Alkermes Plc (ALKS) 2018 Q3 法說會逐字稿

Good morning, and welcome to the Alkermes plc Third Quarter 2018 Financial Results. My name is Brandon, and I'll be your operator for today. (Operator Instructions) Please note, this conference is being recorded.

And I will now turn it over to Sandy Coombs, Co-Head of Investor Relations. Sandy, you may begin.

Thank you. Welcome to the Alkermes plc conference call to discuss our financial results and business update for the quarter ended September 30, 2018. With me today are Richard Pops, our CEO; Jim Robinson, our President and COO; and Jim Frates, our CFO.

Before we begin, I encourage everyone to go to the Investors section of alkermes.com to find our press release and related financial tables, including a reconciliation of the GAAP to non-GAAP financial measures that we'll discuss today. We believe the non-GAAP financial results in conjunction with the GAAP results are useful in understanding the ongoing economics of our business.

Our discussions during this conference will call include forward-looking statements. Actual results could differ materially from these forward-looking statements. Please see Slide 2 of the accompanying presentation and our most recent annual and quarterly reports for important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the information provided on this call or in the accompanying presentation as a result of new information or future results or developments.

Today, Jim Frates will discuss our financial results, Jim Robinson will share his perspectives on our commercial portfolio and Richard will provide an update on the company. After our remarks, we'll open the call for Q&A.

Now I'll turn the call over to Jim Frates for a review of our financial results.

Thank you, Sandy. Good morning, everyone. This morning, I'll provide a review of our 2018 third quarter financial results and share a few updates to our full year guidance. The fundamental elements of our business are performing as planned, with additional upside from AMPYRA. Today, we're adjusting our financial expectations for 2018 to reflect increased revenues due to delayed generic entrance for AMPYRA, which has now occurred. The increase in expected revenues will also flow through to our bottom line with improved GAAP net loss and non-GAAP net income for 2018, which I'll detail more fully in a moment.

Turning to the quarter, we delivered strong results highlighted by total revenue growth of approximately 14% year-over-year to $248.7 million and non-GAAP net income of $11.6 million. These results were driven by 24% growth of our proprietary products year-over-year and the continued strength of our base royalty and manufacturing business, including the higher-than-expected AMPYRA revenues resulting from a delay in generics entering the market.

During the quarter, VIVITROL net sales increased approximately 15% year-over-year to $79.9 million, driven by unit growth of approximately 18%. Sequentially, VIVITROL net sales grew approximately 5% compared to the second quarter, driven by favorable gross-to-net adjustments, which were approximately 47% for the third quarter, down from 49% in Q2. The results saw a modest increase in inventory in the channel, which stood at approximately 2.5 weeks at the end of the quarter, well within our normal ranges. We continue to expect VIVITROL net sales to be in the range of $300 million to $330 million for 2018, though likely towards the lower end of that range.

Turning to ARISTADA. Net sales increased approximately 48% year-over-year to $36.1 million in the third quarter and grew approximately 8% sequentially. Gross-to-net adjustments for ARISTADA were 47% for the quarter, up from 43% during the second quarter as expected due to the continued shift in volume towards the largest Medicaid accounts. Today, we're reiterating our expectations for net sales in the range of $140 million to $160 million for ARISTADA in 2018.

Moving on to our manufacturing and royalty business. We saw revenues of $116.4 million in the third quarter compared to $122.7 million in the third quarter of last year. RISPERDAL CONSTA, INVEGA SUSTENNA and INVEGA TRINZA continue to be important drivers of our diverse portfolio of manufacturing and royalty revenue streams. And during the quarter, we recorded revenues of $77.2 million compared to $79.4 million for the same period last year. This reflects continued growth of INVEGA SUSTENNA, which was offset by the timing of manufacturing revenues for RISPERDAL CONSTA during the quarter. Overall, the long-acting injectable atypical market in the United States has continued to demonstrate solid year-over-year growth.

For AMPYRA and FAMPYRA, we recorded manufacturing and royalty revenues of $20.3 million during the third quarter compared to $24.5 million for the same period last year. This was stronger than expected as generic entrants were delayed coming to market. We expect revenues from AMPYRA and FAMPYRA in the fourth quarter to be approximately $20 million.

Due to the recent launch of generic competition in the United States, we expect our AMPYRA revenues will be substantially lower during 2019.

In the third quarter, we recorded R&D revenues of $16.3 million, primarily related to the reimbursement of development expenses for diroximel fumarate or BIIB098 from our collaboration with Biogen. We continue to expect a consistent level of R&D activity around BIIB098 in Q4.

In terms of expenses, our total operating expenses for the third quarter of 2018 were $285.9 million compared to $255.7 million for the same period last year. This year-over-year increase was largely driven by investments in the commercial organization in support of VIVITROL and ARISTADA. Our investment in SG&A decreased slightly compared to the second quarter, primarily driven by the timing of launch activities for ARISTADA INITIO in Q2. Overall, our expenses for the full year of 2018 are expected to be within our previously provided guidance ranges, based on increased investments in our commercial organization and R&D in the fourth quarter.

Let me turn now to our improved financial expectations for 2018. We now expect total revenues in the range of $1,015,000,000 to $1,045,000,000, reflecting an increase of $30 million, driven primarily by upside from AMPYRA during the second half of 2018. This increase in total revenues flows through to the bottom line, resulting in a $30 million improvement to our GAAP net loss expectations to a range of $180 million to $210 million and a corresponding improvement to our non-GAAP net income expectations to a range of $20 million to $50 million. Our complete financial expectations are outlined in our third quarter results press release issued this morning.

Turning to our balance sheet, we're well positioned and ended the third quarter of 2018 with approximately $579 million in cash and total investments compared to approximately $561 million at the end of the second quarter. The change in cash during the quarter was driven primarily by our operating results and fluctuations in working capital. The company's total debt outstanding was approximately $200 million -- $280 million, excuse me, at the end of September.

Overall, we're pleased with our solid third quarter results and our strong financial position heading into the fourth quarter. Our diverse business is well positioned to support the opportunities that lie ahead in the next stage of the company's evolution as we approach the important catalysts in our development portfolio over the next few months.

With that, I'll turn the call over to Jim Robinson for additional updates on VIVITROL and ARISTADA.

Thank you, Jim. Good morning, everyone. Let's start with VIVITROL, an important medicine that continues to grow in the market. As Jim stated, in the third quarter, net sales of VIVITROL increased approximately 15% year-over-year to $79.9 million, driven by underlying unit growth of 18%. We continue to increase access and awareness at both the state and provider level, while improving continuity of care for patients. These elements are fundamental to our long-term success and provide a platform for the growth of VIVITROL. The opioid epidemic is a central theme in our national political dialogue with every community across our country affected. Important pieces of legislation are gaining bipartisan support and progress is being made. We continue to collaborate with federal, state and local policymakers to expand the availability of treatment. The President is expected to sign the SUPPORT for Patients and Communities Act soon. This piece of legislation includes numerous provisions that have the potential to be impactful to VIVITROL, and we will engage with policymakers throughout the implementation process. In particular, we are encouraged by the provision for comprehensive opioid recovery centers, which provides funding to develop federally qualified treatment centers that utilize a full range of FDA-approved medications. This is an opportunity to establish centers of excellence to address the tremendous need for comprehensive treatment and recovery systems, similar to comprehensive cancer treatment centers in oncology. Importantly, the federal legislation also extends funding for State Targeted Response grants for an additional 3 years, with $500 million to be distributed annually between 2019 and 2021. Ensuring consistent availability of funding will be key as long-term investments are made in building new treatment infrastructure and programs. At a state level, we continue to see strong growth of VIVITROL in a number of states, driven by a variety of policy initiatives, both in the community and the criminal justice setting, as well as improvements in access to VIVITROL. While the top 5 states represent approximately 45% of VIVITROL volume overall, growth is widespread across the country.

Year-to-date, 27 states have demonstrated more than 25% growth year-over-year, and we are particularly encouraged by the growth of VIVITROL in states like Pennsylvania, California, Florida, Michigan and Kentucky. Many of the initiatives being implemented today across the country will serve as a foundation for increased utilization of VIVITROL over the long term.

Internally, we continue to refine our approach and organization in order to best serve health care providers and patients as well as increase utilization of VIVITROL. We are expanding our capabilities to respond to the evolving market dynamics, including through the addition of key account managers and field-based reimbursement managers. These initiatives are designed to improve patient and provider accessibility to VIVITROL. Underlying all of our efforts is our commitment to ensuring that patients in need of treatment are provided with options that best fit their recovery journey and treatment objectives.

So now turning to ARISTADA. Again, as Jim stated, in Q3, we recorded net sales of $36.1 million, driven by unit growth of 44% year-over-year. The quarter was highlighted by the launch of our new initiation product ARISTADA INITIO. With the new ARISTADA INITIO regimen, ARISTADA is now the first and only long-acting atypical antipsychotic in the market that can be fully dosed on day 1, providing patients with up to 2 months of coverage. The value proposition of the ARISTADA offering is resonating with physicians. In particular, the 2-month dose in combination with ARISTADA INITIO is differentiated in the market and offers important, real-world utility across treatment settings, including hospitals and crisis stabilization units, where many patients initiate long-acting treatment.

Following the launch of ARISTADA INITIO, we have seen an acceleration in the sequential growth of the 2-month dose, which grew 26% and accounted for 15% of ARISTADA's volume in the third quarter. We also continue to gain traction with ARISTADA's market share for new prescriptions in terms of months of therapy in the long-acting aripiprazole market, which was approximately 28% in September. We are encouraged by our customers' positive response thus far, especially key hospitals and health plans as evidenced by the addition of both ARISTADA and ARISTADA INITIO into formularies at more than 30 hospitals during the quarter. To put that into context, this increases the number of hospital formularies including both products by nearly 30%.

We expect that ARISTADA INITIO coverage will continue to expand, including its addition to the SilverScript Medicare Part D Formulary in the fourth quarter. Additional formulary decisions will be made into next year as part of payers' annual review cycles. To support the ongoing launch of ARISTADA INITIO, we are strategically providing samples to hospitals and physicians in order to foster more experience using INITIO. With the complete ARISTADA product family now available, we are positioning ARISTADA to compete against the current leader in the overall long-acting atypical market. To support this effort, we are conducting a study evaluating ARISTADA and INVEGA SUSTENNA. This 6-month study recently completed enrollment ahead of schedule, and we're looking forward to sharing top line data in the first half of 2019. We will continue to make additional investments in ARISTADA to match the opportunity ahead.

During the fourth quarter, we will further expand our field and hospital-based sales force by approximately 50 sales representatives, based on the opportunities we are identifying and the encouraging trends that we are seeing.

Finally, in addition to our investments in VIVITROL and ARISTADA, we continue to engage in the necessary work to support future commercial opportunities in psychiatry as we prepare for the regulatory decision of ALKS 5461 for major depressive disorder and pivotal data for ALKS 3831 for schizophrenia.

And with that, I'll turn the call over to Richard.

That's great. Thank you, both, and good morning, everyone. So our results this quarter demonstrate the strong and resilient business that we built with important end-market products driving an expected top line in excess of $1 billion and a diverse portfolio of late-stage assets, each with the potential to change the growth trajectory of the company. As we head into the important regulatory and data readouts expected in the fourth quarter, the business is well positioned for future success and for growth. So with that, let me share some updates on the pipeline, and I'll start with ALKS 5461.

As you know, 5461 is our novel opioid system modulator that we're developing for the adjunctive treatment of major depressive disorder. With a PDUFA date of January 31, the regulatory review is well underway. The next milestone in the review process will take place next week, November 1, with a joint meeting of the Psychopharmacologic Drugs and Drug Safety Advisory Committees at FDA. We've been preparing for the AdCom for a number of months, and we're looking forward to a productive discussion on the efficacy and the safety of this important medicine. You've heard me say time and again, we believe the data generated in this large program support registration and that 5461 has the potential to provide benefit to patients through a new mechanism of action. At the same time, we're presenting FDA with an application that differs from what they're used to seeing, including new study designs and analyses. The AdCom will be an important determinant of the approvability of 5461, and we're ready to go. So we'll have a lot more to talk about with 5461 just in the next couple weeks' time.

So moving to 3831, our novel oral atypical antipsychotic for the treatment of schizophrenia. 3831 is designed to provide the antipsychotic efficacy of olanzapine while mitigating its associated weight and metabolic liabilities. We're approaching the end of the pivotal development program. In April, we completed enrollment of second Phase III study, ENLIGHTEN-2, a 6-month head-to-head study evaluating weight gain in patients receiving olanzapine or ALKS 3831, and we're on track for top line results later in the fourth quarter. The goal of the study is to replicate and extend the findings from the successful 3-month Phase II study that evaluated weight gain in a similar manner, head-to-head against olanzapine. If positive, these data would complete the registration package, which is planned for submission in mid-2019.

Next is diroximel fumarate or BIIB098, our novel oral fumarate in late-stage development for relapsing forms of multiple sclerosis, intended to provide a differentiated gastrointestinal tolerability profile. We're developing it in collaboration with Biogen. The exciting news here is that while so much attention has been focused on 5461 and 3831, we continue to make great progress and we're on track to submit the NDA by year-end. This would position Biogen for potential commercial launch in early 2020.

In addition to the required clinical elements of the registration package, enrollment in EVOLVE-MS-2 is ongoing. Top line from this elective head-to-head GI tolerability study versus TECFIDERA are expected in mid-2019. While not required for registration, data from EVOLVE-MS-2 may be useful to clinicians and patients considering their treatment choices for relapsing forms of MS.

I'll finish with an update on 4230, our novel immuno-oncology candidate. ALKS 4230 is a distinct molecular entity, which differs from other approaches being used in the IL-2 space. In the case of 4230, we designed a novel fusion protein comprised of IL-2 and its alpha receptor in a single molecule, intended to preferentially bind to intermediate-affinity IL-2 receptors while being permanently hindered from binding to the high-affinity IL-2 receptor. It's administered in its active form and does not require metabolic conversion and does not metabolize into native IL-2, so it has its own distinctive pharmacology, which is now being demonstrated in the clinic.

During the quarter, we initiated our first evaluation of 4230 in combination with the checkpoint inhibitor pembrolizumab in a variety of tumor types, and that enrollment is now underway.

Separately, in the ongoing monotherapy dose-escalation part of the Phase I study, we are in the process of implementing the protocol amendment we discussed last quarter and expect to reopen enrollment of the fifth cohort next month. Once we complete dose escalation with the identified optimal dose of 4230, we will advance into monotherapy dose expansion in patients with renal cell carcinoma or melanoma.

In the meantime, next month, at the Society for Immunotherapy of Cancer meeting, we'll present data from the 4 initial dose-escalation cohorts. Data from these cohorts demonstrated dose-dependent pharmacodynamic effects on circulating CD8-positive T cells and natural killer cells with minimal and nondose-dependent effect on immunosuppressive regulatory T cells and provide evidence of 4230's pharmacologic and biologic activity. In addition, at SITC, we'll be presenting data from 2 preclinical studies comparing subcutaneous administration of 4230 to IV administration. These data underlie our decision to evaluate subcu administration of 4230 as an alternative to IV dosing. During the third quarter, we submitted the new clinical protocol to the 4230 IND for a subcutaneous dosing Phase I study, and we expect to initiate that study early next year.

So 2019 will be an important year for the 4230 program with an expanded clinical activity and the potential to generate initial antitumor efficacy data in a range of tumor types. In the meantime, separate from the programs I've just outlined, we've continued to invest in our internal research and discovery efforts and expanding our capabilities in biologics. We're making good progress here, and we look forward to nominating new candidates into the clinic and sharing our progress with you as we approach the finish line for our late-stage development programs over the coming year.

Drug development is challenging work, particularly in psychiatry. We carry on because of the significant opportunity we see to use our scientific insights to positively impact the lives of patients and families. Both the ALKS 5461 Advisory Committee and the ALKS 3831 Phase III data readout are important catalysts for the company, and we're planning for success. We are a resilient and diverse business, and many opportunities for growth. The cards will be turning over soon, and we look forward to updating you on our progress and the opportunities that lie ahead.

With that, I'll turn it back over to Sandy.

Thanks, Richard. We'll now open the call for questions.

(Operator Instructions) And from Bank of America, we have Jason Gerberry.

Just two on 3831. Rich, maybe just first one. Have discontinuation rates on a blinded basis tracked in line with your assumptions? I know that in the past you've commented on that. And then secondly, just a question about as we think about patients in the study who are getting Zyprexa and may be outliers with the largest weight gain, do you have a sense when these patients tend to discontinue therapy? Just trying to get a rough sense of how to think about when those patients could potentially drop out. And then, I guess, my last question just on BIIB098. As you guys approach the NDA filing or Biogen does, I'd be curious just to get your thoughts on the proportion of TECFIDERA patients that you actually think are switch candidates. And the reason I ask is, when we hear from some physicians, patients' GI tolerability issues on that drug tend to become more manageable and subside after the first couple of months of treatment. So I'd be curious just to get a sense of how much of the market you think is up for grabs.

Sure, Jason. So I'll take those in turn. Actually, I'm interested in the inverse of discontinuation rate, which is the retention rate. That's what you've heard us talk about before, because our thesis has always been, with 3831, in a setting like this ENLIGHTEN-2, if we can keep patients in the study on olanzapine, they'll continue to gain weight. And conversely, if we can keep the people on 3831 in this study, they'll -- their weight differentiation will accentuate over time. So retention is a critical part of the study. And so the answer to your question is yes, because the -- on a blinded basis, from what we see, it looks about what we would've modeled. I didn't completely understand your second question about the profile patients on Zyprexa who might discontinue, but the general consideration is that we tend to pick sites and centers that have the ability to keep people in the study. That's -- even with that said, we would model for something on the order of 40% lost to follow-up in these types of studies, because these are patients with schizophrenia, but that's all built into our powering calculations. On BIIB098, obviously Biogen are the experts on this, but I can tell you that the -- my own view is that patients who get through the GI tolerability challenges in the beginning and are stable on TECFIDERA wouldn't seem to me to be the most likely patients to switch. This is all about as people initiate on new medicines, the whole offering for BIIB098 is with a favorable GI tolerability profile and equivalent efficacy, it seems to be the logical starting place. But it will -- I'll refer you to Biogen. I will say that as we approach NDA submission and the data come together from this program and we have the benefit of the open label safety study now has been running for a couple of years, we see GI AE discontinuation rates below 1%. We saw it was really excellent efficacy. We hear anecdotes from patients in the clinic. I think the whole aura around this program is getting stronger and stronger as we move into the NDA phase.

From JPMorgan, we have Cory Kasimov.

This is Matthew on for Cory. Just a couple of questions, first on 4230. On the subcu dosing, just curious to get your thoughts about how quickly you can escalate this, and if we should expect to see data in 2019 from this program.

Yes, we expect to see data in 2019. We'll -- we're still experimenting here to see what the actual regimen may be, how infrequent the dosing may be. But because we have the comparative controls from the IV daily times 5, we can see how the expansion of CD8-positive lymphocytes as well as natural killer cells compares to what we see with IV. So I expect -- everything is driven by how fast you can enroll folks in the study, but I think we should get information fairly quickly.

Okay, great. And then just on the announced sales force expansion for ARISTADA. Any overlap here with either a potential 5461 or 3831 sales force?

Yes, on both accounts. So the expansion not only supports ARISTADA today, but also can be used to support the launch of 5461 and 3831.

From Crédit Suisse, we have Uy Ear.

This is Uy for Vamil. On ALKS 5461, the AdCom is soon. Just wondering if you would be able to share with us any info or any sort of exchange you might have had with the FDA, such as have you seen the briefing documents and the type of questions that you are expecting the FDA to ask?

This is Rich. I think the questions going into the AdCom are the ones that have been obvious or self-evident from the very beginning when we made the submission, which is, number one, is the substantial evidence of efficacy. Is the committee comfortable with the efficacy data that we've shown throughout the program, which incorporates using new study designs and new methods of analysis to confirm that efficacy? We obviously feel quite strongly about it. You've seen those data represented and you'll continue to see it published. So we obviously believe that that's a compelling story and we're looking forward to telling it. The second piece of it is almost a more general point and you can see is -- by the fact that FDA has convened both the psychopharmacologic AdCom as well as the drug safety AdCom, which is because 5461 is an opioid system modulator, what are the issues of about launching an opioid-modulating compound, even one with -- directly designed to address the addictive potential of buprenorphine, into the midst of an opioid crisis? What's the right labeling? What's the right information? What's the right setting or presentation of this drug for education purposes and for making sure that it gets to the patients it needs to get to? So I think those are the 2 major issues for the AdCom.

Okay. And I think you also said that you are looking to new -- move new candidates into the clinics. Would you be able to share with us, whether it's the kind of molecules, whether it's small molecules, biologics and the therapeutic categories you're looking at will be further in CNS or more in oncology or others?

Yes. I won't make any new disclosures today other than highlight what I said earlier, which is we have a historic strength in our small molecule drug discovery and our small molecule chemistry, and I think it's getting -- that's getting stronger and stronger. It's been augmented, and it was triggered by the 4230 program at the beginning, by this increasing interest in and expertise in biologics. So we're actually advancing programs in the labs now that are both small molecule-based as well as large molecules. And so we're interested in oncology as an area, particularly 4230 may be foundational for a number of -- types of combinations. And obviously, we have deep expertise in CNS and psychiatry, so those are natural lanes that we'll progress along.

From Cowen, we have Chris Shibutani.

Can you just confirm for us that for 5461, the data that will have been reviewed and discussed in the briefing documents as far as the overall clinical profile, efficacy and whatnot, has substantially or entirely been presented already? Should we anticipate that there is anything additional that was part of the NDA filing that perhaps hasn't been disclosed?

Chris, yes. You've seen the data from the pivotal efficacy studies as well as the 202 study, which was another efficacy study of the Phase II study. What you probably haven't seen yet is the human abuse-potential data. I know it's in publication and we haven't -- I don't think it's been presented yet.

That poster at APA.

There was one poster APA, but we'll have more of the human abuse liability or human abuse-potential data, which we think is very strong as well. There may be some long-term data that is supportive that you might not have seen. So I can't say you've seen all of it, but I think that everything that you haven't seen will be consistent with what you would've seen before.

Great. And then it's difficult sometimes to think about approaching an event like an FDA AdCom not as a binary event, thumbs up, thumbs down. But there frequently is a question of, what potential alternative scenario might we see? And I'm -- particularly, I'm asking this in the context of the Phase IIIb study, which I believe you call study 217, which was commenced a while back and I believe is a study that theoretically could be framed as an additional Phase III-type study. So in a scenario, for instance, where if the Advisory Committee does not recommend for approval, is it realistic to believe that there is path forward, that you'll be committed to study 217 and that we be looking to continued development? Sort of beyond thumbs up, thumbs down, are there other scenarios based upon on the work you've been doing and your point of view on it? And I realized that the team is obviously looking to be optimistic and need to prepare, but nonetheless, we do have kind of these different paths. Is there a path 3 that 5461 could continue on, so that we could think about implications of the outcome beyond November 1?

I think that's a thoughtful question, and indeed, we believe deeply in the mechanism and the value of 5461 as a medicine for patients with major depressive disorder, and potentially other indications as well. 217 is underway, you're correct. And it's one, as you know, from the outset, we were interested in exploring quantitatively some of the other clinical features of 5461, different than what might be captured in the classic MADRS or HAM-D scales. But in the event that the Advisory Committee comes back and says, "We need another study. We need more data," we have the ability to tune that study in order to provide those data. With, of course, the caveat or the admonition always being, we know that in studies of major depressive disorder, active agents often don't separate from placebo due to the high placebo response. So depending on what we've learned coming out of the Advisory Committee meeting, how definitive or not it is, we'll make further decisions about whether we initiate any of the other clinical trials, whether we run out 217 as designed or whether we make modifications to 217 itself. So we'll make that call in a couple of weeks' time on the other side of the AdCom and on the other side of our completion of the review with FDA, because there is a space of time between November 1 and January 31 where quite a bit happens as well, where the review actually gets completed and you really figure out what the deficiencies, if any, are, or you then prepare for the launch of the drug.

From Evercore ISI, we have Umer Raffat.

Rich, first, so as we head into the AdCom, something that's been on my mind is, why shouldn't FDA make the same request as they were making in the RTF letter for multiple trials? Secondly, on your IL-2, we saw Roche put up single-agent monotherapy responses, as you saw with the FAP, and I was curious how that -- how you think that ties into 4230, what we've seen to date as well as plans going forward in terms of type of tumors you're looking at. And then finally, strategically, it seems like given all the Alkermes expertise in the long-acting injectables, presumably the concept of developing an injectable buprenorphine could have potentially been very much doable. So I'm curious, as you guys internally thought about whether or not to have an injectable buprenorphine offering, what was sort of the thought process? And is that still something of consideration?

Umer, good questions as always. The first one, just to be clear, in the refuse to file last March, the FDA didn't request multiple trials. The reason the RTF was reversed is because it was actually just a misunderstanding, what we've talked about before. Facial deficiencies were the basis for an RTF. And once we cleared up that the things that FDA was asking for were actually in the application, we got it back on track, and since that time, the review has been normal course. I was interested in the Roche data because we've long posited for 4230 that if we've done what we set out to do, the specific design intention of minimizing expansion of Tregs while preserving binding to intermediate-affinity receptors and getting the appropriate cellular expansion, we should be able to recapitulate the single-agent efficacy that you see with IL-2. And so that's why we carry on with our monotherapy dose escalation. So I think it's an important check box and I'm hopeful that we can check it as well, and I think that you'll see us continue to do that. With that said, [once] established in monotherapy efficacy, I think that's a foundational piece, and then you can continue to explore, obviously, combinations that make sense. And the long-acting injectables in the addiction space, I don't think anybody in the world has more experience in the injection space than Alkermes, particularly -- I'm sorry, in the addiction injection space than we do. It's just -- you'll hear us say to policymakers and to the media and to you all, the major impediment to new drug development and launching in the addiction space is the fact that this treatment system is outside of the medical system. New agents are not adopted with any speed at all because the treatment systems are ossified. They use the approaches they've used forever. So we're going to fight our way into success with VIVITROL as we've been doing, step-by-step. And we continue to be incredibly optimistic about the role of a long-acting injectable antagonist in this world. We're interested in long-acting injectable buprenorphine products, but you can even see from the launch, it's a slow growth, and I think we'll have plenty of time to play there if we choose to do so.

And, Rich, just to sort of confirm on the IL-2, I noticed you guys mentioned monotherapy dose expansion will be in renal and melanoma, and the Roche response -- the 2 responses were in squamous cell types. So I was curious if that's of consideration as well as you think about the dose expansion, the tumor cell...

Yes. I thought that was interesting too, we'll talk about that. We don't have a -- I don't have a formal answer to that, Umer, but of course, we noted those data with interest and the team will be talking about that as well.

From Stifel, we have Paul Matteis.

A couple on 3831. One, I was wondering if you could opine on what might be a clinically meaningful or commercially meaningful benefit on weight gain outliers? And then just separately, if you think that the mean weight gain analysis in this study does have commercial relevance of if it's more of a regulatory -- relevant endpoint? And then I just have one follow-up question.

Paul, yes, it's a good question because there's the matter of statistics and regulatory confirmation necessary for NDA submission and then there is little clinical relevance of it at all. And we often hear people, I think, inappropriately characterize it, say, "Well, it's just a few pounds difference. Who cares?" And you've heard us say many times before, that primary analysis, which is -- a co-primary analysis, which is mean weight change, so the center of the bell curve shifting to the left, as well as the categorical determination of patients who gain more than 10% of their body weight, those are 2 co-primary endpoints. They're both statistically important to correlate and they're -- but I think you've heard us say many times, the most important thing, I think, is the shape of the 3831 curve. If we see like what we saw in Phase II, which is essentially a zeroing out of the slope, a flattening of that slope after a few weeks' time compared to an ascending slope for olanzapine over time, we hear from clinicians that that's really important. So the 2 statistical measurements of that flatness will be the mean change and the categorical change of greater than 10%. But I think the meaningfulness of the data will be, have we essentially arrested that weight gain after a short period of time.

Okay, got it. Appreciated. And then just one more follow-up on 5461, and not to beat a dead horse, but I guess just taking a step back, if -- I think -- and the hypothetical scenario that is more relevant, I think, to interrogate is, if it doesn't get through in the first try, would it make sense to start a second Phase III study, given just that for antidepressants that do work, you can have half the studies fail, and we know in this case you are functionally 1 out of 3 in Phase III? I guess, would you consider starting another Phase III is really my question, if you end up getting a CRL, so that if you go 1 out of 2 the next time around, maybe then it's more clearly approvable?

Yes, we'll make the call after November 1. Let's see the whites of the eyes of the FDA and the AdCom, and then I think we'll have a lot more information to make decisions on. But as you've heard me say before, we really believe this drug is helping patients. And so we want to figure out a way to get it to patients. But if the regulatory hurdles are insurmountable, then it's -- if it's a fool's errand, then you don't do it. We think we're far from that. And we think that the -- and you'll see at the AdCom as we finish off the -- preparing for the presentation, it's a strong case. And you can make your own determination while -- when you watch it, but we'll see where we land on the other side of it.

From B. Riley FBR, we have David Buck.

Just a couple of questions. First on VIVITROL, can you talk a little bit about what you see in '19, if -- as the effect of new money from the opioid bill, how you'd see that filtering down into treatment and potentially growth of your product? And can you talk a little bit about, Richard, for any questions that you've seen from the -- or for the AdCom that were surprising to you? And anything that we should be aware of just in terms of other types of questioning that you haven't mentioned?

I'll start with VIVITROL. It's Jim Frates. I think we see very much the opportunity for continued growth for VIVITROL, right? As Rich mentioned, the treatment system has been slow to change, and you're seeing the federal dollars come as well as legislative initiatives, both at the federal level and state levels, that are moving more towards a quality improvement in the system. And I go back to the amfAR data that came out earlier this year, where they basically said roughly 4% of the treatment centers in the country are using all 3 medications when it comes to the treatment of opioid addiction. So as the breadth of growth in various states increases, and as we move to more understanding that patient-centered approaches are the way to treat this disorder and many patients are different and that option for a relapse prevention medication with a monthly injection is a very attractive option for patients and sees excellent data as we've seen with X:BOT and the Tanum data, I think we continue to see growth for VIVITROL. It's hard to predict exactly that slope quarter-to-quarter, and so we'll give you our predictions for '19 when we do our annual guidance in February, but we certainly have not lost our optimism for the long-term growth of VIVITROL.

And viz-a-viz the AdCom, I think so far the review is proceeding as we would have anticipated. So we'll see the final briefing materials when you guys see them, but we're prepared for the meeting as we would have prepared for it all along, so we're looking forward to it.

From Jefferies, we have Biren Amin.

Richard, just wanted to get more color on the head-to-head ARISTADA study versus SUSTENNA that reports out next year. What do you hope to achieve in the study? And will this be label-enabling?

Biren, yes, we're -- it's been an interesting study because it was considered to be a pretty aggressive idea when we first floated it a few months ago. Remember about a year ago at this time, we presented data at a congress that showed patients who were failing to get adequate clinical relief on SUSTENNA, switching to ARISTADA, which was surprising for some people because the common belief is that ARISTADA isn't and aripiprazole formulations are not as powerful for -- as antipsychotics compared to the paliperidone or risperidone. We never really thought that was true and those data bore it out in the sense that patients switching had really nice responses to ARISTADA, suggesting that sometimes different may be better rather than one of the agents being more or less powerful than the other. So that led us to say, let's -- with the INITIO approval coming, let's run a study in a real-world setting that is really meaningful to providers and to patients and to payers, which is if we can initiate on INITIO in the hospital and discharge with a 2-month dose, that's a very powerful offering in the community. Let's compare that head-to-head versus SUSTENNA. So the primary comparison is not an intergroup, it's just looking at the baseline of the patients in each group compared to their results at a certain time point, a month or 2 months or something like that. But then it'll also give us the opportunity in a parallel way to look at the relative efficacy of the 2 medicines. So I don't know if it'll give us label indications, but it'll certainly give us the information that a lot of the opinion leaders and folks in the community are interested in seeing.

From Goldman Sachs, we have Terence Flynn.

Maybe just on 5461, can you remind us, Rich, where you guys stand with commercial prep? And is the outcome of the AdCom really a key input into the next stage of that build? Or is it the FDA decision? Maybe just remind us also how you're thinking about the size of the footprint.

Sure, I'll take the first part, I'll ask Jim to do the second part. So 5461, I think the AdCom is really central to the FDA's decision-making on this. And so we're really -- that doesn't mean there's not some spacing between November 1 and January 31. It doesn't guarantee approval, but it certainly is an important and necessary step, in our view. So we are -- we've done an enormous amount of preparation for launch of 5461, but we won't pull the trigger on hiring the next level of sales force expansion until such time as we really have a sense that the drug is going to be approved. Remember, with a drug like this, which is expected to be scheduled, so it will receive FDA approval, if we're fortunate, and then it'll go into the DEA scheduling process, which is another 3 months, typically. So that 3 months actually is very useful to us as we begin to operationalize for the launch, which we expect to happen in the summertime. Jim, you want to clarify?

Yes, just a few things on the preparation for the launch. Obviously, a lot of work has gone into creating awareness about the fact that there's still a high unmet medical need and the role of adjunctive therapy in treating major depressive disorder. So also a lot of discussion regarding the mechanism action of how 5461 will work and how it'll benefit patients. So a lot of work going into meeting with key-opinion leaders, meeting with providers as well as meeting with payers to make sure there's awareness of the value of a product like 5461. And as you would expect, there's been a tremendous amount of work done in sales force sizing and ensuring that we've got the right sales force from a size perspective, as well as from a quality perspective, in the field at the right time upon approval. So a lot of work going into that, and we're well prepared for the launch of 5461.

It's also -- Terence, just to finish the thought, it's a bit of a simultaneous equation, because we'll have an important data readout on 3831 before the end of the year as well. So as Jim thinks about sizing our commercial footprint in psychiatry, is it ARISTADA and VIVITROL or is it ARISTADA, VIVITROL and 5461 or is it ARISTADA, VIVITROL, 5461 and 3831, and those are all different configurations that are in play.

And from Morgan Stanley, we have David Risinger.

I was hoping that you could talk a little bit about the acceleration in VIVITROL in recent weeks. So what we've seen in the IMS data is that the performance has picked up and just wanted to better understand what you would attribute that to. I mean, obviously, you've been working on improving the commercial effectiveness of your efforts, but wanted to understand that. And then also just wanted to understand your take and how you are planning to respond to ICER if their report is negative on the value of VIVITROL?

So maybe I'll take it, and then Jim Frates and Jim Robinson can chime in if they want to, Dave. But -- so for me, I smiled when you asked about the acceleration in the VIVITROL, because I really don't even look at it week-to-week. It just -- VIVITROL moves on a different wavelength than your typical pharmaceutical product. So I wouldn't overinterpret any single or 2- to 3-week trend, and we'll try to guide you guys as we -- best as we can see, as we've done in the past, with VIVITROL. But the basic hydraulics for VIVITROL are that policy is shifting in favor of more long-acting injectable and antagonist therapy, more money is flowing into the treatment system. And so those positive forces run up against the institutionalized forces of inertia and a broken treatment system that's slow to change, but it is changing and we're chipping away at it, so we remain very optimistic about VIVITROL. And the ICER thing, I expect the ICER review to be negative. The preliminary report is negative, and I think it's actually an example of the wrongheaded approach that policymakers sometimes take to the treatment. The idea that long-acting injectable antagonist medication is substitutable or should be viewed as interchangeable based on cost with replacement therapy is really a disservice to patients who have different treatment alternatives and different objectives for their care. And so I actually don't think the ICER report is going to matter a whole hell of a lot.

All right. So I think that concludes our Q&A for today. Everybody, thanks for dialing into the call. Please don't hesitate to reach out to the company if you have questions later today. Thank you.

Thank you. Ladies and gentlemen, this concludes today's conference. Thank you for joining. You may now disconnect.