Edge of Yesterday: A 3-part podcast series by ViiV Healthcare

ViiV PODCAST SERIES: EDGE OF YESTERDAY

EPISODE 1: HTE PATIENTS WITH HIV-1: A WINDOW TO THE PAST

VO:

GOLKOO MORCOS (MODERATOR):

Welcome to the ViiV podcast series Edge of Yesterday. You’re listening to Episode One: “Heavily Treatment-Experienced Patients With HIV-1: A Window to the Past.” Please note that the participants in this podcast are employees or paid consultants of ViiV Healthcare. Before we get into the conversation today, here's some important information about RUKOBIA (fostemsavir).

INDICATION

RUKOBIA, also known as fostemsavir, a 600-milligram extended-release tablet, in combination with other antiretrovirals, is indicated to treat HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations.

IMPORTANT SAFETY INFORMATION

Contraindications

• Do not use in patients with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA.
• Do not use RUKOBIA in patients receiving strong cytochrome P450 (CYP)3A inducers, including but not limited to enzalutamide, carbamazepine, phenytoin, rifampin, mitotane, and St John’s wort, also known as Hypericum perforatum.

Please listen to additional Important Safety Information for RUKOBIA later in the podcast. Please use the link on this page to view the full Prescribing Information for RUKOBIA.

For more information on content discussed in this podcast episode, please click the reference list link that appears on this page.

[Static noise of old analog radio, switching stations.]

“People were dying at an incredibly high rate.”
“Something that you shouldn’t be telling people.”
“Of course, we had no idea it would ultimately be a pandemic.”
“There seemed to be nothing that we could do.”

[Radio station is switched, static noise softens.]

“We think that the disease unfortunately is going to be with us for a long time. It will get more common, because the epidemic is still growing.”

[Static noise transforms into a rush of noise and wind taking us from the past to the present.]

GOLKOO MORCOS:

Hello, everyone, and welcome to the Edge of Yesterday, where we will be discussing the treatment of HIV then and now. My name is Golkoo Morcos and I am a U.S. medical director here at ViiV Healthcare. That was Dr. Paul Volberding, of San Francisco General Hospital, speaking about the emerging AIDS epidemic in 1985.

We will discuss the early days of the HIV/AIDS epidemic, the development of the first antiretroviral therapy, and later antiretroviral regimens. We will discuss similar challenges facing heavily treatment- experienced, or HTE patients, with HIV-1.

Additionally, we'll be discussing the use of RUKOBIA for HIV-1 treatment in heavily treatment- experienced adults. Today, I'm honored to be joined by two guests, Marty St. Clair and Dr. Michael Gottlieb.

Marty St. Clair is a virologist and has been working as a research scientist since the early 1980s. And she was part of the team that discovered and helped develop the first HIV drug, azidothymidine, otherwise known as AZT, or zidovudine. She continues to be directly involved in HIV drug discovery and development and is currently the manager of clinical virology here at ViiV Healthcare.

GOLKOO MORCOS:

Marty, it’s great to have you.

MARTY ST. CLAIR:

Hi, Golkoo. I'm very happy to be here.

GOLKOO MORCOS:

So we also have Dr. Gottlieb with us. And as you know, in 1981, Dr. Gottlieb was responsible for describing the syndrome of opportunistic infections in CD4 T-cell deficiency that we now call AIDS.

He authored the first report of the syndrome to the CDC, which was published on June 5th, 1981, in the Morbidity Mortality Weekly Report, and eventually a set of cases that were published in the New England Journal of Medicine.

Dr. Gottlieb has treated patients with HIV over the last 40 years and is an associate clinical professor at the UCLA School of Medicine. Today, he continues to help patients as an allergist and immunologist practicing out of Los Angeles, California. Welcome, Dr. Gottlieb.

DR. MICHAEL GOTTLIEB:

Thanks, Golkoo. It’s great to be here.

GOLKOO MORCOS:

Just curious. Um, have you and Marty ever crossed paths, um, in the past?

DR. MICHAEL GOTTLIEB:

Yes, we have. In the early days of, uh, HIV, I recall a number of visits to Los Angeles by Marty, and then we had a chance to connect just a few years ago at a, uh, reunion of people involved in the early days of the HIV epidemic. So I remember, uh, seeing Marty, and I've admired her work.

MARTY ST. CLAIR:

I've admired you, Michael, my entire career so, um, every time I have an opportunity to meet you, I have to kind of hold my breath and thank you for-for your part in identifying this new disease, um, that allowed scientists like myself to actually work on, uh, discovering and developing drugs that can be used against it.

GOLKOO MORCOS:

Yeah, it's quite remarkable to be sitting with, uh, two of the first individuals that were–really had, um, pivotal roles in the development of, um, early antiretroviral agents and treating, um, patients early on in the epidemic. And, uh, HIV treatment has really evolved over the last 20 to 30 years. So it's gonna be great to be able to capture, um, your experiences and your stories from the early days.

So, Marty, if you could paint us a picture of the early years of the epidemic-where were you and-and what were you doing?

[A rush of noise and wind takes us from the present to the past.]

MARTY ST. CLAIR:

So, I was working, uh, for Burroughs Wellcome. I was a virologist. Um, at the time that the AIDS epidemic first started, I was working on herpes simplex virus. Um, you should probably know that retroviruses were my first love. I worked on retroviruses as an undergraduate.

And then in 1983 it was determined that HIV was a retrovirus. Oh my god, a retrovirus. And then, and then, Burroughs Wellcome decided that we would have a drug discovery and development program to find a drug that could be used against HIV/AIDS, a retrovirus. I immediately raised my hand and I said, "Please let me be a part of this. This is where I want to be. I don't want to work on herpes simplex virus anymore; I want to work on HIV.”

GOLKOO MORCOS:

Dr. Gottlieb, did you have a moment like that when you were treating patients?

DR. MICHAEL GOTTLIEB:

So, at the time, I was, uh, working at the lab, uh, with mice on transplantation, but also teaching and seeing patients, uh, with various immune conditions. And I remember the very first patient, uh, who turned out to have AIDS, and in fact I remember all of the first four or five patients perhaps better than patients I saw last week.

The illness was so striking and so unusual, uh, that, uh, it was really, uh, kind of grabbed me, and-and, I-I, determined that this was something I was going to pursue and find out what was going on. Of course, we had no information whatsoever other than that, uh, young people, uh, were coming in with opportunistic infections.

GOLKOO MORCOS:

If you could take us back in time, could you describe your feelings, or the type of feelings that arose during the early days of the epidemic?

MARTY ST. CLAIR:

We knew in 1983 that HIV/AIDS was caused by a retrovirus, but we didn't know much more than that. I think that I can honestly say that both the, um, pharmaceutical industry and the academic industry did not believe that we could successfully treat this virus with a small-molecule pharmaceutical, primarily because HIV genome intercalates into the cellular genome.

Every cell that is infected with HIV is always infected with HIV, as are the daughter cells of that infected cell. And so I think, in general, people thought this was a lost cause, that there wasn't much you could do about treating the virus, that, in fact, your success would be in treating the opportunistic infections and not the virus.

So I think in that arena, I think Burroughs Wellcome was different, that we wanted to target the virus. We wanted to discover and develop a pharmaceutical that would inhibit the virus. And I think that was unusual among people at that time.

GOLKOO MORCOS:

Dr. Gottlieb, if you could tell us what it was like treating patients early on—uh, what-what kind of medications or treatments were available to give patients at the time?

DR. MICHAEL GOTTLIEB:

We started with no information, uh, whatsoever. Uh, all we saw was that young people were dying of opportunistic infections. And we scratched our heads over what was causing the immune deficiency. We-we found that CD4 cells had gone missing, but we, we didn't know how to address it. And as immunologists we thought, "Oh, this is an immunologic disease" because the virus hadn't been discovered.

And so we tried to treat it with various, uh, immune modulators that-that were basically, uh, compounds looking for a disease to treat. Uh, and that wasn't very successful. And, of course, the discovery of the virus in 1983 and…was the major step forward in, uh, developing useful therapy.

And in terms of what I was feeling, the-the early pandemic, uh, was, uh, unnoticed by the general population. It was the doctors and nurses, uh, in the large cities of the U.S. and Europe knew that something big was going on. They were in the thick of it. They were taking care of, uh, young people who had one opportunistic infection after another and trying to explain this to the patients and to their loved ones, uh, just why healthy people were suddenly so sick. And that was very challenging as a doctor, you know, to have nothing in your armamentarium whatsoever other than your compassion, your empathy, your ability to sit with people and-and help them through a trying time.

GOLKOO MORCOS:

Is there a particular moment or an experience that really stands out for you from that time?

DR. MICHAEL GOTTLIEB:

Well, I remember these very first patients of mine, uh, remarkably well. I can remember what they looked like, how they sounded, who their friends and family were.

But that moment is-is when the ICUs suddenly filled up, when a seven-bed respiratory care unit was suddenly full of patients with pneumocystis pneumonia and other opportunistic infections. And at the time, the syndrome didn't even have a name.

GOLKOO MORCOS:

What was it like, Dr. Gottlieb, working to figure out a syndrome that didn't have a name and that no one knew what it actually was?

DR. MICHAEL GOTTLIEB:

We also knew, Golkoo, that, uh, there were lots of other patients out there in the community, uh, particularly gay men here in Los Angeles, who were suffering from less severe manifestations of something. They had swollen lymph glands. They didn't feel well.

Uh, in many cases, they were shedding cytomegalovirus in their secretions, uh, an indication that they might be immune deficient. But we, so we knew from the very start that whatever this was, it was a lot larger than five cases.

And that was a scary thought, that it was much larger than five cases. But of course, we had no idea it would ultimately be a pandemic that involved tens of millions of people.

Working with those early patients was really very difficult for me, and I'll tell you that I was 33 at the time, and, uh, the very first patients were all contemporaries. Uh, these kids or young people reminded me of, uh, people I had gone to school with, uh, college.

Uh, starting out, uh, in their careers, in their early 30s. And, uh, I empathized, uh, with them. I identified with them. And I wanted to help them. But it was so, so frustrating to see these patients get one serious infection after another and have to explain to, uh, their families, um, significant others, that we really didn't have, uh, any idea what was going on.

It really captured me, and-and I knew at that time that this was what I was gonna do for my-my career, that I was gonna try to help out, uh, in this, uh, unusual circumstance, that I was gonna be involved in clinical trials, if medications came along, and that, uh, that this was something worthy of, uh, devoting a career to, uh, not knowing whether we'd ever be successful in treating this.

GOLKOO MORCOS:

Marty, what was it like for you, since you weren't in front of patients, per se, but in your own way sort of trying to be an investigator and figure out—what is this retrovirus and how does it work exactly, and how can we develop treatments for it?

MARTY ST. CLAIR:

As soon as Burroughs Wellcome made the decision that we would discover and develop a drug to be used against this new virus, um, I immediately started working on an assay that I could use to discover activity.

I was pummeled with compounds from our organic chemists, and I was putting them in the assay as quickly as I could and getting results as quickly as I could. And I think that summer of 1984 was so busy running the assay that I could barely have time to talk to physicians.

And then November 1984, the results of AZT came out. And I had about 350 petri dishes in an assay.

I had them set up so that I would have 100 active viruses in each petri dish, meaning I would count 100 plaques. That's an area of dead cells that fall off at the end of the assay. I would hold my plates up to the window and I'd count, and they all had 100 plaques because the compounds that I was putting in my assay did not inhibit HIV replication until I came to the 16 plates that all had been treated with AZT.

I am a scientist through and through. This was such a phenomenal finding, um, that I honestly believed I forgot to put the virus in those 16 plates.

And I, and I said to my manager, who was sitting next door to me, I said, "Hey, Phil, come look at this. Out of this entire assay of 350 plates, I have these 16 that have no plaques. Do you suppose I forgot to put the virus in these 16 plates?" And he said, "Uh, yeah, right. Out of this entire assay you forgot to put the virus in these plates that were all treated with AZT? Hmm. Don't think so." We were a little company; we were just Burroughs Wellcome. There weren't many of us here.

Um, this was late on a Friday. I told my manager. I think I maybe told two other people. When I came to work on Monday morning, my phone message machine was absolutely full of people who had heard this-this news over the weekend and called to say, "Did we hear it right? Did you find something that could be used against HIV?"

People were dying. People were dying at an incredibly high rate. There seemed to be nothing that we could do. And then we demonstrated the activity of AZT in our little in vitro petri dish assay.

That didn't say for sure that it would work in people, but it was certainly a start. And a start that a lotta people didn't think that we could make. It was amazingly exciting. Being a scientist, we never believe anything the first time, so I immediately put AZT back in the assay to get a repeat, which did repeat, and did give us an IC50.

I sent AZT under code to several other laboratories and asked them to put it in their assays, and they all came back with, "Yes, AZT is active against HIV." So we all submitted abstracts to ICAAC. They put them all in the same session.

Went to ICAAC. I had an oral presentation, which I had never ever given the oral presentation at a major scientific meeting before. I'm just a little lab rat. I don't think I had ever talked to more than five people in my entire life, and I was at this major scientific meeting, uh, with the other people that also had abstracts.

The night before, because of course I was absolutely terrified, the night before, I decided I wanted to go look at the room where the presentations were gonna be. And that's when I first realized that it was the basketball stadium, the basketball stadium that would hold, like, 30,000 people.

Absolutely terrified. How in the world was I ever gonna do this? Well, I can tell you how I did this. The entire front row was filled with reporters that all had their Klieg lights focused on the stage. And so when I got up on the stage, all I could see was white.

I did not see a single face behind the white Klieg lights. Phew. That's the only reason that I managed to get through that. But people knew what we were doing. People were behind us. People had faith. People believed that we were gonna make a difference in this disease, maybe even more than we did.

GOLKOO MORCOS:

Dr. Gottlieb, from Marty's lab to, you know, bringing this medication to patients, w-what were some of the pros and cons of utilizing AZT and maybe some of the earlier other antiretrovirals in patients in your experience?

DR. MICHAEL GOTTLIEB:

So I remember when AZT was approved. Uh, I said something to the LA Times that, uh, the approval of, uh, AZT should, uh-uh, bring a ray of hope to patients living with HIV and their families. Uh, and-and it was. Uh, but it was at least a start, and it helped patients, uh, transiently, as a single medication.

But, as Marty pointed out, we needed more. We needed to target multiple enzymes, multiple sites of the virus, that it wasn't enough just to inhibit the reverse transcriptase. And as information accrued about these other enzymes of the virus, pharmaceutical companies following in the path of Burroughs Wellcome decided to devote efforts to find medications that would act on these other targets.

And so, ultimately, what we came around to was the so-called cocktail, combination antiviral therapy, hitting multiple targets at the same time, multiple medications. And, of course, in those early days, we didn't know what the end point should be.

We were following things like CD4 T-cell counts, whereas we really needed to be looking at the viral load, the level of virus in the plasma. But that assay wasn't developed until 1995. And so we spent 14 years in the dark, not knowing what is now considered the gold standard for, uh, success in antiviral therapy, an undetectable viral load.

If you look at the epidemiologic curve of deaths from AIDS, it is in 1995, '96 that there's an inflection point, and that the curve starts declining ever since that time, uh, proving that combination therapy was the ticket. On the other hand, many of these early drugs did have side effects.

The patients needed treatment. Uh, we needed to find useful combinations. And clinical trials showed that some combinations were useful and better than single agents alone. However, we soon found, with experience, that there were toxicities to some of these early agents.

GOLKOO MORCOS:

So what would you say in terms of the evolution of antiretroviral therapy? You know, how have we evolved with our treatments today compared to those early days?

DR. MICHAEL GOTTLIEB:

Over these last few decades, as a scientific community, have worked to, uh, find more effective medications, to improve their safety profile, and to make them easier for patients to take and adhere to their regimens.

[A rush of noise and wind takes us from the present to the past. The ambient sounds of San Francisco’s Market Street fade in, along with the growing chants of ACT UP protesters. People are shouting, clapping, and whistling.]

“…under attack, what do we do? ACT UP! Fight back!”

[The tones of the ACT UP chants rise “ACT UP! Fight back!” over and over until we fade out.]

GOLKOO MORCOS:

That was San Francisco in June 1990, where thousands of doctors and researchers gathered for the Sixth Annual Conference on AIDS, and where thousands of protesters rallied for increased research funding and changes to medical processes.

We’ve come far from those days, but let's pivot our conversation now and talk about heavily treatment-experienced HIV-1 patients today. They're often referred to as being mirrors of the past. Would you agree?

DR. MICHAEL GOTTLIEB:

I think the analogy is correct, and that both patients in the early years of the epidemic and heavily treatment-experienced patients today represent a challenge to the clinician. It's challenging in that both types of patient often have detectable viral loads, and our objective is to get the viral load to undetectable. And so we're dealing with both situations with the fallout from earlier therapies.

We're having to deal with the after-effects of older antiretrovirals with multidrug resistance, which we saw in the early years as a result of sequential monotherapy. And in some cases today we're even dealing with the after-effects of sequential monotherapy with multidrug resistance.

We're dealing with possible nonadherence during various times of the patient's treatment, possibly due to, uh, adverse effects of medications, and so today, as was the case in the earlier years, we have to be creative.

In that regard, uh, we need to know how to build optimized backgrounds so that newer therapies can be used in combination with older ones. And so the analogy is-is a good one, uh, and we’re still moving forward.

GOLKOO MORCOS:

Are there any similarities—in terms of challenges from putting together regimens that are effective—uh, for heavily treatment-experienced patients with HIV-1 today?

DR. MICHAEL GOTTLIEB:

Well, you're right. There are challenges. Some patients have been through so many regimens already that they, uh, appear to have exhausted, uh, what's available. And it's kinda comparable to the frustration that we felt in the early years when we didn't think we could get where we needed to go.

All regimens—uh, I've always looked at this as a series of leaky lifeboats. Where patients, uh, started on one drug and were able to segue to another when it was no longer successful. And, these days, we still have patients who are not successful with their current regimen, having jumped from multiple lifeboats before.

And those patients are certainly candidates to have RUKOBIA to build into their latest regimen.

GOLKOO MORCOS:

What are your thoughts, Marty?

MARTY ST. CLAIR:

Well, yes, I do believe that the, um, heavily treatment-experienced patients we have today are actually very similar to the patients that we had in the very early days. So the patients that we had in the very early days had access to very few drugs.

AZT was the first, others came along. We discovered quickly that we needed combination therapy to provide efficacy for these patients. And we thought we were doing pretty well. And, you know, we slowly got more and more drugs approved for patients.

And now today we have patients who have seen most of the drugs that have been approved in the past. Whether due to resistance or due to tolerability or due to lack of adherence, these patients are no longer responding.

So now we need to go back to the science. We need to go back to the laboratory. We need to ask our scientists to discover and develop new drugs that maybe inhibit new activities of the virus so that we can help these patients that are no longer responding.

And our most recent addition to the drugs, uh, that are helping these patients is-is RUKOBIA, which is an attachment inhibitor. It's a new activity.

DR. MICHAEL GOTTLIEB:

Exciting thing to me is the mechanism of action of RUKOBIA, which is different from that of other classes.

The introduction of RUKOBIA, uh, reminds me of several other pivotal times in the development of HIV regimens. First there was AZT in 1987. And then the triple combination, uh, cocktail regimens in the mid- '90s. And then the, uh, introduction of single-tablet regimens in the early part of this millennium. And then, again, the, uh, regimens for patients who were no longer responding that came about in 2008 with the introduction of integrase inhibitors, combined with non-nucleoside reverse transcriptase inhibitors that saved the lives of lots of patients, many of whom are alive today and still on those, uh, regimens that date from, uh, 15 years ago. And that's why we're so excited about RUKOBIA at this time point.

GOLKOO MORCOS:

Yeah, absolutely agree, Dr. Gottlieb. Having more options is-is exciting. It seems like at every decade time point there is a pivotal moment in the evolution of antiretroviral therapy, as you mentioned.

And-and here we have a medication now that is specifically giving an option to heavily treatment-experienced patients. And even in that, uh, that time frame that you gave, it's important to note that there haven't been very many agents that have come to market specifically for heavily treatment-experienced patients.

DR. MICHAEL GOTTLIEB:

I think it's an important message to patients that the work goes on, people are still looking at options, that, uh, the status quo is not sufficient, and that there is ongoing, uh, drug development, uh-uh, in the HIV sector. And that should give people hope, uh, especially those patients who are no longer responding to the current crop of medicines.

GOLKOO MORCOS:

As a reminder to listeners, RUKOBIA is a first-in-class treatment with a novel mechanism of action. It’s the first FDA-approved HIV-1 attachment inhibitor that prevents HIV-1 from interacting with host immune cells, leaving CD4 T-cells untouched.

GOLKOO MORCOS:

IMPORTANT SAFETY INFORMATION continued

Warnings and precautions

Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of RUKOBIA.

QTc Prolongation with Higher than Recommended Dosages: RUKOBIA at 2,400 milligrams twice daily has been shown to significantly prolong the QTc interval of the electrocardiogram. Use RUKOBIA with caution in patients with a history of QTc interval prolongation or in patients with relevant pre-existing cardiac disease or who are taking drugs with a known risk of Torsade de Pointes. Elderly patients may be more susceptible to drug-induced QT interval prolongation.

Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-infection:

• Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection.
• Diligence should be applied in initiating or maintaining effective hepatitis B therapy when starting RUKOBIA in patients co-infected with hepatitis B.

Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of RUKOBIA and other drugs may occur (see Contraindications and Drug Interactions).

Adverse reactions

• The most common adverse reaction (all grades, randomized cohort) observed in greater than or equal to 5 percent of subjects was nausea (10 percent).
• 81 percent of adverse reactions reported with RUKOBIA were mild or moderate in severity.

Drug interactions

• See the full Prescribing Information for RUKOBIA for a complete list of significant drug interactions.
• Temsavir may increase plasma concentrations of grazoprevir and voxilaprevir. Use an alternative hepatitis C virus regimen if possible.
• Use the lowest possible starting dose for statins and monitor for statin-associated adverse events.
• Patients receiving RUKOBIA should not take doses of estrogen-based therapies, including oral contraceptives, that contain more than 30 micrograms per day of ethinyl estradiol. Caution is advised particularly in patients with additional risk factors for thromboembolic events.

Use in specific populations

• Pregnancy: There are insufficient human data on the use of RUKOBIA during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established.
• Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance, and adverse reactions in a breastfed infant.

Please use the link on this page to view the full Prescribing Information for RUKOBIA.

GOLKOO MORCOS:

Dr. Gottlieb, Marty, honestly, thank you so much for your time. I've had so much fun doing this. I’ve learned so much from you. What an excellent opportunity for me to learn from you, so thank you for doing this.

DR. MICHAEL GOTTLIEB:

Thank you, Golkoo. I enjoyed being here.

MARTY ST. CLAIR:

This was a great honor for me to have a discussion with, uh, Dr. Gottlieb. We don't get together often enough, so this has been very much fun for me. Thank you.

GOLKOO MORCOS:

Thank you to our listeners, as well, for joining us. Next time, we're gonna be talking about some of the characteristics of heavily treatment-experienced patients and the clinical considerations for the management of these individuals.

End of VO

ViiV PODCAST SERIES: EDGE OF YESTERDAY

EPISODE 2: WHO ARE HEAVILY TREATMENT-EXPERIENCED PATIENTS, AND WHAT ARE THEIR PRIORITIES?

VO:

GOLKOO MORCOS (MODERATOR):

Welcome to the ViiV podcast series Edge of Yesterday. You're listening to Episode Two, "Who Are Heavily Treatment-Experienced Patients, And What Are Their Treatment Priorities?" Please note that the participants in this podcast are employees or paid consultants of ViiV Healthcare. Before we get into the conversation today, here is some important information about RUKOBIA, fostemsavir.

INDICATION

RUKOBIA, also known as fostemsavir, a 600-milligram extended-release tablet, in combination with other antiretrovirals, is indicated to treat HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations.

IMPORTANT SAFETY INFORMATION

Contraindications

• Do not use in patients with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA.
• Do not use RUKOBIA in patients receiving strong cytochrome P450 (CYP)3A inducers, including but not limited to enzalutamide, carbamazepine, phenytoin, rifampin, mitotane, and St John’s wort, also known as Hypericum perforatum.

Please listen to additional Important Safety Information for RUKOBIA later in the podcast. Please use the link on this page to view the full Prescribing Information for RUKOBIA.

For more information on content discussed in this podcast episode, please click the reference list link that appears on this page.

[Static noise of old analog radio, switching stations.]

“After a while we would start seeing virus returning.”
“Please, tell me I'm undetectable. Please tell me my T-cells have gone up.”
“I didn’t have many other choices.”

[Radio station is switched, static noise softens.]

“There has to be something else out there.”

[Static noise transforms into a rush of noise and wind taking us from the past to the present.]

GOLKOO MORCOS:

Hello, everyone, and welcome to The Edge of Yesterday. Today we will be discussing who heavily treatment-experienced patients, living with HIV-1, are; the characteristics of this patient type; and what makes them unique. We will also be discussing the use of RUKOBIA for HIV-1 treatment in heavily treatment-experienced adults.

My name is Golkoo Morcos and I'm a medical director here at ViiV Healthcare. And now I'd like to introduce our first guest, Dr. Frank Spinelli, medical director of patient affairs here at ViiV Healthcare. Dr. Spinelli, tell us a little bit about yourself.

DR. FRANK SPINELLI:

Hi, Golkoo, thanks for having me. My name is Dr. Frank Spinelli, I'm a physician based out of New York. I've been practicing in Manhattan, as an HIV provider, for the past 20 years. And 6 years ago, I joined ViiV Healthcare and I head their patient affairs department in the US as the medical director.

GOLKOO MORCOS:

Thank you, Dr. Spinelli, and welcome.

DR. FRANK SPINELLI:

Thanks for having me, again.

GOLKOO MORCOS:

So, Dr. Spinelli, let's talk a little bit about heavily treatment-experienced patients. What does that terminology mean to you, as a treater of HIV?

DR. FRANK SPINELLI:

Well, I think what's most important to remember is that not all heavily treatment-experienced patients are the same. But there are certain factors that you have to consider.

So, for example, someone who may be someone that's diagnosed many years ago, or decades ago, might have exposure to multiple antiretroviral regimens, which may have led to the development of multidrug resistance.

Then, when you have multidrug resistance, you have to also consider that you have few or limited treatment options, in some cases two or less active classes. Remember that, you know, the older medications if you got a certain mutation that would have wiped out the entire class. So that really limits your choices.

Historically, ongoing adherence is an issue. You have to remember, we're asking people to take, in the past, multiple pills a day. Now, thankfully, we have single-tablet regimens. But if you have a history of heavily treatment-experienced you may not be able to take those single-tablet regimens.

And then you have to consider comorbidities, which means you have to take other medications, and that could lead to drug-to-drug interactions and tolerability and safety issues.

GOLKOO MORCOS:

So it just sounds like, to me, that there are a lot of factors at play here. But probably the ones that are really key characteristics of heavily treatment-experienced patients are individuals who have been exposed to multiple antiretroviral regimens in the past and who have developed multidrug resistance with few classes of antiretrovirals remaining for them.

Heavily treatment-experienced patients have certainly encountered difficulties along their journey. I'm also excited to introduce Dennis, our second guest, who is taking RUKOBIA as part of an HIV-1 regimen. Dennis, tell us a little bit about yourself.

DENNIS:

Hello, everyone. My name is Dennis. I'm married, I live with my husband, and we like to take in rescue animals so we currently are living with two rescue dogs and a cat. I was diagnosed with HIV in 1991. So that's, like, three decades ago, and therefore I've been on many treatment regimens. So, I'm considered a heavily treatment-experienced person living with HIV. About, around 2000, 2001, I started working in the field of HIV. Um, and my first job was as a case manager.

GOLKOO MORCOS:

Dennis, I'm so excited to have you on our podcast today. I've been meaning to have an opportunity to speak with you one on one as I'd heard your story a while back and realized you were in the BRIGHTE trial.

When I first heard your story it brought me to tears. And, um, this is just such an honor to be able to speak with you.

Can you also share with us what your early treatment journey was like with HIV-1?

DENNIS:

In the beginning, uh, treatment was rather rough. And so you would think, "Okay, I feel good right now, but I know if I take this, these medications, in about an hour or so I'm gonna feel like I have a hangover. And that feeling is gonna be with me for 8, 12 hours."

Also, I'm not really sure I was prepared to accept my HIV diagnosis, or successfully start treatment at that time. I started takin' treatment much more seriously when I came down with an AIDS-related illness and I was hospitalized.

I remember some of that, that hospitalization, not all of it. But I do remember the first time when I woke up and I looked up, I was lying in bed and I looked up and one of my friends had come and put a disco ball, um, above my bed. And then I looked around and there were flowers everywhere and there was a mini-fridge, and that was stocked with food, um, though I don't think I was eating any of it. (LAUGH)

But, anyhow, and people were coming in and out of the room all the time. And my doctor said sometimes there'd be so many people there she would ask them to go and visit others down the hall who may not be getting as many visitors as I was.

And when I got home from that experience, I remember lookin' in the mirror one day, and I said, "You know what? Look at all this love that was given you, and all this caring that people had. If they can love you that much, why can't you love yourself like that?" And that's really when the whole thing just hit home for me and I started takin' life more seriously, and then of course, then taking treatment much more seriously.

GOLKOO MORCOS:

I got goose bumps, you telling that story. I can certainly understand that, you know, being able to experience the love and the care of your friends, or your family, um, must have really meant a lot to you. And so that was sort of a wake-up moment for you, then?

DENNIS:

Exactly.

GOLKOO MORCOS:

So it's pretty remarkable. You got home from the hospital, your perspective changed, and you decided that you wanted to take care of yourself and get your HIV-1 under control. So tell us a little bit about that. What was your perspective then, at that moment, on taking medicines as well as did your relationship with your HIV doctor change?

DENNIS:

Oh, definitely the relationship I had with my HIV doctor became much stronger. 'Cause she had seen me through this hospitalization; she was very caring. And one thing I really liked about her and all my other providers since then, uh, is their level of optimism that they had.

Also I had a lotta support around me, uh, to take on this new task of being really serious about treatment. And my roommate at the time would leave for work in the morning, and he had these little cups. And he would put all the medications in 'em, 'cause I was takin' a ton of medications. And he would have little stickers: "Take this at 8 o’clock," "Take these at 10 o’clock," "Take these at 12 with food," "Take this at 2 without food," like that. And, um, that just made it much easier, as well, until I finally got back to my old self again.

GOLKOO MORCOS:

So you're getting back on track, you have people who are helping you be adherent to your medications, you're taking things seriously at this point. Were you able to get your viral load under control right away? Or were there hiccups or other issues?

DENNIS:

No, I was always very fortunate to getting my viral load, uh, to undetectable fairly quickly. But then, after a while, we would start seeing, uh, virus returning. And sometimes that would be, you know, I would get to undetectable, maybe 12 months, 14, 18 months later we would see virus returning.

And that was very, very frustrating for me. It was a real low point because I knew I was taking my meds, as directed, and for some unknown reason, to me, you know, I was, you know, the virus would start returning.

DR. FRANK SPINELLI:

You know, Golkoo, if I can just jump in, I just want to say about your journey that it just really personifies what a lot of people, particularly those who were diagnosed years ago, experienced. And I, I want to really commend you for having that turning point. Unfortunately, it took an AIDS-related, uh, illness for you to really come out of it and ask yourself, "What do I want outta my life?" And you've really come away from this, um, as a, I think, as a role model for others who may be listening, or others who may be struggling as well, with doing all the right things, but just, it's not working. Thankfully, there's been innovations.

[A rush of wind and noise takes us from the present to the past.]

We will not hide. We cannot. HIV cares only that we are flesh and blood. And we are. All of us. We are human, and we are worthy of help, love, and support. We only ask for that.

[A rush of wind and noise takes us from the past to the present.]

GOLKOO MORCOS:

Dennis, so you mentioned that, despite taking your medicines, you would have some period of time that you would remain suppressed, but ultimately the viral load would start to increase or the virus would come back. So what happened after that?

DENNIS:

So we got to the point where, you know, my viral load was getting pretty high. And I said, "There has to be something else out there, I'm not sure what." And my doctor mentioned that there might be, uh, there was a drug in clinical trials. And, um, between him and then a contact I had, who worked in the field as well, they said, "Yeah, there is this new study. It's called the BRIGHTE trial. And it's designed for people like you, heavily treatment-experienced."

So, you know, I investigated. And I, you know, I said, "Well, to me, personally, I didn't have many other choices. It was that or go on salvage therapy.” And so I said, "No, I'm gonna try this." And so I got in contact to the study coordinator, came in, had my assessment, and I was put in the trial.

GOLKOO MORCOS:

Oh, that's excellent. So your first experience with RUKOBIA essentially was in the investigational trial, uh, with BRIGHTE?

DENNIS:

Yes, uh-huh.

GOLKOO MORCOS:

Dr. Spinelli, maybe you can tell us about the BRIGHTE trial? How it was designed, and, uh, the criteria in terms of the kinds of patients who were included in it?

DR. FRANK SPINELLI:

Oh, I would be happy to. And, you know, again, Dennis, I have to thank you again for participating in a clinical trial. It's—clinical trials are not easy; I mean, it takes a lot of effort and dedication. And so, what you've done, again, is be a role model for other people and actually help pave the way for getting this drug approved.

So BRIGHTE was a Phase 3 international, partially randomized trial involving 371 heavily treatment-experienced participants. And 272 were in the randomized cohort, and 99 in the non-randomized cohort. BRIGHTE included heavily treatment-experienced patients with advanced HIV-1.

You were eligible to enroll in the study, but you had to be an adult, 18 years of age or older, who had undergone multiple treatments for HIV-1 infection. The average age was mid-to-late 40s. Because why?

These are heavily treatment-experienced so they probably were around a little bit longer. Baseline, 73 percent had CD4 cell counts of less than 200, and 89 percent had viral loads greater than or equal to 1000 copies per milliliter.

GOLKOO MORCOS:

Thank you, Dr. Spinelli. I mean, I think that last line you said right there, with almost three-quarters of the participants having baseline T-cell counts less than 200…thinking about other kinds of studies, particularly in naïve patients, or early treatment-experienced patients, that particular component, um, of the demographics really underlines how immunocompromised these individuals were, really a reflection of limited treatment options and an ongoing viremia.

DR. FRANK SPINELLI:

And advanced HIV. I mean, we're talking about people who are living with less than 200 T-cells, and a, you know, viral load which we said was greater than 1000.

GOLKOO MORCOS:

Exactly—multidrug resistance and very few options here. But it still sounds like there was a range of heavily treatment-experienced patients in BRIGHTE. So what other criteria were involved?

DR. FRANK SPINELLI:

So, the randomized cohort was double-blind and placebo-controlled through Day 8 and then was open-label after that. All the patients had failure of their current antiretroviral regimen, as defined as having a viral load greater than or equal to 400 copies per mL. No viable antiretroviral combination therapy was available to them because they exhausted their options and had no more than 2 classes of antiretrovirals remaining at baseline, due to resistance, intolerability, contraindication, or other safety concerns.

DENNIS:

And speaking of exhaustion, um, I had no classes of medications that were available to me. I, um, had worked through everything.

DR. FRANK SPINELLI:

Wow. So you were actually an exact appropriate participant for the BRIGHTE study.

DENNIS:

Yes, I was.

GOLKOO MORCOS:

Thank you for walking through all of that with us, Dr. Spinelli. Can you also share the primary endpoint that was studied in BRIGHTE? You mentioned there was a Day 8 time point in the randomized cohort.

DR. FRANK SPINELLI:

So, the primary endpoint was the adjusted mean decline in HIV-1 RNA at Day 8, which was a log reduction of 0.79. And that was while taking RUKOBIA twice daily plus the failing regimen. And that was exactly 201 patients. The comparator was placebo plus the failing regimen. And those patients had a log reduction of 0.17, and that population consisted of 69 participants and had a significant p-value of less than 0.0001.

GOLKOO MORCOS:

Okay, so, you know, Day 8, it's significant as the primary endpoint. But what were the other endpoints that they looked at in the BRIGHTE trial?

DR. FRANK SPINELLI:

The secondary endpoint results were as follows. So at Week 96, 60 percent of patients were virologically suppressed, which was an increase from 53 percent at Week 24. Now, CD4 cell recovery was demonstrated across all baseline subgroups. The mean increase in CD4 cell count from baseline, at Week 96, was 205 cells per cubic millimeter in a subgroup summary analysis. Those with a baseline CD4 cell count less than 20 had a mean increase of 240 cells per cubic millimeter. And the most common adverse reaction of all grades observed, and greater than or equal to 5 percent of patients, was nausea at 10 percent.

GOLKOO MORCOS:

So that's pretty interesting. You just mentioned, um, 60 percent of the patients were virologically suppressed at the 96-week time point. Which is actually an increase from the 24-week time point. So there were additional participants who were able to achieve an undetectable, um, viral load by the second year of the study. And then, furthermore, you mentioned that the mean increase in T-cell count was 205 cells overall. But particularly with those individuals who had T-cell counts that were less than 20 cells at baseline, those folks had a mean increase of 240 cells. And so I think this was, um, a bit of a hallmark for us in the study.

You know, generally in these in HIV studies we don't tend to see increases in suppression over time, particularly in an intent-to-treat analysis. We'll see decreases over time because, of course, there are, uh, dropouts.

DR. FRANK SPINELLI:

Attrition, yeah.

GOLKOO MORCOS:

So, Dennis, can you tell us more about your experience in the BRIGHTE trial?

DENNIS:

When I found out about the trial, um, as I mentioned before, I was, you know, out of options and so I was pretty much elated when I heard about it. Um, I remember a colleague saying to me, "But, but aren't you scared? Um, do you know if this is even gonna work?" And I said, "You know what? This has to work; this is going to work for me."

And, uh, shortly after joining the study I did get, uh, to undetectable viral load with RUKOBIA and the other agents that I was taking.

GOLKOO MORCOS:

Well how did it feel to get to undetectable after so long?

DENNIS:

It was (LAUGH), it was beyond, I was beyond ecstatic. I mean, I remember the study coordinator, I had gone in a couple weeks after I started taking the meds and had blood drawn. And she called and said, "Um, I wanted to give you this message instead of waiting till you got to your next visit. You've already reached undetectable status."

And I screamed. And I screamed in the phone, and I was jumpin' up and down. And that was just really, really, uh, good news. And I know not everybody gets to undetectable, uh, that quickly, or undetectable at all. Um, but I did. And it just, you know, just made me so happy. And every three months, going in and getting that result, "Well, you're undetectable," just kept me going.

Like Dr. Spinelli said earlier, uh, being in a study is hard. Uh, there's a lotta visits, there's a lotta blood draws, there's a lot of things you have to do. But every time I got that undetectable result it just made it all worthwhile.

GOLKOO MORCOS:

Wow. I just have to say I love hearing your story, Dennis.

I just wanted to personally thank you for contributing to the study and the outcomes that, you know, ultimately have now provided an option for individuals like yourself who are heavily treatment-experienced.

Prior to me joining the pharmaceutical industry, I was an HIV pharmacist and I had a lot of patients I developed relationships with over time, where I knew that they also had few, few options.

We tried to make the study one where we expanded sites all over the country, but I know that there are a lot of folks out there who had similar journeys, uh, to yours, who may not have had the opportunity to be a part of the study. And, uh, but again I wanted to thank you for, for contributing to the data and the evidence that ultimately brought RUKOBIA to market.

DENNIS:

You’re welcome.

GOLKOO MORCOS:

So, Dr. Spinelli, what's at stake when someone who's heavily treatment-experienced has an unsuccessful antiretroviral regimen? Is there anything else that's important in terms of treatment goals for these individuals, besides, uh, getting an undetectable viral load?

DR. FRANK SPINELLI:

Yeah. And, and, you know, listening to Dennis, it reminds me of all those patients I took care of that would come in and all they would want to know is their numbers, their numbers. And, you know, that's a great goal to have.

The goal of initiating antiretroviral treatment is to achieve undetectability and to increase CD4 cell count. But what I encourage my patients to do, and all patients out there, is to not forget you are more than just a set of numbers.

[A rush of wind and noise takes us from the present to the past.]

By itself, hope does not suffice. But hope must be given to all of us if we expect to move forward. To carry on. And for those of us living with HIV, it’s essential.

[A rush of wind and noise takes us from the past to the present.]

GOLKOO MORCOS:

We're gonna discuss the DHHS guidelines on, on treatment goals for heavily treatment-experienced patients. And these goals are all-important for HIV patients. But what, in particular, about the guidelines is specific to patients who are treatment-experienced?

DR. FRANK SPINELLI:

Mmm, guidelines—that's my favorite topic. When I first started practicing, I would go to dinners where I would speak to other providers, and I would bring case studies and we would talk about them and see what we would do next.

Now we have the DHHS guidelines and international guidelines. And they are very helpful in guiding healthcare providers to create a regimen for their heavily treatment-experienced patients.

And as we discussed, the treatment goals are, what, to achieve viral suppression and increase CD4 cell counts? Now, for most patients, like I mentioned earlier, they've been trained, they want to know, "Please, tell me I'm undetectable. Please tell me my T-cells have gone up."

I have escorted many a patient out the door because, why? They had a blip. And they were just depressed and, uh, I saw that happening. And there was probably nothing I could do or say that was gonna change their mind. And so I think the impact of the numbers is significant. But I'd just encourage patients over and over again to remember it was about how they felt as opposed to just one set of numbers.

DENNIS:

I became less of a number-driven guy as time went on. When, like I said, when a number, when I'd see a blip, I'd get a little concerned. But like I said the doctor was always so optimistic. And they would say, "You know, how do you feel? How are you feeling, you know, physically?" And I'd be like, "Well, I'm fine. I'm working full-time, I'm off disability, I feel great." And they said, "You know what? Then maybe you don't have to worry about that so much."

I learned to live like that instead of just concentrating on the numbers.

GOLKOO MORCOS:

So let's talk a little bit more specifically about RUKOBIA. How do you feel RUKOBIA fits into your perspective on some of the goals you just mentioned for patients?

DR. FRANK SPINELLI:

Well, I think it's important to note that the use of fostemsavir, or RUKOBIA, in the BRIGHTE study also resulted in progressive improvements in CD4 cell count through Week 96. And that was in the randomized cohort, including among patients who had the highest level of the immunosuppression at baseline.

Remember, those who came into the study at less than 20 CD4 cell counts per cubic millimeter at baseline had a mean increase in 240 cells per cubic millimeter. So we just heard from Dennis talk about becoming undetectable, and saying he, I think the word you used Dennis was, what, "ecstatic"? Which I kind of loved that word.

But, again, could you imagine? You came into a study with less than 20 T-cells, and then, at 96 weeks, they're above 240. I mean, it's gotta be, it’s just gotta be, astounding, and, it made people probably a lot of us ecstatic, if I could use, uh, Dennis' term.

GOLKOO MORCOS:

IMPORTANT SAFETY INFORMATION continued

Warnings and precautions

Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of RUKOBIA.

QTc Prolongation with Higher than Recommended Dosages: RUKOBIA at 2,400 milligrams twice daily has been shown to significantly prolong the QTc interval of the electrocardiogram. Use RUKOBIA with caution in patients with a history of QTc interval prolongation or in patients with relevant pre-existing cardiac disease or who are taking drugs with a known risk of Torsade de Pointes. Elderly patients may be more susceptible to drug-induced QT interval prolongation.

Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-infection:

• Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection.
• Diligence should be applied in initiating or maintaining effective hepatitis B therapy when starting RUKOBIA in patients co-infected with hepatitis B.

Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of RUKOBIA and other drugs may occur (see Contraindications and Drug Interactions).

Adverse reactions

• The most common adverse reaction (all grades, randomized cohort) observed in greater than or equal to 5 percent of subjects was nausea (10 percent).
• 81 percent of adverse reactions reported with RUKOBIA were mild or moderate in severity.

Drug interactions

• See the full Prescribing Information for RUKOBIA for a complete list of significant drug interactions.
• Temsavir may increase plasma concentrations of grazoprevir and voxilaprevir. Use an alternative hepatitis C virus regimen if possible.
• Use the lowest possible starting dose for statins and monitor for statin-associated adverse events.
• Patients receiving RUKOBIA should not take doses of estrogen-based therapies, including oral contraceptives, that contain more than 30 micrograms per day of ethinyl estradiol. Caution is advised particularly in patients with additional risk factors for thromboembolic events.

Use in specific populations

• Pregnancy: There are insufficient human data on the use of RUKOBIA during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established.
• Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance, and adverse reactions in a breastfed infant.

Please use the link on this page to view the full Prescribing Information for RUKOBIA.

GOLKOO MORCOS:

Well, thank you, Dr. Spinelli, and Dennis, for joining us today. It's been an honor to have both of you on, and to hear both of your perspectives. And, Dennis, um, your story, in particular, I think, um, personally moved me and I'm sure a lot of our listeners here today.

DENNIS:

Thank you.

DR. FRANK SPINELLI:

Thank you, Golkoo, and thank you, Dennis.

GOLKOO MORCOS:

Thank you to our listeners, as well, for joining us. Join us next time for another in-depth discussion on RUKOBIA.

End of VO

ViiV PODCAST SERIES: EDGE OF YESTERDAY

EPISODE 3: A TURNING POINT FOR HEAVILY TREATMENT-EXPERIENCED PATIENTS

VO:

GOLKOO MORCOS (MODERATOR):

Welcome to the ViiV podcast series Edge of Yesterday. You're listening to Episode Three, “Discovering RUKOBIA, a Turning Point for Heavily Treatment-Experienced Patients.” Please note that the participants in this podcast are employees or paid consultants of ViiV Healthcare. Before we get into the conversation today, here's some important information about RUKOBIA, fostemsavir.

INDICATION

RUKOBIA, also known as fostemsavir, a 600-milligram extended-release tablet, in combination with other antiretrovirals, is indicated to treat HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations.

IMPORTANT SAFETY INFORMATION

Contraindications

• Do not use in patients with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA.
• Do not use RUKOBIA in patients receiving strong cytochrome P450 (CYP)3A inducers, including but not limited to enzalutamide, carbamazepine, phenytoin, rifampin, mitotane, and St John’s wort, also known as Hypericum perforatum.

Please listen to additional Important Safety Information for RUKOBIA later in the podcast. Please use the link on this page to view the full Prescribing Information for RUKOBIA.

For more information on content discussed in this podcast episode, please click the reference list link that appears on this page.

Voices overlapping, static, whooshing, voice clips from this episode.
"You're doing the most you can, we just have to wait"
"Leave no patient behind"
"A step forward for this patient population"
[Static crackle for a few seconds]
"It was, um, a sign of hope, a brightness in a dark space for patients"
—WHOOOOOOOOOSH—

GOLKOO MORCOS:

Hello, everyone, and welcome to The Edge of Yesterday. My name is Golkoo Morcos and I'm a medical director here at ViiV Healthcare. This podcast episode is about perseverance, particularly the perseverance of heavily treatment-experienced patients who have faced their share of challenges over the years but who kept on going and, of course, the perseverance of the clinicians and researchers who made RUKOBIA possible, people like the two I have in the studio today.

Just a note before we start: We'll be using RUKOBIA interchangeably with its generic name, fostemsavir. This is because we'll be discussing much of its early clinical development today.

And now I'd like to introduce our guests: Dr. Peter Ackerman, the Medicine Development lead here at ViiV Healthcare, along with Dr. Cathy Creticos, Medical Director of Clinical Research and Director of Infectious Diseases at Howard Brown Health in Chicago, Illinois.

DR. PETER ACKERMAN:

Hi Golkoo, it's really nice to be with you and Dr. Creticos today. My name is Pete Ackerman and I'm the current medicine development lead for the fostemsavir clinical development program within ViiV Healthcare.

I've been an employee of ViiV Healthcare since 2016, and I've been conducting clinical trials within the pharmaceutical industry for the past 10 years. Prior to joining pharma, I was a practicing physician.

GOLKOO MORCOS:

Dr. Ackerman, thank you for joining us remotely today.

DR. CATHY CRETICOS:

Very happy to be participating in this podcast today. Uh, I'm an infectious disease specialist and I started in HIV care back in 1985 with involvement as a fellow in infectious disease when our site was selected as a site to test azidothymidine, or AZT, the very first drug for HIV treatment.

That really started my career in HIV medicine. I've been in private practice, uh, since that time, taking care of people living with HIV. And the site where I practice in the Chicago area is an area that has been very heavily impacted by HIV.

I started at Howard Brown Health Center, which is the largest, uh, gay, lesbian, transgendered healthcare facility in the Midwest, in the mid-1990s doing HIV primary care and continuing with HIV research at that location.

I've been really very passionate about my care for people with HIV because I've been involved since the beginning, and it's a great situation to have today, treatment options for people, including for people who are heavily treatment-experienced.

GOLKOO MORCOS:

Thank you and welcome, Dr. Creticos. On our first podcast episode we actually had, uh, Marty St. Clair, who was the lead virologist, as you know, uh, who had contributed to the development of AZT at Burroughs-Wellcome. So it's absolutely great to have you on since you're a clinician who was involved, as well, in that early research, uh, with AZT and with that team in those days. So before we get into our discussion, I'm curious, do you know one another or have you met before?

DR. PETER ACKERMAN:

Certainly I was aware of Dr. Creticos and her contributions to HIV research before our working together on the fostemsavir Phase 3 study, which we call the BRIGHTE study. Since that time, over the past 5 years, we've gotten to know each other, uh, quite a bit better.

DR. CATHY CRETICOS:

It was great to finally meet in person and have the opportunity to exchange our experiences, and, uh, really throughout this entire time I've been very lucky to have the support of Dr. Ackerman and his expertise, uh, when it comes to dealing with heavily treatment-experienced patients.

GOLKOO MORCOS:

Well, it's great to have you both on here. And now, let's get into your involvement in the BRIGHTE trial, which is actually a topic we discussed with Dr. Frank Spinelli and one of our RUKOBIA patients from the BRIGHTE trial, Dennis, in our last episode.

Dr. Ackerman, what was your role like as the project physician lead for BRIGHTE?

DR. PETER ACKERMAN:

Yeah, thanks, Golkoo. My primary role, uh, within the fostemsavir program was as the program's clinical lead. And essentially what that meant is that I was responsible for setting clinical strategy and key messaging around the clinical trials that we were conducting, including the Phase 3 BRIGHTE study.

In early 2015, I joined the fostemsavir team, uh, to help, uh, with the conduct of its Phase 3 program. And at that time fostemsavir was an owned asset at another pharmaceutical company. It was within about 8 or 10 months of my joining the fostemsavir team that it was announced that all virology-related activities would be discontinued at that company.

And that was a time of real uncertainty for us, and, uh, what would happen to us as employees, but also what would happen to fostemsavir in its further development.

And it certainly made us anxious for, uh, heavily treatment-experienced individuals. Fostemsavir was specifically developed for this patient population. It was developed, you know, 20 years ago specifically to meet this unmet medical need.

And I was really thankful that ViiV Healthcare stepped up and took fostemsavir on board.

And, uh, was very pleased with the fact that they were gonna continue to develop fostemsavir for heavily treatment-experienced individuals. And shortly after that I was extended the opportunity to join ViiV as a full-time employee and continue my work as the fostemsavir clinical development lead.

DR. CATHY CRETICOS:

I'm gonna just jump in here as one of the investigators during this time period. Um, certainly, the sites had heard rumors about what was gonna happen with this, uh, this medication. Our patients were already taking it. We had a lotta concern about continuation for our heavily treatment-experienced population.

And there was tremendous relief and, really, jubilation that ViiV was gonna take it over.

DR. PETER ACKERMAN:

Yeah, thanks for saying that, Dr. Creticos. You know, it wasn't a foregone conclusion in our minds that someone was gonna pick fostemsavir up. We believed in fostemsavir. Uh, we had spent a long time and a lot of part of our professional careers working on fostemsavir.

But fostemsavir again was specifically developed for a very small sub-segment of the overall HIV-infected patient population. And a sub-segment that, in many regards, had become, um, marginalized, or altogether forgotten, in this era where patients are generally doing very well and being served very well on their HIV regimens.

And I can tell you the first day that I moved into the new ViiV facility, here in Connecticut, that they made available to us, my desk was right beside a big red wall that said, "Leave no patient behind." And that's a, that's a ViiV principle. And it is something that, uh, I believe—ViiV has lived through its commitment to fostemsavir—and seeing this project through, through to its end.

GOLKOO MORCOS:

Can't imagine. Did you take a picture of it that day?

DR. PETER ACKERMAN:

Oh, yeah. We have a picture of our team in front of that wall the first day, yep.

GOLKOO MORCOS:

Oh, wow.

DR. PETER ACKERMAN:

It was a big day for us.

[The sound of wind and noise takes us from the present to the past.]
Those against the odds are the ones who often change the world.
[The sound of wind and noise takes us from the past to the present.]

GOLKOO MORCOS:

Dr. Creticos, how did you come to be involved as a clinical investigator in BRIGHTE?

DR. CATHY CRETICOS:

So, Golkoo, this medication, fostemsavir, had been something that we had heard about for quite a few years. Actually, data had been presented at clinical meetings and we had seen, uh, some papers about fostemsavir. And we knew that this was a medication that had a different mechanism of action.

As mentioned before, I've been taking care of people living with HIV for over 3 decades. And some of those patients have really been alive through that whole time period, but had sort of reached the end of their treatment options. So, we had patients who were pretty much waiting for an agent that could make a difference for them.

Um, and fostemsavir certainly had that promise. So, uh, through connections and understanding who would be moving forward with, uh, trials for this medication, we really worked hard to become a site for fostemsavir's clinical trial. And after we'd submitted feasibility, et cetera, we were very, very thrilled to be a participant in this site.

And, in fact, we had already lined up patients who, as I said, were waiting, uh, for this medication because it represented to them hope in terms of managing their HIV. And this was something that was really unique to the area, the Chicago area, our sites in Chicago.

But we had patients referred to us from other states. We had patients from other practices. Because again, this was, uh, really one of the agents that people had been waiting for. And something that really represented, um, hope for patients who'd been heavily treatment-experienced.

GOLKOO MORCOS:

Dr. Ackerman, can you remind our listeners on how the BRIGHTE study was designed as well as its patient demographics?

DR. PETER ACKERMAN:

Yeah, BRIGHTE was a Phase 3 international, partially randomized trial involving 371 HTE participants, with 272 in the randomized cohort and 99 in the non-randomized cohort. BRIGHTE included a range of the HTE patient population, while also including HTE patients with advanced HIV-1 disease.

The cohort was double-blind and placebo-controlled through Day 8, and was open-label after that.

Eligible patients were adults, 18 years of age or older, who had undergone multiple treatments for HIV-1 infection.

Exclusively conducted in heavily treatment-experienced adults who were failing their current antiretroviral regimen, with a confirmed HIV-1 viral load greater than or equal to 400 copies per mL and were otherwise unable to form a suppressive antiretroviral regimen.

The average age was mid-to-late 40s. Also, at baseline, 73 percent had CD4 T-cell counts of less than 200 cells per cubic millimeter. And 89 percent had an HIV-1 RNA greater than or equal to 1000 copies per mL.

GOLKOO MORCOS:

And what were some of the other reasons—I mean, aside from having multidrug resistance—that some of these participants may not have been able to be virologically suppressed on their current antiretroviral regimen?

DR. PETER ACKERMAN:

Yeah, good question, Golkoo. Uh, so, the fact of the matter is that these are patients that have been living with HIV for a long part of their lives. 70 percent of them had, had been living with HIV for an excess of 15 years. 85 percent of them had been on at least 5 previous ARV regimens.

And over that time there was some development of resistance, as we talked about, but also difficulty with, uh, tolerability of certain antiretroviral agents. Patients were running into issues around drug-drug interactions with other medications that they were taking for their, their chronic disease.

And so all of those factors together contributed to their inability to form a suppressive antiretroviral regimen. And one of the most unique aspects of the BRIGHTE trial is that the BRIGHTE study required all eligible participants to have exhausted all agents across 4 of 6 antiretroviral classes. Nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, CCR5 antagonists, and entry inhibitors. Exhaustion was defined as having less than or equal to 2 classes of antiretrovirals remaining at baseline due to resistance, intolerability, contraindication, or other safety concerns.

GOLKOO MORCOS:

Yeah, so in other words these are individuals who, more or less, have limited antiretroviral regimen options. And Dr. Creticos is probably nodding her head because I'm sure she's thinking of a few of these participants that she's enrolled who not only had, you know, limited options from, um, a drug-resistance perspective but on top of that they may have had a number of tolerability issues in their past or with their past regimens and may have had drug-drug interactions or other safety considerations or contraindications that further limited their treatment options. Dr. Creticos, would you like to share any particular patient story that you can remember? Someone who might, uh, fit this description that I just mentioned?

DR. CATHY CRETICOS:

Yes, yes, absolutely, Golkoo. As you said, um, there are definitely patients who have been living with HIV who have been through a variety of different treatment regimens, had developed resistance, had intolerability issues.

I'm thinking of one individual who I had taken care of for over 20 years who, um, at one point I had referred the patient to colleagues at every single university in Chicago to see if they had any additional recommendations for treatment for this patient.

And one by one they sent him back to me, saying, "You're doing the most you can, we just have to wait for an investigational agent to be available." And he was, uh, definitely the first patient I lined up, uh, to participate in fostemsavir. And he did participate.

GOLKOO MORCOS:

Dr. Ackerman, can you also remind our listeners of the primary endpoint that was studied in BRIGHTE? And what were the other endpoints that were studied?

DR. PETER ACKERMAN:

The primary endpoint was the adjusted mean decline in HIV-1 RNA at Day 8, which was a log-10 reduction of 0.79 copies per mL while taking RUKOBIA twice daily plus the failing regimen. N equal to 201 patients.

The comparator was placebo plus the failing regimen. And those patients had a log-10 reduction of 0.17 copies per mL. N equal to 69 patients.

And a significant p-value of less than 0.0001.

The secondary endpoints were: At Week 96, 60 percent of patients were virologically suppressed, an increase from 53 percent at Week 24. The mean increase in CD4 T-cell counts from baseline at Week 96 was 205 cells per microliter.

In a subgroup summary analysis, those with a baseline CD4 T-cell count less than 20 cells per microliter had a mean increase of 240 cells per microliter.

The most common adverse reaction for all grades observed in greater than or equal to 5 percent of patients was nausea at 10 percent.

In addition, 76 percent of participants in the randomized cohort broke the threshold of CD4 T-cell counts greater than or equal to 200 cells per microliter.

By subgroup analysis, these efficacy outcomes, both in terms of virologic response and mean change in CD4 T-cell count over time, were generally consistent across demographic and disease characteristics such as age, sex, race, geographic region, and the number of fully active agents available in the optimized background regimen.

Those participants in the randomized cohort who were most immune suppressed coming into the trial with a baseline CD4 count less than 20 cells per microliter, were able to achieve the greatest mean increase in CD4 count over time, an observed mean increase of 240 cells per microliter. These kinds of changes are incredibly important for HTE individuals living with HIV.

GOLKOO MORCOS:

Dr. Creticos, at the very start of the trial, when you first talked to your patients about fostemsavir, what was the reaction and were they hopeful for an antiretroviral option?

DR. CATHY CRETICOS:

Yes, Golkoo, they were really very excited about this treatment. Uh, several patients had actually been waiting for a treatment option.

So, they were waiting for an additional effective agent to really create a regimen that would be, uh, workable, that would do something for them. And when RUKOBIA, uh, was available through clinical trial, they were extremely excited. In fact, there was a lot of excitement among my colleagues who had similar kinds of patients. And I did have patients referred to me from other practices and other states as well. So, this was definitely, um, a beacon of hope for patients who had been heavily treatment-experienced and were waiting for a treatment option.

GOLKOO MORCOS:

Was there a moment in the study, perhaps maybe a turning point or something that happened with one of the patients that you had enrolled, that stands out to you in particular?

DR. CATHY CRETICOS:

Well, I think as their initial lab reports started to come back and they saw that there was, uh, some improvement, they were actually getting response to this regimen, patients were just overwhelmed with excitement and, and joy that they were finally on a regimen that seemed to be making progress for them.

In particular, there was one patient, was able to enroll in the RUKOBIA trial and he was just really elated. Um, in fact, he had special, uh, earrings made for me that were a die that had 6 and 1 because I was his lucky number 7. So, um, he just felt very appreciative of being able to participate in this RUKOBIA trial.

GOLKOO MORCOS:

You were his lucky number 7?

DR. CATHY CRETICOS:

Yes. (laughs)

DR. PETER ACKERMAN:

Hi, Dr. Creticos. Just to comment. You spoke about hope. And, and hope is something that we talked a lot about in the development of RUKOBIA.

And that's one of the reasons why we named the Phase 3 trial BRIGHTE. Uh, B-R-I-G-H-T-E. Uh, H.T.E. for the heavily treatment-experienced, uh, patients that were to receive, uh, RUKOBIA. And "bright" because it was…a sign of hope, um, a brightness in a dark space for patients. So, um, I thought it was apt that you, you, talked about the hope that fostemsavir brought to you and, and your group and to your patients.

GOLKOO MORCOS:

So, Dr. Ackerman, that was actually, um, that’s actually a great segue, um, into talking about the development of RUKOBIA. And there's a pretty remarkable story there. So, can you walk us through sort of the development journey that you all went through to get this medicine through its clinical program?

DR. PETER ACKERMAN:

I certainly can try. The RUKOBIA journey, like a lot of other medicines, uh, was a long and arduous one. It started more than 20 years ago with, uh, a survey of chemical compounds, uh, in the thousands, looking for the right physical and chemical properties of a drug, uh, the appropriate potency and safety profile.

As I've said before, uh, RUKOBIA was specifically developed for the treatment of heavily treatment-experienced patients who had exhausted other viable treatment options. And to be able to meet that end, it had to bring forward a mechanism of action with no cross resistance to currently available, uh, ARV classes. And we were able to do that with RUKOBIA.

The challenge didn't end there, ha, however. We had a lot of challenges, including on the chemical side of the ledger. Um, this included the compound's permeability and solubility—things that our chemists worked very hard to overcome.

And then we ran into the challenge of half-life, how long the active form of the drug remained viable in the human bloodstream. And there was more years of development around that to try to optimize longer half-life of the drug.

It became apparent that we would have to develop a manufacturing facility solely dedicated to the development of this drug.

That's a huge capital investment on behalf of the company and it’s for a small patient population, a small and often neglected patient population. And I give ViiV a lot of credit for sticking to its core principles of leaving no patient living with HIV behind and making the decision that "We're going to do the right thing. We're gonna build the new facility. And we're gonna continue on with the development of fostemsavir."

That was a huge moment for this program. We went ahead and did that and then finally in 2020, fostemsavir was approved to be used in patients as an approved, marketed medication for the treatment of heavily treatment-experienced HIV-infected individuals.

[The sound of wind and noise takes us from the present to the past.]
How much good has been achieved by waiting for others to act first?
We cannot disappoint those who depend on us. Let us not just make promises, let us act.
[The sound of wind and noise takes us from the past to the present.]

GOLKOO MORCOS:

So now, Dr. Ackerman, can you tell us why the unique mechanism of action of RUKOBIA is so important when it comes to heavily treatment-experienced patients with limited antiretroviral options?

DR. PETER ACKERMAN:

Yeah, absolutely. In the development of RUKOBIA, we knew that we needed to come up with a novel mode of action that could meet the needs of these, uh, individual patients.

And therefore we came up with RUKOBIA. Uh, RUKOBIA is a first-in-class attachment inhibitor. It's a prodrug, meaning that the parent form needs to be converted to an active moiety inside the patient after they ingest the medication. And the active component of the drug is called temsavir.

Temsavir has a unique mode of action in that it seeks out and binds to the glycoprotein 120 protein that's on the surface of HIV virions. This is an active protein that has a lot of movement to it. And it's critical to the virus binding to host immune cells and then allowing for the virus genome to be injected into the host immune cell.

Temsavir, the active moiety of RUKOBIA, binds to this surface protein on the virus, HIV virions, locking that protein into a fixed, closed formation that doesn't allow the binding to the receptors on host immune cells, thereby interrupting the HIV life cycle at its very beginning.

GOLKOO MORCOS:

Yeah, that's so neat. I could probably hear that, uh, mechanism of action described over and over again and never get tired of it. In my mind, to sum up what you said, Dr. Ackerman, temsavir basically locks and blocks gp120 from binding to CD4 receptor target cells. So really, really neat, um, mechanism of action there.

DR. PETER ACKERMAN:

That's absolutely right, Golkoo. And in that way, RUKOBIA is the first antiretroviral that's taking the fight to the virus. It's attacking the virus before it engages in our host immune system, before it attaches to CD4 cells and the receptors on their surfaces. And that's a key component.

GOLKOO MORCOS:

And that's a little different than how other medicines that block the entry of HIV work, is that right?

DR. PETER ACKERMAN:

That's absolutely true. There are other antiretrovirals that we consider or classify as entry inhibitors but each of those inhibitors allows the virus to initially attach to our host immune cells, uh, and then further blocks the entry of the viral genome into that host cell. But RUKOBIA works in a different way, attacking the virus and preventing that initial interaction.

GOLKOO MORCOS:

So, Dr. Creticos, from your perspective, why would this aspect of RUKOBIA be so important when building regimens for heavily treatment-experienced patients?

DR. CATHY CRETICOS:

Yeah, so really the fact that this is, uh, a unique mechanism of action allows us to have reassurance that our patient, who's been through so many other categories of medications, will have an agent. Many of our patients have not only been through a number of medications, but they've been to a number of different providers over the course of several years.

Uh, records are lost or sometimes not able to be accessed easily, so we don't always know exactly which medicines they've taken in the past and why they were no longer working for a patient. Um, sometimes it is resistance. Sometimes it's tolerability. Sometimes it's some other issue, uh, such as, you know, drug interactions.

But we don't know if there's a resistance problem. So, when we finally have a class of medications that's not a recycled medication from an old class but a medication that is the first in its class, something that is a unique mechanism of action, we can have a lot of reassurance.

So that's a tremendous step forward for this patient population. Um, as was described, it's also really exciting to have a medication that works to really hold the virus up from getting into the CD4 cell, or actually, it doesn't even allow the, uh, virus to attach to the CD4 cell.

GOLKOO MORCOS

Dr. Creticos, let's close on your reflections on how the development of RUKOBIA represented ViiV's commitment to people living with HIV.

DR. CATHY CRETICOS:

Well, we've looked at the fact that heavily treatment-experienced patients have really been living with HIV for many, many years and they're not a large part of the population, but they're the people who have really survived and continued to, um, really work hard to try to stay healthy and, um, and move forward in their treatment regimens.

And this is something that ViiV has shown a commitment to.

And this patient population not only has a lot of virus circulating, but they have low immune systems, so their CD4 counts are low. One thing that our patients who were involved in the RUKOBIA trial and, actually, patients since RUKOBIA has been approved and, uh, available for use, uh, have experienced, and this is something, again, very exciting for patients, they, they're excited that their viral load goes down, but they're even more excited when they see their CD4 count go up.

And RUKOBIA is just, uh, a unique drug in the fact that because it does not allow the virus to interact with the CD4. That's the way I like to think of it. And we see the, the reality of that in seeing robust and, you know, persistent increases in CD4 cell recovery. Patients love this. This is, uh, meaningful for them. So, I would say, you know, that's, that’s been a large part of the excitement about RUKOBIA.

GOLKOO MORCOS:

IMPORTANT SAFETY INFORMATION continued

Warnings and precautions

Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of RUKOBIA.

QTc Prolongation with Higher than Recommended Dosages: RUKOBIA at 2,400 milligrams twice daily has been shown to significantly prolong the QTc interval of the electrocardiogram. Use RUKOBIA with caution in patients with a history of QTc interval prolongation or in patients with relevant pre-existing cardiac disease or who are taking drugs with a known risk of Torsade de Pointes. Elderly patients may be more susceptible to drug-induced QT interval prolongation.

Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-infection:

• Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection.
• Diligence should be applied in initiating or maintaining effective hepatitis B therapy when starting RUKOBIA in patients co-infected with hepatitis B.

Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of RUKOBIA and other drugs may occur (see Contraindications and Drug Interactions).

Adverse reactions

• The most common adverse reaction (all grades, randomized cohort) observed in greater than or equal to 5 percent of subjects was nausea (10 percent).
• 81 percent of adverse reactions reported with RUKOBIA were mild or moderate in severity.

Drug interactions

• See the full Prescribing Information for RUKOBIA for a complete list of significant drug interactions.
• Temsavir may increase plasma concentrations of grazoprevir and voxilaprevir. Use an alternative hepatitis C virus regimen if possible.
• Use the lowest possible starting dose for statins and monitor for statin-associated adverse events.
• Patients receiving RUKOBIA should not take doses of estrogen-based therapies, including oral contraceptives, that contain more than 30 micrograms per day of ethinyl Caution is advised particularly in patients with additional risk factors for thromboembolic events.

Use in specific populations

• Pregnancy: There are insufficient human data on the use of RUKOBIA during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established.
• Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance, and adverse reactions in a breastfed infant.

Please use the link on this page to view the full Prescribing Information for RUKOBIA.

GOLKOO MORCOS:

Well, thank you so much, Dr. Ackerman and Dr. Creticos, for joining us today. It's been an absolute pleasure having you on. Anything else you'd like to say to our listeners before we sign off here?

DR. CATHY CRETICOS:

Well, um, I'd like to say that, you know, we spent a lot of time talking about patients who were involved in the clinical trial, but I've had the opportunity to use RUKOBIA since it's been commercially approved and available. And I see the same responses from patients.

They, uh, see the CD4 count increasing. They see viral loads going down. And, again, a lot of excitement for patients who have either had some progression on their older regimens—for example, the development of an opportunistic infection or an AIDS-defining cancer—uh, you know, they were in a situation where they felt, "Oh, my gosh. My time is up. I, I don't know where else to turn."

And we have another agent for them, something that really can provide, uh, a good clinical response. So, I've continued to see the same, you know, positive responses in patients who have been receiving RUKOBIA since it's been, uh, FDA approved.

DR. PETER ACKERMAN:

Yeah, I would like to just add, um, thanks to you, Golkoo, and Dr. Creticos. It's been great joining the two of you on the podcast. And, really, I would like to take this opportunity just to thank so many people. Um, this has been a tough journey for the drug, but it's been a shared journey.

And it's really been a great privilege of mine to work with people like you, Dr. Creticos, and people across ViiV and GlaxoSmithKline and patient advocates and others in taking this journey together. And, um, you know, I think we all have a lot to be proud of here. And it's been a real privilege. So just, uh, a big thank you.

DR. CATHY CRETICOS:

And, of course, uh, a big thank you to the patients who have continued to show strength and, um, perseverance and have participated so that others can benefit from the approval of this medication.

DR. PETER ACKERMAN:

Yeah, absolutely. Thank you.

GOLKOO MORCOS:

And thank you to our listeners, as well, for joining us.

End of VO