A New Level of Immunology: Sanjay Shukla, aTyr Pharma

Dr. Sanjay S. Shukla is a medical doctor, scientist, researcher, and global pharma executive. Currently, he is the President, CEO, and Executive Board Member of aTyr Pharma, Inc., a public clinical-stage biotherapeutics company engaged in the discovery and development of innovative medicines based on novel biological pathways.

Before working with aTyr Pharma — as the CEO and, prior to that, CMO — Dr. Shukla served as Vice President and Global Head of Integrated Medical Services for Novartis, where he led global medical affairs operations, with oversight for all general pharma therapies, both inline and in development. Prior to that, he was the CEO of RXMD, a clinical development consultancy that assisted in advancing proof of concept for early-stage drug candidates. He also served in a variety of clinical development, data analytics, and drug safety roles at Vifor Pharma and Aspreva Pharma.

Pharm Exec caught up with Dr. Shukla to talk about why he became interested in the enzyme in our bodies known as tRNA synthetases, that helps us make proteins, and eventually control our local immune environments.

Pharm Exec: Can you tell us about tRNA synthetases enzymes and the new protein class of therapeutics aTyr Pharma is developing?

Dr. Sanjay S. Shukla

Sanjay Shukla: The enzyme, tRNA synthetases is a basic building block enzyme that helps our bodies make proteins. They work inside the cell by shepherding an amino acid to a tRNA, and this in turn helps us make proteins.

Dr. Paul Schimmel discovered and published this scientific breakthrough in both Science and Nature publications 12 years ago. These enzymes break apart into fragments and those fragments migrate out of the cell and travel to different tissues and organ systems in our bodies. They are mostly involved in controlling local immune environments. Our job at aTyr is to look back at this new protein class of therapeutics and determine where they might best fit in helping patients and different disease pathways.

Is aTyr Pharma working on a new therapy for lung disease?

Yes, we are focused on a group of diseases called interstitial lung disease, where we believe we have a real opportunity to help patients.

We noticed of the hundreds of fragments in our systems, one was particularly enriched in the lung tissue. Early experiments in vitro demonstrated that this fragment had potent anti-inflammatory effects. It down-regulated activated T-cells, and other immune cells that are critical in regards to inflammation.This gave us an early clue that this fragment may be an important player in controlling inflammation of the lung.

Our lead therapy is ATYR1923 and 1923 is a fragment we followed in the lung that is interacting with immune cells. We ran a receptor screen to better understand how it is binding to these immune cells and got a very selective target on a receptor known as NRP-2, or Neuropilin-2.

Neuropilin-2 is a potent regulator of immune cells during inflammatory response, so now it’s started to make sense to use mechanistically that this fragment binds to Neuropilin-2, which is activated during an inflammatory response.From there, it took different types of studies looking at lung injury and inflammation. Whether we used direct or indirect toxic agents, we saw very consistent anti-inflammatory effects.

aTyr just announced positive data from the Phase Ib/IIa clinical trial demonstrating consistent dose response for ATYR1923 in pulmonary sarcoidosis.

That is correct. The trial met the primary endpoint and was safe and well tolerated in 37 patients with pulmonary sarcoidosis. In addition, ATYR1923 demonstrated dose response and improvements compared to placebo on key efficacy endpoints, including measures of steroid reduction, lung function, sarcoidosis symptom measures and inflammatory biomarkers. This trial was the first proof-of-concept for ATYR1923, as well as validation for our tRNA synthetase biology platform and Neuropilin-2 as a target. The data provided gives us great confidence that ATYR1923 could be a transformative disease modifying therapy for pulmonary sarcoidosis patients.

Interstitial lung disease includes four major types of lung disease. Will this therapy be effective in all major types?

We are working towards that goal. Idiopathic pulmonary fibrosis is the most well-known type of lung disease and there are few approved therapies. But there are a number of other conditions such as sarcoidosis, hypersensitivity pneumonitis, and the connective tissue disease related ILDs, such as scleroderma-ILD, where we believe our therapy may be impactful in all immune pathology in that the inflammatory response is elevated, and there’s a progression of fibrosis.

We believe our drug can address the inflammation, and help patients with their quality of life and prevent the progression of fibrosis, which is the most serious outcome that we don’t have a therapy available yet to prevent.

How will the therapy be administered?

ATYR1923 will be administered through a monthly one-hour IV infusion. This is much better than requiring steroid therapy every day. We believe our therapy is well-built for chronic inflammatory diseases of the lung.

What did you learn from the COVID pandemic and how your therapy affects COVID pneumonia?

We learned that inflammation plays a large role in the morbidity and mortality of COVID pneumonia patients. We ran a small study to see if our therapy would help patients suffering from COVID pneumonia get out of the hospital faster, but also to look at inflammatory markers. Our trial of 32 patients did reveal thatour drug offered modest benefits to patients and they were able to be discharged from the hospital within about 5 days.This was on top of dexamethasone and remdesivir. ATYR1923 did a great job of knocking down extremely high inflammatory biomarkers at a more substantial rate compared to the standard of care treated patients.

Tell us about your second therapy, ATYR2810, in development to treat aggressive cancers.

We are a data-driven company. When we looked at ATYR1923 and it bound to Neuropilin-2, we began to look at this receptor in a different way and much of the literature pointed to Neuropilin as being an important marker in some resistant and aggressive tumors.

We created a suite of antibodies to different epitopes of this Neuropilin-2 receptor.

One of which is currently in early preclinical testing that enhances immune response against some solid tumors. We have demonstrated in models, tumor inhibitory effects that have been published in the American Academy of Cancer Research with a monoclonal therapy, ATYR2810, which modulates Neuropilin-2 in a different manner. It seems to increase sensitivity to chemotherapy. We expect to have ATYR2810 in the clinic in 2022 in solid tumor protocol where it could potentially be useful in resistant and aggressive cancers.

What’s the next step for ATYR1923?

Based on the results of our phase1b/2a clinical trial, we plan to meet with the FDA to present these data and our plans for subsequent clinical development and path to registration for ATYR1923 for pulmonary sarcoidosis, and we expect to initiate a larger, worldwide registrational trial next year.

What inspired Dr. Paul Schimmel, a renowned biochemist and translational medicine pioneer, to launch aTyr?

It was really Paul’s research surrounded tRNA synthetases that led him to founding this company. tRNA synthesis were originally thought to only play a role in protein synthesis by catalyzing the aminoacylation of tRNAs to their respective amino acids.

Paul, along with colleagues at The Scripps Research Institute, discovered that a protein derived from one tRNA synthetase gene could act as an extracellular modulator of angiogenesis.

Recent research developments have further reinforced the idea that tRNA synthetases may more broadly play important roles in cellular responses to certain disease states, in particular, cellular stress, and tissue homeostasis.

aTyr has built and intellectual property portfolio covering >300 protein compositions derived from all 20 tRNA synthetase genes, and is engaged in the discovery and development of potential first-in-class medicines based on newly discovered pathways effected by extracellular tRNA synthetases.