Jack D. Sobel, MD

I don’t believe that the companies are going to take on fluconazole. It’s easy when somebody doesn’t tolerate, when someone has adverse effects, when someone’s allergic, when someone’s failing fluconazole and you understand the mechanism of the failure, when someone’s got resistance, when you’ve got a yeast that is broader that you can’t clear with fluconazole; that’s easier. You look at the 2 new drugs and both companies are coming up with novelty ideas of how to allow the patient to afford these drugs. They’re coming up with coupon systems and they’re being very creative in coming up with methods to afford these 2 drugs. That’s easy. So, I’ve told you all the easy reasons for turning to these 2 drugs. But in the patients who have none of the above, but a sensitive organism in there, and they’ve got no allergies and no adverse effects in the same drug; should I now use it? It’s going to be an economic factor more than anything else.

Jack, I’m wondering if you have any last minute clinical pearls, takeaways for our listeners today?

The only other thing I think that I’m very impressed about in my practice is that if you look at any standard text and textbook that deals with recurrent candida, and they go through triggers and underlying mechanisms, the one thing that is consistently absent is the role of bacterial vaginosis. Bacterial vaginosis is the most common trigger for yeast infections that I see in my clinical practice. You can’t control yeast, recurrent yeast, until you control the bacterial infections. We can spend hours and we don’t have time now, but we can spend hours talking about what the link is. But I would tell you that the commonest cause of recurrent candida vaginitis in my city where I live in Detroit, forget about the genetic factors because you can’t control them, is bacterial vaginosis.

I think your point is well taken. Don’t think that BVC and RVBC exist in a vacuum and understand that it’s a complex interaction. I think for me, an important take-home message is, and I always say this, it’s not just a yeast infection. It’s not just another yeast infection and signs symptoms are very impactful not only on medical economics, but on a woman’s psychosocial, sexual behavior. There are certainly shortcomings in existing treatments, and I think we need to follow the data, follow the science, understand a little bit more about half lives and drug exposures and drug-drug interactions. I’m very excited about innovation. I’m very excited about ibrexafungerp and oteseconazole. I think more weapons in our war chest to help women who are suffering in silence and recurrently suffering in silence could very well change the landscape. I’m really excited that there’s new life into an existing condition that we didn’t really focus that much on as ob-gyns and women health care professionals. Dr Sobel, I want to thank you today; it’s been a really insightful, enjoyable discussion. Thank you to our audience for watching this presentation. We do hope that you found this 

 discussion useful, informative, and we want to thank you. Stay tuned for more emerging data and more science.

Videos

Michael L. Krychman, MD, and Jack D. Sobel, MD, discuss the importance of awareness and education about RVVC, particularly given the impact of symptoms on patients’ psychosocial and sexual behavior.

Future Directions in Recurrent Vulvovaginal Candidiasis Care

Are there certain pearls where you would use one over the other? Once ibrexafungerp came to fruition and was FDA [Food and Drug Administration] approved, I looked at the data, the 25-day efficacy. Oteseconazole wasn’t even on the horizon, and I said, “Well maybe this would be an opportunity for RVBC.” I started using it but then had challenges getting reimbursement and cost and what have you. So, there are a lot of factors that go into this. I know you had mentioned more than likely, most of us will stay with fluconazole. But, as these drugs become more known and we start answering some of these questions and they’re approved, I think it’s going to be hard-pressed. I can tell you, I’ve been there where I said, look I’ve had a medication that’s approved for a condition and the insurance company came back and said, “We don’t want to approve this drug because it’s more expensive; we want you to use something that’s not approved, off-label.” And I said, “So for clarification, you’re telling me to use a medication that is not FDA-approved for a condition when I have an FDA-approved product? And you don’t want to use it because it’s too expensive?” It was very interesting, about 10 minutes later, often the approval came for an FDA-approved drug. So, I hear what you’re saying. I think in all good intentions, once we have FDA-approved products that have done the vigorous studies with safety, efficacy, and patient reliability, I think that you’re going to see an up-ticking of these. I’m wondering what your thoughts are.

 I would just be repeating what you’ve now just said. It’s easy to consider using 2 new drugs and any additional drugs that come down and for the most part, the pipeline is pretty empty after these 2 new agents. But we don’t know the optimal dose of these drugs, the optimal duration of therapy, the optimal frequency. And unfortunately, we as practitioners are forced to make decisions where we don’t have the comparative data of either of these 2 new drugs compared to fluconazole. So, if you ask me whether ibrexafungerp, given once a month, is it better than placebo? Of course, statistically significant. It is better than weekly fluconazole? I don’t know.

I think your point is well taken. I think we’re more likely to see ibrexafungerp versus fluconazole and oteseconazole versus fluconazole. I don’t think either company is going to want to do ibrexafungerp versus oteseconazole. But I think everyone will kind of try to getfluconazole. The landscape is certainly changing and it’s interesting.

Michael L. Krychman, MD, and Jack D. Sobel, MD, discuss the practical challenges of access to newer, FDA-approved medications for RVVC and how the third-party reimbursement landscape may take shape in coming years.

Tips for Treatment Selection in Recurrent Vulvovaginal Candidiasis

Fast forwarding a little bit, I can’t read the future but I am very optimistic that we’ll have 2 approved drugs for recurrent VVC [vulvovaginal candidiasis]. We’ll still have the old, tested, tried-and-true off-label fluconazole as well as what you’re saying: in some cases, we must go back to the old paradigm of treating each infection, especially as we have no alternatives in pregnancy. How do you see the emerging landscape in terms of the overall treatment paradigms? Do you think that clinicians will adapt these newer medications? I appreciate your medical economics and insurance background. We’ve all been there, holding those insurance handcuffs. We have all best intentions with prescribing and getting our patients the right drugs that are safe and effective. Cost and access certainly is an issue but let’s be in an imaginary fantasy world and say cost and access is not an issue and we can get the drugs at appropriate, affordable pricing for all of our patients. Do you feel like the guidelines are going to change? I know myself; there’s no ICD10 code for recurrent vulvovaginal candidiasis? We’re already having problems at the get-go. We have a drug approved for a non-condition.

You’re asking the zillion dollar question today because it’s important to recognize that even though fluconazole is not approved by the FDA [Food and Drug Administration], it is the treatment of choice for recurrent VVC from ACOL, CDC [Centers for Disease Control], every professional society in the world recommends fluconazole given weekly. It’s most important to understand that when you want to prescribe fluconazole for 6 months once a week, you’re not curing recurrent candida vaginitis. They have a greater than 90%, which is a wonderful chance of remaining asymptomatic, having a normal life, a normal sex life, no symptoms, as long as they’re taking the medication. They stop the fluconazole the end of 6 months, you haven’t changed the genes, they still could become recolonized again, and they can still have the inflammatory response. Once you stop the fluconazole, an overwhelming majority of women will go back to the same. So it’s easy to say if I have recurrent candida vaginitis and the patient’s not responding to fluconazole, and they’re breaking through on fluconazole, or they can’t tolerate fluconazole, or are allergic to fluconazole, we clearly must think about these 2 new drugs, whether we will actually use them will depend on availability and cost. On the other hand, we don’t know what the comparative short- and long-term success rate is with ibrexafungerp versus fluconazole. They’ve never been compared in a long-term study for recurrent candida vaginitis. What’s most important is to see how well the patient does once you stop the medication. The advantage of oteseconazole in this context, given the limitation of the patients who can be given the oteseconazole is that, because the drug sits around for a long time, the freedom of recolonization extends for more than just 3 to 6 months. It may continue for up to 2 years after stopping the medication. It’s got to be a limited market availability. I still think that probably in your private practice or your clinical practice in the next 6 months to a year, as we learn about these 2 new drugs, you probably are still going to be predominantly using fluconazole.

Right. Your point is very well taken, just because you have availability of medications doesn’t mean they’re going to be clinically implicated. Besides the fact of cost and access, I think one of the issues that has me thinking about medication choice is patient compliance and patient adherence. We both struggle with what is going to be best accepted. If all things are considered, the cost and the access, what is going to be best for the patient in the end of the day? There’s other considerations that go into making this hardcore decision: drug interactions. With every medication that you take, there are multiple drug interactions. There are some with ibrexafungerp, and there are some with oteseconazole and those may factor in. It’s also patient awareness and compliance. I would say the drug regimen is a little more intricate for oteseconazole versus ibrexafungerp. I think they went to monthly because that’s relatively simple and easy for women. There’s a lot of variables as you had mentioned, safety, efficacy, drug interactions, cost, and access, and compliance. These all factor into our clinical decision-making about prescribing drugs. I think very often we have our best intentions, but access may be a problem and cost may be a problem. But, if you take those out of the equation, remember that there’s a lot of other facets as well for doing that.

Experts explore the availability and cost as well as other unanswered questions regarding emerging agents for the treatment of RVVC.

How Emerging Agents Will Shape the Treatment Landscape for Recurrent Vulvovaginal Candidiasis

I want to shift gears and talk about ibrexafungerp, which is a glucan synthase inhibitor. It’s fungicidal. I know you’re very familiar with it. It’s approved for acute VVC [vulvovaginal candidiasis]. They’ve submitted their SNDA [supplemental new drug application] for recurrent VVC by phase 3 clinical trials, with a PDUFA [Prescription Drug User Fee Act] date in November. I’d love to get your take on this newer medication and how you feel this 1 may fit in to the overall treatment paradigm.

Before we go on, we need to mention that fluconazole isn’t used in pregnant women.

We also don’t give fluconazole to women who are trying to become pregnant. For example, if a patient is 20 to 23 years old and would like to start a family, but they have recurrent candidal vaginitis and have been on fluconazole maintenance therapy once a week for the last 2 weeks, months, or years, depending on the clinical scenario. They’d like to start having a baby. But we warn her that the risk of fluconazole in pregnancy is greatest in women who aren’t aware that they’re pregnant. It’s the inadvertent administration of fluconazole to a pregnant woman, and the risks are greatest in the first trimester. We have to warn women who are doing wonderfully well on fluconazole about avoiding it if they’re trying to become pregnant. That’s not such an easy thing. Of course, oteseconazole, ibrexafungerp, and fluconazole also shouldn’t be used in pregnancy. Managing pregnant women with recurrent VVC requires going back 30, 40 years, when we used repeated courses of topical agents, either nystatin or clotrimazole, during pregnancy. That was long, but I wanted to clarify that none of these 3 drugs is to be used during pregnancy.

I appreciate that. People are pushing the envelope and forgetting the basics. We have to throw in the concept of adequate contraception if they’re trying to get pregnant or are pregnant. That’s an important point.

Oteseconazole is contraindicated in pregnancy, as are fluconazole and ibrexafungerp, but it’s also not approved. It shouldn’t be used by a woman with reproductive ability or who had their tubes tied or a hysterectomy or who is postmenopausal. At this stage, they shouldn’t be given oteseconazole. That may change as more data arrive, but for the next few months, these are some of the limitations.

The FDA is likely to approve ibrexafungerp. It’s given once a month for 6 months. As with many new drugs, like oteseconazole and ibrexafungerp, physicians are going to learn how to use these drugs. They’re going to learn how to master these drugs. There’s never been a study with ibrexafungerp given once a month. If it was given once a week, would it be better? They haven’t done a study comparing 1 week with 1 month. We don’t know the optimal dosage for the maintenance. It will probably be approved at once a month, but maybe it would be better at once a week.

Likewise, it’s going to get approval for 6 months’ use in recurrent candidal vaginitis. Would it be as effective if you gave it for only 4 months? Those dosage-duration studies haven’t been done. If we have the same discussion in 5 or 10 years, we’ll have a whole different perspective with these new agents based on information that doesn’t exist today.

There are lots of unanswered questions. In the meantime, I suspect that ibrexafungerp will be an alternative, constitute fluconazole. Regardless of whether it will be used in women, it will definitely be useful for patients allergic to or intolerant of fluconazole. It has some contraindication or resistance to fluconazole. That will immediately make you think of oteseconazole or ibrexafungerp. As we know from our clinical practice, what you prescribe depends not on your science and knowledge of genetics but on what the insurance company makes available.

Michael L. Krychman, MD, and Jack D. Sobel, MD, review the mechanisms of ibrexafungerp and how it might fit in the treatment spectrum for RVVC.

Exploring Ibrexafungerp for the Treatment of Vulvovaginal Candidiasis

Let’s turn to the recently approved drug oteseconazole. Can you give me a high-level overview of this novel drug, which was just approved for recurrent VVC [vulvovaginal candidiasis]? It’s the only drug approved for recurrent VVC. Feel free to highlight some of the high-level data from the VIOLET and ultraVIOLET studies. Are there any potential problems or pitfalls? This is exciting. There haven’t been a lot of new developments in the field of VVC or RVVC [recurrent VVC]. It’s first in class for recurrent VVC. I’d love to hear your general take, and then we’ll dive deep into things that are emerging.

Oteseconazole was approved in August 2022 for the treatment of recurrent candidal vaginitis. It’s the first drug approved. Even though fluconazole was used for 20 years, nobody ever applied for approval. No company was interested in getting the drug approved. Along comes oteseconazole, which is a second cousin of fluconazole, tetrazole, and clotrimazole, but it’s still the same family that’s been designed to be more potent than fluconazole in the test tube against yeast and not only the common 

. It’s also designed to have an affinity for the yeast target enzymes, which are present in human epithelial cells and subvert. The affinity for the fungus target toward enzymes is far greater than it is for fluconazole. It’s more active and more potent, but it doesn’t have the toxicity that’s part of fluconazole’s identity. It’s a safer drug.

Remember, fluconazole isn’t approved; it’s contraindicated in pregnancy. The biggest drawback of fluconazole is that it can’t be used for pregnancy, yet many practitioners continue to do this unwisely. I never prescribe fluconazole in pregnancy. Along comes oteseconazole, which is more potent. Most important, in addition to its potency, it doesn’t affect QTc [QT interval corrected for heart rate] and doesn’t have the same tendency to cause lots of drug injury reactions. It’s a well-tolerated, safe drug for patients with candidal vaginitis. It has increased potency, and it has 1 other major advantage: it stays in the tissues; it sticks around. That’s in contrast with fluconazole, which has a half-life of under 30 hours, closer to 20 hours. Oteseconazole has a half-life of about 130 days.

The reason why this drug was designed to be effective in recurrent candidal vaginitis is that if it stays in the tissues for a prolonged period of time, it’s going to prevent vaginal recolonization. Long after they’ve stopped taking the medication, patients remain free of recolonization. Not forever—you can’t change your genes—but that’s part of its potency. In clinical studies done with women all over the world, called VIOLET and ultraVIOLET, the drug was found to be highly effective in reducing attacks of recurrent candidal vaginitis. It reduces not only 

, which is 85% to 90% of recurrent infections, but in the other 10%, which is when you start getting resistance because it’s more potent.

The issue we’re hearing is from the clinical perspective. I appreciate your discussion about the tissue, the half-life, and staying effective. That can be looked at as a double-edged sword, in terms of a half-life of 2 years and drug exposure. With every drug, there are positives and negatives. No one is doubting efficacy or safety. But there are some discussions about potential shortcomings, study population vs approved population, long half-life, and drug exposure can be problematic. I appreciate your insight about the benefits of a long half-life. That’s very important in terms of maintaining the effectiveness, and it’s the only drug approved for recurrent VVC.

Michael L. Krychman, MD, and Jack D. Sobel, MD, review the clinical implications of the recent approval of oteseconazole, which has been shown to be efficacious and well tolerated in RVVC treatment. 

The Role of Oteseconazole in the Treatment of Recurrent Vulvovaginal Candidiasis

Let’s talk a little bit about treatment, and what kind of unmet needs or kind of goals there are for RVVC [recurrent vulvovaginal candidiasis]? Where do you think we are? Where do you think we will be? What are some of the problems and pitfalls and shortcomings globally? Talking about the therapeutic need, and then we’ll do a deep dive on some of the newer medications as I know you and I are both very interested in them as well.

We get this focus on recurrent candida vaginitis treatment, because acute sporadic—getting a yeast infection once every 10 years, a sporadic episode—is, well over 90% of the time, as you will see, is albicans and whatever you treat it with, topically a local measure or something by mouth, it’s going to get better in a matter of days, just a few days. With recurrent candida vaginitis, the first thing to recognize is the overwhelming majority of the women are going to have recurrent disease caused by the good old regular species, Candida albicans. It may not be 95% anymore, but it’s going to be 85% to 90%. The chances are a woman having repeated infections, you don’t have to run out to do resistance tests and look for do I have a unique unusual species? Eighty-five percent to 90% of recurrences are still going to have the regular old hyphae-producing Candida albicans one. But up to 10% will have nonalbicans species and include even resistant strains of Candida albicans. But it’s 1 of 10. We don’t need to focus immediately on the exceptions. We talk about the 90% that are recurrent due to C. albicans [Candida albicans]. The reason why it’s recurrent is genetic and trigger mechanisms and nothing else. How do we treat it? In the past prior to the onset of some sort of long-term programs, we used to treat recurrent attacks simply by treating each individual attack. You had 10 attacks, you got 10 causes of them. You had 5 attacks per year, you had appropriate therapy for each attack. That was what we were faced in the 1980s and ’90s, just treating each individual attack. But we learned from many other infectious diseases: Can we prevent somebody having 3 or more attacks per year? The answer is yes, but you need a maintenance program. Literally in 1985, with the arrival of the first oral drug called ketoconazole, but no longer available because of toxicity. We learned about the ability to prevent recurrences by using a maintenance program. The antifungal mechanisms that we’ve used are based on using an induction dose, which takes a symptomatic patient who’s got acute flare of a recurrent disease today, she takes an induction dose, most commonly in the last 30 years it’s been fluconazole. She ends up within a week or 10 days she’s asymptomatic. This usually requires more than 1 tablet of fluconazole. Then you place her on a maintenance program, and the maintenance program continues for approximately a minimum of 6 months. During the minimum you give them a maintenance dose. That was the biggest advance firstly, with ketoconazole and then itraconazole, and it’s been fluconazole that has been the dominant treatment mechanism for recurrent candida vaginitis just for the last 20 years.

Yeah, your point is well taken about the utilization. But again, you’re saying that’s what we’ve been doing, but it’s certainly not FDA [Food and Drug Administration] approved. There are also some shortcomings with fluconazole. I certainly have seen changes in liver functions, alcohol may affect the liver, fluconazole, as well. There are some monitoring issues that may be of concern. And again, if you see what’s going on in the community, we certainly see people using boric acid, probiotics, limited data, etc.

Thought leaders discuss the history of RVVC treatment, including the use of unapproved topical antifungals and the shortcomings of fluconazole.