Q&A: Yutrepia for PAH, pulmonary hypertension-ILD receives tentative FDA approval

Key takeaways:

• Only one drug has final FDA approval for pulmonary hypertension-ILD; more options are needed.
• Yutrepia, an inhaled dry power formulation of treprostinil, was preferred over the nebulized Tyvaso option in PAH.

Around 7 months after not meeting the Prescription Drug User Fee Act goal date for Yutrepia, the FDA has tentatively approved the drug for pulmonary arterial hypertension and pulmonary hypertension-associated interstitial lung disease.

As Healio previously reported, the FDA did not make a decision on Yutrepia (treprostinil, Liquidia Corporation) to treat patients with PAH and pulmonary hypertension (PH) associated with ILD by its goal date of Jan. 24 earlier this year.

According to a press release from Liquidia, the recent tentative approval of Yutrepia — an investigational, inhaled dry powder formulation of treprostinil — means that the drug “has met all regulatory standards for quality, safety and efficacy required for approval in the United States but must await the expiration of regulatory exclusivity of a competing product before final approval can be granted.”

A previous release from Liquidia said that United Therapeutics, another company developing/selling treatments for PAH and PH-ILD, has filed two complaints related to patent infringement against Yutrepia, but only one remains as of Jan. 22, 2024. United Therapeutics received FDA approval for its dry powder inhaler (Tyvaso) for PAH and PH-ILD in May 2022.

Shortly after the FDA’s tentative approval decision, Liquidia announced that it is suing the FDA due to the administration granting exclusive 3-year clinical investigation to Tyvaso, potentially further delaying Yutrepia’s final approval until May 2025.

To learn more about why the FDA should grant final approval to Yutrepia, the current treatment options for PAH and PH-ILD and next steps upon final approval, Healio spoke with Rajeev Saggar, MD, chief medical officer at Liquidia, prior to the FDA’s tentative approval decision.

Healio: What do current PAH and PH-ILD treatments look like?

Saggar: In PAH treatment, we have four developed pathways. The first one is endothelial receptor antagonists (ERAs). In this pathway, there is an over-amount of endothelial cells, a potent vasoconstrictor, in the system, so drugs have been developed to block this pathway. These are primarily oral medications that are taken once a day.

The second pathway is what’s known as a phosphodiesterase 5 (PDE5) inhibitor. These are drugs like sildenafil, which are given to bring back nitric oxide into the blood, which allows vasodilation to occur. These drugs are also an oral pill, and depending on the medication used, these can either be given up to three times a day or once a day. ERAs and PDE5 inhibitors are used in combination and, for the most part, are what is usually given upfront to the patients in some form of combination.

The third pathway is the prostacyclin pathway. In PH, prostacyclin is a very potent vasodilator. It tends to be deficient in patients with PH. This mechanism of action is where the first therapies were ever created. In 1998, the first one was approved in an intravenous form. It was given to the patient via pump, and there was a permanent catheter placed into the vein delivering the drug slowly but continuously 24/7. As the treatment was modified, it was developed into an inhaled form. This is given four times a day while the patient is awake. Finally, we have oral forms of the prostacyclin analogs. Depending on the drug used, it can either be given two or three times a day.

A fourth pathway is the soluble guanylate cyclase (sGC) pathway, which is given three times a day in an oral pathway. Those were the standard drugs up until March 2024.

In March 2024, sotatercept (Winrevair, Merck) was approved by the FDA on a novel pathway known as the transforming growth factor or TGF beta ligand trap. It is given as an injection once every 3 weeks and used on top of what is now known as the standard therapies. As the field advances, patients can be on two to up to four drugs simultaneously in their treatment modality.

In contrast to PAH treatments, Tyvaso is the first and only drug approved for PH-ILD. This is the same drug in PAH that’s inhaled four times a day.

Healio: How do patients with PAH feel about these options?

Saggar: The first thing patients with PAH will realize is that while this still is a disease that doesn’t have a cure, there are opportunities to treat and slow down disease progression. What’s unique about patients with PAH is that even though the disease has a poor prognosis, the majority do not look sick. They look like they go to work and have a lifestyle that is conducive to where quality matters. In that regard, when they look at therapies, they want a therapy that allows them to be compliant. The frequency of dosing matters, as does the way the treatment is delivered because those things can affect daily life.

When patients come in, the treatment provided is going to be a reflection on where the patient is in his or her clinical progression. Quality of life, dosing frequency, what is easiest and has the least side effects are first and foremost in the minds of these patients.

Healio: What should clinicians know about Yutrepia? How is it different/unique from other PAH treatments?

Saggar: Yutrepia is a dry powder formulation of treprostinil, which is a prostacyclin analog. It’s the only mechanism of action and pathway that’s approved for patients with PH-ILD. Yutrepia is formulated through PRINT, a proprietary technology that we have at Liquidia, and stands for particle replication in non-wetting templates, which means we can bespoke the design of the actual particle.

When you inhale treprostinil, you want to optimize it so that it’s delivered to the right areas of the lung. PH is a disease of the vessels inside the lungs, so when you inhale it, we want to get access right where those vessels lie and communicate with the airways of the lungs. Using this technology, we can design the particle to be of a specific size and shape, so that it maximizes that efficiency. In that design, we’re able to place it into a dry powder inhaler. We use an off-the-shelf inhaler that’s been used to treat patients with COPD and asthma for at least 2 decades. Once the designed particles are placed in a capsule, you put the capsule into the inhaler, pierce it and take two breaths. This is done four times a day.

We conducted the INSPIRE open-label phase 3 study with Yutrepia in patients with PAH, and in this trial, we achieved a high bar in terms of safety and showed that our drug has the standard efficacy parameters that people are looking for. We have shown patients with PAH taking Yutrepia on a background of the standard therapies either remain stable or improve after 1 year of therapy, have decreased risk scores and have improvements in quality of life.

Most importantly, we showed that patients prefer our handheld and portable device over the original Tyvaso option, which is traditionally delivered in a nebulized fashion. The therapy is still done four times a day at least 4 hours apart, so that is still a process, but it can take patients less than a minute to do this therapy.

Healio: Why should the FDA grant final approval to Yutrepia? How has it been shown to benefit patients with PAH and PH-ILD?

Saggar: Yutrepia has a similar safety profile to what is known about inhaled treprostinil. In our study, 55% of the patients had never seen a prostacyclin, and these patients were able to tolerate and stay on the drug over the course of time. The remaining 45% of patients were already on Tyvaso and we switched them to Yutrepia. In this population, over 99% of patients liked the switch because of the ease and comfort. We were also able to show the FDA that patients who transitioned to Yutrepia did not get worse.

In our open-label, extension safety study, patients were able to dose the drug higher than what is traditionally used in patients with PAH that use Tyvaso. Typically, there’s a range we try to get to that we say is therapeutic, and we have shown that at 1 year, we’re not only able to get patients to that range, but we’re able to exceed it. We have upcoming data showing that we’re able to go even beyond that typical therapeutic dose to even a higher level, which is exciting.

The FDA should grant final approval to Yutrepia because it’s always good to give patients more options. Because of the way we formulate our drug, this option may be more tolerable and lead to higher doses, which could then lead to better efficacy.

Healio: How will the potential FDA approval impact physicians and health care providers?

Saggar: Prostacyclin is still the gold standard for PAH, but its utility in treating patients is limited because when you give it in an oral form or the continuous pump version, there’s a lot of systemic side effects. Patients have a lot of gastrointestinal intolerance to the oral pills to where it affects their lifestyle. Even though the simplicity of ingesting something is easy, if it messes with your quality of life, that’s a problem. Additionally, until 2021, the inhaled form of prostacyclin was only in a nebulizer. This therapy took a long time and restricted a patient from being mobile.

With the dry powder formulation that Yutrepia offers, we can minimize the systemic side effect profiles traditionally seen by the oral and intravenous therapies, and we’re able to titrate the drug to higher levels than traditionally offered to patients. A provider now will look at Yutrepia and say that single drug can potentially offer my patient a very effective option without compromising efficacy with side effects.

Further, because we have shown that Yutrepia can be titrated to higher doses than traditionally used, you don’t need to switch the drug to something else or add on another therapy. You can just titrate the drug higher.

In PH-ILD, Tyvaso is the only one choice, but the same processes are what I think providers are going to be encouraged about. Nobody has ever run a study with the dry powder form of inhaled treprostinil to date. Although Tyvaso is offering its dry powder version, it was never prospectively studied.

We are actively studying patients with PH-ILD taking Yutrepia in the ASCENT study and are excited about showcasing several things: what is our true safety profile in this population, how are patients titrating the drug and can we actually mimic what we did with PAH patients in our INSPIRE study with patients of PH-ILD by getting them to doses that go beyond the therapeutic range. Those are the data I think providers are going to be very excited about because that’s the limitation of the current therapy.

Healio: What would be the next steps after Yutrepia receives final FDA approval?

Saggar: The next thing to do is to continue to support the education of both PAH and, in particular, PH-ILD. Everything starts off in large academic and tertiary care facilities that are expert in these conditions, but we need to continue to educate the community at large.

Pulmonologists tend to be the provider patients see first because they first develop ILD and then develop PH. We need to educate providers on how to screen for PH because once you develop PH on top of ILD, your 3-year survival is around 30% to 40%. Proper earlier screening that then leads to earlier diagnosis and initiating treatment is first and foremost.

From a commercial standpoint, we have our sales rep already educating providers about our technology, and we’re engaging them so that we can learn what the provider is looking for, what sort of services they need from Liquidia and if there are any investigational studies they’re looking at that we can support. We’re looking at this from multiple different spokes and lenses to help support PAH and PH-ILD patients.

Healio: What else does Liquidia have in the pipeline?

Saggar: Yutrepia does not solve the fact that we still have to give this therapy four times a day, so we have licensed a drug known as L606 that’s a liposomal sustained released formulation of inhaled treprostinil. What is unique about this is that we now can deliver the drug twice a day. When you wake up in the morning, you inhale the drug, and before you go to sleep, you inhale the drug. We think that will simplify the lifestyle for that patient so that they can maximize quality of life.

What’s exciting about this is that we can deliver this formulation with a seven-fold drop in the C max, which essentially is the amount of drug that hits your bloodstream at a maximum concentration; that’s what leads to the systemic side effects. Yutrepia by inhalation already substantially reduces those systemic side effects, but now we have a twice-a-day treatment with potentially even fewer side effects.

In an open-label, ongoing U.S. study of the drug in patients with PAH and PH-ILD, the side effect profile of the drug is matching our expectations. We are very excited to show what I believe is to be an extremely clean version for L606. We’re not really irritating the upper pharynx with the drug, we have a very small amount of cough, and these patients want to continue our drug.

The second thing the study has shown is that we can titrate our drug to doses that are higher than typically used with the current therapies that are made available with inhaled treprostinil. Patients are able to get to our maximum dose of L606 in this study, which just highlights that they’re not restricted by any side effect profile, they’re able to titrate the drug and maintain long-term durability on the drug.

All that has given us the confidence to advance the drug into a phase 3 placebo-controlled efficacy study, which we will initiate by the end of the year. We specifically are going to be looking at treating patients with PH-ILD. If we’re able to succeed in improving exercise capacity in these patients, we have indicated that we will receive approval for L606, not only in patients with PH-ILD, but also in PAH.

References:

• FDA delays decision on extending Yutrepia to treat PH-ILD. https://pulmonaryhypertensionnews.com/news/fda-delays-decision-yutrepia-treat-ph-ild/. Published Jan. 26, 2024. Accessed Aug. 19, 2024.
• Liquidia Corporation provides update on new drug application for Yutrepia (treprostinil) inhalation powder. https://www.liquidia.com/news-releases/news-release-details/liquidia-corporation-provides-update-new-drug-application. Published Jan. 25, 2024. Accessed June 13, 2024.
• Liquidia files litigation to challenge regulatory exclusivity blocking access to Yutrepia (treprostinil) inhalation powder for patients suffering with PAH and Ph-ILD. https://www.liquidia.com/news-releases/news-release-details/liquidia-files-litigation-challenge-regulatory-exclusivity. Published Aug. 22, 2024. Accessed Aug. 26, 2024.
• U.S. FDA grants tentative approval of Yutrepia (treprostinil) inhalation powder for patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD). https://www.liquidia.com/news-releases/news-release-details/us-fda-grants-tentative-approval-yutrepiatm-treprostinil. Published Aug. 19, 2024. Accessed Aug. 19, 2024.