diabetic retinopathy were recently published in the Lancet.

The medical urgency in this setting is reflected by the fact that the vast majority of proliferative patients are currently treated with pan-retinal photocoagulation laser therapy, or PRP, which has been the standard of care in this indication for almost 4 decades.

Clarity compared EYLEA to PRP and showed that patients treated with EYLEA gained approximately 4 letters in visual acuity compared to patients treated with laser.

This was the first time that an anti-VEGF agent has demonstrated superiority to laser treatment in patients with diabetic retinopathy without macular edema.

According to this published study, compared to PRP, EYLEA lowered the rate of new or increasing vitreous hemorrhage by about 50% and decreased the occurrence of macular edema at 52 weeks by approximately 60%.

In addition, an improvement in retinopathy from proliferative to non-proliferative was observed in 64% of patients treated with EYLEA compared to 34% of patients treated with the PRP.

There were no new safety concerns observed with EYLEA in this study.

Inflammation was more frequent in patients who received EYLEA, with 8% of patients supporting inflammation compared to 3% of patients who received PRP.

Near increasing vitreous hemorrhage was more frequent in the PRP group, with 18% of patients supporting this event compared to 9% in the EYLEA group.

PANORAMA, our Phase III study of EYLEA in patients with non-proliferative diabetic retinopathy without diabetic macular edema, exploring every 8 and 16-week dosing is fully enrolled.

We expect to report data in the first half of 2018 and if positive, expect to make a regulatory submission.

A separate Phase III study in this indication, Protocol-W, which is being conducted by the diabetic retinopathy clinical research network, or the DRCR, continues to enroll patients.

This study will explore every 16-week dosing of EYLEA, which is the only anti-VEGF treatment being investigated in this study.

Finally, on EYLEA, I want to remind you that we expect to have the top line data from our Phase II combination studies of EYLEA and nesvacumab, our antibody to ang-2 later this quarter.

While we have not seen the data, we have been pretty clear about the high bar that EYLEA monotherapy sets for any potential combination studies.

In our view, the results from the ang-2 combination studies are not central to the eye disease strategy that we have just outlined.

Turning now to dupilumab.

Our IL-4/13 blocker that is currently approved for the treatment of moderate to severe atopic dermatitis in adult patients whose disease is not adequately controlled with topical prescription therapies or when therapies -- those therapies are not advisable.

We recently reported positive Phase III results from 2 studies with dupilumab in patients with uncontrolled asthma, LIBERTY ASTHMA QUEST and LIBERTY ASTHMA VENTURE.

These 2 studies, in addition to our first pivotal study, enrolled a broad population of uncontrolled asthma patients and demonstrated reductions in exacerbations or asthma attacks and improvements in lung function as measured by FEV1.

The VENTURE study, which enrolled patients who required chronic systemic corticosteroids for asthma control showed that dupilumab could profoundly reduce systemic corticosteroid dependence with half the patients eliminating this dependence entirely.

Despite the reduction in systemic corticosteroid usage, dupilumab treated patients still had prominent increases in lung functions and fewer exacerbations compared to the control group.

Based on these data, dupilumab offers the potential for an important treatment alternative to systemic corticosteroids for these most serious of asthma patients.

Beyond the profound benefit in terms of exacerbations, I would like to emphasize the importance of dupilumab's demonstrated ability to improve lung function in asthma patients.

Since currently approved biologics do not consistently improve lung functions and were approved based on their ability to reduce exacerbations, this has resulted in a focus away from lung function in asthma.

However, one of the most serious day-to-day issues that patients with uncontrolled asthma suffer from and which dramatically impacts their lives is their inability to breathe normally.

For example, the patients in our pivotal studies only retained an average of 50% to 60% of a predicted FEV1 at baseline despite treatment with steroids and long-acting beta agonist.

Moreover, only a fraction of this lung function could be reversed with high doses of short-acting bronchodilators.

Therefore, we believe our finding that dupilumab improved lung function in all of our clinical trials in addition to reducing exacerbations is an important potential benefit to patients, if approved in this setting.

Results from the QUEST and VENTURE studies along with data from our previously reported and published with pivotal Phase IIb study will support the regulatory submission that we and Sanofi expect to make to the FDA by the end of this year.

As a reminder, the recently reported QUEST and VENTURE studies included adolescent patients between the ages of 12 and 17 years.

We're also currently conducting a Phase III study in pediatric patients between the ages of 6 and 11 years.

Work on the development of dupilumab and other type 2 diseases such as nasal polyposis and eosinophilic esophagitis is ongoing.

Following positive results in Phase II, I'm pleased to report that both Phase III studies in patients with nasal polyposis are now fully enrolled.

Turning to eosinophilic esophagitis, or EOE, a chronic type 2 immune-mediated disease that is strongly associated with food allergies.

EOE is characterized by pain and difficulty swallowing, and the possibility of food impaction, which are consequences of pathological structural changes in the esophagus.

There are currently no approved therapies in the U.S. for the treatment of EOE.

All corticosteroids are used off label, but with limited long-term efficacy and safety data to support their use.

At the recent World Congress of Gastroenterology, we presented additional data from our positive Phase II study.

These data show that dupilumab significantly improved swallowing, in addition to esophageal eosinophil counts, endoscopic features histology and esophageal distensibility in adults with active EOE compared with placebo.

This safety profile seen in the study was consistent with that observed in the other studies of dupilumab.

Dupilumab has been granted orphan drug designation in this indication, and Phase III studies are being planned.

I'd like to now turn to atopic dermatitis, an indication where Dupixent is approved both in the United States and in Europe.

In September, we presented positive data from CAFÉ, a Phase III study of Dupixent in patients with moderate to severe atopic dermatitis who are inadequately controlled with or intolerant of cyclosporine, which is approved in certain countries outside the United States.

This study demonstrated that these -- in these difficult to treat patients, Dupixent in combination with topical steroids significantly improved measures of overall disease severity and patient-reported quality of life measures, with the mean improvement of 80% in the eczema area and severity score or the easy score.

No new adverse events were reported in this study.

We're also continuing to work on expanding development in moderate to severe pediatric atopic dermatitis patients.

Turning to immuno-oncology, which is another area of growing excitement for us.

I'd like to begin with cemiplimab, our foundational PD-1 antibody.

Our lead indication is advanced cutaneous squamous cell carcinoma, or CSCC, for which we have been granted breakthrough designation by the FDA.

We expect to report interim data later this year and to make a regulatory submission to the FDA in the first quarter of 2018.

Our PD-1 program has continued to expand.

We recently initiated a Phase III program of cemiplimab monotherapy in first-line non-small cell lung cancer.

This 300-patient study, which is being conducted outside the United States, will enroll patients who express greater than 50% PD-L1 and will compare cemiplimab to standard of care platinum doublet.

The primary endpoint of this study is progression-free survival.

We're planning additional studies, including combinational studies in non-small cell lung cancer as well as clinical trials in the second-line non-small cell lung cancer.

Remind you that with all the recent failures in this space, there is only one approved PD-1 or PD-L1 agent in the first-line non-small lung cancer setting.

We also recently initiated a Phase III study in second-line cervical cancer.

With our ongoing potentially pivotal study in basal cell carcinoma, this brings us to 4 potentially pivotal programs with our PD-1 antibody.

We also have exploratory studies ongoing in melanoma and head and neck cancer, and we're also conducting and planning studies with cemiplimab in combination with our antibody to LAG3 in a variety of indications as well as a number of other combination approaches with cemiplimab including with our bispecifics.

Turning now to these bispecifics.

We will be presenting further positive data from our CD20xCD3 program, both as monotherapy and in combination with cemiplimab and b-cell malignancies at the December meeting of the American Society of Hematology, or ASH.

As a reminder, the CD20xCD3 program has been granted orphan drug designation for diffuse large cell -- b-cell lymphoma, or DLBCL.

We're also conducting a combination study of our CD20xCD3 bispecific with cemiplimab in CD20-positive malignancies.

We plan to put additional bispecifics into clinical trials over the next several years.

Fasinumab, our NFG antibody, continues to advance in the clinic.

We're currently enrolling patients in the Phase III study in osteoarthritis pain, where we are investigating fasinumab compared to naproxen.

We also plan to initiate a second study of fasinumab in osteoarthritis pain.

I'll turn now to our mid- and earlier-stage pipeline.

Nesvacumab is our antibody to ANGPTL3 for the treatment of severe forms of hyperlipidemia.

We are planning Phase III studies in homozygous familial hypercholesterolemia, or homozygous FH, and Phase II studies in severe hypertriglyceridemia and in heterozygous familial hypercholesterolemia, or HetFH.

We plan to initiate by year-end the Phase II study of Regeneron 2477, our Activin A antibody, in the ultrarare disease of fibrodysplasia ossificans progressiva, or FOP.

We're also exploring the use of our Activin A antibody in combination trevogrumab, our GDF8 antibody, in muscle and metabolic disorders.

Another exciting early-stage program is Regeneron 3500, our antibody to the interleukin-33 ligand, which is in the clinic, and we plan to investigate for asthma, COPD and other indications as both the monotherapy and in combination with dupilumab.

With that overview, I'd like to turn the call over to you Bob Terifay.

Thank you, George, and good morning, everyone.

EYLEA or aflibercept continues to be the market-leading product among FDA-approved anti-VEGF agents for all of its approved indications in the United States.

U.S. EYLEA sales grew 12% year-over-year in the third quarter of 2017 in a market that grew by about 11%.

Ex-U.

S. sales grew by 20% year-over-year in a market that grew 13%.

As was summarized by Len and George, we look forward to the potential of expanding the use of EYLEA in diabetic eye diseases, which we feel is a substantial potential opportunity.

Turning now to the recent launch of Dupixent or dupilumab in the United States for the treatment of adults with moderate to severe atopic dermatitis.

Global sales for Dupixent in the third quarter were $89 million.

This number almost entirely represents sales in the United States, since Dupixent only recently received regulatory approval in Europe at the end of September.

We're pleased with the way the U.S. launch is tracking across a number of important metrics, and the commercial organizations are focused on delivering a successful launch.

Let me begin with the physician perspective.

As of last week, over 7,000 health care providers had written prescriptions for Dupixent for adult patients with moderate to severe atopic dermatitis.

The prescription trajectory as measured by total prescriptions has remained strong and is trending ahead of comparable biologic launches in dermatology.

In terms of new patient starts as assessed by new-to-brand prescriptions, we've seen on average approximately 750 new patients prescribed Dupixent each week and approximately 500 new patients starting therapy each week since the early part of the launch.

Importantly, of the patients who've started on Dupixent, over 90% renew their prescription suggesting a high degree of patient and physician satisfaction.

On the market access side, we're happy to report that about 80% of commercial lives are now covered by health plans that have a published Dupixent policy.

Of these patients, almost half have prior authorization to label.

Or in other words, they can receive Dupixent by stepping through only topical therapy without requiring prior systemic therapy or a severity requirement.

In addition to coverage at Express Scripts and CVS, Dupixent is also on formulary at Optum, Aetna, Anthem and United.

In the coming weeks, we'll be launching unbranded direct-to-consumer television advertising to increase awareness of moderate to severe atopic dermatitis.

Outside of the United States, Dupixent has received regulatory approval in Europe, and we're preparing for launch in Germany.

It's estimated that the addressable European patient population of moderate to severe atopic dermatitis patients is between 150,000 and 200,000 patients.

A regulatory submission for Dupixent has been made in Japan with the decision expected in the first quarter of 2018.

In addition to the ongoing launch in atopic dermatitis, we're also preparing to launch dupilumab in asthma.

As mentioned earlier, we're on track to file a supplemental BLA submission to the FDA by the end of this year.

Additionally, we and Sanofi plan to file a European regulatory submission in adult and adolescent patients in the first quarter of 2018.

Turning now to Kevzara or sarilumab, our IL-6 receptor antibody for the treatment of rheumatoid arthritis.

Net global sales for the third quarter was $3 million.

It's still very early given the Kevzara was approved to launched in the United States towards the end of May and reimbursement decisions for RA biologics take some time.

Initial feedback from physicians has been positive, and we're working on building market access.

We're happy to report that just recently, CVS Health announced that effective January 1, 2018, Kevzara will be designated as the preferred IL-6 receptor antibody on their national formulary.

We've received EMA approval for Kevzara with launches in Germany and the Netherlands underway.

Now let's discuss Praluent or alirocumab.

Net sales in the third quarter were $49 million worldwide, with the U.S. accounting for $32 million of the total.

While we continue to be disappointed with the uptake of the PCSK9 inhibitor class, we're encouraged by ongoing discussions with payers with respect to improvement in utilization management criteria and documentation requirements.

Recently, CVS Health announced that effective January 1, 2018, it would provide co-preferred access to Praluent through its CVS Caremark commercial formularies, which cover approximately 25 million lives.

We remain optimistic about the long-term potential for this class.

We anticipate a cardiovascular outcomes data for Praluent in early 2018 could have an impact on demand.

We remain committed to our efforts to improve Praluent access and bring this important product to more patients who can benefit.

As George mentioned, cemiplimab, our PD-1 inhibitor program in immuno-oncology, is advancing with a regulatory submission in CSCC anticipated in the first quarter of 2018.

We will co-promote cemiplimab in the United States with Sanofi Genzyme.

As a reminder, we would distribute and book U.S sales.

With that, let me turn the call over to our Chief Financial Officer, Bob Landry.

Thanks, Bob, and good morning, everyone.

Regeneron posted strong third quarter 2017 financial results.

These positive results were driven by continued growth in our global EYLEA franchise, a strong U.S. Dupixent launch and a significant contribution of revenue from both our Sanofi and Bayer collaborations.

During today's call, I'll discuss each of these matters in addition to highlighting changes to our full year 2017 guidance line items.

In the third quarter of 2017, we earned $3.99 per diluted share from non-GAAP net income of $470 million.

This represents a year-over-year increase in non-GAAP diluted EPS and net income of 27% and 29%, respectively.

Regeneron's third quarter 2017 non-GAAP net income excludes noncash share-based composition expense, including the income tax effect.

A full reconciliation of GAAP and non-GAAP earnings is set forth in our earnings release, which can be found on our website.

Total revenues in the third quarter of 2017 were $1.5 billion, which represents year-over-year growth of 23% compared to the third quarter of 2016.

Net product sales were $957 million in the third quarter of 2017 compared to $857 million in the third quarter of 2016, which represents year-over-year growth of approximately 12%.

EYLEA net product sales in the United States are $953 million in the third quarter of 2017 compared to $854 million in the third quarter of 2016, which represents an increase of 12%.

For the 9 months ended September 30, 2017, EYLEA net product sales in the United States were $2.73 billion versus $2.47 billion for the 9 months ended September 30, 2016, an increase of 11%.

We are reaffirming our estimated full year 2017 U.S. EYLEA net product sales growth guidance of approximately 10% over 2016.

As a reminder, this is the last quarter where we will be providing U.S. EYLEA net sales guidance.

Similar to the previous 2 quarters of 2017, EYLEA experienced another decrease in U.S. distributor inventory levels, albeit slight during the third quarter, with distributor levels continuing to remain within our normal 1 to 2-week targeted range.

Ex-U.

S. EYLEA net product sales, which are recorded by our collaborator, Bayer, were $564 million in the third quarter of 2017 as compared to $471 million in the third quarter of 2016, representing a 20% increase on a reported basis.

On an operational or constant currency basis, sales increased approximately 19%.

For the 9 months ended September 30, 2017, ex-U.

S. EYLEA net product sales were $1.59 billion versus $1.38 billion for the 9 months ended September 30, 2016, an increase of 16% on a reported basis and 18% on an operational basis.

In the third quarter of 2017, Regeneron recognized $205 million from our share of net profits from EYLEA sales outside the United States.

Total Bayer collaboration revenue for the third quarter 2017 was $237 million.

Total Sanofi collaboration revenue was $245 million for the third quarter of 2017.

The Sanofi collaboration revenue line item primarily consists of reimbursement of Regeneron incurred R&D expenses, reimbursement of Regeneron incurred commercialization-related expenses and the recognition of deferred revenue from the antibody and immuno-oncology upfront payments, partly offset by our share of losses in connection with commercialization of antibodies.

In the third quarter of 2017, our share of losses in connection with the commercialization of Dupixent, Praluent and Kevzara was $98 million compared to a loss of $122 million in the second quarter of 2017 and a loss of $112 million in the third quarter of 2016.

The decrease in our share of losses was primarily based upon the profit contribution from increased third quarter Dupixent sales and lower alliance commercial expenses for Praluent, offset by a modest increase in our alliance commercial expenses for Dupixent and Kevzara.

Global sales of Dupixent, Praluent and Kevzara as recorded by our collaborator, Sanofi, for the third quarter of 2017 were Dupixent $89 million, Praluent $49 million and Kevzara $3 million.

For both Dupixent and Kevzara, the sales were almost exclusively U.S.-based.

As stated by our collaborator, Sanofi, on their earnings call last week, Dupixent third quarter 2017 net sales included modest wholesaler inventory stocking, not unexpected in the $89 million sales figures, is a true representation of the underlying demand.

While we are encouraged with the reduction in our share of alliance losses on the antibody collaboration in the third quarter of 2017, I want to continue to highlight that the alliance's profitability will continue to be negatively impacted by increased global launch expenses to support Kevzara and Dupixent.

As a result, we are expecting a higher alliance loss in connection with commercialization of antibodies in the fourth quarter of 2017 than what was realized in the third quarter of 2017.

The third quarter 2017 Sanofi collaboration revenue also benefited from an acceleration of the recognition of deferred revenue in connection with the termination of the antibody discovery agreement on December 31, 2017.

$130 million of 2017 annual funding from Sanofi under the antibody discovery agreement was fully utilized during the first 9 months of 2017.

Due to this utilization, we expect Sanofi's reimbursement of Regeneron research and development expenses in the fourth quarter 2017 to be lower than any of the 3 previous quarters.

In the third quarter of 2017, other revenue was $62 million versus $27 million during the third quarter of 2016.

This increase was primarily due to the reimbursements from our collaborator, Teva, for the development of fasinumab.

For further details, you can find a summary of the components of other revenue in the MD&A section of our 10-Q.

Turning now to expenses.

Non-GAAP R&D expenses were $460 million for the third quarter of 2017.

Our non-GAAP unreimbursed R&D expense, which is calculated as the total non-GAAP R&D expense less R&D reimbursement from our collaborators, was $227 million in the third quarter of 2017.

Our press release includes all the information that's required to calculate unreimbursed non-GAAP R&D expense.

We are lowering and tightening our full year 2017 guidance for non-GAAP unreimbursed R&D to be in the range of $885 million to $915 million from our previous guidance of $925 million to $965 million.

Non-GAAP SG&A expense was $259 million for the third quarter of 2017.

It represents a slight decrease from the previous quarter.

Given our 9-month actual results and forecasted fourth quarter spend, we are tightening and lowering our full year 2017 guidance of non-GAAP SG&A to $1.07 billion to $1.1 billion from our previous guidance range of $1.12 billion to $1.16 billion.

Based on this revised guidance, you will see that we are forecasting a higher SG&A spend level for the fourth quarter of 2017, resulting from the delayed timing of third quarter spend.

In addition, as I previously mentioned, we are expecting higher fourth quarter incremental global spend on our 2 recently FDA and EMA approved launches.

Dupixent and Kevzara as well as prelaunch expenses for the anticipated 2018 U.S. approvals for dupilumab in cutaneous squamous cell carcinoma in the dupilumab asthma indication.

Sanofi reimbursement of Regeneron commercialization-related expenses, a line item found within Sanofi collaboration revenue, was $90 million for the third quarter of 2017.

We are tightening and lowering our full year 2017 guidance of Sanofi reimbursement of Regeneron commercialization-related expenses to $350 million to $375 million from our previous guidance range of $370 million to $400 million.

Non-GAAP cost of goods sold and cost of collaboration and contract manufacturing increased for the 3 months ended September 30, 2017, compared to the same period in 2016, principally due to an increase in start-up costs and validation activities for our Limerick commercial manufacturing facility.

Turning now to taxes.

Our effective tax rate for the third quarter of 2017 was 31% as compared to 28% for the third quarter of 2016.

For the full year 2017, we are tightening and lowering guidance for our effective tax rate to be in the range of 26% to 29% from the previous range of 27% to 31%.

The updated guidance reflects higher actual and forecasted tax deductions from stock options.

As stated on previous earning calls, there will be volatility in our effective tax rate on a quarter-to-quarter basis since the tax benefit of stock-based compensation is included based on actual exercises in the quarter.

We expect to experience this volatility in the fourth quarter of 2017, as the majority of our options are issued in December and typically a large number of options vest and/or exercised in the fourth quarter.

As a result, we expect our fourth quarter 2017 effective tax rate to be significantly below both the third quarter and full year 2017 tax rates.

From a cash flow and balance sheet perspective, we ended the third quarter of 2017 with cash and marketable securities of $2.7 billion.

Our capital expenditures for the 3 and 9 months ended September 30, 2017, were $60 million and $165 million, respectively.

We are tightening our full year 2017 capital expenditures guidance to be in the range of $265 million to $285 million from our previously provided range of $250 million to $285 million.

With that, I'd like to turn the call back to Manisha.

Thank you, Bob.

Paulette, we'd now like to open the call for Q&A.

In the interest of time, we request you to limit yourself to one question.

We will be available in the office after the call for follow-up questions.

(Operator Instructions) And our first question comes from Chris Raymond from Piper Jaffray.

Just a question on the Dupixent prescriber base, if you don't mind.

I just noticed in previous communications, you guys have talked about an initial target base, I think, of 7,000 derms with previous biologic experience.

I think I heard today, Bob, talk about having had 7,000 docs write a script for the drug.

So maybe can you just talk about that mix?

Is that current 7,000 base -- is that the initial target?

Or were there others that you maybe didn't expect?

And maybe talk about the road in front of you here in terms of getting other docs to prescribe the drug.

Yes, so, Chris, you're correct.

Our original target audience were physicians who have written a biologic for psoriasis in the past.

And that was slightly over 7,000 patients.

What we have found when we've gone out to the dermatologist offices is there is other dermatologists in those offices who take an interest in atopic dermatitis patients and have started to use the product.

For the future, what we anticipate is that we will see other prescribers as patients become aware through our direct-to-consumer campaign on the severity of the condition and the need to seek out a dermatologist and that there could be an increased urgency to treat over time.

Operator, next question please.

Our next question comes from Geoffrey Porges from Leerink.

Number of things, but perhaps we can talk, you suggested sort of part of life cycle management strategy for EYLEA alluded to on the call.

But is there anything you could talk about first with respect to the prefilled syringe offering for EYLEA?

And then secondly, do you have anything in mind that you could do with Dupixent given how important it's going to be to the company to reduce the dosing frequency with the product in some new formulation or preparation?

All right.

Thanks, Geoff.

So we probably don't want to get into Dupixent given the competitive aspect of that space.

But we continue to look at also to different ways to create value.

We can assure you of that.

And in terms of EYLEA in the prefilled syringe, we had 2 issues.

Genentech was ahead of us with the prefilled syringe and now they're fully launched.

But I think, as you saw in Bob's report, our market share was steady.

And so -- and that has not really created a problem for us.

Nevertheless, we're still moving forward with ours, and I think we expect to have a filing, perhaps, sometime in the first half of next year or so.

It's a complicated business, the prefilled syringe, because of the sterilization requirements when you're dealing with eye diseases.

It took Genentech, I don't know, quite a long time to get there, and we hope to be not too far behind them.

Our next question comes from Ying Huang from Bank of America Merrill Lynch.

I have another question on Dupixent.

Right now, Sanofi commented that most of the patients on Dupixent are the severe patients with atopic dermatitis.

When do you think this drug can penetrate into the moderate patient segment?

And then, also, are you planning to increase investment in Praluent now that the court gave you a favored ruling?

Or you have to wait until you have the ODYSSEY OUTCOME?

So with regards to Dupixent, Sanofi was correct.

What we're seeing is that physicians are initiating Dupixent therapy in the patients with severe atopic dermatitis.

Now what is encouraging is that the patients are responding.

So even in those very, very severe patients, we're getting a good response.

We do anticipate that physicians will become more and more comfortable with using a biologic for a condition they have not used one for before, which is atopic dermatitis.

And that we should see expansion into moderate AD over the next several months.

That should also be helped by our direct-to-consumer campaign.

With regards to investment in Praluent.

I think we've been very prudent this year.

We have managed our investment, focused in on where we can best get business, which is primarily on education, and we'll continue to be modest on our spend until we get the OUTCOMES data.

And we move forward with the court case.

Our next question comes up from Robyn Karnauskas from Citi.

So I just wanted to ask a little bit about the pipeline because I thought you did a great job articulating the EYLEA business and how it can grow.

So just the next leg of growth, maybe talk a little bit about how you envision the checkpoint -- your checkpoint drug being a next leg of growth.

And what has to happen for that to succeed?

Robyn, I didn't -- I'm not sure I heard the question.

Was it -- were you asking about the immuno-oncology program?

Is that what your question was about?

Oncology program.

How do you see that being a next leg of growth and what has to happen?

And how do you see that playing out over the next few years?

How do you see that shaping up?

Yes.

Okay.

George may have some comments on it.

But I think the most important thing that he pointed out to me in some of his remarks is that despite all the efforts, despite everybody viewing this is an incredibly crowded space, there is only one anti-PD-1 or PD-L1 that's been approved in frontline -- first-line lung cancer.

And that is sort of the biggest opportunity of all, which we are now busy enrolling a study in that indication in the [greater than] 50%.

Beyond that, of course, combinations and George mentioned LAG3 and bispecifics, and I think we have some pretty encouraging bispecific data coming up at the next meeting.

Right.

I mean, it's just worth noting.

Obviously, it's going to be a long-term growth opportunity over, we think, a long period of time by adding additional opportunities to it and combining things.

We think we have one of the strongest portfolio of combination opportunities that we've already started studying in the clinic and more will follow.

But even the very first indication should not be underestimated.

If you look at the cutaneous squamous cell carcinoma, there's enormous need there.

And the actual -- it is actually that the number of cases is huge.

And it's been largely ignored because of the vast, vast majority of them can be treated surgically.

But because there is something on the order of a million or 2 million cases.

And even though something like over greater than 95% are treated surgically, that still leaves an opportunity of unresectable or metastatic disease, which is on the order of magnitude of melanoma.

And like I said, I think it was largely ignored by the community because of the perspective that though it was one of the, if not the most common cancers, afflicting patients.

The vast, vast majority are treated successfully with these Mohs type surgeries and so forth.

So the important thing to add is even that first opportunity, there's a lot of needed there, there's a lot of patients who are failures or cannot be treated with surgery and that opportunity is on the order of magnitude of melanoma, which as we know was a huge growth driver for the 2 original PD-1 agents.

Our next question comes from Matthew Harrison from Morgan Stanley.

I guess, I was hoping you could talk a little bit about PANORAMA and just talk to us about you obviously outlined the size of the markets for what AMD and DME.

How do you view diabetic retinopathy relative to the size of those other markets and how do you see that being a growth driver for EYLEA, if you were to have a successful study?

So I'm going to let George talk about PANORAMA and why we have a reasonably high degree of confidence in that study in just a second.

I just want to say in terms of the market opportunity, the lowest hanging fruit, obviously, is the proliferative diabetic retinopathy because people recognize that as really vision-threatening and most people get some sort of the laser that's been going on for decades as we mentioned.

So it's hard to know exactly how many people there, but that represents a pretty big opportunity.

And with this clarity study that was published in the Lancet, where you not only saw better visual acuity outcomes in the year, you saw less hemorrhages, you saw less macular edema, less of the complications that you're so worried about, which is why you want to treat proliferative diabetic retinopathy.

But beyond that, even the treatment of severe diabetic retinopathy, which is non-proliferative, is really in its infancy.

There isn't quite the same perceived urgency there, but I think if we can show that we can reverse that, I think that, that's going to sort of maybe change people's view on whether or not people should get treated or should they wait, which is the current thing, wait for them to get the complications.

Perhaps, it is better to treat early.

And now George can comment a little bit about on the study itself and why.

I think Len made all the important points, and let me just echo.

The most important point is that, where the need right now in diabetic retinopathy is perceived as the most urgent as in proliferative eye disease, there's roughly 0.5 million such patients in the United States.

And 80% or 400,000 of them receive ablative laser therapy, the most serious of laser therapies.

And now with the clarity data, what has a head-to-head comparison showing by every measure from visual acuity to just as importantly having the risk of developing vitreous hemorrhages reducing by almost 2/3 the risk of developing macular edema.

This is something that I think patients deserve to have access to and deserve to get in this setting because without ablating their retinas, they can have better vision and better outcomes and avoid catastrophic events like vitreous hemorrhages.

I think that the 2 million or so people who have diabetic retinopathy that's considered little less urgent, I think that this could be an important advance for those patients as well and already all the existing data suggest that, but I think that there'll be probably slower uptick.

It'll be a longer haul to change the practice of medicine there where many of those patients are treated with the wait-and-see attitude because they haven't had a drug like EYLEA thus far.

But I really do think in proliferative eye disease, 500,000 patients, those patients deserve to get a therapy that's been shown in a head-to-head study to be so substantially beneficial, not only in terms of visual acuity, but in terms of preventing catastrophic outcomes, which is why they're treated so urgently with ablative therapy.

And then just the last point on that, Robyn, is that in the competitive environment, it's less acute there, obviously, because the near-term competition hasn't begun any diabetic macular edema studies.

And by the way, in our DME studies, we looked at the same endpoint for the patients with diabetic retinopathy in our PANORAMA study because our DME studies were in patients with diabetic retinopathy.

But we were treating their DME, their diabetic retinopathy improved just the way we hoped and expect that it will improve in PANORAMA, which is what the FDA just asked us to do is to do a study in patients without the DME component and that's why we have some, I would say, reason behind confidence in that study.

Our next question comes from Cory Kasimov from JPMorgan.

I was curious for asthma.

How important do you think baseline eosinophil counts will be when thinking about which patients to prescribe Dupixent in the real world?

Well, I mean, let's just review what the facts are.

If you look at our data and you can't make these cross-study comparisons and take them overly seriously.

But if you look at our data, we enrolled a very broad population, but the drug works better the higher the eosinophil count is.

And if you look in our high eosinophilic count, I would argue some of the best data that's been presented with any of the biologics, including a robust very significant effect on exacerbations as well as the effect on lung function.

But we also were able to enroll a very broad population in all 3 of our studies.

So we would hope and argue that it doesn't really matter if you're worried about treating the eosinophilic type, which has more exacerbations and may represent the more urgent need.

We think our drug will offer a terrific opportunity, especially with the differentiating factors that we talked about around pulmonary function and if you happen to have another allergic disease.

And these things do run in packs if you happen to also have severe atopic dermatitis or moderate to severe, you would get 2 treatments for the cost of one.

But of course, we also think about that across the broad spectrum.

Ours is the first biologic to be studied, of course, that consistently in all of our trials.

So no matter how you look at our data, we like it.

We and Sanofi are very pleased with the data.

Yes, maybe just to put into a little bit of context as Len said, we did 3 pivotal studies.

And in the overall population, as Len said, it's hard to compare across studies, but I don't think anybody would argue that.

In the overall population, even in the worst of the 3 studies in terms of the numbers, they look quite comparable to the highest eosinophilic groups for either approved biologics or for near-term biologics that are coming down there.

But -- and obviously, we also have even better data in the high eosinophilic patients.

And as well as that, I think, the most important differentiator also has to be not only do we have comparable results to what others have in the high EOS in the overall population, but we have these lung function results.

And I think that this has been just -- as we try to communicate during our prepared remarks, this has been somewhere where the field has been going away from only because biologics to date have not been doing such a good job.

If you remember the way XOLAIR got approved, up until that point, lung function was the standard for approval.

But because XOLAIR had no effect on lung function, they switched the focus to these exacerbations, which obviously, are very important and so forth.

But if you know anybody with asthma, you know that the thing that they suffer from and they worry about on a day-to-day basis is the shortness of breath that they can suffer from with a little bit of exercise or some other trigger that they might be suffering from.

And I think it's really important to recognize that the results on lung function are really impressive, not only on the overall population, but even more impressive in the high eosinophilic population.

So once again, I think if anybody honestly looks at the data and looks at the effects not only in the overall population, not only exacerbations, but also on lung function, you would think that this is the treatment that patients deserve to be given to benefit their condition and not only the high eosinophilic patients, but the overall population.

Yes, I also think that you can't ignore mechanism here.

There's been a lot of claims that people are getting to the fundamental mechanisms of allergic disease.

And it's hard to say that you're at the fundamental mechanism of allergic disease if in one allergic disease it works and another allergic disease it doesn't work.

And it's hard to say you're getting it to the fundamental basis of the allergic disease if you're only affecting part of the disease like exacerbations and not affecting lung function.

It's hard to say you're getting at the fundamental part of the disease if in eosinophilic esophagitis, you can lower your eosinophils, but you can't improve the symptoms of the actual inflammation that's going on in the esophagus.

So I think that a lot of this goes back to the choices that were made a long time ago in what is the right fundamental way to interfere with this type 2 allergic inflammation.

And I just want to add to that.

As Len brings up a really good point, which is that part of our clinical development plan is actually to do studies where we show that in the same patients, we will be able to benefit multiple allergic conditions.

And that is I think something that, if you know people who are suffering from any one of these severe allergic conditions, whether it's atopic dermatitis, for example, or severe asthma, they generally are suffering from other allergic conditions as well.

And wouldn't it be wonderful if there was a drug that was essential driver of all of allergic disease that could benefit potentially all of the allergic manifestations of a single patient.

So that is part of our clinical development plan going forward that we are going to be doing studies to actually be able to show that, hopefully.

And we don't think there's any other current biologics out there that even have the opportunity to consider the possibility of doing those studies.

And our last question comes from Josh Schimmer from Evercore ISI.

Just one on the IL-33 antibody.

Can you elaborate on its positioning?

What it brings to the table in addition to or instead of Dupixent?

And is this a general area that you expect to further build pipeline?

Well, I think that, that's a great question.

Thanks for bringing it up.

And obviously, we didn't have enough time to really go into everything.

But this is a really exciting target for us for many reasons.

One of which is a lot of the biology that our group did to understand it.

But just as much is that this is a recent success from our Regeneron Genetics Center.

These large-scale sequencing efforts that we've undertaken to try to see how genetic variation is associated with disease.

And IL-33 is one of the exciting premier targets that has been in our minds identified and validated by the genetics, not only in this disease, but in some other allergic diseases.

So we've actually seen genetic evidence that gain-of-function mutations in IL-33.

It increases the chances of having some of these disease loss-of-function mutations are protective.

And that gets us a lot of confidence.

We've always been driven by genetics.

But in this case, it's using the latest large-scale genetics approaches to actually identify and validate targets that gives us this confidence to move this forward so rapidly.

And the thing that's very exciting to us is this is an area where we already feel.

We have made this advance and have this foundational treatment in dupilumab.

And wouldn't it be great now, if we could improve the benefit in some patients by combining it with the IL-33.

And once again, we're considering doing this in multiple allergic conditions because the genetic support that this can be the case, not only in asthma, but in COPD and maybe atopic dermatitis and other settings as well.

Right, let's just close one point that I think maybe we didn't emphasize enough is that the other thing that's really important about dupilumab is we really do have an extensive clinical development profile from the safety point of view.

And that's building every day in the commercial point of view.

And going forward in this field, Dupixent is now set an extremely high bar, I believe, not just on the efficacy side, but on the safety side.

In the rheumatoid arthritis field, people, because biologics came with a cost, are willing to accept that cost because they had great efficacy.

We've got really what I think is terrific efficacy.

But also, almost unprecedented safety that we've seen thus far in our clinical trials.

We really haven't seen the kinds of immune dysfunction problems that you see when you block other angles of the immune system.

And just to add to that, again, I mean, I think this is the future, the future of medicine and it's the future of drug development.

The genetics that we have to support our targets, for example, IL-33.

Not only are supporting that blocking IL-33 function or loss of function mutants in IL-33 can be protective, but they're also comforting us in terms of the safety profile going in.

So genetics are really offering an opportunity to get insights before you ever do studies in humans into the future potential benefit, but also the safety profile, which is another reason why we're very excited about the IL-33.

Paulette, that concludes our call today.

Thank you, ladies and gentlemen.

This concludes today's conference.

Thank you for participating, and you may now disconnect.