Contagion Connect Episode 7 - The ID Pipeline: Rezafungin & Antiviral Fc-Conjugates

Podcast Description: Cidara Therapeutics is developing a new echinocandin called Rezafungin that's shown promise in clinical trials. Cidara is also developing a new anti-viral technology which isn't a vaccine, but could provide universal flu protection on a different basis.

We talked to CEO Jeff Stein, PhD, about these therapies.

After speaking with Dr. Stein, we hone in on Rezafungin in a chat with George Thompson, MD, associate professor of clinical medicine at the UC Davis School of Medicine.

Dr. Thompson is an infectious disease clinician and an expert in the mycology field. He was an investigator in Cidara’s phase two trial of Rezafungin and is involved in the currently being enrolled phase three trial.

Contagion®: Welcome to Contagion® Connect, a podcast dedicated to bringing you expert insights on key infectious disease topics.

We're here today to discuss the infectious disease pharmaceutical pipeline — particularly, Cidara.

A biotechnology company formed in 2014, Cidara is developing a new echinocandin called Rezafungin that's shown promise in clinical trials. Cidara is also developing a new anti-viral technology which isn't a vaccine, but could provide universal flu protection on a different basis.

We'll talk to CEO Dr. Jeff Stein about these therapies.

After speaking with Dr. Stein, we’ll hone in on Rezafungin and chat with Dr. George Thompson, associate professor of clinical medicine at the UC Davis School of Medicine.

Dr. Thompson is an infectious disease clinician and an expert in the mycology field. He was an investigator in Cidara’s phase two trial of Rezafungin and is involved in the currently being enrolled phase three trial.

Welcome to the show, Dr. Stein. If you could give our listeners a bit of background about yourself and then we can get into detail about these upcoming treatments.

Stein: I've been CEO of Cidara since early 2014, when we got the company up and running. Very much a preclinical company back then, venture backed by some very high profile venture capitalists. And we've been on a very fast track since our formation.

In 2015, we took the company public. Rezafungin is our lead program. That preclinical molecule back in 2014 is now completing a phase three study for the treatment of candidemia and invasive candidiasis.

This is a very lethal infection that people typically get in the hospital. Current standard of care is inadequate insofar as the mortality rate is 25% or greater on current standard of care.

We are also initiating another phase three study for the prevention of a broad array of fungal infections in patients getting bone marrow transplants. These are patients who do not have an immune system, so that that transplant can take hold, and consequently they are very exposed to getting fungal infections. Those that do have a very high mortality rate of about 60%.

So many cancer patients fall into this category, needing a bone marrow transplant and those that currently are receiving the standard of care antifungal therapy or prevention are discontinuing at a very concerning rate and those that do discontinue, which is about 35%, have a 60% or higher risk of mortality. Two really important unmet needs.

The company was also formed on the promise of an immunotherapy platform that we call Cloudbreak.

The objective was to take the principles that have been well established now in oncology and apply that to infectious disease. We do it in a different way than what is being done in oncology. But it appears to be particularly effective in viral infections, and very effective in respiratory viruses.

Our lead program there is an influenza preventative and treatment called cd-377. That is in institutional new drug enabling studies right now.

We hope to put that in the clinic sometime by mid-next year.

Very exciting program, could actually represent a universal preventive and treatment effective against all strains of influenza, both seasonal and pandemic, and importantly in all people, meaning that even people that have debilitated immune systems that have been compromised, that cannot respond to even a perfect vaccine, should be able to benefit from cd-377.

Again, two very exciting programs and we look forward to continuing to develop those in the clinic.

Contagion®: Excellent, thank you. Flu is something we're all talking about in infectious diseases so we can start with those technologies and then pivot back to Rezfungin.

Cidara has that immunotherapy platform called Cloudbreak. Could you tell us a bit about the clinical application of the new therapy?

Stein: The most important distinction is that this is not a vaccine. It's actually a long acting drug that could potentially be administered once a flu season and confer protection against all known strains. We've tested it against dozens of strains in our laboratories, the NIH is now testing it against the very lethal pandemic strains that we are not certified to deal with in our labs.

What they have informed us is that this appears to be the most potent drug that they have tested to date against these pandemic strains. And now we're sending the NIH additional drug supply so that they can conduct animal efficacy studies but if it turns out similar to the animal efficacy studies we've conducted, we know that it will be very effective.

This gives us some confidence that this could potentially be a once a flu season universal preventative against all strains, and importantly, in all people. And this is an important distinction that a lot of people miss when they think about the universal flu vaccine that we have yet to see. It's universal or could potentially be universal only in the sense of the influenza strains, right?

That's not universal in all people because there's over 100 million people in the US that do not respond to vaccines, and so they are going to be susceptible to getting the flu.

In the case of a pandemic that's rapidly spreading, even if you had the perfect vaccine, it takes your body two weeks to respond to the vaccine to build an immune response. And that's if you have a healthy immune system. There's clearly areas of improvement for vaccines. This is a completely different approach.

We have a bi-specific molecule that has a very potent anti-viral small molecule on one end, so in and of itself, it is viricidal. And we have attached it on the back end to a fragment of a human antibody. And that antibody fragment confers an additional mechanism of action that actually provides a localized immune response right at the site of infection and also confers this once flu season exposure.

Plus it directs the drug to the lung where the virus resides. Multiple benefits here, which explain some of the very robust results we are seeing.

Contagion®: One can imagine some pretty huge ramifications if the good results you've seen keep coming back. How do you see these being implemented in existing real-world health systems?

Stein: We, collectively, have never been exposed to a program that has not demonstrated a weakness. Typically when you're at this stage of development, there's some liability in any drug right? “It’s very potent in vitro, but in vivo is cleared very rapidly. So you know, we're going to have to administer this twice a day.”

Or, “it's potent but there's this toxicity limitation, so we can't administer it to the desired level in vivo. So we're going to miss these strains, right?”

We have yet to find a weakness in this program. And that may owe to the fact that it's just a completely novel approach, so there are opportunities here as a broad base preventative, or for use as a treatment as well.

We compared this head to head with existing influenza drugs, such as Tamiflu, and we found that we can expand what is called the efficacy window.

With Tamiflu If you were to start manifesting some signs and symptoms of the flu today you might, if you're like me and many other people, try to tough it out and say, well, let's see if I get over it. Then you make an appointment, you go see the doctor or you go to CVS, you get a script for Tamiflu.

If you take that first tablet more than 48 hours after the first signs and symptoms, that drug is not going to work. We have shown for cd 377, at least in animal models of infection, that we can expand that window to 72 hours, an additional day to treat that infection and that is a very important distinction.

It appears to work very quickly as a treatment but the same time, the animal studies we've done show that we can administer this in mice a month before initiating the infection, and it confers 100% protection. And because of the difference in body size between mice and humans, one month and mice represents about three months in humans. This is why it gives us confidence that this could potentially be a once per flu season preventative as well as a very rapid treatment.

Contagion: To move back to Rezafungin, could you provide some foundational info on where this fits into the antifungal treatment landscape? Particularly, what makes it different from other antifungals in the same class?

Stein: Rezafungin is a member of the echinocandin class. There are three other members of that class that are currently available commercially, one by Pfizer, one by Merck and one by Stellaris.

Those are virtually identical. They are once a day one-hour infusions. The echinocandin class is the newest class of the three broadly use classes of antifungals drugs. Echinocandins are by far the safest class [of the three] with no drug-drug interactions. And number two, it is the standard of care per guidelines for the treatment of candidemia and invasive candidiasis.

The currently available echinocandins are better than any other available antifungal drug for candidemia and invasive candidiasis which is why guidelines in the US and Europe specify that these need to be first line therapy.

The problem is that they are being used in the hospital, but not outside the hospital.

According to guidelines, these patients should be discharged on an echinocandin, but they're not. Because that would necessitate that the patient come back once a day for a one-hour infusion. And that's simply not practical.

What physicians are doing now is they get that initial dose of echinocandin in the hospital, but then they're being discharged on an azole. The azoles are an older class of drugs, you probably are familiar with the name fluconazole.

There are a lot of drug-drug interactions with azoles. And people with fungal infections tend to be what are called complicated patients, meaning they're hospitalized for something else. They had surgery. They get the fungal infection in the hospital, they're discharged on a lot of other drugs, and now are being given an azole, which has very well-known drug-drug interaction, and those can be lethal.

These patients are being discharged on an inferior drug. And I mean that in the statistical sense, meaning that the clinical trials that have tested an echinocandin against an azole, the echinocandin has come out statistically superior.

There is a strong desire to find an echinocandin that can be used in the outpatient setting and that's exactly how we are developing Rezafungin. To provide physicians an option to treat their patients consistent with a guidelines on a superior therapy that can eradicate the infection.

Contagion: Thanks. You've given us a lot of great information about these technologies and therapies. Is there anything else you would like to add about what Cidara is working on?

Stein: We’re in the infectious disease space. With Cloudbreak we know that is a true platform. We're expanding into other viral infections. It seems to work particularly well in respiratory infections, because the drug concentrates to the lung tissue.

It is certainly the topic of partnering discussions because it could represent a fundamentally new approach for these viral infections. We're very excited about that. More broadly, there are some opportunities that we may see legislatively that could fundamentally change reimbursement for products such as this and Rezafungin.

You'll see some news potentially out of Congress with the DISARM act that could change reimbursement for products that treat patients in the hospital. We're very watchful for news in that arena.

Contagion: Now we're going to be speaking with Dr. George Thompson, associate professor of clinical medicine at the University of California Davis School of Medicine.

Dr. Thompson is an infectious disease clinician and an expert in the mycology infectious disease field. He was an investigator in the phase two trial of Rezafungin and is currently enrolling in the phase three ReSTORE trial.

Dr. Thompson, thank you for joining us. If you could give us just a brief introduction of yourself and your background before we jump in?

Thompson: I'm an associate professor of infectious disease at University of California Davis Medical Center. And my clinical and research centers both really focus on patients with invasive fungal infections, which make up about half my practice and the other half is really spread out amongst the bread and butter infections.

Rezafungin is a novel echinocandin with a long half-life, it's about seven days, and that has some potential advantages over currently available echinocandins with a very favorable pharmacokinetic-pharmacodynamic pattern.

Being able to give a medication with that high of serum concentration and also that half-life allows us to leverage the treatment of our patients and really predispose them to have a more favorable outcome.

Contagion: I can imagine with that, over other echinocandins, that there's a possibility to have better treatment adherence for outpatient type of administration with that seven-day coverage you were speaking about.

Thompson: It certainly should help compliance just since it's a intravenous formulation. It also has some big advantages for our patients that are in the hospital, say getting chemotherapy or other medications that may really predispose them to nausea. An intravenous formulation is great but certainly is not what sets it apart from the other echinocandins. It's really the high levels that get into tissue in the blood, and also the long half-life.

We think it can even get into sequestered sites that could actually prevent the development of resistance on therapy.

Contagion: You were involved in the phase 2 trial. Could you give us a bit of background about the study design there?

The phase 2 study for Rezafungin was a prospective study, patients were randomized to 1 of 3 different groups. There was conventional Caspofungin dosing, followed by oral fluconazole. Then the other 2 groups contained different concentrations of Rezafungin.

They either got 400 mg, followed by 400 mg a week later, or 200 mg a week later, really to look at a number of different pharmacokinetics of the drug.

The most favorable results were in the Rezafungin 400 mg followed by 200 mg dosing strategies. Patients numerically did better in that group. It is not a study that was powered for efficacy in that group so it's probably a bit too early to claim superiority over the other groups.

But that dosing strategy is what's going to be used in the ongoing phase 3 study.

The phase 3 study is ongoing. Patients will be randomized to 1 of 2 groups, either the Rezafungin 400 to 200 mg group or Caspofungin and followed by fluconazole. And that's for patients with candidemia or invasive candidiasis.

The phase 2 study showed us that Rezafungin probably clears blood cultures about 24 hours faster than Caspofungin. So that has some potential real advantages for our patients in terms of resolution of infection, also hopefully time to discharge from the hospital.

Contagion: What do you see for clinicians and patients as the implications, if these positive results we've been seeing for Rezafungin keep coming, especially in this phase 3 trial?

Thompson: Another phase 3 study is going to look at Rezafungin as prophylaxis for high risk patients for not only yeast and mold infections, but also pneumocystis.

I think that is a big advantage. A number of new compounds have been developed for the treatment of numerous leukemias and lymphoma. And those new drugs typically have drug-drug interactions with the tri-azoles, if we can put those patients on prophylaxis with Rezafungin they can continue their chemotherapy uninterrupted. That that really would be very helpful and a big advance in the treatment of these patients.

Our patients continue to become more complicated each year. There's new medications developed every year for the treatment of their underlying lymphoma, leukemia, etc. Coordination of care with oncology and hematology colleagues, our pharmacists and colleagues in the ICU, these are really integral conversations and the sort of the total care of these patients. Care continues to be complicated merely by developing new medications and new comorbidities and novel risk factors that had not previously been recognized.

Contagion: I really appreciate the information you've given. I'll just open the floor one last time, if there's anything you want to communicate to our audience about the work you're doing, feel free.

There's a number of novel antifungals in various stages of development and Rezafungin is the furthest along. It would be a welcome advance in the treatment of invasive Candida infections from these favorable PK PD parameters. We look forward to the results of this phase 3 study and seeing how this drug will be used clinically.

Contagion: Alright, thanks so much, Dr. Thompson.

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