Thank you for standing by. Welcome to the Merck & Co., Rahway, New Jersey, USA HIV investor event. At this time, all participants are on a listen-only mode until the question-and-answer session of today's conference. At that time, if you would like to ask a question, you may press star one on your phone and record your name at the prompt. This call is being recorded. If you have any objections, you may disconnect at this time. I would now like to turn the call over to Mr. Peter Dannenbaum, Senior Vice President, Investor Relations. Sir, you may begin.
Thank you, Shirley. Good morning, everyone. Welcome to Merck's HIV investor event, coinciding with the 13th International AIDS Society Conference on HIV Science. Before we get started, I'd like to remind you that some of the statements that we make today may be considered forward-looking statements within the meaning of the Safe Harbor provision of the U.S. Private Securities Litigation Reform Act of 1995. Such statements are made based on the current beliefs of our company's management and are subject to significant risks and uncertainties. If our underlying assumptions prove inaccurate or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Our SEC filings, including item 1A in the 2024 10-K, identify certain risk factors and cautionary statements that could cause the company's actual results to differ materially from those projected in any of our forward-looking statements made this morning.
Merck & Co., Rahway, New Jersey, USA undertakes no obligation to publicly update any forward-looking statements. During today's call, a slide presentation will accompany our speakers' prepared remarks. These slides and our SEC filings are posted to the investor relations section of our company's website. Speaking on today's call will be Dr. Eliav Barr, Senior Vice President, Head of Global Clinical Development and Chief Medical Officer; Dr. Liz Ray, Vice President, Clinical Research, Infectious Disease; and Chirfi Guindo, Chief Marketing Officer, Human Health. The full biographies of the speakers can be found in the appendix of the accompanying slide presentation. Now, moving to the agenda, Eliav will start our prepared remarks with a strategy overview. Liz will then provide a research update across our broad HIV pipeline, and Chirfi will discuss the commercial opportunity. Eliav will then wrap up with closing remarks before we turn to Q&A.
With that, let me turn it over to Eliav.
Thank you, Peter, and good morning, everyone. Thank you for joining us in today's event in conjunction with the International AIDS Society meeting. Today, we'll provide an in-depth review of our HIV treatment and prevention pipeline, as well as the opportunity that stands before us to help more people at risk for or living with HIV infection. Our commitment to HIV started at the very beginning of the AIDS epidemic, and over the years, we've been responsible for the creation of the prototype of each of the potent antiretrovirals that are designated as anchors of HIV treatment regimens. Now, I joined Merck in 1995. At that time, Merck had just announced the results of the Crixivan phase III program, that led to the licensure of this protease inhibitor anchor medicine within weeks of submission.
The company had also discovered the first NNRTI, Efavirenz, a drug that became the anchor medicine in Atripla, the first single-tablet regimen for HIV treatment. After these successes, we continued to innovate. We discovered the integrase strand transfer inhibitor, or INSTI class, of anchor medicines, and we launched Isentress, which is the prototype for this class. Iterations on Isentress's profile led to the development of INSTIs that have become the most common anchors in HIV therapy regimens today. We've continued our innovation by ensuring availability of drugs for pediatrics, even down to newborns. More recently, our goal has been to find new types of antiretrovirals with high barriers to resistance and potency to help enable reductions in the burden of HIV treatment and prevention regimens. With the in-licensing of Islatravir we introduced a new class of anchor medicine, the nucleoside reverse transcriptase translocation inhibitor, NRTTI.
Doravirine/islatravir is a first investigational regimen in the NRTTI era. Now, Merck remains active in the field of HIV research because collectively, the HIV treatment and prevention community has yet to reach full control and prevention of HIV, as defined by the UN AIDS 2030 goals. There still remains significant unmet need globally in HIV, with currently approximately 40 million people living with HIV. An estimated 1.3 million people were infected with HIV in 2023, which equates to about 3,500 new infections per day. For these individuals, it has proven difficult to remove the stigma associated with HIV. We intend to be part of the solution for the continued unmet need in HIV treatment and prevention worldwide. How are we going to do that?
We aspire to be the first in class and best in class with our NRTTIs, which we hope will serve in important roles in both treatment and PrEP or prevention. NRTTIs inhibit HIV reverse transcriptase through immediate and delayed chain termination after incorporation into viral DNA. These agents also block reverse transcriptase translocation, preventing nucleotide incorporation. NRTTIs are potent and long-acting molecules, as exemplified by our candidate medicine for PrEP, which is being studied in a phase III trial at 11 mg once monthly. Because of this, NRTTIs may be appropriate for weekly, monthly, and potentially even longer interval regimens. A longer dosing interval has the potential to reduce treatment failure due to noncompliance, to offer additional treatment options, and to reduce stigma.
Our clinical trials have shown that at the appropriate doses, NRTTIs have had favorable efficacy, safety, and drug-drug interaction profiles, features especially important in older individuals and those people with comorbidities. Finally, our regimens are INSTI-free, reserving this important class of therapies for later if needed. Now, our current in-line portfolio includes the original INSTI Isentress, as well as Pifeltro, or Doravirine, and Delstrigo, which is a fixed-dose combination of Doravirine, TDF, and 3TC. Doravirine is an important part of the current portfolio, but it's also in our current investigational two-drug Islatravir-based regimens. It is an NNRTI with favorable efficacy and safety profile. In the near term, we will leverage our experience with Doravirine to create a single-tablet regimen with Islatravir, our leading NRTTI candidate. Now, Liz will review the data for this regimen.
It's been filed in the U.S., and a PDUFA date has been set for April 28, 2026. We've also invested heavily in our once-weekly treatment regimens, which can reduce the burden of adherence to one-seventh compared with daily regimens, an advantage for individuals with busy or complicated lives. The first of these investigational weekly treatment regimens will combine Islatravir with Lenacapavir, and this is part of our ongoing collaboration with Gilead. This regimen leverages the potency of Islatravir and the proven track record of Lenacapavir to create a two-drug regimen. Our long-term expertise in NNRTIs has enabled us to discover several candidates with different pharmacologic profiles. One of these is Ulonivirine, which we are studying in combination with Islatravir as a weekly single-tablet regimen. Islatravir Eulni has the potential to be the smallest tablet approved and one with a favorable DDI profile. Control of HIV transmission requires multiple PrEP options.
We're very excited about the potential of MK-8527, which is being studied as a once-monthly oral PrEP pill. It's a very small tablet that can be used easily and in a discreet manner, and we think it's going to be very important globally. We also have intensive research efforts to look at new therapies, not only longer-term, longer-acting, longer half-life medicines within the classes we've talked about already, but also new classes of medicine. We've been at the forefront of developing anchor medicines in HIV with features to enable different attacks on the HIV virus. We believe those opportunities also exist in our preclinical and early clinical pipeline. As we move forward to the next period of future innovation in HIV, we'll be considering our ability to develop long-acting formulations, which include assets in the family of NRTTIs and also in the family of NNRTIs.
These leverage our expertise in those classes of drugs. We also have collaborations with Gilead and a variety of options in both treatment and PrEP under development. We're also thinking hard about how we will leverage our expertise to bring forward either cure or long-term control or reset approaches. One of these approaches of interest is the RTTAC mechanism of action. These are NNRTIs that have the additional feature of selectively killing HIV-infected cells. We're currently evaluating candidate medicines in early development. With that, I'd like to turn the virtual podium over to Liz, who's going to be telling us more about the current pipeline, focusing on the results we presented recently at CROI, as well as at IAS this week. Liz?
Thank you, Eliav. I am very excited today to be here with you to share more about our expansive HIV pipeline, which has continued to make great progress. Today, we'll be highlighting the four programs that are currently in late-stage development in our HIV pipeline. These programs are anchored on our NRTTI molecules and are leveraging the properties of this class. Each program has generated data that we think is really exciting and supports the progression of these programs. We have three programs in development for treatment that are anchored by Islatravir, including a once-daily oral treatment program with Doravirine and Islatravir, which has recently filed the initial NDA in the U.S. based on data in adult participants who are virologically stable. The PDUFA date for this filing is set for April in 2026. In addition, we have filed an application for Doravirine and Islatravir in Japan.
We have our first weekly oral treatment with Islatravir in combination with Lenacapavir, which we are developing in partnership with Gilead and which is in phase III development. We have a once-monthly oral PrEP option with a new investigational NRTTI, MK-8527, which is on the cusp of starting phase III. Finally, we have our wholly internal oral weekly treatment regimen candidate where Islatravir is being combined with our new investigational NNRTI, Ulonivirine, which has recently started phase II . With these four programs, we have the potential for four NDAs to be filed over the next few years. This is truly exciting for us as we see that each of these products can be a potentially important option for people living with HIV or people who are at risk of acquiring HIV.
The NDA for Doravirine and Islatravir is currently under review by the FDA, and the basis for this filing was two pivotal studies in virologically suppressed adults who have no history of treatment failure. Importantly, in this program, this was the first set of phase III studies where we were able to demonstrate that a two-drug regimen that does not contain an integrase inhibitor was not inferior to a three-drug regimen containing an integrase inhibitor. The two phase III trials, Protocol 51 and Protocol 52, were conducted in virologically stable participants. In each trial, they were randomized to either continue on their baseline treatment or switch to Doravirine and Islatravir in Protocol 51. The baseline treatment was background antiretroviral therapy, which included different kinds of two and three-drug regimens. In Protocol 52, the comparator was Biktarvy FTC/TAF . In both trials, we were able to demonstrate strong efficacy results.
In both trials, Doravirine and Islatravir was not inferior to the comparator, as demonstrated by the primary endpoint results at week 48, based on people having RNA levels above 50 copies per mL. This is on the left of each of the figures. As you can see in the figures, the second set of bars on the right showed that there were high rates of virologic suppression, greater than 90%, in both trials. Importantly, there was no treatment emergent resistance to either Doravirine or Islatravir that was observed in either study. The tolerability and safety profiles were comparable in each of these trials to the comparator. Also important to note is that we saw that total lymphocyte and CD4 count changes over the course of these studies were similar between Doravirine and Islatravir and the comparator regimens.
These are very promising results because this is the first two-drug regimen that does not contain an integrase inhibitor that's demonstrated comparable efficacy to a three-drug regimen containing an integrase inhibitor. Our filing in the U.S. was accepted for an indication in virologically suppressed adults. We have another study, Protocol 53, being conducted in treatment-naive adults, which has completed enrollment. We expect that the week 48 data will read out by the end of this year and will be presented next year at a scientific meeting. We expect these data to support the initial application in the EU and to support a U.S. label expansion as well.
In addition to a once-daily regimen including Islatravir, we are also developing two once-weekly two-drug oral treatment regimens, both containing Islatravir, and we think that each of these will be an important option for patients who desire a weekly oral regimen as a way to shift away from daily treatment. We believe that once-weekly oral regimens will help to address challenges around pill fatigue that people living with HIV often grapple with. Islatravir and Lenacapavir, which we're developing with Gilead, our partner on this program, is currently phase III and recently completed enrollment for those studies. This combination is being studied in virologically suppressed adults and will include a loading dose strategy followed by a single tablet administered once weekly. We are excited that this has the potential to be the first weekly oral treatment regimen to market and the first complete long-acting oral treatment regimen for HIV.
The Islatravir/Ulonivirine program has recently started phase II and is currently being evaluated in adults who are virologically stable, but we also have plans to study this in adults who are treatment-naive. This regimen is differentiated from Islatravir/Lenacapavir by the inclusion of Ulonivirine, which is an investigational NNRTI. It's being studied at a dose of 200 milligrams in combination with Islatravir, which we think will have the potential for a more simplified regimen as a single tablet that has the potential to be smaller than the Islatravir/Lenacapavir tablet without requiring a loading dose. We also believe, importantly, that this has the potential to have a favorable safety and DDI profile. For the Islatravir/Lenacapavir program, we've conducted a phase II study to evaluate this combination and presented these data last year at CROI and at ID Week.
What's shown on the slide are the week 48 results that were presented at ID Week. In this trial, as you can see, where the comparator was Biktarvy FTC/TAF, Islatravir and Lenacapavir resulted in virologic suppression at high rates that were similar to what we're seeing in the comparator group. Importantly, there were no participants that were discontinued due to decreases in CD4 T-cell or lymphocyte counts, and the overall lymphocyte and CD4 counts were similar across treatment groups. These are the data that gave us confidence to move this program into phase III. This program we're calling the ILN program. This was initiated at the end of last year and enrollment recently completed. ILN 1 and ILN 2 are being conducted in adults who are virologically suppressed, and in ILN 1, the comparator is Biktarvy FTC/TAF. This is a double-blinded randomized control trial.
ILN 2, in contrast, is an open-label randomized trial, and here the comparator is baseline antiretroviral therapy, which can include different two and three-drug regimens. Both of these trials are expected to read out the 48-week results in mid-2026, and we look forward to seeing these results. Ulonivirine or MK-8507, this is our novel investigational NNRTI, and we are moving this forward in development in combination with Islatravir as part of our wholly internal Merck oral weekly treatment regimens. This week, we presented data from this program at IAS. Ulonivirine is a potent NNRTI. This was demonstrated in a phase 1b proof of concept study where we saw excellent virologic activity.
We did conduct a prior phase IIb study where we dose-ranged Ulonivirine in combination with a higher dose of Islatravir, and this study, while stopped early, did provide helpful supporting data for the combination and for the selection of the Ulonivirine dose. As shown on the slide, the predicted Ulonivirine exposures with a 200 once-weekly dose met the PK threshold to cover wild-type and common NNRTI variants. We've also generated data to demonstrate that there's no clinically meaningful drug-drug interaction between Islatravir and Ulonivirine and that repeat dosing of Ulonivirine has no adverse effect on total lymphocyte counts and CD4 counts. The phase II study of the combination is currently enrolling, and we look forward to seeing the results next year for week 24 primary endpoint. In addition to creating meaningful options for treatment, we believe it's really important as well to provide meaningful options for HIV PrEP.
We're very excited that we have the opportunity with MK-8527 and that we've made progress in advancing this program. The concept of a once-monthly oral pill to prevent HIV infection has many potential benefits for people who are at high risk for HIV. MK-8527 is being uniquely developed only for PrEP, and we believe it can have a potential very important impact on global public health. Based on the pharmacokinetic profile of this molecule, we anticipate a fast onset of protection so that within an hour of taking the first dose of MK-8527, people would be able to have a month of protection from HIV. There would also be no need for a loading dose.
In addition, with the discretion that's allowed with a small once-monthly oral pill, we believe this will be easy to use and address concerns around stigma that are associated with taking a pill for PrEP every day. This will also, we believe, offer different ways for implementation that may be more convenient for people compared to an injection that patients would have to go to a physician's office to receive. Importantly, based on the data seen so far, MK-8527 has the potential to provide favorable efficacy, safety, and DDI profile for those people who could benefit from using PrEP. This week at IAS, we've presented phase II data for MK-8527, and these are the results that supported advancing this program to phase III. MK-8527 is an NRTTI with the same mechanism of action as Islatravir; it is also highly potent and has excellent resistance in vitro.
The phase II study results informed our selection of a dose for phase III trials, which will be starting imminently. As you can see in the top figure, which shows the study schema, we conducted a phase II dose-ranging study of MK-8527 compared to a placebo where we looked at three different doses of MK-8527. The study was conducted in people who are at low risk for HIV infection and evaluated safety, tolerability, and pharmacokinetics. As you can see from the concentration over time figure, the pharmacokinetic results support monthly dosing of MK-8527 for PrEP. Based on the modeling that's been conducted from these data, we selected a dose of 11 milligrams to advance into the phase III program. Importantly, all three doses were well tolerated and demonstrated a safety profile that was comparable across the different doses of MK-8527 and to the placebo group.
We are moving forward to initiate the phase III express PrEP program for MK-8527 PrEP. This program is comprised of two phase III trials, EXPRESS-10 and EXPRESS-11. EXPRESS-10 is being conducted in adolescent girls and young women at greater likelihood of HIV exposure, and EXPRESS-11 is being conducted in populations at greater risk of HIV exposure, which include men who have sex with men and transgender individuals. Both of these trials are large studies evaluating MK-8527 once monthly against the daily oral comparator FTC TDF. Of note, EXPRESS-10 will include not only older adolescents, meaning 16 to 17 years old, but also women who become pregnant while on the trial may opt to stay on the study. We anticipate data in pregnancy and lactation in this trial.
EXPrESSIVE-10 is being conducted in partnership with the Gates Foundation, and this is a collaboration that both the Gates Foundation and we are very excited about. We do see the great potential here to bring forward a meaningful option for people around the world, as well as an opportunity to impact the global epidemic in areas where there are still very high rates of infection, such as sub-Saharan Africa. EXPrESSIVE-11 is slated to start any day now, and we anticipate the first participant will be enrolled in early August, and this study will be conducted globally. We look forward to the initiation of the phase III program and sharing the progress with you in the future. With that, I will turn this call over to Chirfi.
Thank you, Liz. Good morning, everyone. As we have mentioned before, Merck has a long and rich legacy in HIV.
We have a track record dating back to the early 2000s of working in partnership with governments and global partners, such as the Gates Foundation, to enable broad, sustainable global access to our HIV innovations. I'm proud to have been part of several of these important access initiatives when I led global marketing for HIV at our company and before that when I served as managing director for Merck in South Africa. It is humbling to now be in a position to potentially bring forward four very important options for both treatment and PrEP in the near future. HIV is a large market that is anticipated to continue to grow rapidly, primarily driven by demand for PrEP. The treatment market is also expected to continue to grow to approximately $25 billion by the mid-2030s. As you heard from Eliav earlier in the presentation, high unmet needs remain in HIV.
Up to one in every five people living with HIV switch their treatment regimens annually due to tolerability, resistance, or the desire for simpler regimens. On the PrEP side, a substantial opportunity exists to bring new options into the market, including a monthly oral option like MK-8527. This is particularly exciting for people who are seeking flexibility and the discretion that comes with having a monthly pill that can protect against HIV. The HIV landscape, next slide, the HIV landscape is continuing to evolve, and the needs of the community are becoming more and more clear. We have done a lot of work in market research interacting with patients, advocacy groups, providers, and other members of the community. Four main insights have emerged from those interactions. First and foremost, people with HIV are aging. Currently, half of people living with HIV in the U.S. are 50 or older.
Roughly one-third of people living with HIV have comorbidities. It is therefore important to bring forward suitable options for these individuals. The second insight is on the growing need for simplification and two drug regimens in particular. People on treatment are wanting less drug while enabling viral control and the efficacy that these regimens provide. The third insight is the need for additional options and choice because adherence challenges continue, with many people living with HIV missing doses on their existing treatments. Finally, stigma continues to be a challenge. As Eliav noted, almost half of adults have discriminatory attitudes towards people living with HIV. It is important to be able to bring forward options that allow for discreet dosing and potentially have minimal interaction with the healthcare system. Approximately one-third of people, when asked, would prefer long-acting oral options for both treatment as well as for PrEP.
This is precisely what we will offer as we continue to develop our exciting pipeline. On the treatment side, we have Doravirine/Islatravir as a potential daily oral regimen, Islatravir/Lenacapavir, in collaboration with Gilead, as a potential first oral weekly regimen, and Islatravir/Ulonivirine as a wholly owned potential weekly oral regimen. For these options, these options provide virologically suppressed people living with HIV with a simpler two-drug regimen that do not contain an INSTI. This can be particularly meaningful for people who are getting older and for whom drug-drug interactions, cardiometabolic toxicities, and other tolerability issues may be a concern. Our new treatment options may be able to offer choices for both switch as well as treatment naive populations of people living with HIV. Importantly, they can reduce pill burden with weekly dosing for Islatravir/Lenacapavir and Islatravir/Ulonivirine.
On the PrEP side, we're aiming to launch the first and only monthly tablet for HIV prevention with MK-8527, our investigational NRTTI that has been specifically developed for PrEP and PrEP only. This is important because there will be less concern about the potential for resistance when thinking about use of the same molecule for treatment and for PrEP. MK-8527 has the potential to enable fast onset of protection within one hour of intake with no loading dose needed. It would provide discreet monthly oral dosing to meet the preferences of many people seeking long-acting protection who do not want injections. We expect this program will be meaningful for public health on a global basis, and we fully recognize the responsibility our company has to work with partners to address public health needs both in high-income countries as well as in low and middle-income countries.
We feel we are well positioned to drive important progress for people impacted by HIV around the world. Earlier this year, we laid out the components of our expansive late-stage pipeline that comprise a potential revenue opportunity of over $50 billion by the mid-2030s, putting MFN aside. With that, we see an opportunity of greater than $5 billion for our late-stage HIV portfolio, which consists of four impactful new product launches anticipated over the next few years, the first of which is Doravirine/Islatravir for daily oral treatment. Last week, the FDA accepted for review the NDA of Doravirine/Islatravir and set a PDUFA date of April 28, 2026. This would be the first regimen containing an NRTTI to be approved by the FDA. It would also be the first complete two-drug regimen that does not contain an INSTI.
Subsequently, we have a potential first long-acting oral treatment to be approved with EZOLEN in partnership with Gilead, which is currently in phase III and has primary completion dates next year. Next, we have our potential once-monthly oral PrEP, MK-8527, which will begin in phase III imminently. Finally, we have EZOULO, which combines Islatravir with our investigational next-generation long-acting NRTTI, Ulonivirine, with a high barrier to resistance. EZOULO, which is fully owned by Merck and currently in phase II, has the potential to be the smallest pill approved for once-weekly treatment, which also does not require loading dose. This greater than $5 billion opportunity on a non-risk-adjusted basis underlines our confidence in this pipeline of HIV treatment and prevention options. Our excitement to bring forward these innovations is matched by the enthusiasm of the community, as we heard this very week at IAS.
It identifies our important presence in HIV since day one. We are eager to leverage our commercial engine and our global footprint to bring forward these great new options for people impacted by HIV around the world. With that, I turn the call back to Eliav.
Thank you, Chirfi. From all that has been shared, it should be evident that we are highly interested in continuing to contribute to HIV treatment and prevention. We are confident in our ability to play an important role with these programs we have laid out. We are pioneering potentially novel options, including with an NRTI anchor medicine that has a unique mechanism of action, high potency, high barrier to resistance, favorable DDI profile, and the capability for longer-acting impacts in treatment and prevention regimens.
We anticipate four new approvals in the near term, and we are working with speed to ensure that we can get these important medicines to people globally. We continue to work with the community to ensure that HIV treatment and prevention remains a top priority for public health officials. We want to make sure that people are not defined by their HIV, firstly by preventing infection and secondly by bringing forward regimens that enable people to control their HIV without having to think about it often. With that, I'll hand the call back to Peter.
Thank you, Eliav. Surely, we're ready for Q&A. Before we get started, two things, please. First, Katherine Hayward, Senior Vice President, U.S. Pharma, will be available for questions. Secondly, if I could request that questioners please limit the subject matter today to our HIV program. Thank you.
Thank you, ladies and gentlemen. If you wish to ask a question, please press star one on your telephone keypad. You may withdraw your question anytime by pressing star two. If you're using a speakerphone, please pick up the handset before pressing the numbers. Once again, if you have a question, please press star one. One moment, please, for our first question. Our first question comes from Trong Lin with UBS. Your line is open. You may ask your question.
Oh, great. Thanks for taking our questions. We've just got two on 8527. I guess first, what makes you confident that 8527 doesn't have the lymphocyte lowering issues when used at higher doses for the monthly combos?
Secondly, and perhaps linked to the first question, is there a roadmap for injections for longer durations for this product, like at four or six months, or even resuming the implant development for 12 months, which you previously had for Islatravir? Or can you not push that dose higher because of those lymphocyte lowering issues? Thank you.
Right. I'll take that, Eliav. We have had an extensive de-risking program for MK-8527 that followed the same path that led to the successful de-risking of MK-8591, or Islatravir. We have the right models and the right clinical data that have given us that confidence. Equally, the data that we've presented today or this week at IAS and also reviewed extensively with regulatory authorities has convinced them that we are on the right track here with a drug that has enormous potential.
We're very excited about that. With respect to your second question, we're exploring a variety of different injectable options. That work is in earlier stages of development, and we're confident that we'll be able to bring forward medicines that will allow for a whole variety of different durations of therapy and hopefully as long as possible. Thanks.
Great. Thanks, Trong. Next question, please, Shirley. Thank you.
A question comes from Mohit Benza with Wells Fargo. You may ask your question.
Thank you very much for taking my question. Just a couple of questions. One is that it does seem like the market might shift to injectables in longer term, especially for the PrEP market. What does your market research suggest which makes you more confident around the monthly oral? Yes, it is monthly.
Number two, with the Islatravir or Ulonivirine combo, you are combining two NRTTI. Is there any potential for added toxicity given that they are two similar mechanisms and one of them did cause, at higher doses, lymphodepletion? Thank you.
Yeah. Let me start by the second with a correction. The Islatravir or Ulonivirine are actually two different mechanisms of action. Islatravir, I know that the letters are very similar, but they're different mechanisms of action. Islatravir is an NRTTI, and Ulonivirine is an NNRTI. There is natural confusion, but they're different. We do not expect any, and we've actually de-risked both molecules pretty well, including a long-duration dosing of Ulonivirine monotherapy just to make sure it has absolutely no lymphocyte effect. That combination, I think, will be a very exciting one.
With respect to the Q monthly, I'm going to turn that to Chirfi to answer. Yeah. No, thank you for the question, Mohit. I think it's important to highlight that despite the availability of daily options for PrEP, the availability of injectables, still 1.3 million people get infected on an annual basis. Clearly, more is needed to protect individuals who want to avoid HIV infection around the world. We believe when we did the market research, we presented options to these individuals. About a third of them have signaled preference for a monthly oral option to protect themselves. The reason for that is really the fact that it would be more convenient for them. It would give them the option of having a potent, rapid protection within an hour. In the case of MK-8527, sorry, they could take this medicine in the comfort of their home.
You could think about telemedicine in this context where individuals would not need to necessarily go to the doctor to get their injection. We believe that this oral monthly PrEP option would actually expand access and facilitate access to many individuals in the United States and around the world. We are excited about this opportunity, frankly. You should have been at IAS. You would have heard the community super enthusiastic about this monthly oral option.
Great. Thanks, Mohit. Next question, please, Shirley. Thank you.
Our next question comes from Evan Sigerman with BMO Capital Markets. Your line is open. You may ask your question.
Hi. Mark Hoffman on for Evan. Thanks for taking our question. Thinking about MK-8527 again, can you talk about how Merck may be able to capture a greater opportunity in the lower-risk patients not exposed to HIV?
Also, I know this is not the majority of the market opportunity in this patient population, but could you maybe contextualize how you think about the opportunity for these patients? Thanks.
Chirfi, why do not you take that?
Yeah. For us, I mean, the opportunity is so huge in the people who are at risk, as I mentioned, 1.3 million who are getting infected on an annual basis. Our studies were done specifically in those populations. This is really the opportunity that we are going to go after in the coming periods.
Great. Thank you, Malcolm. Next question, please, Shirley. Thank you.
Our next question comes from Ahsaad Haider with Goldman Sachs. Your line is open. You may ask your question.
Great. Thanks for taking the question and doing the call. Two quick ones.
First, for PrEP, can you maybe talk about how you'll position and what market share you think is possible versus generic daily orals? Gilead's Discovery will also be generic around the time you launch. Also against Gilead's Lenacapavir, where there will likely be a yearly injection formulation when you launch as well. Second, on treatment, how do you think about how much share you could pull from Biktarvy with the Gilead-partnered weekly oral? How might that compete with Gilead's wholly-owned weekly oral if both make it to market, recognizing, of course, that the latter is currently on a clinical hold? Thank you.
This is Eliav. I'll just make a couple of general comments. I think it's really important in the PrEP space to have options that enable people to have discrete and low-compliance burden options.
When we talk to folks in both high and middle and low-income countries, the idea of having a monthly pill discrete at home, telemedicine, or not having to go to a healthcare center to get an injection is a real home run winner for them. I think it's a very important one. In terms of the treatment, again, there'll be a lot of options needed for treatment. With our Q weekly, we have the power of working together with Gilead. We'll have our own wholly-owned drug that will have some very unique properties and a broader label. In terms of looking at the opportunities, I'll turn it over to Chirfi for more contextualization.
Yeah. I would go back to what I said about PrEP to start with.
Eliav summarized it nicely in terms of what the community is wanting, the options that the community is seeking for protection. I think the advantage of MK-8527 really is the fact that it is a small pill. It works very, very fast within an hour of intake. You get full protection for a whole month, and you even have forgiveness up to seven days beyond that. You can take it with the discretion that Eliav talked about. You do not have to go to the doctor and get a needle injection and so on and so forth. We believe that many, many individuals will choose this option. Market research suggested about a third of people would opt for this for their protection if it were available. On the treatment side, again, I agree with what Eliav said.
We believe that our weekly options are going to be well-positioned, and we will have a meaningful share for both EZOLEN when approved as well as EZOULO when approved. These are very good options that provide differentiated benefits for patients going forward.
Great. Thanks, Ahsaad. Next question, please, Shirley. Thank you.
Our next question comes from Louisa Hector with Berenberg. Your line is open. You may ask your question.
Hello. Thank you for the call. On MK-8527, I wonder if you could comment on the amount of data you have on drug-to-drug interactions, including perhaps recreational drug use. And then secondly, on your sales ambitions by therapy area, they do tend to arrive in $5 billion increments. Given the amount of data that you have in-house in HIV, could you comment on whether your over $5 billion sales potential has increased towards $10 billion? If not, why not?
Thank you.
Great. Maybe we'll start with a DDI question, and I'll ask Liz to comment on that. Yeah.
Thank you, Eliav. MK-8527's potential for drug-drug interactions is low. This is based on the preclinical profiling that's been done for this compound as well as some phase one dedicated studies that we've conducted. We do think that overall, the potential for meaningful DDIs is low with this compound.
I'd just add to that that the NRTIs are, the metabolism is such that the drug-drug interaction potential is really quite minor. Obviously, we can't do direct drug-drug interaction studies in people with recreational drugs. Based on our understanding of the metabolism of those drugs, we don't anticipate any drug-drug interactions there necessarily. Of course, there's a lot of impurities in these drugs, and we don't really know what might happen, unfortunately, on an individual basis.
Let's talk about the commercial side.
Yeah. I don't want to give our confidence continues to be reinforced with respect to our HIV pipeline based on the data, obviously. One thing I would give to you is that we believe that DUREZOL, which will be the first out of the gate, is likely to be, in fact, the preferred switch option for many individuals who are going to be switched from their existing regimen, which usually contains an INSTI, right? DUREZOL being the first in a new class of NRTIs, which provides robust viral control, high barrier to resistance, and the convenience and the tolerability and the DDI benefits that we've talked about, we believe that—and importantly, it does not include an INSTI—we believe that DUREZOL would actually be the preferred switch option for those individuals.
Just as we mentioned earlier, one in five patients treated with the HIV regimen will be switched on an annual basis. This gives you an indication of how we are thinking about the opportunity for the first out of the gate. Similarly, we are equally excited about the weekly options going forward.
Louisa, it's Peter. When we're asked about what's underappreciated at Merck, one of the subjects that we typically lead with is HIV. When we look at consensus estimates, there's not a lot in models for our HIV pipeline and portfolio. That is one of the reasons why we did this call today. We are very confident in the $5 billion+ opportunity that we've spoken about, and we're not going to update that today. We look forward to continuing to see progress across this program.
Hopefully, today's event will help you understand why we're so confident. Next question, please, Shirley.
Thank you. Our next question comes from Courtney Breen with Bernstein. Your line is open. You may ask your question.
Hi, everyone. This is Courtney. Thanks for taking my question today. I just wanted to dig a little bit into the PrEP opportunity specifically. One of the pieces that you've pointed out as being kind of the convenience and the ability to kind of dose a monthly oral at home. What we've learned with the labeling update recently for YEZTugo, the Lenacapavir asset from Gilead, is that another key component that requires doctor's visits is actually testing to ensure that the patient doesn't have HIV. For the injectables today, for YEZTugo with the longer dosing interval of every six months, that's a six-month requirement.
Whereas for Discovery, which is the daily oral, it's a three-monthly requirement for HIV testing to ensure that that patient hasn't contracted the disease. Can you give us some context as to what we should expect for the monthly oral? Would this be a requirement for an HIV test every month, every three months, or something even longer than that? Thank you so much.
Sally, I'll turn it over to Liz in a second, but I'll just say we can't anticipate labeling. Obviously, that's something that we'll discuss with FDA. I'd point out that HIV testing can be done rather anonymously and also not necessarily through a visit to a hospital center. In terms of how we are doing it in the clinical trials, I'll turn it to Liz for her comments.
Yeah. Thanks, Eliav. In the trials, we are testing for HIV status monthly, actually, in this trial.
This is not necessarily what we expect the position to be when we bring this product forward for regulatory submission. I mean, I think that every three-month frequency that is associated with the daily options is something that we think is probably more realistic.
Right. Although, again, we cannot speculate on what FDA or other agencies would say, considering the standard of care in the field, the ability to get HIV testing, again, without having to visit a hospital center, is relatively well-established.
I will just add the reason why we are checking HIV status monthly is to understand if we do see any infections, when they happen. This is really to enable us to collect the kind of data that we need to really fully characterize any infections that do occur in the treatment when participants are in treatment in this trial.
So it's to answer a scientific question, but this is not what we expect in terms of how it would be used in the real world and how testing would be used.
Great. Thanks, Courtney. Next question, please, Shirley.
Thank you. Our next question comes from Jeff Beecham with Citibank. Your line is open. You may ask your question.
Great. Morning, guys. Thanks for the question and for doing this session. Just have two. The first is in the treatment setting, I was curious how you guys think about resistance, especially as you develop doublets in HIV from what is three or four drug combos today. And then how would you compare the resistance of Isol or EULO versus, say, an Integrase or a CAPSID? And then the second question, more of a commercial one on PrEP.
It's been mostly a U.S.-based market, but what do you think is a tipping point for Europe or Asia more broadly adopting PrEP commercially? Thank you.
Right. With the first one on resistance, let me turn it over to Liz.
Yeah. Thank you. I think when you think about resistance in the context of multi-drug HIV regimens, the number of compounds is not really what's driving the emergence of resistance. If you think about this historically, we went from three drug regimens being standard to now, more recently, two drug regimens showing really excellent efficacy. What's really key, I think, based on the last 20 years that we've learned, is that you need to have at least one agent with a really strong barrier to resistance to protect the regimen.
I think this is often what's behind the concept of an anchor agent in an HIV treatment regimen. With Islatravir, one of the features that got us really excited about this molecule is the potency. You need to make sure you've got adequate potency and levels with the doses that you pick. Also, the resistance profile, meaning that Islatravir, if you test it in vitro, really takes a while to get resistance-associated mutations detected. The one that we do see is M184B, which is a relatively less problematic mutation. This is why it's important when we're looking at our data in our phase three Doravirine and Islatravir trials that we saw no emergence of resistance to either Islatravir or Doravirine.
This is why the concept of EZOLOTRIVIR anchoring our treatment regimens is one that we've been talking about because we see this molecule as really bringing the potency and barrier to resistance that you need for a drug to anchor a regimen, whether it's a two-drug regimen or a three-drug regimen. Right.
I just would add that this is why we've chosen these two drug classes together. They're actually quite complementary. One of the interesting things with EZOLOTRIVIR is that it actually, some mutations that occur to older medicines actually potentiate the effect of EZOLOTRIVIR. That is an interesting biological plus that we see. In addition to that, I think that we've shown in our studies, which is actually the most important thing, the lack of emergence of resistance. I'll turn it over to Turfy to talk about the commercial elements. Yeah.
For PrEP outside of the U.S., you're quite right that today the PrEP market is disproportionately a U.S. market. There are many reasons for that outside of the U.S. I'm leaving aside the low-income countries in Sub-Saharan Africa and so forth, where there's actually quite a bit of PrEP use in the daily form and then going forward in the long-acting as well. If you look at other high-income countries, there's still a lack of perception of risk by many individuals, low awareness of PrEP, and concerns for side effects and the stigma associated with daily use of PrEP. I think that by having Merck coming back with our global footprint, our commercial engine, we believe that we will actually make a meaningful difference in helping to develop the PrEP market in these other high-income countries. We have done this.
We have done this in other therapeutic areas. We know how to reach consumers in many of those markets. We've done that. We believe that that engine will help us really enhance the level of awareness. The once-monthly oral option will help address many of those barriers that I just talked about. Finally, in terms of implementation, right, to have an option where you're not relying on going to the clinic, right, with all the challenges of having a nurse in the clinic in many of those countries, I think the monthly oral option will really help develop PrEP in those high-income countries outside of the U.S.
Great. Thanks, Jeff. Next question, please, Shirley.
Thank you. Our next question comes from Valnor Duvan with Guggenheim. Your line is open. You may ask your question.
Great. Thanks for hosting this. It's been helpful.
Thanks for taking my questions. Maybe one clinical, one commercial. One, just on the Islatravir/Ulonivirine combination. Can you talk about how that would differentiate from Islatravir/Lenacapavir? I think both would be weekly orals. Obviously, you only own one, and the other one is shared with Gilead. Just curious from a clinical side how you expect to differentiate there. Maybe just in terms of the commercial side, again, kind of going back to that $5 billion HIV pipeline potential that you've highlighted, can you break that down further as you think about for U.S. versus ex-U.S. or treatment versus PrEP, just to give a little bit more of a sense of where the $5 billion or $5 billion-plus would be coming from? Thank you.
Let me take the clinical one.
EZOLOTRIVIR/EULONIVIRINE, I think, will be, first of all, both options are very nice, are terrific. EZOLOTRIVIR/EULONIVIRINE will be a very small tablet and a very favorable DDI profile drug that will also have a treatment-naive indication. You'll have a set of attributes that I think will be very important for some people, which is not to take away from EZOLOTRIVIR/Lenacapavir, which will have the potency of EZOLOTRIVIR and the proven track record of Lenacapavir. I think that these are going to be complementary drugs that will have very, very important uptake in different segments of the population. On the commercial side, I'll turn it to Turfy.
Yeah. We're not breaking down the $5 billion opportunity. We're equally excited about all four of these major innovations. We see opportunity, meaningful opportunity for each one of them.
Cumulatively, we believe there will be greater than $5 billion. As I mentioned earlier, we do anticipate significant opportunity outside of the U.S. as well, based on our engine and our capabilities in those high-income countries outside of the U.S.
Great. Thanks, Valmel. Next question, please.
Thank you. Our next question comes from Terrence Flynn with Morgan Stanley. You may ask your question.
Great. Thanks so much for taking the question. Two for me, I guess on 8527, I noticed that you're taking the 11-mg dose forward, but it looks like 12-mg was studied. Not a significant difference there, but just wondering why that decision was made. On MK8239 plus Len, I know you highlighted it early on. You did not talk too much about it, but maybe just talk about the target profile there and timing of when we might see the phase one data.
Thank you.
I'll take the first one in Alaska, Liz, to talk about the 8239. We chose the 11 mg dose because we have a very strict modeling program that looks at all the different factors that are necessary for patients to—for individuals. I'm sorry. This is PrEP. For individuals to have control. It could have been even lower dose. We had no issues with the 12 mg dose either. We went through a pretty rigorous algorithmic approach and chose the 11 mg because it was the sweet spot for all the different attributes we wanted to get. There are no issues with them going to 12 or anything like that. It was really just from our modeling point of view. Maybe you can tell us a little bit, Liz, about the earlier development compounds.
Yeah. MK—sorry, MK8239, which we are developing in collaboration with Gilead.
This is a molecule that's part of our partnership, is in phase I. The phase I work is ongoing. At this point, I don't have a time yet when we can share results from that study. The intention here is this is an Islatravir prodrug that we think could be suitable as a long-acting injectable to be included as part of potentially a long-acting complete treatment regimen that's injectable. That's the general concept behind the program, but it remains still early in development.
Right. We're continuing to do our dosing, and we're working through the details to make sure that the studies are done appropriately and with the sufficient rigor that regulatory authorities and both companies will feel comfortable to advance forward and look forward to presenting those data in due course.
Great. Thanks, Terrence. Next question, please. Thank you.
Our next question comes from Dana Greybosh with Luring Partners. Your line is open. You may ask your question.
Hi. Thanks for the question. I wonder if you could talk about payers for a moment from your market research and of the attributes that have value both for your treatment and PrEP around stigma and convenience and also DDI, which resonate across treatment and PrEP most with the payers?
Katherine, maybe I or I mean, Katherine, maybe you'd like to address that?
For the U.S.-specific situation, yes.
Sure. I mean, I can provide a perspective from a U.S. payer standpoint related to some of the attributes. I think one thing that's really important and that is recognized by payers within the U.S. market is that effective treatment and PrEP requires individualization and optimization of treatment based on people's individual needs.
I think the importance of retaining choice and access to treatments will continue to be critical ultimately to achieve favorable clinical outcomes. Obviously, improved adherence, the ability to actually take and stay on treatment is an important attribute for payers. Clinical efficacy and the ability to actually address unmet needs within our population of people living with HIV is also critically important as well.
Yep. What I would add is as people get older on their meds and get older with their HIV, obviously, you have to worry about comorbid conditions. You have to worry about drug-deriving reactions. Those are attributes that are also important. This is where our portfolio overall anchored on the NRTTI class really is well differentiated. We believe that we will be well positioned for early payer access.
Great. Thanks, Dana. Next question, please, Shirley. Thank you.
Our next question comes from Richard Wagner with Bank of America. Your line is open. You may ask your question.
Hello. Thank you for the question, Richard Wagner from Bank of America and for Tim Anderson. During the presentation, Merck cited market research indicating a one-third preference for monthly oral regimen for PrEP. What can you say about the market demand for a once-weekly regimen? I believe the target was described in the presentation as individuals with busier, complicated lives. I wanted to get a better understanding of that. Then related, clearly, it seems to me that Merck is confident that there would be adherence advantages for once-weekly and once-monthly compared to once-daily. It's easier for me to see that for the once-monthly. I would like to hear your thoughts on potential adherence advantages for once-weekly orals. Thank you very much.
Let me turn it back to Chirfi. Yeah.
Yeah. Just to clarify the insights from the research, Richard. So we put in front of individuals who are patients and non-patients, right, options for treatment as well as for PrEP. And about a third of those individuals on either category, right, those who have HIV and those who are at risk of contracting HIV, they opted for one-third long-acting orals. On the treatment side, this was a weekly treatment. On the PrEP side, it was the monthly PrEP, just to clarify what I presented on the slide earlier.
Right. I think that in terms of adherence, the idea here is certainly once-daily is complicated. Once-weekly allows you to say, "Right before the work week, I'm going to start," or, "On the one day that I'm at home and not traveling," or other kind of lifestyle issues.
It certainly is great to have one-seventh of the burden of a daily tablet. I think that would be very useful. Obviously, we'll be monitoring this in the real world. I think from the point of view of reducing the burden of adherence and HIV, and remember, you have to take these drugs every day very, very fastidiously. It's not like cholesterol where you miss a couple of days here and there. It's not such a big deal. It's a big deal here. Having a once-weekly approach, I think, would be really quite life-changing for patients.
Yeah. If I may add one more point, Elliot, the other insight that we got from patients—these are patients, people who are living with HIV—is that on the daily regimens, you're reminded every day that you have HIV in your body, right?
To have the option of taking your pill, a small pill, maybe every Sunday or maybe whatever fits your lifestyle, it has an emotional benefit in addition to the convenience benefit as well for these individuals. You are not really stressed out every day in case you happen to miss a pill or something.
Yeah. Right. Thanks, Richard.
Next question, please, Shirley. Thank you.
Our next question comes from Steve Scallo with TD Securities. Your line is open. You may ask your question.
Hi. This is Chris on for Steve. Thanks for taking our question. We had two on MK-8527. First, are the phase three trials sufficiently powered to show statistically superior efficacy to Truvada? Is that the bow for success? Second, do you expect commercial launch for this asset before late 2028? Thank you.
I'll ask Liz to talk about the phase three designs. Yeah.
For the expressive trials, expressive 10, which is the study that's being conducted in women, that study is designed and powered to be a superiority trial. That is the primary hypothesis study. Yes.
On the commercial side?
We're not providing a specific date for launch. I mean, obviously, we have to—we're ready to go into phase three, very excited about that. We'll just have to wait. We will obviously look forward to getting this to the finish line as quickly as possible so we can bring it to people who want to be protected with this once-monthly oral. Yeah. I'll add, I mean, these are event-driven trials, these phase three studies. We have estimates of how long it'll take to complete these studies that are reflected in the postings. It's possible it could take a little bit longer or less time even.
Yeah. Yeah. Great. Thank you. Next question, please, Shirley. Thank you.
Our next question comes from Alex Hammond with Wolfe Research. Your line is open. You may ask your question.
Thanks for taking the question. On MK-8527, in the phase two, we saw one SAE of spontaneous abortion at six weeks of gestation that was considered related to drug. I know you mentioned in the EXPRESSIVE-10 trial that there will be data generation in pregnancy and lactation patients. Can you walk us through the risk-benefit of treatment here?
Thanks. I'll turn that over to Liz. Yeah.
The decision to allow women in EXPRESS 10 who become pregnant to stay on MK-8527 if they choose to do so is based on the overall data from the program, which includes not just the clinical trial data but also the non-clinical safety assessment in terms of safety to the embryofetal toxicity and juvenile safety as well. Overall, the data was very clean and supported the approach that we are taking with use in pregnancy.
These studies have been vetted through the regulatory authorities, and we look forward to getting the results. We are confident that we will be able to get the proper safety profile. It is a very important patient population to help with prevention of HIV infection.
Great. Thanks, Alex. Next question, please.
Thank you. Our next question comes from Umer Raffat with Evercore. Your line is open. You may ask your question.
Hi, guys. Thanks for taking my question. Thank you for all your transparency on the intracellular triphosphate dose exposures. That is really where my question was as well. At the 6 mg dose, it looks like by the end of month one, the PBMC triphosphate levels are almost basically at that efficacy threshold of 0.3 picomolars. I am curious what % of the patients that drove that mean were already below that threshold, and less so focused on the 6 mg dose and more so really asking about the 12 mg dose. What % of patients—I realize mean is above—but what percentage of patients are below the threshold? Secondly, since Chirfi is on, and I am dying to ask him a question, Chirfi, in your view, what percentage of the market by the time you guys launch will be on orals, meaning not on an every-four to every-six-month long-acting injection? Thank you very much.
Umar, thank you. Let me take the first one. When we do our modeling work to look at the doses that we chose to go into phase three studies, as you know, mean is mean. There's people below, people above. The 6 mg dose was good, but we wanted to make sure that it would be covering all different weights, all different potential metabolic profiles, and various circumstances along with a little bit of forgiveness as well. When you add all of that together, and we did through both our safety and efficacy modeling, the 11 mg dose got us to the point where we were able to have high confidence that the vast, vast, vast majority would be well above the bottom threshold for what we anticipated to be efficacy. In that regard, the 6 mg dose was pretty good.
We wanted to be able to not just go for mean but also take the lowermost in the distribution of variability and make sure that that lower 5% we're able to get above. That is why we chose 11. Twelve was just nearby, but 11 was just good enough for that. You always want whatever dose you want, the minimal best effective dose, even if it's a scooch lower than the highest dose that you've tested. Chirfi
Yeah. Umar, I assume your question is in regards to PrEP, correct? I think he's off. All right. Assuming it's in regards to PrEP, what we do know is that you have a number—many, many individuals have needle phobia. That is the first consideration, the first insight that I wanted to highlight and reinforce.
The implementation challenges, having to go to a clinic, having to have a nurse inject these meds and so forth. We anticipate that by the time we come to market with MK-8527, there will still be a significant number of people at risk of HIV infection who would be either on Truvada daily, right, daily PrEP, or who would want to be on an oral long-acting option. The opportunity will be meaningful when we do come to market. Great. Thank you. Shirley, any further questions?
At this time, I'm showing no further questions.
Great. I want to thank you all for your interest and time this morning. Appreciate you being with us. Please reach out to the IR team if you have any follow-up questions. We look forward to connecting with you all soon. Thank you so much. Thank you.
This does conclude today's conference. We thank you for your participation. At this time, you may disconnect your line.