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Faron Schonfeld, a successful investment portfolio manager from Philadelphia, Pennsylvania, had for years suffered chronic coughing and sinus infections that only seemed to get worse. He was finally referred to a pulmonologist at National Jewish Health in Denver, Colorado. 

That’s where he got the diagnosis: Schonfeld had alpha-1 antitrypsin deficiency (AATD, or simply alpha-1) — an autosomal, recessive condition that may cause serious lung disease in adults, as well as liver disease at any age.

“Despite thinking I’d be a very uninteresting case, unfortunately I discovered that I had numerous microbacterial infections in my lungs, and quite a bit of bronchiectasis as a result of these infections being undetected for so many years,” said Schonfeld, 42.


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He was diagnosed as having the MZ genotype, meaning he doesn’t have severe AATD but is a genetic carrier of the Z mutation. While the MZ genotype isn’t linked to increased risk of lung disease, it is associated with a slightly increased risk for liver disease.

“I went on a course of antibiotics for 18 months and resolved the lung infections,” Schonfeld said. “My goal, once resolving my own health, was to make sure that I’d do whatever I can to help find a cure for this disease.”

Schonfeld, a newly appointed board member of the Alpha-1 Foundation, kicked off a June 25 webinar on emerging AATD therapies as part of its 2021 Virtual Alpha-1 National Conference. The event was moderated by Mark Brantly, MD, scientific director of the Miami, Florida-based charity.

The role of RNAi, or ribonucleic acid interference, was the focus of a presentation by Hardean E. Achneck, MD, vice president of early-stage clinical development and clinical research at Dicerna Pharmaceuticals. In his talk, Achneck noted that RNAi has led to gene targeting across multiple tissue types and approved products in multiple disease areas, as well as simple and convenient dosing regimens.

“The RNAi modality has come of age. RNAi has been successful where traditional modalities have often not worked,” Dr. Achneck said. “Multiple large pharmaceutical companies are committed to this type of research. Dicerna was founded to specialize in RNAi.”

The company, based in Lexington, Massachusetts, is developing belcesiran (DCR-A1AT) to treat alpha-1 by preventing the production of the mutated protein that causes the disease. SHINE, an ongoing placebo-controlled clinical trial to evaluate the drug’s safety and tolerability, included healthy adult volunteers who were followed for a minimum of 56 days in phase 1.

In phase 2, Dicerna has 2 parallel groups of up to 27 participants per group, all of whom are adults with the PiZZ genotype of alpha-1. The first cohort receives the therapy for 24 weeks, the second for 48 weeks. The trial is open only to enrollment in New Zealand for now.

Also on the webinar, Javier San Martin, MD, chief medical officer at Arrowhead Pharmaceuticals, described how its experimental drug, ARO-AAT — an RNAi therapy designed to silence expression of the Z-AAT protein — led to a “rapid and profound reduction in serum and intrahepatic levels of Z-AAT.” In addition, all 9 patients in the trial showed a reduction in histologic globule assessment scores. 

Also, 6 of the 9 patients, including 2 with baseline cirrhosis, saw an improvement in their Metavir fibrosis scores.

Arrowhead, based in Pasadena, California, is in talks with the US Food and Drug Administration (FDA) to get the drug approved, Dr. San Martin said, adding that a joint marketing agreement signed in October 2020 with Takeda remains on target.

It’s no wonder so many companies are pursuing treatments for AATD. Mark Lappe, CEO of INHIBRx, estimated the global AATD augmentation therapy market at $1.1 billion annually in 2018, a number expected to reach $1.9 billion by 2026. 

“The current augmentation therapies, as I’m sure you’re all aware, are suboptimal,” Lappe said. “Even with weekly infusions of the PK profile, it is poor. Patients are below normal range within 3-4 days of infusion.”

In contrast, his company’s therapy for alpha-1, INBRX-101, is a “precisely engineered recombinant human AAT-Fc fusion protein” that has the potential to extend the dosing range, from weekly to every 3 weeks, while maintaining patients in the normal range of AAT exposure. That means 17 infusions per year rather than 52, Lappe said.

“The whole goal here is less frequent dosing, normal therapeutic ranges, potentially better activity in the lung, and an unlimited supply capacity with no pathogenic risk,” he explained. A phase 1 trial of INBRX-101 is underway in the US, UK, and New Zealand.

Israel’s Kamada is taking a different approach. The biotech firm, founded in 1990 and headquartered at the Weizmann Institute of Science in Rehovot, recently developed Glassia, the first liquid, FDA-approved, plasma-derived product to treat alpha-1.

Naveh Tov, MD, PhD, the company’s medical director, offered an update on Kamada’s inhaled AAT program, currently in development.

“The advantages of inhaled AAT as a next-generation augmentation therapy are focused in 3 areas,” Dr. Tov said. “One, by inhalation we can bring [more into the lung while using a smaller amount of the drug], we have demonstrated improvement in lung function more than by IV, and clearly, it’s a noninvasive treatment that everyone can take at home, and it’s easier to use than IV.”

Previous Kamada studies have shown that 80 mg a day of inhaled AAT restores ELF (endothelial lining fluid) AAT to the upper normal level. In addition, Dr. Tov said, “AATD patients with moderate COPD [chronic obstructive pulmonary disease] have the highest rate of lung function decline and should benefit the most from inhaled AAT.”

Alvelestat — Image Credit: PubChem

Jackie Parkin, PhD, MB, senior vice president and therapeutic head of Mereo BioPharma Group, spoke at the webinar about Mereo’s ongoing trials for alvelestat, an investigational oral elastase inhibitor. 

“Being involved in potentially new therapies for alpha-1 lung disease is meaningful for me,” Dr. Parkin said, adding that “it appears to be a very exciting time in research” for rare diseases.  

Alvelestat, a tablet taken orally twice a day, has been tested in more than 1000 people. Two 12-week studies in AATD — ASTRAEUS (NCT03636347) and ATALANTa (NCT03679598) — are underway.

“It is the lack of anti-elastase alpha-1 antitrypsin that predisposes the lung to damage. This is because aggressive enzymes, chiefly elastase, produced by white cells called neutrophils, are not adequately controlled and attack lung tissue,” Dr. Parkin said.

“The balance between elastase and anti-elastase is not right. Alvelestat is a potent oral inhibitor and we believe that alvelestat could have the same effect as the natural protein alpha-1 antitrypsin on this enzyme, thereby reducing lung damage, and redress the imbalance that we see.”