New antifungal drug for recurrent vaginal yeast approved by the FDA

But it's not exactly time to party

Recurrent vaginal yeast infections are a significant health issue. They affect between 5-9% of women and are uncomfortable, can cause significant distress, affect sexual relationships, and be expensive when you factor in the cost of buying multiple therapies, trips to the doctor’s office, and missed work. In addition, many people end up spending lots of money on useless therapies, cleanses, and diets recommended by medical predators.

Current therapy for recurrent yeast infections requires an accurate diagnosis, the gold standard is a culture, and then oral fluconazole–three doses are taken as induction therapy over a week and then the treatment is continued once a week for 6 months. As long as the yeast is sensitive to the fluconazole (meaning it can be treated with this drug) this therapy is highly effective. The problem is when the fluconazole is stopped at 6 months, the recurrence rate is about 50%. Consequently, some people end up on weekly fluconazole for a year or even longer. 

The reason a new antifungal is a potential vaginal celebration is we actually have a limited number of options for recurrent yeast. This is one circumstance where it is less about the patriarchy and more about the difficulty in developing safe and effective antifungals. We humans are much more closely related to yeast than you might think, so lots of drugs that are toxic to yeast cells are also unfortunately toxic for us. Pharma appreciates there is a large market for new yeast medications (antifungals), so there has been research here, but true breakthroughs are challenging to come by. 

A few months ago I reported on the new drug ibrexafungerp (trade name Brexafemme, read about that drug here), which I have since prescribed many times with great success for yeast that is resistant to the traditional antifungals. Ecstatic doesn’t come close to describing how I feel about ibrexafungerp (although the name sounds more like a bad belch, but hey, I can look past that because all I care about is how well the drug works and its safety profile).

There isn’t a protocol for ibrexafungerp and resistant yeast that is recurrent, so to appropriately people in this situation requires cobbling together other options, such as vaginal boric acid, vaginal nystatin (which must be compounded in the United States), and even vaginal gentian violet. I have used oral itraconazole for some, but this requires more monitoring. 

(There are always lots of questions about boric acid, so you can read more about that here).

I’d recently heard fantastic things about the new antifungal oteseconazole (trade name VIVJOA™), so with its approval by the FDA for recurrent yeast infections, it is time for a closer look. 

What is the new drug?

Oteseconazole is also an azole, so it is in the same class of drugs as fluconazole or the over-the-counter miconazole (that you might know as Monistat). Azoles work by inhibiting an enzyme called lanosterol 14-alpha-demethylase, also known as CYP51. This enzyme is important in making ergosterol, an essential component of fungal cells. When there is no ergosterol, the fungal cell dies. The problem is this enzyme is also important for humans, so inhibiting it with medication can sometimes lead to side effects or the metabolism of other medications.

Oteseconazole has been modified so it preferentially binds to fungal CYP51, essentially ignoring human CYP51. This means it should be more effective at attacking yeast, and not just Candida albicans, the yeast that causes over 80% of vaginal infections, but other types of Candida against which the azole drugs are typically ineffective. It is also very effective against Candida albicans that has acquired resistance overtime to other azoles. The lab data is very impressive. 

Still really good!

So how well does oteseconazole work for vaginal yeast infections?

For an acute infection, meaning a one off vaginal yeast infection, oteseconazole performs about well as oral fluconazole at 28 days post treatment. However, more people remained cured at 3 and 6 months, leading researchers to wonder about exploring oteseconazole as an option for resistant infections. The drug has a very long half life (meaning it circulates for a long time before the body can remove it all), so this might explain some of the prolonged effect. Basically, because oteseconazole loiters in the body it can keep killing yeast longer.

The company behind oteseconazole did three phase III studies, the type of studies needed for FDA approval. I am just going to say up front that these studies are clunky, meaning I had to read through the available data several times to get to the bottom line. This is my area of expertise, I know these kinds of studies well, and I actually had to make a chart and take notes for each study to keep it straight in a way I have not needed to do before. This irritated me and it made me feel like there were some smoke and mirrors in play.

The other issue is these three studies aren’t yet peer reviewed, only one abstracts is published, and four of the six investigators work for the company that makes oteseconazole. This isn’t atypical, as the company did the work, but it is always important to bear that connection in mind. 

Finally, oteseconazole was not studied head-to-head against fluconazole, the gold standard for recurrent yeast. The three studies use an induction regimen, meaning more drug in the first week to get the yeast under control, and then weekly dosing to keep the yeast away for 11 weeks. After the medication was completed, the subjects were followed for 48-50 weeks (depending on the study) to see how many remained free of yeast. Oteseconazole was studied in two ways, it was either compared with placebo or it was studied against fluconazole for induction and then only oteseconazole was continued weekly versus a placebo.

Not comparing oteseconazole head-to-head with the gold standard is not unexpected. If your drug performs as well as the generic that is already available you’ve just shrunk your market before you’ve made your first pill, and if it performs worse, you’ve torpedoed yourself. 

So with all of these caveats, the findings were pretty good. In the two studies with oteseconazole vs. placebo it outperformed placebo, no shocker. At week 48 in one of the studies the recurrence rate was 6.7% by week 48 and and in the other it was 3.9%. As recurrence rates with fluconazole after 6 months are about 50%, this seems impressive. 

In the study where oteseconazole induction and maintenance was compared with fluconazole induction and placebo maintenance, the induction arms were the same. Meaning at day 28 oteseconazole did not outperform fluconazole. By week 50, about 5% of people had a positive culture for yeast with oteseconazole maintenance and with the fluconazole/placebo group it was just over 40%. 

This feels encouraging. It appears that oteseconazole might outperform fluconazole suppression for recurrent yeast, and that is with an 11 week course or oteseconazole versus 24 weeks for fluconazole.

But wait, this isn’t all a bed of roses

The animal data shows oteseconazole is associated with ocular (eye) birth defects. And, as previously mentioned, it has a very long half-life, 138 days, meaning it takes a very long time to get out of the body. However, a drug that might cause birth defects that hangs around in the system for 690 days is an issue. Until we have more data, oteseconazole is not recommended for anyone who can theoretically get pregnant. The FDA has limited the medication to people who are postmenopausal or who have had a tubal ligation, hysterectomy, or had their ovaries and/or oviducts (Fallopian tubes) removed. 

This obviously excludes a lot of people. Recurrent yeast infections after menopause are uncommon and tubal ligations/surgical sterilization is not the most common method of contraception for most people with recurrent yeast infections. 

This is bound to be upsetting for lots of people using long-acting reversible contraception, such as IUDs, the implant, and the DMPA shot, which are as effective as a tubal ligation or for people whose sexual partner(s) don’t place them at risk of pregnancy. If your partner doesn’t make sperm, because they have ovaries or because they’ve had a vasectomy, oteseconazole is still not recommended. And of course there are people with no plans to be sexually active with anyone. 

This is one of those balancing acts. How do we balance the importance of limiting teratogenicity (birth defects), with treating as many people as possible who might need a medication?

While it’s true that there are some people who may change their mind about pregnancy, there has to be a more flexible middle ground. I am trying to figure out how I would tell a theoretical 46 year old patient who has been monogamous and married to her wife for 8 years with no interest in attempting a pregnancy via infertility therapy that she can’t take oteseconazole in case she were to get pregnant? Or how I would tell a 32 year old who partners with men, but is on her second IUD and is sure that she doesn’t want to be pregnant that she can’t have the drug? In fact, she was going to have a tubal ligation, but changed her mind because she loves her IUD so much. “Why have surgery when the IUD is as effective?” she said. And finally, tubal ligation or removing the tubes doesn’t preclude pregnancy. IVF is an excellent workaround.

The FDA has managed to thread this needle with Accutane, an acne drug that is known to cause birth defects. It can only be prescribed to people who can get pregnant and then only by physicians who have completed specific training and then be dispensed from pharmacies with the right certification. This is a restricted distribution program called iPLEDGE™. Patients also must be using two forms of contraception.

Often, and appropriately so, there is more caution at the beginning with drugs that have the potential to cause birth defects, and it is possible we may get data that informs us it is safer than we think. But if the data holds out that there is an elevated risk of birth defects, that is going to present some huge barriers. Some people who are devastated with recurrent yeast are simply not at risk for getting pregnant, and so excluding them from this therapy is wrong. If we can figure out how to prescribe Accutane, surely with more data we can figure this out as well. But it will take a lot of counseling to ensure informed consent.

How it Oteseconazole Prescribed?

There are two regimens, one where oteseconazole is prescribed alone and the other where you start with fluconazole and then switch. 

Osteseconazole only:

• Day 1: 600 mg (as a single dose), then

• Day 2: 450 mg (as a single dose), then

• Beginning on Day 14: Administer 150 mg once a week (every 7 days) for 11 weeks 

Or 

Fluconazole plus Oteseconazole: 

• On Day 1, Day 4, and Day 7: Fluconazole 150 mg orally

• On Days 14 through 20: Oteseconazole 150 mg once daily for 7 days

• Day 28: Oteseconazole 150 mg once a week for 11 weeks 

Yeah, I know. It’s a bit complicated.

So that’s the new yeast medication

The pregnancy issue is problematic and I really hope we can figure a way around it. In my experience, when you explain this kind of data to women they are firmly in the No way, I might one day want to get pregnant camp or they are in the No way am I ever getting pregnant camp. But I also understand the potential for lawsuits and given 50% of pregnancies in the United States are unplanned, there are many people who underestimate their risk of getting pregnant.

And hopefully we’ll see a study that actually compares oteseconazole head-to-head with fluconazole so we can properly assess its place in treating recurrent yeast infections. 

And now you all know what I know about oteseconazole. 

Bottom Line

Oteseconazole is unlikely to revolutionize therapy for yeast, but it may end up being a good option for a small group of people. If concerns about birth defects can be addressed, then perhaps it may become something that more people can use.

References

1. Prescribing information oteseconazole https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215888s000lbl.pdf

2. Sobel JD, Nyirjesy P. Oteseconazole: an advance in treatment of recurrent vulvovaginal candidiasis. Future Microbiol 2021;16:1453-1461.

3. Mark G Martens, MD, Bassem Maximos, MD, Thorsten Degenhardt, Ph.D, Karen Person, M.S, Stacey Curelop, MPH, Mahmoud Ghannoum, PhD, Stephen Brand, Ph.D. A Phase 3, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Oteseconazole (VT-1161) Oral Capsules versus Fluconazole and Placebo in the Treatment of Acute Vulvovaginal Candidiasis Episodes in Subjects with Recurrent Vulvovaginal Candidiasis (ultraViolet)

   Mark G Martens, MD, Bassem Maximos, MD, Thorsten Degenhardt, Ph.D, Karen Person, M.S, Stacey Curelop, MPH, Mahmoud Ghannoum, PhD, Stephen Brand, Ph.D. Open Forum Infectious Diseases, Volume 8, Issue Supplement_1, November 2021, Pages S66–S67.