FDA Grants RMAT Designation to KB707, an Inhaled Gene Therapy for Advanced Lung Cancer

The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to KB707, an investigational inhaled gene therapy developed by Krystal Biotech for patients with locally advanced or metastatic lung tumors that have progressed on standard-of-care treatment.

The RMAT designation, established under the 21st Century Cures Act, is intended to accelerate development of regenerative medicines for serious or life-threatening diseases. To qualify, therapies must show preliminary clinical evidence suggesting potential to address unmet medical needs. RMAT provides benefits similar to Fast Track and Breakthrough Therapy designations, including intensive FDA guidance, priority review eligibility, and potential accelerated approval pathways.

According to Suma Krishnan, president of R&D at Krystal Biotech, the designation reflects both the urgent unmet need in advanced non–small cell lung cancer (NSCLC) and encouraging early clinical data observed with KB707.

A Redosable Gene Therapy Approach Distinct from AAV Platforms

KB707 represents a differentiated strategy in gene therapy. While many systemic gene therapies utilize adeno-associated virus (AAV) vectors, which are typically non-redosable and often delivered intravenously, KB707 is based on a modified herpes simplex virus type 1 (HSV-1) vector designed for localized, repeat administration.

Unlike AAV-based gene therapies that commonly aim for long-term transgene expression after a single systemic dose, KB707 is engineered as a nonreplicating, nonintegrating, redosable gene therapy delivered via nebulization. This allows for repeated dosing directly to the lungs — a key advantage in oncology settings where durable yet controllable expression may be preferred over permanent systemic gene transfer.

The therapy encodes functional human interleukin-12 (IL-12) and interleukin-2 (IL-2). Historically, systemic administration of these cytokines has been limited by severe toxicities such as vascular leak syndrome and cytokine storm. By delivering the genes locally to the lung tumor microenvironment, KB707 seeks to induce strong local immune activation while minimizing systemic exposure.

This localized inhalation strategy contrasts with systemic AAV gene therapies and highlights how vector selection — AAV versus HSV — can shape durability, redosing potential, and safety profile in gene therapy design.

Clinical Data from the Phase 1/2 KYANITE-1 Trial

The RMAT designation is supported by interim data from the ongoing Phase 1/2 KYANITE-1 study (NCT06228326) evaluating inhaled KB707 in advanced solid tumors involving the lungs.

As of the January 8, 2025 data cutoff:

• Maximum tolerated dose (MTD) was not reached

• No grade 4 or 5 treatment-related adverse events were reported

• Most adverse events were mild to moderate and transient

• Among 11 response-evaluable patients:

  • Overall response rate (ORR): 27%

  • Disease control rate (DCR): 73%

  • Lung target lesion response rate: 36%

• Median duration of response has not yet been reached

The median patient age was 71 years (range 54–77), and participants were heavily pretreated, with a median of four prior lines of therapy. All had previously received immunotherapy.

Strategic Implications

The RMAT designation positions KB707 as a potentially accelerated gene therapy candidate in advanced NSCLC. While AAV-based gene therapies dominate many genetic and rare disease indications, oncology applications increasingly explore alternative vector systems that enable localized, redosable expression.

If clinical benefit is confirmed in later-stage trials, KB707 could represent an important expansion of gene therapy into immuno-oncology using non-AAV delivery systems.