Aridis Pharmaceuticals is developing new drugs for infections prone to antibiotic resistance, including bacteria that regularly invade the lungs of cystic fibrosis patients.

Cystic fibrosis is a rare disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene, which leaves patients’ lungs susceptible to persistent infections and makes it difficult for them to breathe. The life-threatening disease affects about 30,000 people in the US and more than 70,000 worldwide, according to the Cystic Fibrosis Foundation.

Aridis CEO Vu L. Truong said rare diseases present more challenges for drug developers than common illnesses, but cystic fibrosis “is one rare disease where the patients can feel very optimistic.”

Truong explained that recently new drugs (such as Vertex Pharmaceuticals’ Trikafta), which target the underlying genetic defect in cystic fibrosis, have improved lung function, raising hopes of a cure.

“But we also know there isn’t an on and off switch for cystic fibrosis,” Truong added. “Patients who have progressed from moderate to severe disease – and have lived with chronic lung infections and inflammation – have a lot of fibrotic (damaged) tissue in their lungs,” meaning they are still susceptible to severe infections.

Inhaled antibiotics are the standard of care, Truong observed, but because patients must use them three times daily there is a high risk of the infections developing resistance.

Aridis’ drug candidate is an inhaled alternative to antibiotics that kills bacterial infections through a different mechanism of action. Not only is the risk of resistance low, but also patients only need to take the drug once a week.

As part of an exclusive series spotlighting rare diseases and the challenges of developing new drugs for these illnesses, WuXi AppTec spoke with Truong about his company’s innovative anti-infective therapy for cystic fibrosis patients.

Truong is a founder of Aridis and was named CEO in 2015 after serving as chief scientific officer since 2005. He earned his Ph.D. in pharmacology and molecular sciences at Johns Hopkins University School of Medicine, and he has more than 20 years of experience in biopharmaceutical drug development.

WuXi AppTec: What are the major differences in developing drugs for rare diseases compared with more common illnesses? What are some of the unique regulatory and business challenges you face in developing drugs for rare diseases?

Vu L. Truong: In the rare disease area, there obviously are benefits and challenges that are quite different from that of common diseases, such as understanding the patient population, the unmet medical need, and the market opportunity. Scientifically the challenge is understanding if there are rational mechanisms of action in the disease that could be addressed to change the patient’s clinical outcome.

With common diseases usually there are a number of solutions that have been examined and there are drugs in the marketplace. An understanding of some of the underlying disease mechanisms that would impart a positive outcome is reasonably established. And, of course, the patient population is relatively well-defined, as is the market opportunity. You have a good understanding of who is doing what among your peer companies.

In rare diseases, typically you don’t have that luxury. You have less of an opportunity to leverage existing data on disease mechanisms and interventional approaches that could possibly help reverse the outcome.

WuXi AppTec: Is clinical trial design more problematic? Is it more challenging to identify the outcomes you want to achieve?

Vu L. Truong: That is part of the regulatory challenge because in rare diseases you often don’t have good clinical endpoints that are clear and pre-established. You have to do your best scientific work to estimate the primary and secondary endpoints that would be clinically meaningful and that can be objectively measured and robust enough to allow the regulators to have confidence the drug is going to result in a positive outcome when it is launched to a wider patient population.

WuXi AppTec: On the business side of the challenges, is it more important to work closely with the patient advocacy groups when you’re trying to develop a drug for rare diseases? Is the relationship with patient groups different than when developing a drug for a more common illness, such as heart disease?

Vu L. Truong: Absolutely. The rarer the disease, especially neglected rare diseases, the greater the challenges in terms of educating the public, the investment community, and the regulators of the pain points that the patient population is going through.

Oftentimes you have diseases that are so rare it is hard to get even drug developers’ attention because the perceived market opportunity is not there. The rarer the disease the harder it is to get everybody’s attention, which adds to the importance of working with patient advocacy groups.

WuXi AppTec: Aridis Pharmaceuticals is developing new drugs for infectious diseases. So how did you choose to focus on cystic fibrosis?

Vu L. Truong: We felt that treating the chronic infectious diseases affecting cystic fibrosis patients was a well understood need with a defined clinical development pathway and clinical endpoint.

When we looked at the dependency of these patients on chronic inhaled antibiotics – or even intravenous (IV) antibiotics – we knew there was a need for an alternative because chronic use of antibiotics eventually leads to a rise in antibiotic resistance and gradual decline in effectiveness.

We noted an anti-infective with a novel mechanism of action and a low drug resistance profile would be differentiating. We also sought to improve the patient’s dosing regimen by developing something the patient would take less frequently. Current standard of care for these patients involves being tethered to an inhaler for about 20 or 30 minutes, three times a day.

If you add up all time it takes these patients to administer their antibiotics and compound the time over their life span, the incremental years in life extension afforded by the antibiotics are spent by the patients treating themselves.

So we sought to develop a differentiating anti-infective that has a combination of a novel mechanism of action (it is completely different from any antibiotic), a very low to no drug resistance profile, and a much less frequent dosing regimen such as once a week versus three times a day.

WuXi AppTec: How important are US government incentives, such as the Orphan Drug Tax Credit, for developing rare diseases? Is that a critical component of getting drugs to these patients?

Vu L. Truong: Absolutely. It is of critical importance because of the many challenges rare disease drug developers have to contend with.

For example, some of the analytical assays used to define drug potency in vitro or in vivo are sometimes not well defined and the regulatory requirements to demonstrate fitness of a drug candidate to be tested clinically can be burdensome.

Also by definition rare disease patient populations are smaller and therefore clinical trial enrollment is oftentimes a great challenge. This affects the requirement for patient sample size to demonstrate efficacy. A lot of times in rare diseases you barely reach statistical significance because there are just not enough patients to test and you may have to do a study that lasts three, five or seven years. That puts a lot of strain on the capital resources of companies, especially smaller companies like us.

The selection of the clinical trial’s primary endpoint also is very important, and you need to have buy-in from the regulator. Sometimes the requirement of the U.S. Food and Drug Administration (FDA) for outcome measures may make it overwhelmingly difficult to obtain the patient population to achieve a magnitude of difference between the drug candidate and the placebo to get approval. So regulatory incentives are critical for drug developers to take a risk on rare diseases.

And then of course there is also the risk of drug pricing. There is an increase in government pressure that filters down to the FDA, and that affects how much a drug developer should charge. Just the increased pressure on reimbursement has given drug developers pause for certain rare diseases.

WuXi AppTec: How much progress has been made in developing drugs for cystic fibrosis?

Vu L. Truong: There has been substantial progress. This is one rare disease where the patients can feel very good of the prospect of a cure. The (chloride) channel correctors (that address the underlying genetic cause of cystic fibrosis) have given these patients more hope than they have ever had. They are starting to work, and the life extension data are starting to come in. The data on moderate decline in dependency on chronic inhaled anti-infectives also are starting to come in. There is a great sense of optimism that a cure already has arrived.

With channel correctors, such as the drug (Trikafta) that Vertex Pharmaceticals makes and the drugs other companies are developing, there is a steady improvement in channel function and these patients are starting to have fewer pulmonary exacerbations. They are starting to feel healthier. I wouldn’t say there is a complete cure. The data are still being accumulated. But certainly there has been a dramatic impact on clinical outcome.

But we also know there isn’t an on and off switch for cystic fibrosis. Patients are not cured right away. Those who have progressed from moderate to severe disease – and have lived with chronic lung infections and inflammation – have a lot of fibrotic tissue in their lungs that may be very difficult to reverse. You may be able to correct the genetic defect, which is the function of the chloride channel, but as the disease accumulates over years and decades, patients’ lungs become more fibrotic; that is, the lung tissue becomes damaged and scarred.

So there always is a set of conditions that cannot be reversed even though you have corrected the genetic defect. The lung damage that has accumulated over the years means that the patients’ lungs are always going to be compromised.

WuXi AppTec: Now let’s talk about your research and drug develop program. What is your drug candidate and how does it work? What will it accomplish?

Vu L. Truong: When we looked at the anti-infective standard of care that these patients are using – and we were also keeping an eye on these channel correctors that were being developed – we asked, if you’re going to develop an anti-infective where are the unmet needs?

Standard of care has been the inhaled antibiotics. Two drugs of note are TOBI, inhaled tobramycin, which was commercialized by Novartis. The other one is Cayston (sold by Gilead Sciences), which is inhaled aztreonam. These are off-the-shelf antibiotics that have been reformulated for inhaled delivery.

These drugs are prone to antibiotic resistance just like all antibiotics. They have a demanding dosing regimen – three times a day, every day, for a month and then a month off. So these patients get the antibiotic treatment for a month and then they have a drug holiday month. The month-long drug holiday is imposed because of the worry of chronic exposure to antibiotics and development of antibiotic resistance.

When the patients are on the drug holiday month, the bacteria begin to build right back up in their lungs and they feel terrible.

We asked, how can we make a difference? We wanted to find a drug candidate that uses a different mechanism of action and is less vulnerable to drug resistance, eliminating the need for a drug holiday. The drug also would have to be effective throughout the patients’ lives whenever they show a high bacterial burden in their lungs.

So we sought to develop gallium citrate, which is not an antibiotic. It’s a small molecule anti-infective. It works very differently from all antibiotics in that this drug acts as an iron analog to starve bacteria of iron.

All microbes require iron as a key nutrient. If you withhold iron from bacteria, both gram negative and gram positive, they all die. So wherever iron binds to bacterial cells, the drug also binds, blocking the iron. The drug may even dislodge iron.

Iron is involved in many enzyme mechanisms in the bacteria, and gallium citrate is one drug that hits multiple gene products inhibiting these mechanisms, such as cell wall synthesis, protein synthesis, and metabolic maintenance.

For bacteria to mount an effective mutation leading to drug resistance, the mutations would have to occur simultaneously in multiple enzyme pathways. Antibiotics, however, target only one pathway. All the bacteria have to do is develop resistance to that one target and the antibiotic is ineffective.

We call our drug candidate, AR-501, and it is currently in Phase 1/2 clinical testing. We are working with the Cystic Fibrosis Foundation, which is sponsoring the clinical study. The patients receive inhaled AR-501 once a week, instead of three times a day every day.

We think the combination of a much more convenient dosing regimen, much lower drug resistance risk, and no month-long drug holiday, will be a game-changer for inhaled anti-infectives for cystic fibrosis patients. We expect to submit a new drug application for approval with the FDA some time in 2026.

Even with all the channel correctors rolling out, these patients are still going to be dependent on inhaled antibiotics or inhaled anti-infectives for decades to come before we know for sure whether there is a complete cure for cystic fibrosis.

WuXi AppTec: This last question is aimed at getting your insights on drug development in general. What technological breakthroughs in the drug development process might be game-changing in the next 5 years?

Vu L. Truong: CRISPR will continue to provide the next revolution in the drug development process. Rare diseases will likely have among the most benefit from CRISPR because of the ease with which gene editing can be applied to correct genetic defects.