A particular protein deficiency that leads to liver and lung damage is currently treatable only with decades-old therapies that all have limitations. Biotech startup AIRNA is part of a field of companies developing novel treatments for this inherited disorder, and it aims to stand apart with a genetic medicine it contends could become best in class. AIRNA is preparing to advance this program to clinical testing and on Wednesday it revealed a fresh round of $60 million to support its plans.
The disease that Cambridge, Massachusetts-based AIRNA aims to treat is alpha-1 antitrypsin deficiency, or AATD. This rare disease, affecting an estimated 100,000 Americans, leads to low levels of alpha-1 antitrypsin, a liver protein that suppresses enzymes that are abundant when inflammation develops. Low alpha-1 antitrypsin levels result in progressively worsening damage to the liver, the lungs, or both. This damage can reach the point of requiring hospitalization.
Standard AATD treatment is intravenous infusions of alpha-1 antitrypsin obtained from healthy donors. Such augmentation therapies commercially available from CSL Behring and Grifols require weekly dosing. These therapies only address the lung damage from AATD, not liver damage. Other AATD treatments include corticosteroids and bronchodilators to open airways and reduce inflammation. None of these AATD treatments address the underlying cause of the disease. AIRNA aims to do so by editing RNA.
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“There are no disease-modifying treatments for AATD biology,” CEO Kris Elverum said. “That biology is particularly suited for our technology. It’s driven by a mutation in RNA that our technology can repair.”
The AIRNA therapy is comprised of an oligonucleotide that recruits an enzyme in the body called adenosine deaminase acting on RNA (ADAR). One of ADAR’s roles is to edit RNA, Elverum explained. AIRNA’s platform technology, called RESTORE+, enables the company to understand the rules of editing RNA with ADAR. It also optimizes the oligonucleotide sequence and chemistry for the therapy. AIRNA’s science comes from the research of academic co-founders Thorsten Stafforst, a professor of RNA biochemistry at the University of Tübingen, and Jin Billy Li, a Stanford University professor of genetics.
AIRNA, whose name comes from the adenosine-to-inosine (A-to-I) RNA editing mediated by ADAR, faces competition from two of its Cambridge neighbors. Both Wave Life Sciences and Korro Bio are developing A-to-I RNA-editing therapies that leverage ADAR. Each biotech also claims its therapy is potentially best-in-class. Wave’s preclinical results showed its therapeutic candidate, WVE-006, led to AAT protein levels reaching up to 30 micromolar, a measure of concentration. This therapy is now being evaluated in a randomized, placebo-controlled Phase 1/2 study with a targeted enrollment of 56 participants. The dose-escalation Phase 1 portion is underway; Wave expects human proof-of-mechanism data later this year. Under an agreement with GSK, the pharma giant has global rights to this program and will take over development after Wave completes the Phase 1/2 study.
Korro Bio’s AATD drug contender, KRRO-110, is on track for an investigational new drug application in the second half of this year. In mouse study results presented in January during the J.P. Morgan Healthcare Conference in San Francisco, Korro reported a single dose led to a “best-in-class profile” with secretion of functional AAT protein of about 50 micromolar. In monkey studies, Korro reported its therapy activated a transcription factor by creating a de novo protein variant whose activity was sustained for more than 21 days. Strong tests results in monkeys are viewed as a sign that a therapy’s effect will translate to humans. Additional supportive preclinical data were presented in May during the American Thoracic Society 2024 International Conference.
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Like the experimental Wave and Korro AATD therapies, AIRNA is developing its therapy for subcutaneous administration. Elverum said the company is not yet in a position to understand what this therapy’s dosing frequency would be, but he added that he expects physicians and patients will prefer subcutaneous dosing over the weekly intravenously infused augmentation therapies that make up the current standard of care. Asked to specify why he calls AIRNA’s therapy best in class, Elverum said details from the preclinical research have not yet been publicly released.
“What we have to date is a best-in-class therapy compared to what we’ve seen from others in the space,” he said.
Biopharmaceutical companies are pursuing a range of approaches for treating AATD. Arrowhead Pharmaceuticals is developing a small interfering RNA therapy that knocks down production of mutant versions of the protein to treat the disease’s effects on the liver. This Takeda Pharmaceutical-partnered drug candidate, fazirisiran, is in Phase 3 testing. Beam Therapeutics has an in vivo gene-editing therapy in Phase 1/2 clinical development. Vertex Pharmaceuticals is in early clinical development with two small molecules designed to correct the underlying genetic cause of AATD. Sanofi is a newer entrant to this field with an engineered version of the alpha-1 antitrypsin protein currently in mid-stage clinical testing. This therapy, developed for monthly dosing, comes from Sanofi’s $1.7 billion acquisition of Inhibrx earlier this year.
Elverum said AIRNA’s new capital will support plans to advance its AATD program to the clinic in 2025. The startup will also broaden its technology platform and expand its drug pipeline to indications amenable to RNA editing, such as cardiovascular diseases, metabolic disorders, and blood disorders. As for finding partners for these programs or for the technology platform, Elverum said the company is open to alliances but is not actively pursuing them right now.
AIRNA launched last September with $30 million in Series A financing led by Arch Venture Partners. The new financing announced Wednesday extends that round to $90 million total. This additional financing was led by Forbion. Other disclosed investors in the new financing are Ono Venture Investment and Alexandria Venture Investments. Earlier investors Arch and ND Capital also participated.
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