Nebulized KB408 for Alpha-1 Antitrypsin Deficiency

(Serpentine-1 Trial)

Recruiting at 1 trial location

Overseen By David Chien, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Krystal Biotech, Inc.

Disqualifiers: Pulmonary impairment, Smoking, Liver dysfunction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 2 months

12 Participants Needed

Trial Summary

What is the purpose of this trial?

The Sponsor is developing KB408, a replication-defective, non-integrating herpes simplex virus type 1 (HSV-1)-derived vector engineered to deliver functional full-length human SERPINA1 to the airways of people with alpha-1 antitrypsin deficiency (AATD) via nebulization. This study is designed to evaluate safety and pharmacodynamics of KB408 in adults with AATD with a PI\*ZZ or PI\*ZNull genotype. Three planned dose levels of KB408 will be evaluated in single dose escalation cohorts. Subjects taking intravenous AAT augmentation therapy are not required to wash out from IV AAT in the low and mid dose cohorts. At the high dose, two cohorts will be conducted in parallel to evaluate patients on and off IV augmentation therapy.

Will I have to stop taking my current medications?

If you are in the high dose group and currently on AAT augmentation therapy, you will need to stop this therapy for at least 6 weeks before the study and remain off it during the study. For other medications, the protocol does not specify, but you should stay on a stable treatment regimen.

What data supports the effectiveness of the drug KB408 for Alpha-1 Antitrypsin Deficiency?

Research on similar treatments, like intravenous augmentation therapy with alpha 1-antitrypsin, shows it may slow the decline in lung function for patients with Alpha-1 Antitrypsin Deficiency, suggesting potential benefits for KB408 as well. ^{1 2 3 4 5}

How is the drug KB408 different from other treatments for Alpha-1 Antitrypsin Deficiency?

KB408 is unique because it is administered through nebulization (inhalation), which may offer a more convenient and potentially more direct delivery method to the lungs compared to the traditional intravenous (IV) augmentation therapy used for Alpha-1 Antitrypsin Deficiency. ^{1 2 4 6 7}

Research Team

David Chien, MD

Principal Investigator

Senior Vice President of Clinical Development

Eligibility Criteria

Adults aged 18-70 with Alpha-1 Antitrypsin Deficiency and PI*ZZ genotype can join. They must be in good health except for AATD, not smoke, and agree to avoid certain medications. Those on augmentation therapy must stop it before joining the trial.

Inclusion Criteria

The subject or legally authorized representative must have read, understood, and signed an Institutional Review Board (IRB) approved Informed Consent Form and must be willing and able to comply with study procedures and instructions.

Willing to remain on a stable regimen of treatment during the study.

Your oxygen level is at least 92% when measured while at rest and not using extra oxygen.

Exclusion Criteria

Your lungs' ability to take in carbon monoxide is less than 30% of what is expected.

I am not pregnant or nursing.

I have lung problems not related to Alpha-1 Antitrypsin Deficiency.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of KB408 at low, mid, or high dose levels to evaluate safety and pharmacodynamics

2 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including changes in serum and lung AAT and NE levels

2 months

Treatment Details

Interventions

• KB408

Trial Overview KB408 is a new treatment delivered through nebulization aiming to provide a functional SERPINA1 gene to those with AATD. The study will test three different doses of KB408 in adults, some of whom may also be receiving IV augmentation therapy.

Participant Groups

Group I: Cohort 3a/3b: High dose KB408 Experimental Treatment 1 Intervention

Single dose of KB408 (high dose)

Group II: Cohort 2: Mid dose KB408 Experimental Treatment 1 Intervention

Single dose of KB408 (mid dose)

Group III: Cohort 1: Low dose KB408 Experimental Treatment 1 Intervention

Single dose of KB408 (low dose)

Who Is Running the Clinical Trial?

Krystal Biotech, Inc.

Lead Sponsor

Trials

15

Recruited

770+

Findings from Research

Long-term intravenous augmentation therapy with alpha 1-antitrypsin (alpha 1-AT) is safe and well-tolerated in 443 patients with severe alpha 1-AT deficiency and pulmonary emphysema, with few adverse reactions reported.

The therapy appears to slow the decline in lung function, as indicated by a measured decline in forced expiratory volume in 1 second (delta FEV1) of 57.1 ml per year, which varies based on the patient's initial lung function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Long-term therapy of alpha 1-antitrypsin-deficiency-associated pulmonary emphysema with human alpha 1-antitrypsin]. Wencker, M., Banik, N., Buhl, R., et al.[2009]

A nonrandomized study comparing Danish patients with severe hereditary alpha1-antitrypsin deficiency who did not receive treatment to German patients receiving weekly infusions of alpha1-antitrypsin showed that the treated group had a significantly slower decline in lung function, with an annual decline of 53 mL/year compared to 75 mL/year in the untreated group.

The treatment was particularly effective in patients with an initial forced expiratory volume (FEV1) between 31-65% predicted, where the decline was reduced by 21 mL/year, suggesting that intravenous alpha1-antitrypsin therapy may benefit those with moderate lung impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does alpha1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary alpha1-antitrypsin deficiency? Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL) alpha1-AT study group. Seersholm, N., Wencker, M., Banik, N., et al.[2019]

A randomized clinical trial is feasible for testing intravenous augmentation therapy in patients with alpha 1-antitrypsin deficiency, requiring 147 subjects per treatment arm to detect a significant reduction in FEV(1) decline over 4 years.

To assess a potential 40% reduction in mortality over 5 years, the study would need 342 subjects per treatment arm, highlighting the challenges of recruitment and costs for such trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of a clinical trial of augmentation therapy for alpha(1)-antitrypsin deficiency. The Alpha 1-Antitrypsin Deficiency Registry Study Group. Schluchter, MD., Stoller, JK., Barker, AF., et al.[2007]

Alpha 1-antitrypsin (AAT) augmentation therapy has shown promising efficacy in treating conditions beyond pulmonary emphysema, such as fibromyalgia, systemic vasculitis, and bronchial asthma, based on ten case reports and two clinical trials.

Despite being primarily approved for severe AAT deficiency-related pulmonary emphysema, the therapy has demonstrated success in patients where conventional treatments failed, indicating a need for further research to confirm its safety and efficacy in these other conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of alpha1-antitrypsin augmentation therapy in conditions other than pulmonary emphysema. Blanco, I., Lara, B., de Serres, F.[2021]

In a long-term study of seven patients with Alpha-1-Antitrypsin Deficiency, weekly intravenous augmentation therapy significantly slowed the decline in lung function (FEV1) compared to the three years prior to the program, indicating its efficacy in managing COPD symptoms.

The home care program, 'Alpha-1-Mobile', was found to be safe and well-accepted, with minimal hospitalizations due to exacerbations and no adverse events related to the augmentation therapy, highlighting its practicality for ongoing patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Longterm Homecare Augmentation Program in Alpha-1-Antitrypsin Deficient Patients]. Wilke, A., Semper, H., Gross, C., et al.[2022]

Long-term intravenous augmentation therapy with alpha1-antitrypsin is feasible and safe for patients with severe alpha1-antitrypsin deficiency, as shown in a study of 443 patients with few adverse reactions.

The study found that the decline in lung function (measured by forced expiratory volume in one second) was related to the initial lung function levels, indicating that while therapy is beneficial, the rate of decline varies based on the severity of the disease at baseline.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term treatment of alpha1-antitrypsin deficiency-related pulmonary emphysema with human alpha1-antitrypsin. Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL)-alpha1-AT-study group. Wencker, M., Banik, N., Buhl, R., et al.[2019]

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition that can lead to serious lung and liver diseases, and recent European initiatives aim to improve detection, management, and access to the only treatment available, intravenous AAT therapy.

The European Reference Network for Rare Lung Diseases (ERN-LUNG) and the European Alpha-1 Research Collaboration (EARCO) are working to establish quality control programs and patient registries to enhance understanding and treatment of AATD, including making AAT therapy more accessible and convenient for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Patient-Centric Approaches to the Management of Alpha-1 Antitrypsin Deficiency. Chorostowska-Wynimko, J., Barrecheguren, M., Ferrarotti, I., et al.[2021]

References

1. Germany pubmed.ncbi.nlm.nih.gov

[Long-term therapy of alpha 1-antitrypsin-deficiency-associated pulmonary emphysema with human alpha 1-antitrypsin]. [2009]

2. England pubmed.ncbi.nlm.nih.gov

Does alpha1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary alpha1-antitrypsin deficiency? Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL) alpha1-AT study group. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Feasibility of a clinical trial of augmentation therapy for alpha(1)-antitrypsin deficiency. The Alpha 1-Antitrypsin Deficiency Registry Study Group. [2007]

4. England pubmed.ncbi.nlm.nih.gov

Efficacy of alpha1-antitrypsin augmentation therapy in conditions other than pulmonary emphysema. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

[Longterm Homecare Augmentation Program in Alpha-1-Antitrypsin Deficient Patients]. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Long-term treatment of alpha1-antitrypsin deficiency-related pulmonary emphysema with human alpha1-antitrypsin. Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL)-alpha1-AT-study group. [2019]

7. New Zealand pubmed.ncbi.nlm.nih.gov

New Patient-Centric Approaches to the Management of Alpha-1 Antitrypsin Deficiency. [2021]