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Diane Newman: Welcome everyone. I'm Diane Newman, a nurse practitioner specialist at the University of Pennsylvania in Philadelphia. My practice is in urology. And I'm here today for UroToday, to introduce a speaker that I heard at the American Urologic Association, Dr. Curtis Nickel.  I've known him for many years, way back he and I were involved in interstitial cystitis research by NIDDK. And Dr. Nickel is a Professor of Urology at Queens University in Kingston, Ontario, Canada. So he is going to present some of his cutting-edge research on a sublingual vaccine. Welcome, Dr. Nickel.

Curtis Nickel: Thank you, Diane. And it will be a privilege to be able to present, on behalf of my fellow investigators, the late-breaking science story, that I presented at the AUA on Sunday, September 12th.

At the AUA, I presented the story of a novel sublingual vaccine for the prevention of urinary tract infections in women. Recurrent UTI is a major problem with women, with a significant number experiencing a UTI each year, and three out of 100, having recurrent urinary tract infections. That is three or more a year. And you know, the only North American evidence-based, guideline-recommended therapy is antibiotics, usually antibiotic prophylaxis, with significant morbidity, which can be serious, and even irreversible, costs to patients and society, poor long-term efficacy after the prophylaxis has been discontinued. And it promotes that worldwide major medical problem, antibiotic resistance.

MV140 is a self-administered submucosal vaccine. Two sprays, once daily, typically for three months.

Five studies have previously looked at MV140 in Europe for the prevention of recurrent urinary tract infections. And in these studies, over 1,400 women, provided urinary tract infection-free rates, ranging from 33% to 90%. And the two studies which compared to prophylactic antibiotics, there was a superior clinical benefit, and only less than 2% adverse reactions were reported with this vaccine.

There have been over 40,000 patients outside North America who have received this vaccine in special access programs. Since 2017, we've been collecting safety data, and we now have safety data on almost 21,000 individuals, which represent 1.5 million doses. And we've only had eight safety case reports, and most were mild and self-limited. It appears to be a very safe vaccine.

In Kingston, we have the only North American early clinical experience. We have 67 female subjects to date, vaccinated, and data on the pre-COVID cohort. Those are the ones that were vaccinated before the temporary COVID mandatory clinical trial shutdown in our institution. In that cohort, the UTI-free rate, that is no urinary tract infection after vaccination, was almost 50%, with an overall reduction in UTIs of 82%, and only two mild and self-limited vaccine-related adverse reports, in one of these patients.

But the only way to prove whether or not a vaccine is efficacious is with a randomized placebo-controlled trial. And it was at the AUA that I presented the pivotal, randomized placebo-controlled trial, in which subjects were randomized to either placebo for six months, a vaccine for three months, followed by three months of placebo, or a vaccine for six months, with six months further follow-up. The efficacy period started at three months after the intervention, either placebo or the vaccine.

And in this trial, I reported that in females with recurrent UTI, this novel vaccine, MV140, significantly reduced the risk of UTI, from a median UTI rate in the placebo group of three over the nine months, to zero, a median in both the three and six-month groups. The UTI-free rate, in these patients who had on average, or median, six UTIs per year, prior to vaccination, the UTI-free rate was around 55% to 58%. That's in fact, no UTIs at all. If patients did suffer a UTI, those in the vaccinated group had significantly fewer symptoms and more self-limited disease.

The time to UTI was only 48 days in the placebo group, compared to 275 days for a median time to UTI rate in the treated group.

The UTI morbidity was reduced, and patients had an improved quality of life, as measured by the SF-36 quality of life measurement. It decreased the overall need for the use of antibiotics, healthcare resources, and costs associated with recurrent urinary tract infection management, in this population of subjects. It was extremely safe, with very few adverse events related to the vaccine. And only three patients in the entire study stopped the intervention. One of them was in the placebo group, due to an adverse event.

We determined that the three-month dosing that was typically being used in the named patient, or special access program, was as efficacious as a longer six-month schedule. And there is no doubt that this approach will improve antibiotic stewardship and decrease the overall risk of antibiotic resistance, in this patient population, but also in society as a whole.

There is no doubt in my mind that this vaccine will be a game-changer in the management of recurrent urinary tract infections in women.

Thank you for letting me provide the results of our presentation at the AUA several days ago.

Diane Newman: Thank you very much, Dr. Nickel, because as a clinician, recurrent urinary tract infections are so frustrating, and this is such a large group of patients that we see, of course, in urology.  Because in the United States, primary care does not know what to do with them. And there are not very many options for us. So I think this is really cutting edge, and we are all waiting for that vaccine.

I have a question for you. You did give us the age group, what did you do with women that were on transvaginal estrogen? Because we do know that has been shown possibly to improve and be somewhat preventative for UTIs.

Curtis Nickel: This intervention trial was for women with recurrent urinary tract infections, and included pre-menopausal, perimenopausal, and post-menopausal women, who had been treated by urologists and urogynecologists, using natural estrogen, if indicated, or supplements if indicated. Almost all of them had been on prophylactic antibiotics, and it failed all these various therapeutic avenues.

Diane Newman: I see. And when you talked about side effects, what kind of side effects did you see? What were common ones?

Curtis Nickel: This was a sublingual vaccine, which is sprayed under the tongue, held for a minute, and then swallowed. The very mild side effect that we saw, was tingling under the tongue or in the mouth. We had some patients who had some tenderness in the mouth and teeth. But no serious reactions resulted, just very few that resulted in discontinuation. Almost all were mild and self-limited, and everybody recovered from these mild adverse events.

Diane Newman: Now, how long are you going to follow these women? I see what your data is currently, but what are your plans with it, with this group of women? Because it sounds like you've been following them for quite a period of time, now.

Curtis Nickel: Right. This randomized placebo-controlled trial was a pivotal trial. It was for 12 months. After 12 months, the patients ended the trial and the data were censored. There will be no follow-up in this particular cohort after 12 months.

However, other observational studies, that went out for two years, did show that there may be a [inaudible 00:09:22] tack of laxes of effect. In other words, the effect of the vaccine may wear off. And some patients did revert to having UTIs, or recurrent UTIs again. Future plans are to look at revaccination, after a year's time, in those patients who have transitioned back into a recurrent UTI state. That might have to be the case. But because the vaccine is so safe and self-administered, we do not believe this will be a major problem, compared to restarting something like weeks, or even months, of prophylactic antibiotics.

Diane Newman: No. You're 100% right. Because of the resistance we are seeing, it's just universal now, and it's getting to be so frustrating. Now, do you look for, is it going to be approved in Europe first, and then you're going to come to the FDA in the United States, or what's the plan, and what about Canada?

Curtis Nickel: So the plans are right now because we have that early experience in the clinical trial in Kingston, and Health Canada is very aware of the huge unmet need in this population, even though it does not entail mortality, it is a huge unmet need and promotes antibiotic resistance. It appears that the Canadian, Health Canada, is going to provide the expedited review on the regulatory approval process. It will be submitted likely this fall, the data from the RCT, the Canadian study, and the observational studies, as well as a special access program's safety data. And it is our hope that we will have this vaccine available in North America, or in Canada North America, sometime second or third quarter next year would be the earliest.

The United States is problematic in having vaccines approved for non-lethal conditions. And right now, there is a huge impetus against vaccines when there is another effective treatment. So right now, the FDA certainly believes that their effective treatment is antibiotic prophylaxis. However, the FDA will be approached, now that we have a pivotal trial, for advice on how to proceed next, to receive approval. But I do know that it's going to take a little while longer in the US, compared to everywhere else in the world.

Diane Newman: Who is the manufacturer of the vaccine? I didn't see that in your presentation, but which company is it?

Curtis Nickel: Well, the inventor and the manufacturer is Immunotec. And Immunotec, I was earlier on, an advisor/consultant in helping them design the trial I did. And then I became an investigator and helped them analyze and interpret, and write up the data.

Diane Newman: Well, listen, thank you very much. Seriously, this is such, well, you know this, this is such a significant problem for women. I just can't believe when you said that they think that the prophylactics antibiotics are preventative, because you and I know, they work for a period of time. These women, I have so many women that are resistant now to almost all antibiotics, because they have been prescribed over and over and for years. So this is very, very exciting. And when I heard you speak, I thought, we got to have this on our website, and get it out to our viewers. So thanks very much, Dr. Nickel.

Curtis Nickel: Diane, thanks for letting me have a chance to tell this story again. I think it may have a major impact on women's health.

Diane Newman: Exactly right. Thanks so much. Have a good day.

Curtis Nickel: Bye now.