Turning A Historically Limited Modality Into A Respiratory Drug Opportunity

A conversation between Vast Therapeutics CEO Nate Stasko, Ph.D., and Clinical Leader Executive Editor Abby Proch

Nitric oxide has long held promise as an antimicrobial and immunomodulatory therapy in respiratory medicine, but its use has been limited by practical and safety limitations. Yet, Vast Therapeutics CEO Nate Stasko, who has spent much of his career developing nitric oxide-based therapeutics, persists.

As he has done in a previous role, he is supporting a novel nitric oxide therapy in ALX1, an inhaled nitric oxide prodrug for muco-obstructive airway diseases, such as bronchiectasis and COPD.

In this conversation, Stasko discusses how ALX1 was designed to revisit a challenging modality by addressing its known failure points early in development — from drug substance design and targeted lung delivery to Phase 1 protocol decisions that tested whether lower, more efficient nitric oxide exposure could avoid the safety issues associated with higher-dose gas.

Clinical Leader: When a modality has known safety issues, such as with inhaled nitric oxide gas, how early should a company begin designing around those concerns, and what did that look like for ALX1?

Nate Stasko, Ph.D.: The known safety issues with nitric oxide gas are when it is used at high levels, five to eight times the FDA approved concentration of INOMax for the treatment of neonatal infants. These high levels are sought after because of the antimicrobial activity observed at high concentrations of nitric oxide. There are some really nasty pathogens out there, where we need better solutions. Nitric oxide has always been in the mix as potential answer for drug-resistant bugs.

One of the other reasons the gas is so ineffective at these potentially toxic levels is that it doesn’t diffuse into the mucus or water layer in the lung lining fluid.

To overcome these known challenges, we began very early in development (lead optimization) with a water-soluble prodrug that overcomes the diffusion barrier by getting nitric oxide released from our drug in the water layer, where the bacteria live and where the inflammation occurs. This stable new chemical entity allows Vast to use less than 2% of the high-dose nitric oxide gas that has proven antimicrobial in small clinical trials.

Using ALX1 as an example, how should sponsors think about delivery technology as a core part of drug development rather than a downstream formulation decision?

Formulation changes to enhance delivery to the patient do lead to better products with longer patent lives. However, as you suggest, controlling drug delivery upstream at the drug substance stage should be considered when tighter control is required. For example, companies utilize conjugation chemistry to put two things together that enhances the biodistribution or water solubility of a known drug. This concept is essentially what we did with nitric oxide. We take the gas, combine it with a backbone molecule, and together they form a new chemical entity for regulatory purposes. The beauty for us is it’s not just a re-patenting strategy for nitric oxide. Our proprietary chemistry actually allows us to take a molecule with a less than 1 second half-life and create a new drug that has a 5-hour half-life for nitric oxide release.

In ALX1’s case, which design decisions were made specifically to reduce risks such as bronchospasm, methemoglobinemia, systemic exposure, or blood pressure effects?

ALX1 is the product patients inhale. It’s the combination of the nitric oxide prodrug, the final formulation, and the device used to deliver it. In our case it is delivered via nebulization, an orally inhaled aerosol solution. To reduce methemoglobinemia, we keep the dose low, as stated above. The targeted delivery to the cells lining the lung is key to our story. To reduce bronchospasm, we carefully balanced the osmolality, or amount of salt provided in the solution. And to reduce (not completely eliminate) systemic exposure, ALX1 had special design considerations to maximize delivery of our cargo, i.e., nitric oxide, prior to leaving the lung. Based on our studies, we estimate that at any given time, there is 20X concentration of drug in the lung than in the blood stream.

What did you learn about building a Phase 1 protocol that not only establishes tolerability but directly tests the historical failure points of a therapeutic class?

Our first in kind new chemical entity defines a new therapeutic class, as we are aiming to be the first FDA-approved nitric oxide prodrug (or delivery technology) in respiratory medicine. When building the Phase 1 protocol, we made sure that we selected doses that we believe can be therapeutically effective in COPD and bronchiectasis. It was key for us to prove our hypothesis that at the targeted levels of nitric oxide we are achieving, there would be no methemoglobinemia. And there wasn’t. Not a single measurement for any ALX1 treated subject exceeded normal background levels.

The study escalated above the calculated human effective dose. What principles guided that decision?

We wanted to ensure that in healthy volunteers we had multi-fold greater exposure levels to demonstrate the safety of ALX1. This approach gives us tremendous comfort as we move to subjects with disease.

As ALX1 moves toward patients with bronchiectasis, COPD, or other muco-obstructive airway diseases, what protocol design lessons are most important to carry from Phase 1 into Phase 2?

We will most certainly continue to measure the known safety biomarker for nitric oxide exposure of methemoglobin. In fact, absence of elevated methemoglobin will be a key determinant for dose escalation in our ascending dose design. Our goal is to unlock nitric oxide for use in respiratory medicine in a safe, easy to use delivery method for daily at-home use.

What advice would you give sponsors trying to communicate safety progress in a field where clinicians, regulators, or investors may remember prior limitations of the modality?

Trust the data. Trust the numbers. The calculated doses of nitric oxide that Vast is delivering are a small fraction of the levels that have led to cough, intolerability, and systemic methemoglobinemia. Our efficiency, lung deposition, and ability to deliver nitric oxide into the aqueous layer of the lung provides a gateway for executing on the promise of nitric oxide that has existed for 30 years.

If ALX1 ultimately succeeds, what broader development playbook could it offer for companies revisiting promising mechanisms that were previously constrained by delivery or safety limitations?

The playbook is wide open. Beyond our focus on muco-obstructive airway disease, it would offer companies a patent-protected technology to finally realize the effects of low-dose nitric oxide on diseases like pulmonary hypertension. Acute care settings would have a new option to manage ARDS (acute respiratory distress syndrome). Some of the most multi-drug-resistant pneumonia cases would have a new treatment option at high doses. Our vision is to create indication-specific formulations of nitric oxide – ALX2, ALX3. The breadth of respiratory ailments addressable with nitric oxide is truly Vast.

About The Expert:

Nate Stasko leads Vast's development of nitric oxide-based therapeutics targeting immunomodulation and pathogen elimination on epithelial surfaces — expertise directly applied to ALX1. He holds over 100 international patent filings, leading to two commercial therapies. He previously served as president & CEO of Novan, Inc. from inception through its 2016 NASDAQ IPO, leading development of the berdazimer drug substance that resulted in FDA approval of the first nitric oxide-based drug (Zelsuvmi, 2024) — direct experience in taking a nitric oxide therapy from concept through FDA approval that he now brings to Vast. As principal investigator on 10 federally-funded projects, he scaled berdazimer from academic research to commercial production, earning a Tibbetts Award for Excellence in Small Business Innovation Research.