For patients with pulmonary fibrosis, the act of breathing itself is difficult. As their lungs become lined with scar tissue, air sacs stiffen and become less adept at delivering oxygen into the lungs, and immune cell responses lead to chronic inflammation that worsens the functioning of lung tissue.
There are only three medications approved for pulmonary fibrosis, all of which focus on slowing the progression of damage to the lungs. But currently, these medications are only offered as oral pills that require high doses and, as a result, come with a high frequency of side effects that are tough for patients to tolerate.
To better treat pulmonary fibrosis and other rare lung diseases in a more targeted fashion, Avalyn Pharma is developing inhaled versions of common pulmonary fibrosis drugs. They have two clinical-stage programs — inhaled pirfenidone (AP01) and inhaled nintedanib (AP02) — currently being tested in clinical trials, with a third in preclinical development that will combine both inhaled pirfenidone and nintedanib together. In July, Avalyn Pharma raised $100 million in series D financing to continue advancing these programs.
As CEO of Avalyn Pharma, Lyn Baranowski leads a team focused on advancing inhaled versions of drugs for rare lung diseases.
Credit: Avalyn Pharma
“Inhaled delivery gives us a chance to reimagine the treatment paradigm by targeting the lungs directly, enhancing efficacy and reducing side effects,” Lyn Baranowski, CEO of Avalyn Pharma, told DDN.
So far, their team has already made a difference in many patients’ lives through their trials. In one response Avalyn shared with DDN, a patient who received inhaled pirfenidone said, “One of the booklets I looked at said that life expectancy from diagnosis was three to five years. That was seven years ago. So, I think I'm winning at the moment.”
DDN talked with Baranowski about the advantages of inhaled therapies for pulmonary fibrosis, why it’s been challenging to develop them, and what their results have shown so far.
What makes the oral drug versions so difficult for patients to tolerate?
Orally administered medications like pirfenidone and nintedanib are notoriously difficult for many patients with idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) to tolerate due to the high doses required. These doses are necessary to overcome the inefficiencies of gut absorption, first-pass metabolism, and blood dilution before the medicine reaches the lungs. Common adverse events (AEs) observed for the oral drugs are largely gastrointestinal (GI) in nature, including nausea, diarrhea, and vomiting. These are patients who are very sick to begin with, often breathless, coughing, and experiencing shallow breathing. When the side effects of oral medications are added, patients often discontinue treatment.
Our inhaled therapies hold promise to substantially improve the oral drugs’ safety and tolerability profiles. Because inhaled medications can be delivered directly to the site of disease in the lungs, we can reduce the doses required compared to oral administration. The resulting blood levels following absorption from the lungs are well below those following oral delivery.
Our AP01 demonstrated improved tolerability in the ATLAS trial compared to historical data on oral pirfenidone across multiple AEs including nausea, rash, fatigue, headache, dizziness, and abdominal pain. While lung exposure is higher with inhaled delivery, plasma exposure from AP01 100mg twice daily is markedly lower than that from oral pirfenidone 801mg three times daily.
It makes logical sense to use an inhaled formulation for a medication that needs to go to the lungs. Why has no one worked on this before, or why have previous attempts not been successful?
Despite the clear potential of inhaled therapies, few companies in the IPF/PPF space have pursued such formulations for two reasons. First, inhaled delivery introduces complexity to drug development that relatively few individuals and organizations have experience with. Second, many companies initiate IPF/PPF programs with molecules and targets that address systemic fibrosis outside the lungs. Fibrosis also occurs in other non-pulmonary diseases like oncology and liver diseases. For this reason, companies pursuing fibrosis more broadly often develop IPF/PPF drugs alongside treatments for other systemic diseases.
By leveraging our expertise in inhaled formulation, particle engineering, pharmacokinetics, device compatibility, as well as clinical expertise in interstitial lung diseases (ILDs), we aim to provide effective, patient-centric therapeutic solutions that address the key medical unmet needs. Our team’s extensive experience in ILDs and inhaled expertise sets us apart in advancing respiratory medicine.
It's important to understand that patients with pulmonary fibrosis are typically older, may not be able to breathe vigorously, and frequently have a cough as a primary symptom of their disease. We have evaluated various inhalation technologies across all our programs and believe our nebulized formulation is particularly well-suited for this patient population. The PARI eFlow nebulizer is a patented, high-efficiency nebulizer capable of generating very small particles that reach the right place in the lungs. It delivers the drug in approximately 8.5 minutes. This same level of drug would require 27 inhalations from a dry powder inhaler and 45–60 minutes using an off-the-shelf, general-purpose nebulizer.
How is AP01 thought to work to treat PPF through inhalation?
AP01 is an optimized inhaled formulation of pirfenidone being developed as a potential next-generation standard-of-care treatment for patients with PPF. Pirfenidone is a small molecule inhibitor with anti-inflammatory and anti-fibrotic properties. While its exact mechanism of action is not fully understood, it modulates a range of cytokines and growth factors involved in the pathogenesis of pulmonary fibrosis, including effects on fibroblasts, collagen production, and the TGF-β (transforming growth factor-beta) pathway.
We believe that delivering small, inhaled doses of AP01 that bypass the GI tract and first-pass metabolism will achieve a high local lung concentration and maintain low systemic exposure. These characteristics are designed to reduce the known side effects of oral pirfenidone and enable targeted drug delivery directly to the lungs.
AP01 is administered using the PARI eFlow Nebulizer System. This customized, handheld nebulizer is clinically and commercially validated, with five drug-device combinations approved worldwide. Its particle size is fully optimized for effective deposition in peripheral airways and the alveoli.
Inhaled delivery gives us a chance to reimagine the treatment paradigm by targeting the lungs directly, enhancing efficacy and reducing side effects.
– Lyn Baranowski, Avalyn Pharma
What have you found so far in clinical trials with AP01 and AP02?
AP01 has been studied in over 150 participants, with more than 3,000 cumulative months of exposure. We successfully completed the Phase 1b randomized, open-label ATLAS clinical trial and its open-label extension (OLE) trial is ongoing. AP01 has shown promise in both ATLAS and the ongoing OLE trial, demonstrating long-term antifibrotic effects and continued favorable safety extending beyond 4.5 years. These findings suggest potential for disease modification. AP01 also demonstrated a near-stabilization of lung function.
With AP02, our topline Phase 1 clinical data presented at the American Thoracic Society 2025 conference confirmed safety and tolerability with limited systemic exposure and substantially improved lung exposure compared to oral nintedanib in patients with IPF. We are excited to rapidly advance AP02 into a Phase 2 clinical trial as a next step.
Why are you developing AP03 to combine the active ingredients in AP01 and AP02 together?
While the combination of pirfenidone and nintedanib is an opportunity to enhance therapeutic effects, the challenging systemic side effects of each of the orals make the oral combination impossible for patients to tolerate. If inhaled delivery solves the tolerability challenge of these molecules, we can then combine the two molecules as they are mechanistically different. AP03 is designed to minimize systemic exposure and reduce the risk of side effects, while further improving tolerability and potentially offering additive, or even synergistic, efficacy compared to monotherapies. Preclinical development is in progress, with plans for a Phase 1 study in 2026.
What drives you to continue doing this work?
Despite its severity and the clear unmet need, innovation in this space has been extremely limited, and the few available treatments are difficult for many patients to tolerate. Inhaled delivery is a technically challenging approach, but one we’ve deliberately built the company around. The potential to not only improve treatment but also enhance quality of life and long-term outcomes for the patients is what drives me every day.
This interview has been condensed and edited for clarity.
