Nebulized KB408 for Alpha-1 Antitrypsin Deficiency

(Serpentine-1 Trial)

Recruiting at 2 trial locations

Overseen By David Sweet, MD, PhD

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

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called KB408 for individuals with alpha-1 antitrypsin deficiency (AATD), a condition that can cause lung problems. The trial aims to assess the treatment's safety and effectiveness. Participants will receive varying doses of KB408 through a nebulizer, a device that turns medicine into a breathable mist. Ideal candidates for this trial have a confirmed genetic diagnosis of AATD, are not currently experiencing a lung flare-up, and can pause certain other treatments if necessary. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

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.

Is there any evidence suggesting that KB408 is likely to be safe for humans?

Research has shown that KB408, a new treatment for alpha-1 antitrypsin deficiency (AATD), appears promising in early studies. This treatment uses a special virus to deliver beneficial genes directly to the lungs, aiming to assist individuals with AATD, a condition affecting the lungs and liver.

In an earlier study, the treatment was well-tolerated, with no serious side effects reported. Most participants did not require hospital care due to the treatment, and there were no major issues. As this trial is in an early stage, the primary focus is on safety, and the results have been positive so far. Although much remains to be learned, early findings suggest that KB408 could be a safe option for individuals with AATD. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about KB408 for Alpha-1 Antitrypsin Deficiency because it offers a new delivery method—nebulization—that could directly target the lungs where the deficiency causes the most damage. Unlike current treatments, which often involve intravenous infusions of the missing protein, KB408 is administered via inhalation, potentially allowing for more efficient and convenient delivery. This approach might improve lung function more effectively by delivering the treatment directly to the site of need, providing a promising alternative to existing therapies.

What evidence suggests that KB408 might be an effective treatment for alpha-1 antitrypsin deficiency?

Research has shown that KB408 could be a promising treatment for alpha-1 antitrypsin deficiency (AATD). This trial will evaluate different doses of KB408, which uses a virus to deliver a healthy version of the gene needed to produce alpha-1 antitrypsin, a protein that protects the lungs. Early results suggest that KB408 has been safe and well-tolerated by patients. Specifically, for patients with a certain level of lung function, the treatment slowed the worsening of their lung function. Laboratory studies also support the potential of KB408 to improve lung health in AATD. This new approach could offer hope for people with AATD. ^{1 2 4 6 7}

Who Is on the Research Team?

David Sweet, MD, PhD

Principal Investigator

Director of Clinical Development

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Single dose of KB408 (high dose)

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

Multiple doses of KB408 (mid dose)

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

Single dose of KB408 (mid dose)

Group IV: 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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06049082

A Study of KB408 for the Treatment of Alpha-1 Antitrypsin ... Clinically stable and in good general health, except for AATD, as determined by the Investigator. Exclusion Criteria: Pulmonary function test with percent ...

2. ir.krystalbio.com ir.krystalbio.com/news-releases/news-release-details/krystal-biotech-announces-initial-clinical-update-rare

Krystal Biotech Announces Initial Clinical Update for Rare ... Both KB408 for AATD patients and KB407 for patients with cystic fibrosis were safe and well tolerated at all dosing regimens evaluated to date.

3. withpower.com withpower.com/trial/phase-1-alpha-1-antitrypsin-deficiency-2024-3b9be

Nebulized KB408 for Alpha-1 Antitrypsin Deficiency The treatment was particularly effective in patients with an initial forced expiratory volume (FEV1) between 31-65% predicted, where the decline was reduced by ...

4. rarediseaseadvisor.com rarediseaseadvisor.com/news/fda-clears-ind-kb408-aatd-treatment/

FDA Clears IND Application for KB408 in Treating Patients ... The FDA has cleared the Investigational New Drug (IND) Application for KB408 for the treatment of alpha-1 antitrypsin deficiency (AATD).

5. ir.krystalbio.com ir.krystalbio.com/static-files/9e0358dc-9ed6-41b4-930c-8ba245674186

Preclinical pharmacology of KB408, an HSV-1-based gene ... Taken together, these data provide strong support for the potential of inhaled KB408 as a novel gene therapy candidate for the treatment of AATD lung disease.

6. scge.mcw.edu scge.mcw.edu/platform/data/clinicalTrials/report/NCT06049082

A Study of KB408 for the Treatment of Alpha-1 Antitrypsin ... ... alpha-1 antitrypsin deficiency (AATD) via nebulization. This study is designed to evaluate safety and pharmacodynamics of KB408 in adults ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11999460/

Alpha-1 antitrypsin deficiency-associated liver disease We present both cross-sectional and longitudinal data informing about the natural disease history and noninvasive tools that can be used for ...