Good morning. My name is Melissa, and I will be your conference operator today. At this time, I would like to welcome everyone to the Biogen Idec Fourth Quarter and Year-End Earnings Conference Call. [Operator Instructions] Ms. Kia Khaleghpour, Associate Director of Investor Relations, you may begin your conference.
Thank you, and welcome to Biogen Idec's Fourth Quarter 2011 Earnings Conference Call. Before we begin, I encourage everyone to go to the Investors section of biogenidec.com to find the press release and related financial tables, including a reconciliation of the non-GAAP financial measures, that we'll discuss today.
Our GAAP financials are provided in Tables 1 and 2. Table 3 include a reconciliation of the GAAP to non-GAAP results, which we believe better represents the ongoing economics of our business and reflects how we manage the business internally. We have also posted slides on our website that follow the discussions related to this call.
As usual, we'll start with the Safe Harbor statement. Comments made in this conference call include forward-looking statements that are subject to risks and uncertainties. Words such as believe, expect, may, plan, will and similar expressions are intended to identify such statements. Actual results could differ materially from our expectations, and you should carefully review the risks and uncertainties that are described in our earnings slides, earnings release and in the risk factors section of our most recent annual and quarterly reports filed with the SEC. We do not undertake any obligation to publicly update any forward-looking statements.
Today on the call, I'm joined by Dr. George Scangos, Chief Executive Officer; Dr. Doug Williams, Executive Vice President of Research and Development; Tony Kingsley, Executive Vice President of Global Commercial Operations; and Paul Clancy, Executive Vice President of Finance and Chief Financial Officer.
We'll also be joined for the Q&A portion of the call by Dr. Al Sandrock, Senior Vice President of Development, Sciences and Chief Medical Officer. Now I'll turn the call over to George.
George A. Scangos
Okay, thanks, Kia, and good morning, everyone. We had a very productive fourth quarter and -- which concluded a really, I think, great year for Biogen Idec. Recall that in 2011, our goals were to deliver double-digit EPS growth, grow AVONEX and TYSABRI share while pursuing the serological assay and risk stratification to further unlock the value of TYSABRI, advance our late stage pipeline and continue to drive cultural change. We delivered on all these goals and we've run a long way towards building a foundation for long term growth for Biogen Idec.
In 2011, our product -- total product revenues were up 11% year-over-year and non-GAAP diluted EPS ended the year at $5.90, a 15% increase over 2010. In 2011, our AVONEX commercial team substantially improved the business and AVONEX global sales reached $2.7 billion, a 7% increase year-over-year.
We introduced the AVONEX PEN to the European markets and Canada, thereby improving the administration for patients and reinvigorating physician interest and we filed for marketing authorization of the AVONEX PEN in the U.S.
TYSABRI end-market sales grew 23% year-over-year to reach $1.5 billion in 2011, and we hit key milestones that are important for unlocking the value of TYSABRI. First, the assay for JC virus antibodies was made broadly available in both the U.S. and the EU. Second, the TYSABRI product label was updated in both the EU and the U.S. to include JC virus antibody status as a risk factor for the development of PML.
There's been tremendous interest from the MS community in risk stratification and we believe that the large majority of TYSABRI patients now know their antibody status and that increasing numbers of patients considering TYSABRI are being tested as well.
Against long odds, we were able to convince the EMA to reverse their initially negative opinion for FAMPYRA and we obtained conditional EU marketing approval. We launched FAMPYRA in Germany in 2011 and plan additional launches this year.
Turning to R&D, our late-stage pipeline advanced substantially in 2011, led obviously by BG-12, but also including significant advances in many other portfolio compounds, both early and late. As you know, BG-12 data in 2 large clinical trials were very encouraging. These 2 clinical trials, with more than 2,600 patients, represent the largest data set for any new drug in relapsing-remitting MS to date. We're now focused on bringing this potentially major new therapy to patients with MS as soon as possible.
SELECT, the first of 2 registrational trials for Daclizumab, showed impressive clinical results in 2011 and supported the continuation of the second registrational study, DECIDE. We also completed enrollment for ADVANCE, our Phase III trial, evaluating once monthly subcutaneous PEGylated Interferon for relapsing-remitting MS, and we completed enrollment for EMPOWER, the first global Phase III study of dexpramipexole for the treatment of ALS or Lou Gehrig's disease.
Turning to our Hemophilia programs, Phase I/II data were presented for our Long-Lasting Factor VIII product in Kyoto candidate [ph] in Japan in 2011, addressing an important unmet need in the Hemophilia community, where less frequent injections will reduce the treatment burden and potentially provide better long-term outcomes for patients.
Our Phase III trials continued to enroll successfully during the year. In fact, our clinical trial enrollment improved so much during the year that we substantially overspent our budget for these trials. That, of course, is a good over-expenditure that resulted from improved execution. In 2011, we were able to meet or exceed our enrollment targets for almost everyone of our clinical trials.
And I'd like to point out that even with these additional clinical expenses, we surpassed our earnings target. As part of our goal to drive cultural change and reinvigorate R&D, we focused on the areas where we have the most expertise and where we have the most promising assets: neurology, immunology and Hemophilia. We increased our efforts to move internal programs forward and looked for new high-quality assets to grow our early-stage pipeline.
We successfully advanced our Anti-Lingo program in relapsing MS, as well as our Anti-TWEAK program for lupus nephritis. We announced the collaboration with Portola Pharmaceuticals to develop and commercialize an oral, highly selective Syk Inhibitor and with ISIS for compounds to target spinal muscular atrophy. We also announced the joint venture with Samsung for the development of Biosimilars, leveraging our world-class protein engineering and biologics manufacturing capabilities while allowing us to remain focus -- maintain focus on discovering, developing and delivering innovative new therapies for patients.
Because of our successes in 2011, we've entered 2012 with a lot to do. We'll continue to focus on execution as we invest in our future success. Our goals for this year are to grow our leadership in multiple sclerosis by growing TYSABRI market shares, stabilizing worldwide AVONEX market share and growing FAMPYRA revenue. We'll invest significantly to ensure that we're well prepared for the potential launch of BG-12 in MS and Factors VIII and IX in Hemophilia A and B. These activities include successful regulatory filings for BG-12 this year and the appropriate ramp-up of commercial and medical capabilities for both BG-12 and Hemophilia to ensure successful future product launches.
2012 is a building year for Biogen Idec. All of these activities, of course, take substantial resources. Additionally, we'll continue to build our early-stage pipeline and continue our focus on culture. I'm pleased to say that we expect to accomplish this year of building and preparation for product launches while at the same time delivering revenue and EPS growth.
And with that, I'll now turn the call over to Doug Williams, our Executive VP of R&D.
Douglas Edward Williams
Thanks, George. Let me start by thanking and congratulating the R&D organization for all their efforts and success in 2011. It's been a year of significant accomplishments, spanning the entire pipeline from research to marketed products.
During Q4, we continued to make considerable progress on several aspects of our late stage R&D programs, which positions the company to launch a series of meaningful new drugs, addressing significant unmet medical needs for patients and positioning the company for future revenue growth.
Let me recap progress in Q4, starting with our MS pipeline. Earlier this month, we announced that the FDA approved a product label change for TYSABRI, which identifies antiJCV antibody status as a risk factor for developing PML. This is the third distinct risk factor identified, and reflects our commitment to providing important benefit risk information to treating physicians and their patients when considering TYSABRI as a treatment option.
Infection with the JC virus is required for the development of PML, and patients who are antiJCV antibody positive, therefore, have a greater risk of developing PML.
Moving on to BG-12, the team is aggressively working on regulatory submissions for BG-12 and we plan to file with the FDA and EMA in the first half of this year. The profile of BG-12 seen in the DEFINE and CONFIRM Phase III studies indicates a favorable benefit risk profile for this drug with the convenience of oral dosing. While we conducted the Phase III studies with the formulation administered as 2 capsules twice or 3 times a day, we have since completed a bioequivalent study for 1 capsule formulation, which could allow for 1 capsule twice a day. We plan to also include this new formulation as part of the filing.
ADVANCE, the Phase III registrational study of PEG-Interferon and 1,500 patients with relapsing-remitting MS completed enrollment in Q4. This trial is being conducted under a Special Protocol Assessment with the FDA with an annualized relapse rate at 1 year as the primary endpoint. We anticipate top-line data to be available in early 2013.
In the U.S., we've also focused on providing a better patient experience with the AVONEX PEN and the AVONEX Titration Kit to make self-administration more convenient and to help reduce flu-like symptoms at the outset of therapy. The PDUFA date for both the AVONEX PEN and the Titration Kit is in the first half of this year.
Turning to the rest of our neurology pipeline. Top-line data for the EMPOWER study, the first Phase III study of dexpramipexole and ALS is anticipated in the second half of 2012. Dex is a novel, oral compound that appears to have neuroprotective properties based on experimental and preclinical studies and may slow the loss of motor neuron function by improving mitochondrial energy utilization. EMPOWER, which has been conducted under a Special Protocol Assessment approved by the FDA, utilizes a novel primary endpoint, which combines survival and functional decline. The Phase II results of dex published in Nature Medicine in November of last year, was the first positive dose-ranging study of a new agent in ALS in nearly 15 years. In this study, the combined endpoint of survival and functional decline was statistically significant when comparing low versus high doses of dex. Our current plans are to initiate endeavor, the second Phase III study of dexpramipexole, which incorporates higher drug doses subsequent to the EMPOWER data readout. This will allow us to incorporate any learnings from EMPOWER into the endeavor design. I want to clarify that the EMPOWER study is ongoing, and thus, remains blinded. We're not making the change in the second trial timing due to any knowledge or speculation about EMPOWER or due to any other signals, but rather as a way of optimizing the overall data set from the 2 clinical studies.
Moving on to our Hemophilia programs. Enrollment is nearly complete in our A-LONG study. We're dosing the last nonsurgical patients now, and we'll continue to enroll surgery patients through the first half of the year. We expect top-line data readout for both B-LONG and A-LONG studies for Long-Lasting Recombinant Factor IX and VIII, respectively, in the second half of this year. We believe that both of these product candidates have the potential to offer compelling innovation and benefits to Hemophilia patients.
Along with the substantial progress I just reviewed on our late-stage clinical programs, we've also taken concrete steps to bolster our earlier stage development pipeline. Rebuilding the Phase I and II pipeline is a long-term strategic imperative for the company and will be accomplished by disciplined investments in internal discoveries and targeted transactions to obtain highly differentiated assets in our core focus areas.
We previously announced the global collaboration with Isis Pharmaceuticals, targeting spinal muscular atrophy, also known as SMA. SMA is a genetic neuromuscular disease characterized by muscle atrophy and weakness, and is the most common genetic cause of infant mortality. One child out of every 10,000 births worldwide is born with SMA. Children with SMA generally appear normal at birth, with symptoms developing as early as a few months after birth. The most severe forms of the disease children have significant neuromuscular defects and a lifespan of approximately 2 years. Isis anti-sense therapy is designed to correct the underlying genetic defect that causes SMA. This collaboration fits with our mission of bringing innovative therapies to patients with serious neurologic diseases. I'm also pleased with the progress that the R&D team has made advancing and adding to our Phase I and II portfolio. The Anti-Lingo and relapsing MS and the Anti-TWEAK antibody and lupus nephritis programs have been approved to go to Phase II, and we expect patient dosing to start in the first half and second half of 2012, respectively.
These 2 programs are highly differentiated therapies, discovered and developed internally, and we'll have more to say about these 2 programs as Phase II dosing begins.
We've also advanced 2 additional programs from research into development in 2011. We plan to hold an R&D day this year to highlight progress in the strength in innovation of our growing early-stage pipeline. More details to follow on this event.
In summary, I'm extremely pleased with the progress that the R&D organization has shown this past quarter. Our late-stage pipeline is one of the most enviable in the industry and we're making tangible progress on building a sustainable and high-value early-stage pipeline. I look forward to providing you with further updates on our progress in the coming quarters. With that, I'll now pass the call to Tony Kingsley, our Executive Vice President of Global Commercial Operations.
Thank you, Doug. The MS franchise continued its strong momentum into the fourth quarter as we delivered double-digit revenue growth for both the quarter and the full year. In the fourth quarter, AVONEX continued to show resilience in the U.S. while we experienced growth ex-U.S. Worldwide, units grew 1% while revenue increased 8% in the fourth quarter, capping off a solid year for the franchise and highlighting our refocused commercial execution. Despite pressure on the ABCRE market, fourth quarter U.S. AVONEX units were in line with the previous quarter, with the anticipated U.S. approval of AVONEX PEN, and for the AVONEX Titration Kit in 2012, we will continue to build upon these 2011 results.
Outside the U.S., fourth quarter units and revenues both grew 4% year-on-year, and for the full year, units gained 6%. AVONEX remains the market leader, and share growth was strong in countries where we have launched the AVONEX PEN such as the U.K., Germany, Canada and the Netherlands.
Moving to TYSABRI. We made tremendous progress with both sales performance and the advancement of risk stratification, which continues to drive interest in the brand. The JCV assay became commercially available in both the EU and U.S. last year. And as of December 31, there have been approximately 87,000 JCV tests globally, some of which are patients being tested for the second time. We believe that the majority of TYSABRI patients have now been tested for their JCV antibody status. As we saw last quarter, the very rapid uptake of the assay created uneven net new patient growth due to increased discontinuation as more patients became aware of the their JCV antibody status. At the same time, demand for TYSABRI remained robust and we remain confident that the increased interest in risk stratification will continue to drive strong demand going forward.
Full-year global units increased 16% while revenues to Biogen Idec increased 20%. Net new patients increased by 7,200 for the year, an increase of 13%.
In the U.S., fourth quarter TYSABRI units grew 10% year-on-year. This is the fifth consecutive quarter where we delivered unit growth for TYSABRI. For the full year, units grew 12%. With the recent FDA label approval that identified the antiJCV antibody status as an additional risk factor, we are now able to speak actively with neurologists and provide the MS community with more confidence when considering treatment options. Outside of the U.S., TYSABRI units grew 19% for the full year and 20% in the fourth quarter. In these markets, TYSABRI also grew 2x faster than the overall MS market growth rate, driven by both patient growth and additional country launches.
While we're still in the beginning stages of the FAMPYRA launch, we're encouraged by the early strong results. There's been pent-up demand for the therapy, and given our strong position in the MS marketplace, we continue to gain access to physician and drive additional interest.
In Germany, we've seen strong uptake, with more than 7,000 patients exposed to FAMPYRA through year end since its launch in September 2011. This important therapy is currently available in Germany, the U.K., Australia, Denmark, Norway and Iceland. Additional launch preparation is underway for the rest of Europe and regulatory filings are planned in over 20 additional countries this year.
In 2012, our focus will be to drive our existing commercial therapies, keeping the momentum we've seen in 2011 going forward. We're excited about preparing our organization for potentially multiple product launches. With the expectation of the first-half 2013 launch for BG-12, we are making investments now in product positioning, promotional planning, scientific outreach, shaping our patient support services and supply chain. We plan to build customer-facing resources later in the year.
Similarly, preparations are underway as we make investments in our Hemophilia franchise for an expected mid-2013 launch. We are new to the Hemophilia market but we've already put in place a commercial team composed of seasoned professionals with significant experience in the Hemophilia space, which we will scale up as we get closer to launch. We are developing relationships with the medical and scientific community globally and we will be leveraging our strengths in patient services.
We believe that this will offer a competitive advantage to the Hemophilia marketplace. We're making great progress and are on track for successfully executing multiple product launches in the coming years. I'm confident that we'll continue to build upon our commercial foundation and that will drive future growth.
With that, I'll turn the call over to Paul Clancy, our Chief Financial Officer.
Paul J. Clancy
Thanks, Tony. Our GAAP diluted earnings per share was $1.22 in the fourth quarter and $5.04 for the full year. The difference between our GAAP and non-GAAP results for the fourth quarter include $50 million related to the amortization of acquired intangibles, $30 million for contingent consideration and $3 million in stock compensation expense. This was partially offset by the tax impact on these items. Our non-GAAP diluted earnings per share was $1.51 for Q4, representing a 6% increase versus prior year, and for the full year, non-GAAP diluted earnings per share was $5.90, representing a 15% increase. Total revenue for the fourth quarter grew 9% to $1.3 billion and grew 7% for the full year, surpassing $5 billion.
In the U.S., AVONEX grew 10% in Q4 to $421 million, while the full year U.S. AVONEX revenues increased 9% to $1.6 billion. Inventory in the channel ended at just over 2.3 weeks. Internationally, Q4 AVONEX revenue was $282 million, an increase of 4% compared to the fourth quarter of 2010. Foreign exchange had a minimal impact this quarter. For the full year and -- international AVONEX revenue increased 3% to $1.1 billion.
Foreign exchange strengthened AVONEX revenue by $51 million. However, this was offset by a $31 million hedge loss as compared to a $35 million hedge gain in 2010.
TYSABRI worldwide end-market sales were $381 million in Q4 and $1.5 billion for the year, up 14% and 23%, respectively. Biogen Idec reported TYSABRI revenue of $269 million in Q4 and $1.1 billion for the full year.
In the U.S., Q4 TYSABRI revenue to Biogen Idec grew 25% to $87 million. Full year TYSABRI product revenue was $326 million, an increase of 29%.
Q4 international TYSABRI product revenue was $182 million and $753 million for the full year. Fourth quarter revenues were impacted by a $14 million accrual related to a discount in our Italian affiliate. We received notification from the Italian National Medicines Agency stating that the sales of TYSABRI had exceeded a limit established during our 2006 price determination. We've challenged the agency's claim. However, our fourth quarter accounting treatment has resulted in a $14 million reserve related to this issue. We hope to have resolution in the first half of 2012.
The impact of foreign exchange for full year TYSABRI added $38 million to international revenues versus prior year, which was offset by a $6 million loss from hedging compared to an $11 million hedge gain in 2010.
Note also similar to prior quarters, we've updated prior quarter TYSABRI patient numbers to reflect the best information available.
U.S. RITUXAN sales were $721 million in the fourth quarter, up 4%. For the full year, U.S. RITUXAN sales were $2.9 billion, up 6% driven by an increase in the maintenance setting in NHL and continued uptake in CLL. Our profit-sharing expense reimbursement from this business was $228 million for Q4 and $879 million for the full year. Royalties and profit share in sales of Rituximab outside the U.S. in Q4 were $30 million and $118 million for the full year.
The result was $258 million of revenue from unconsolidated joint business in Q4 and $997 million for the full year. FAMPYRA revenue was $10 million for Q4, largely driven by Germany, but also includes sales from select European countries and Australia.
Royalties were $53 million for the fourth quarter, an increase of 16%. The increase was mainly due to hitting a new royalty tier on sales of ANGIOMAX. This new tier is applied to all year-to-date revenue in our accounting model. For the full year 2011, royalty revenue was $158 million, an increase of 15%.
We recorded $20 million of corporate partner revenue in the quarter, driven by third-party manufacturing contracts with strategic partners. For 2011, we recorded $57 million of corporate partner revenue.
Now turning to expense lines from the non-GAAP P&L. Fourth quarter cost of sales were $140 million or 11% of revenues, which included increased global JC virus assay test and the increased costs for the AVONEX PEN. Fourth quarter R&D expense was $338 million or 25% of revenues, which included the $36 million payment to Portola and an increased spending related to our late-stage programs.
For the full year, R&D expense was $1.2 billion or 24% of revenues. Q4 SG&A expense was $282 million or 21% of revenues, an increase of 3% over the same period last year. Continuing down the P&L, our collaboration profit sharing line totaled $73 million in expense for the quarter and $318 million for the year.
Our Q4 non-GAAP tax rate was 24.3%, benefiting from a higher level of orphan drug research credits in favorable settlements from prior-year audits. In the fourth quarter, our weighted average diluted shares were 245 million, essentially flat versus prior quarters.
During Q4, we repurchased approximately 1 million shares for a total cost of $111 million for the purpose of 2012 share stabilization. We ended the quarter with $3.1 billion in cash and marketable securities, split approximately 70-30 between the U.S. and outside the U.S. This brings us to our non-GAAP diluted earnings per share, which were $1.51 in the fourth quarter and $5.90 for full year. Now let me turn to full year 2012 guidance.
We expect full-year revenue growth of low to mid-single digits. Cost of sales is expected to be between 9% and 10% of sales, driven by third-party manufacturing, JC virus assay test and increased costs for the AVONEX PEN. R&D is expected to be between 24% and 25% of total revenue, a modest increase versus 2011. The R&D spend continues to be driven by several Phase III trials, which will be at the high point of patient accruals, including PEG-Interferon, dexpramipexole, the 2 blood factor trials, Daclizumab and the safety extension studies for BG-12. Additionally, in January, we initiated sites for the new pediatric studies for Factor VIII and Factor IX. R&D also reflects the recent business development deals with Portola and Isis, which are important steps to rebuilding our early-stage pipeline.
SG&A expense is expected to be approximately 22% to 23% of total revenue, up from 2011, primarily driven by the commercial ramp-up in preparation for the potential multiple product launches in 2013.
We expect our effective tax rate in 2012 to be between 24% and 26% of pretax income. We expect the tax rate to benefit from higher orphan drug credit and also benefit from the expected conclusion in mid-2012 of the interferon beta royalty payment from our foreign affiliate to our U.S. affiliate.
As a result, we anticipate non-GAAP earnings per share results between $6.10 and $6.20 and GAAP EPS to be between $5.46 and $5.56. These anticipated results assume the current FX rates and exclude any material risk related to the macroeconomic environment in Europe. Also full-year EPS guidance assumes share stabilization.
While we don't provide quarterly guidance, I do want to call out that we expect the first quarter of 2012 to be unfavorably impacted by certain items. Specifically, ANGIOMAX royalties will reset to a low revenue level in Q1 as in the past, and our R&D expenses will include the $29 million upfront payment to Isis.
Overall, we expect 2012 to be a very important financial year. Our business plan strikes a proper balance in making prudent, pre-launch investments, continuing to build in advance to promising pipeline while delivering earnings growth. These investments by design should have a relatively quick and meaningful put payback, poising our company for future bottom-line expansion.
Now over to George for his closing comments
George A. Scangos
Okay. Thanks, Paul. So before I conclude, I would like to congratulate the entire organization on their accomplishments in 2011. The performance and our outlook are a credit to the entire team, and without their dedication and passion, our overall solid financial performance and the remarkable progress we've made, advancing one of the strongest late-stage pipelines in the industry, would not have been possible.
We continued our transformation of the company and met the goals we set for ourselves at the beginning of 2011. Although we've accomplished a lot so far, we still have a lot to do. In 2012, we'll focus on execution as we invest in our future success, and at the same time, deliver product and EPS growth. I'm confident that we can do this and I'm looking forward to updating you on our progress along the way during the year. So with that, we'll close our remarks and open up the call for questions.
Thanks, George. Melissa, we're ready to open up the call for Q&A. We ask that you please limit yourself to one question and then reenter the queue for follow-up questions. Please state your name and your company affiliation. Melissa, we're ready for the first question.
Your first question comes from the line of Geoff Meacham from JPMorgan.
Geoffrey C. Meacham - JP Morgan Chase & Co, Research Division
When I look at the net new TYSABRI adds in 2011, it's about 1,100 less than 2010 and about 4,000 less than '09. So my question to you guys is, has the discontinuation rate changed over a multiyear period? And are the patients added in 2011 any different, so maybe more first line or less treatment-experienced patients?
Jeff, it's Tony. So we did see an increase in discontinuation rate in sort of 2 chapters in 2011. In the early part of the year, we saw an increase in discontinuations in the U.S. as I think we've talked about because as patients went through the STRATIFY study, we got some lumpiness in the -- particularly the first quarter and the first half of the year. We saw a nice recovery from that and lots of increased demand through the year. We are facing on a country-by-country basis in Europe, somewhat of a repeat of that in the later part of 2011 into early 2012. So I think that's what you've seen. If the U.S. experience plays out, we're confident that those numbers will recover because we see more demand for the product after you get through that initial discount. In terms of the nature of the patients, I think we have seen that the general trend is more confidence -- making physicians confident moving the treatment earlier in the period [ph]. And I think we'll continue to see that going forward.
Your next question comes from the line of Robyn Karnauskas from Deutsche Bank.
Robyn Karnauskas - Deutsche Bank AG, Research Division
I guess the first question I had was maybe you can provide an update of the EXPLORER combo study and the timing of that. And second, just as a follow-up to Jeff's question, can you give maybe a little bit more color on, I think, the last thing you said about 70% of JCV positive patients are staying on drug and I'm wondering if you're seeing that trend continue of positive patients remaining on therapy?
This is Al Sandrock. I'll take the first question on the combo study. We'll see data this year and -- but we probably won't present it at a scientific meeting until either the second half of this year or the first half of next year.
It's Tony. On the topic of positive patients, I don’t think we've seen a meaningful change in that trend. We track that largely outside the U.S. through market research on a periodic basis. I don't think we have a meaningful update to that, country-by-country.
Your next question comes from the line of Mark Schoenebaum from ISI.
Mark J. Schoenebaum - ISI Group Inc., Research Division
I was just wondering on the ALS trials, could you let us know if you think, Al, that -- and I realize that this could change over time, just what's your current thinking in terms of whether or not you can file -- whether or not the FDA would approve the drug based upon one trial? And then maybe on the commercial side of that, could you help us understand how many patients are out there? And then within the ALS population in the U.S., maybe roughly what percent do you think might be eligible for a drug like this? I know it's difficult without seeing the data, but any pointers I think we'd all really appreciate.
Hi, Mark, it's Al. The approvability based on a single trial, I think it's possible if the data are compelling, particularly on a survival endpoint. But it's hard to speculate exactly until you see the data. I think in addition to survival, you'd want to see movement in all endpoints in the same direction. So I guess we'll know it when we see the data, but it is a possibility. In terms of the numbers of patients, there's 20,000 to 30,000 patients with ALS in the United States and probably an equal number in Europe. Who would be eligible? I mean, if the results are compelling, I think it's really not too much else for these patients except for Riluzole, which has a very, very modest treatment effect. So I think a lot of patients would probably opt to go on the drug. Remember that when we opened enrollment in this trial, the interest was so high that we enrolled patients in record speed and we completed enrollment far ahead of schedule. So if that's any indication, there is a high unmet need for drugs like this.
Your next question comes from the line of Matt Roden from UBS.
Matthew Roden - UBS Investment Bank, Research Division
George, a question for you on the expense guidance in the context of the changes that you delivered to the organization a little more than a year ago. I think your plan was to improve strategic focus, deliver $300 million in savings and 350 basis points improvement in operating expenses as a percentage of revenue. But if I look at the midpoint of the guidance range for 2012, we're looking at 47% of revenues going to SG&A and R&D, which is about, in my calculation, is 40 -- about 40 basis points better than 2010. So can you maybe reflect on the changes that you've made into the organization, the opportunities that you have here, and maybe is it just a matter of having to wait another year to see that margin improvement pull through? Can you help us reconcile all that?
George A. Scangos
Yes, sure. I mean, that's a good question. I'm glad you asked it, so we have a chance to address it. It's -- you know what is true is that the $300 million in savings that we achieved are still there, they're in there. We are in a year now when our clinical -- our late-stage clinical trial enrollment is likely at its maximum points. As Paul went through in his statement, PEGylated Interferon, dexpramipexole, the 2 blood factors, daclizumab, the safety extension studies for BG-12 are all at their peak. And so a large fraction of our R&D dollars, now way over half of our R&D dollars, is going just to pay for those trial. They enrolled more quickly than we had anticipated, which means we got up to the maximum costs more quickly than we had anticipated. And frankly, as you think about the company going forward, you expect to have some attrition. And that's the normal. We didn't have any. And failure is cheap and success costs money, and so we are paying for those trials. At the same time, because we know the data for BG-12, and we are, let's say, preparing and optimistic about Factor VIII and IX, we're spending substantially -- let's say, substantial amount of resources to prepare for the launches of those products. You can look at many of the product launches that have been done recently. Some of them have gone well, some of them haven't. And we need to make sure we get ours right, and that takes some preparation. And so we're spending on those as well. So we have -- I think, there's a difference in spend where you are inefficient and wasting money. Not spending adequately on the commercial preparation would be foolish savings. So we're not, not doing that. We're spending, I think, prudently and thoughtfully, but we are investing appropriately. And we are, I guess, saddled with a lot of Phase III costs, which is, in the end, a good thing. But this is the year when I think all those are maximized.
Your next question comes from the line of Eric Schmidt from Cowen and Company.
Eric Schmidt - Cowen and Company, LLC, Research Division
George, if I could just press you a little bit more on the R&D budget, we get that 2012 is a peak year. But I think in 2010, we were also talking about R&D as a percent of sales coming down to the maybe 20% range in the outyears. Is that still an appropriate target? And then also for Paul on the tax rate, maybe you could explain why things have gotten so much better there in 2012 and whether that's sustainable?
George A. Scangos
Yes, let me take the first part of that. And Eric, I think R&D expenses as a percentage of revenues will come down. There's no question about that. I think 20% is not a bad target. I would -- and I'm not trying to back away from that. But what is important for me mostly is that we don't waste money, right? And this year, where we have all the late-stage trials to invest in, we have to invest in them. And that's really what's causing R&D budget to be higher. And those will naturally come to an end and the cost will taper down and R&D costs will come down. And assuming that our early-stage pipeline develops along normal metrics, yes, it'll probably come down to that number you said. If the pipeline is less successful than we hoped, it could be lower. If it's more successful than we hoped, it could be somewhat higher. But I think that's a reasonable target.
Paul J. Clancy
And then Eric, this is Paul. Just to give a little bit more color on the tax rate. Yes, the guidance for 2012 shows a little bit of improvement vis-à-vis our last few years of guidance. And that's a couple of factors. The orphan drug programs that we have, specifically Factor VIII, Factor IX, dex, all have this ability to capture orphan drug research credits, which over the long haul, it depends on the shape of programs kind of coming forward that may kind of apply for that. Isis would be one that would. But that is a number of years off. Additionally, what I had noted is that outside the United States, we have heretofore had a royalty payment that is paid from a foreign affiliate to a U.S. affiliate that will end in mid-2012. So that is sustainable going forward. Over the longer term, I think that all in all, there's downward pressure on our effective tax rate as BG-12 becomes a greater part of our profit mix. And conversely, the RITUXAN cash flow that is subject to essentially all U.S. taxes becomes a lower percentage of our profit mix. Both of those are probably offset by the fact that we intend to do or continue to do cost sharing on programs. So we intend to still -- which has the effect of -- for a portion of R&D not capturing some tax deduction on those expenses. But all told, I think it's a modestly favorable story over the next couple of years and a good story over the longer term.
Your next question comes from the line of Michael Yee from RBC Capital Markets.
Michael J. Yee - RBC Capital Markets, LLC, Research Division
A question for Al or Doug on ALS. Can you comment on whether the protocol there was ever, any interim futility or safety analysis ever that have passed? And then on Riluzole, there's a few months of mortality benefit there. Maybe you can comment on how you've designed the study to -- or powered the study for what types of benefits, whether disability and mortality?
Douglas Edward Williams
We have not talked about the study conduct itself with respect to any futility analysis or anything along those lines. This is Doug, by the way. So no, we have nothing to say about that at this point, except that the study is continuing to run and we'll see the data in the second half of this year.
William D. Young
Yes, the study was powered based on a primary endpoint called the CAFS, or Combined Assessment of Function and Survival. It's well powered for that. I would remind you that the Phase II study, which was about 100 patients, actually achieved significance on that endpoint. This study is 943 patients, so we're pretty confident that we're well powered on that endpoint. It's -- this Phase II study also had a trend toward an effective survival, even though it was a relatively short and small study. And so consequently, if the results -- if the treatment effect holds for a 900-patient, 1-year minimum follow-up, we should be well powered for a survival effect as well.
Your next question comes from the line of Rachel McMinn from Bank of America Merrill Lynch.
Rachel L. McMinn - BofA Merrill Lynch, Research Division
Just wanted to ask about your outlook on capital allocation. You still have very high cash generation but you're talking about share stabilization. So should we think about just a lot more BD this year or is there option here for share repurchases beyond what you're guiding for?
Paul J. Clancy
Good problem, this is Paul, Rachel. Cash flow generation, the company still remains very, very strong, puts us in a great position. And certainly, I think our -- we feel no doubt that a very productive use of the cash has been building the early-stage pipeline. The Phase I/II assets have matured into largely what is the late-stage pipeline now. And I think that we have created a really good late-stage pipeline. It's been an important way to do that and create shareholder value. The Portola and ISIS deals kind of show our indication to continue that strategic kind of point of view. Historically, we've been very disciplined on our deployment of cash, and continue to do so and look for all ways. I mean, the guidance is share stabilization if we decide to kind of return cash to shareholders, we're going to communicate that and update accordingly.
Your next question comes from the line of Yaron Werber from Citi.
Yaron Werber - Citigroup Inc, Research Division
If you don't mind, just 2 quick ones. BG-12, just the timing of the press release mentions filing in the first half. But there's a mention in there "as soon as possible." So I'm just trying to get a sense is there any way this could be in Q1 and are you counting on the 6-month review? And then just on Hemophilia, is there any way we can get B-LONG, the data, in Q3 or are both data sets going to be in Q4?
Douglas Edward Williams
This is Doug. We're not providing any additional granularity around first half for BG-12. And as far as the blood factors are concerned, both of those are going to readout in the second half. I can't give you anymore guidance than that at this point, but we're on track with all the studies to submit to both the EU and U.S. authorities first half for BG-12 and then we'll see data for both of the factors in the second half.
William D. Young
And then, I think on the other part, Yaron -- just correct me Doug. Our planning assumption is 10-month PDUFA review for the United States. So we will seek certainly prior to review. But our planning assumption, as Tony had indicated, does not include revenues for this year. If that happens, we'll kind of come back and talk about what the implications of that are. That would be another great problem to have. But our planning assumption right now is for kind of a standard review in the U.S. as well as outside the United States.
Your next question comes from the line of Ravi Mehrotra from Credit Suisse.
Ravi Mehrotra - Crédit Suisse AG, Research Division
Rachel took my agency cost question, so let me ask Doug a question on BG-12 and the one-capsule bioequivalent study. Could you just give us some color on that and remind us of the regulatory hurdles of trying to get a drug approved on a different formulation than what you used in Phase III? It's obviously, not the first time you've done it, but any color would be useful.
Douglas Edward Williams
As I mentioned, we conducted a bioequivalent study to essentially look at a single capsule as opposed to 2 capsules. As you know, we're going forward. We believe that the drug will be a BID drug. The way it has been formulated and the way the Phase III study was done was with 2 capsules in the morning, 2 capsules in the evening. We've now created a single capsule that has the same drug dose, done the bioequivalent study and demonstrated obviously bioequivalence. So we plan to file that with the regulators and seek approval for what we believe will be a more convenient dosing approach for patients with the single capsule twice a day. That will be part of the package and we believe we have appropriate data to support being able to move to that as we get the drug approved.
Your next question comes from the line of Geoff Porges from Bernstein.
Geoffrey C. Porges - Sanford C. Bernstein & Co., LLC., Research Division
Just quickly on the P&L, Paul. Specifically on gross margins. It ticked up a bit to 11% in Q4 but your guidance is sort of 9% to 10%. Anything going on there that we should be aware of? What drove it in Q4? And then is 9% to 10% where you think you can be as you look at the product mix going forward and how is the reduction in the mix contribution of RITUXAN and the other products coming in going to affect that?
Paul J. Clancy
Great question, Jeff. Yes, I think the other reason it ticked up a little bit was we had a little bit more than normal write-offs in Q4 of 2011. Most of those write-offs were excess in obsolescence write-offs related to ZEVALIN. So we have actually a supply agreement that is, obviously, a number of years old related to the divested product and just literally because the end market sales have attenuated there. We've had to take a write-off in Q4. We think that is for the most part, behind us. Our yields across the plant have been on track. And then I think the other thing going into 2012 is that we will benefit a little bit from a more productive, if you will, biologics manufacturing going back in late 2009 and into 2010. So I mean, curiously, our productivity in a given year benefits the P&L a number of years down the line simply because of the inventory balances that we hold in this business. We will continue to have costs that are related to the assay that we do think that are very important, particularly at this stage of TYSABRI and in risk stratification to be behind the brand. There's an opportunity for improvement if we can get that reimbursed in the United States, because currently we and Elan bear the burden of that on the P&L. As you had inferred that as RITUXAN may become lower percentage of the mix, that has a very favorable gross margin obviously. But I think the products that come on also are pretty strong gross margins, kind of BG-12, et cetera. So I think we're -- that where we're thinking in the zone of 90% to 91% of sales on the gross margin line is a good number to have.
Your next question comes from the line of Thomas Wei from Jefferies.
Thomas Wei - Jefferies & Company, Inc., Research Division
I had a question on TYSABRI. Just if you could help us reconcile the different numbers on the cumulative TYSABRI patient count. So what is in your slides today is 95,200 as of the end of December, but in the FDA communication, when the JC virus assay was approved, they had mentioned 96,582 as of January 4. And I thought that maybe I was getting confused and it was the clinical trial patient numbers that was throwing things off. But then you mentioned today that, that number is 4,700. So I'm actually not sure what the disconnect there is and maybe if you could help us understand that a little bit better?
Paul J. Clancy
Thomas, this is Paul. Look, we always go back at this point in every quarter and try to, particularly on the international TYSABRI patient numbers, reflect the best of information available that generally will move numbers around a not very meaningful amount. That probably is the biggest reason for the change vis-à-vis the January 4 medical communication. We'll look into and try to get back to you if there's anything further than that. But I believe it's owing to, in essence, the international numbers. The U.S. numbers aren't subject to a lot of changes because of the TOUCH program. We have a tremendous amount of visibility so we don't see a lot of changes in that. It's just that country by country, there are different methodologies that we use on the TYSABRI patient numbers and we always try to look hard and quality-control those to try to get the best information available.
Your next question comes from the line of Josh Schimmer from Leerink Swann.
Joshua Schimmer - Leerink Swann LLC, Research Division
Question on Europe, maybe for Tony. What is there to challenge regarding the Italy claim that TYSABRI sales have surpassed the limit? Is that limit expected to rise in the future years and how quickly and are there similar limits in other European countries? And then on FAMPYRA, what are your expectations for the IQWIG and GBA added benefit assessments?
So this is Tony. Maybe I'll take the second one and let Paul talk to the first one. So on IQWIG, because FAMPYRA was launched in July 2011, it's actually in an extended version of the [indiscernible] process, which takes 18 months. So we expect to get an IQWIG rating in Q2 of 2012.
Paul J. Clancy
And then Josh, just a little bit more color on the Italian situation on TYSABRI. We were granted authorization in 2006. So this actually goes back to 2006. And we entered into agreement with the Italian Medicines Agency known as AIFA, that's just the initials for that, to set a price. And that price was subject to a reimbursement ceiling for the first 24 months. In the fourth quarter of 2011, we got a notification from the Italian Medicine Agency saying that we had exceeded the ceiling for a subsequent 24-month period. And that's what we're contesting. And -- but it has a peculiar impact of really just trying to look at our revenue recognition going forward from the receipt of that letter. So it really gets into an accounting judgment and reserves around fixed and determinable pricing. And we're simply booking to that new ceiling until we resolve the issue, until we negotiate it or have a new set of facts, which we hope will happen in the first half of 2012 and then that will create some changes to the estimates that we have accrued heretofore.
Your next question comes from the line of Tony Butler from Barclays Capital.
Charles Anthony Butler - Barclays Capital, Research Division
And Paul, could we just stick with the last question. Does that imply that you would then reverse the accrual in the first half? Would that be a goal? And then second, would other countries perhaps have similar ceilings based upon any other austerity or do you get even a much more reduced price from Italy on the next, say, 2 years?
Paul J. Clancy
I don't want to comment on how -- where it will land but if there will be a change to whatever we kind of have is the reserve once we get a new set of facts, the actual facts. I think -- we don't believe that we were unique in this perspective. We had heard that other companies actually have gone through similar things, that's from our advisers. And with respect to other countries, nothing meaningful to report in terms of similar type of analogs at all.
That was our last question. Thank you for participating in today's call. You may now disconnect.
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