Krystal Biotech’s Type 1 Alpha-1 Antitrypsin Deficiency Gene Therapy KB408 Cleared for US Trial


Krystal also noted that earlier this month the gene therapy received orphan drug designation from the FDA.

Krystal Biotech’s KB408, an investigational herpes simplex virus type 1 (HSV-1)-derived vector-based gene therapy, has been cleared by the FDA for a phase 1 clinical trial (NCT06049082; Serpentine-1) in patients with type 1 alpha-1 antitrypsin deficiency (AATD).1

In light of the clearance of the investigational new drug (IND) application, which Krystal Biotech submitted to the FDA on August 15, 2023, the company expects to dose the first patient in the trial by the first quarter of next year. The planned study will seek to recruit adults with AATD who have the PI*ZZ genotype. Participants will be assigned to cohorts in which they will be treated with either a low, middle, or high dose of the gene therapy. There will be 2 high dose cohorts, one that will treat patients who remain on standard of care intravenous plasma-derived alpha-1 antitrypsin (AAT) augmentation therapy and one that will treat patients off of augmentation therapy. Krystal also noted that earlier this month the gene therapy received orphan drug designation from the FDA.

“We are excited to advance KB408, our investigational gene therapy for patients with AATD, into the clinic in our Serpentine-1 study,” Hubert Chen, MD, the senior vice president of clinical development at Krystal Biotech, said in a statement.1 “This IND acceptance represents an important milestone for us as we work to address a serious lung disease with limited treatment options, and also allows us to demonstrate the potential of our platform to deliver genes repeatedly to epithelial cells of the lung.”

KB408 consists of a modified and replication-defective non-integrating HSV-1-derived vector that contains 2 copies of the disease-targeted serpin family A member 1 (SERPINA1) gene. Notably, it is administered in nebulized form via inhalation in order to reach the lungs’ respiratory cells, with the expectation that it will restore production of AAT.

The IND clearance is the latest success for Krystal Biotech, which in May 2023 obtained FDA approval of its topical and redosable gene therapy beremagene geperpavec (B-VEC) for the treatment of dystrophic epidermolysis bullosa (DEB) in patients 6 months or older.2 B-VEC, which is marketed with the name Vyjuvek, is the firstredosable gene therapy and the first medicine for DEB to be approved by the agency.

That said, Krystal Biotech is not the only company exploring the potential of genomic medicines for the treatment of AATD. Earlier this month, AlveoGene, a new company launched with funding from investors including Oxford Science Enterprises and Harrington Discovery Institute, announced that it will pursue the development of a lentiviral gene therapy for AATD.3 The company similarly intends to utilize a nebulizer for an inhalation delivery method to the epithelial cells of the lungs. AlveoGene hopes that its investigational product, which remains in preclinical development, may enter clinical trials within 2 to 3 years.

Furthermore, this month Wave Life Sciences submitted a clinical trial application (CTA) for WVE-006, an investigational RNA editing oligonucleotide intended to treat AATD.4 Although Wave Life Sciences did not indicate in which country the CTA was submitted, in a request for comment a representative for the company told CGTLive™ that the first locations for a potential clinical trial are expected to be in Australia and Europe. Notably, WVE-006 is expected to address both the lung and liver manifestations of AATD.

1. Krystal Biotech announces FDA clearance of investigational new drug application for KB408 for the treatment of type 1 alpha-1 antitrypsin deficiency. News release. Krystal Biotech, Inc. September 21, 2023. Accessed September 22, 2023.
2. Krystal Biotech Receives FDA Approval for the First-Ever Redosable Gene Therapy, VYJUVEK™ (beremagene geperpavec-svdt) for the Treatment of Dystrophic Epidermolysis Bullosa. News release. Krystal Biotech. May 19, 2023. Accessed September 22, 2023.
3. AlveoGene Launches to Develop Unique Inhaled Gene Therapies for Rare Respiratory Disorders. News release. AlveoGene. September 14, 2023. Accessed September 22, 2023.
4. Wave Life Sciences announces submission of first clinical trial application for WVE-006, the first-ever RNA editing clinical candidate, and plans for upcoming virtual “R&D day”. News release. Wave Life Sciences Ltd. September 5, 2023. Accessed September 22, 2023.
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