Nebulized KB407 for Cystic Fibrosis
Recruiting in Palo Alto (17 mi)
+3 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Krystal Biotech, Inc.
Disqualifiers: Organ transplant, Substance abuse, Asthma, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
This study will evaluate safety and tolerability of ascending doses of nebulized KB407 in adults with cystic fibrosis.
Will I have to stop taking my current medications?
The trial does not specify if you must stop taking your current medications, but you cannot start any new chronic therapies or change existing ones (except for pancreatic enzyme replacement therapy) within 28 days before the first dose.
What data supports the effectiveness of the drug KB407 for Cystic Fibrosis?
Research on a similar compound, c407, shows it can improve the function of the CFTR protein, which is often defective in Cystic Fibrosis patients. This improvement was observed in mice with the common F508del mutation, suggesting potential benefits for human patients with similar genetic profiles.12345
How does the drug KB407 differ from other cystic fibrosis treatments?
KB407 is unique because it is delivered through a nebulizer, which can enhance drug delivery to the lungs by producing smaller aerosol particles that reach the lower respiratory tract more effectively. This method may improve the clinical benefits of the treatment compared to traditional nebulizers, which are often inefficient.678910
Eligibility Criteria
Adults with cystic fibrosis who understand and agree to the study's procedures can join. They must have a confirmed diagnosis, stable health, specific lung function levels, normal oxygen saturation without assistance, and two CFTR gene mutations. Excluded are those recently ill or hospitalized, vaccinated close to treatment start, on certain antibiotics recently or with conditions that could affect safety assessments.Inclusion Criteria
I have two CFTR gene mutations causing my condition.
The subject must have read, understood, and signed an Institutional Review Board/Ethics Committee (IRB/IEC) approved Informed Consent Form and must be able to and willing to follow study procedures and instructions
I am 18 years old or older.
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Exclusion Criteria
I have not been vaccinated within 72 hours before starting treatment and have no plans for vaccination during treatment.
I haven't been hospitalized or had a significant infection in the last 14 days.
I cannot undergo a bronchoscopy as per my doctor's advice.
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive ascending doses of nebulized KB407
2 months
Multiple visits for administration and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Treatment Details
Interventions
- KB407 (Virus Therapy)
Trial OverviewThe trial is testing KB407 through nebulization to see how safe it is and how well people tolerate different doses. It's for adults with cystic fibrosis. Participants will receive ascending doses of KB407 via a nebulizer which turns liquid medication into a mist.
Participant Groups
3Treatment groups
Experimental Treatment
Group I: Cohort 3 (open label)Experimental Treatment1 Intervention
Four administrations of KB407
Group II: Cohort 2 (open label)Experimental Treatment1 Intervention
Two administrations of KB407
Group III: Cohort 1 (open label)Experimental Treatment1 Intervention
A single administration of KB407
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Florida, GainesvilleGainesville, FL
Atrium Health Wake Forest Baptist Medical CenterWinston-Salem, NC
Yale University School of MedicineNew Haven, CT
The Cystic Fibrosis InstituteNorthfield, IL
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Who Is Running the Clinical Trial?
Krystal Biotech, Inc.Lead Sponsor
References
Systemic bis-phosphinic acid derivative restores chloride transport in Cystic Fibrosis mice. [2022]Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) are responsible for Cystic Fibrosis (CF). The most common CF-causing mutation is the deletion of the 508th amino-acid of CFTR (F508del), leading to dysregulation of the epithelial fluid transport in the airway's epithelium and the production of a thickened mucus favoring chronic bacterial colonization, sustained inflammation and ultimately respiratory failure. c407 is a bis-phosphinic acid derivative which corrects CFTR dysfunction in epithelial cells carrying the F508del mutation. This study aimed to investigate c407 in vivo activity in the F508del Cftrtm1Eur murine model of CF. Using nasal potential difference measurement, we showed that in vivo administration of c407 by topical, short-term intraperitoneal and long-term subcutaneous route significantly increased the CFTR dependent chloride (Cl-) conductance in F508del Cftrtm1Eur mice. This functional improvement was correlated with a relocalization of F508del-cftr to the apical membrane in nasal epithelial cells. Importantly, c407 long-term administration was well tolerated and in vitro ADME toxicologic studies did not evidence any obvious issue. Our data provide the first in vivo preclinical evidence of c407 efficacy and absence of toxicity after systemic administration for the treatment of Cystic Fibrosis.
Treatment strategies for cystic fibrosis: what's in the pipeline? [2019]Cystic fibrosis (CF) is an inherited disease, characterised by pancreatic malabsorption (with poor growth) and impaired mucociliary clearance (leading to recurrent pulmonary infection). The prognosis has markedly improved over the last 40 years. This was achieved initially by improving pancreatic enzyme supplements and more recently through drugs designed to treat pulmonary infection, reduce inflammation and enhance mucociliary clearance. The CF gene has been sequenced, allowing new therapeutic targets to be identified. Currently the greatest therapeutic challenges are to correct the biochemical defect of CF and to identify effective treatments for chronic respiratory infection. This review provides an overview of CF, the treatment strategies currently used, and new drugs undergoing clinical trials.
Pooled analysis of two large randomised phase III inhaled mannitol studies in cystic fibrosis. [2016]To evaluate safety and efficacy of inhaled mannitol treatment in subgroups of a large global CF population.
Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles. [2023]Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR) that result in diminished quantity and/or function of the CFTR anion channel. F508del-CFTR, the most common CF-causing mutation (found in ∼90% of patients), causes severe processing and trafficking defects, resulting in decreased CFTR quantity and function. CFTR modulators are medications that increase the amount of mature CFTR protein (correctors) or enhance channel function (potentiators) at the cell surface. Combinations of CFTR correctors and potentiators (i.e. lumacaftor/ivacaftor, tezacaftor/ivacaftor) have demonstrated clinical benefit in subsets of patients. However, none are approved for patients with CF heterozygous for F508del-CFTR and a minimal function mutation, i.e. a mutation that produces either no protein or protein that is unresponsive to currently approved CFTR modulators. Next-generation CFTR correctors VX-659 and VX-445, each in triple combination with tezacaftor and ivacaftor, improve CFTR processing, trafficking and function in vitro and have demonstrated clinical improvements in phase 2 studies in patients with CF with one or two F508del-CFTR alleles. Here, we present the rationale and design of four randomised phase 3 studies, and their open-label extensions, evaluating VX-659 (ECLIPSE) or VX-445 (AURORA) plus tezacaftor and ivacaftor in patients with one or two F508del-CFTR alleles.
Targeted therapies to improve CFTR function in cystic fibrosis. [2022]Cystic fibrosis is the most common genetically determined, life-limiting disorder in populations of European ancestry. The genetic basis of cystic fibrosis is well established to be mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for an apical membrane chloride channel principally expressed by epithelial cells. Conventional approaches to cystic fibrosis care involve a heavy daily burden of supportive treatments to combat lung infection, help clear airway secretions and maintain nutritional status. In 2012, a new era of precision medicine in cystic fibrosis therapeutics began with the licensing of a small molecule, ivacaftor, which successfully targets the underlying defect and improves CFTR function in a subgroup of patients in a genotype-specific manner. Here, we review the three main targeted approaches that have been adopted to improve CFTR function: potentiators, which recover the function of CFTR at the apical surface of epithelial cells that is disrupted in class III and IV genetic mutations; correctors, which improve intracellular processing of CFTR, increasing surface expression, in class II mutations; and production correctors or read-through agents, which promote transcription of CFTR in class I mutations. The further development of such approaches offers great promise for future therapeutic strategies in cystic fibrosis.
Choosing a nebulizer for cystic fibrosis applications. [2019]As the number of inhaled drugs available for cystic fibrosis grows, there is increasing awareness of delivery device issues. Current jet and ultrasonic nebulizers are inefficient at delivering drugs to the lower respiratory tract. There are large differences in output characteristics between nebulizers and high intersubject variability in lung deposition. The clinical effects of inhaled drugs depend on adequate dosing to the lower airway, so we must choose a nebulizer and patient characteristics that will affect lung deposition positively. Aerosols with particle sizes at the smaller end of the respirable range (2 to 3 microns) may enhance the clinical benefit of some drugs, regardless of patient age or disease severity. Breath-enhanced (Venturi) jet nebulizers are less wasteful than constant-output nebulizers and perform better than conventional nebulizers with many drugs. Patient breathing patterns and degree of airway obstruction are important in determining the site of airway deposition. With increased attention to aerosol delivery issues by clinicians, industry, and regulatory agencies, improved technologies will evolve to target therapies to the lung.
In vitro evaluation of positive expiratory pressure devices attached to nebulizers. [2019]Patients with cystic fibrosis perform airway clearance techniques and receive nebulized medications on a regular basis. Some positive expiratory pressure (PEP) devices allow concomitant administration of aerosol. I hypothesized that this practice alters the aerosol characteristics and patient dose. I compared the aerosol characteristics and patient dose of nebulized albuterol from 2 types of nebulizer, alone and when connected to different PEP and vibratory PEP devices.
A comparison of amount and speed of deposition between the PARI LC STAR® jet nebulizer and an investigational eFlow® nebulizer. [2011]The potency and physical properties of many of the drugs used in the treatment of cystic fibrosis necessitates the use of nebulization, a relatively time-consuming pulmonary delivery method. Newer, faster, and more efficient delivery systems are being proposed. The purposes of this study was to compare the length of time it took to deliver the equivalent of normal saline nebulized for 10 min in a PARI LC STAR(®) nebulizer to that of an investigational PARI eFlow(®).
Nebulizer Care and Inhalation Technique in Children with Cystic Fibrosis. [2020]Nebulizers are used by the great majority of cystic fibrosis patients for delivery of cornerstone treatments. Inhalation technique and adequate disinfection and maintenance are important for optimizing medication delivery. In this study, inhalation technique and nebulizer disinfection/maintenance were assessed in cystic fibrosis patients by direct observation in clinic and completion of a scoring sheet. A total of 108 patients were recruited. The maximum inhalation technique score was attained by 30.5% and adequate inhalation technique score by 74.08% of patients. The inhalation technique score was best with the vibrating mesh nebulizer (p = 0.038), while patient age and number of nebulized medications did not affect ITS significantly (p > 0.05). Nebulizer disinfection/maintenance score was excellent in only 31.48%. Most families kept the nebulizer clean and used appropriate disinfection method, but only half of them replaced the nebulizer and nebulizer cup at the recommended time intervals. Nebulizer disinfection/maintenance score was positively affected by a number of nebulized medications and negatively by years of equipment use (p = 0.009 and p = 0.001, respectively). Even though inhalation technique and disinfection/maintenance practices were found to be adequate in a large proportion of cases, there is still a need for regular review and education. The type of nebulizer was associated with improved inhalation technique, but more data are required before making specific recommendations.
Effect of dry powder inhaler resistance on the inspiratory flow rates and volumes of cystic fibrosis patients of six years and older. [2007]Several inhaled drugs for use by cystic fibrosis (CF) patients are formulated for nebulizer use only. This therapy is time consuming and includes the risk of contamination of the nebulizers. Dry powder inhalers (DPI) can be an attractive alternative for CF drugs. Inhaled flow rate and volume, and the device resistance are important determinants for optimal dispersion of drug from a DPI. It is important to understand how these variables interact in the CF population in order to properly design a new DPI formulation targeted for these patients. The objective of this study was to assess the inspiratory variables of a representative population of CF subjects 6 years and older with varying degrees of lung disease while inhaling through resistances that simulate DPI devices. Ninety-six stable CF patients were enrolled, ages 6-54 years, FEV(1) 19-126% predicted. Subjects inhaled forcefully through four different resistances (0.019, 0.024, 0.038, and 0.048 kP(0.5)/LPM, respectively), while inspiratory time (IT(DPI)), peak inspiratory flow (PIF(DPI)), and volumes (V(DPI)) were measured. For any resistance, inspired V(DPI) increased with the older age groups; PIF(DPI) was similar between adults and adolescents but lower in the children. Subjects with lower FEV(1) had lower V(DPI) and PIF(DPI). As resistance increased, PIF(DPI) decreased, IT(DPI) increased, with no significant change in V(DPI). At the lowest resistance mean PIF(DPI) was 105 LPM (range 45-163) for all patients; 112 LPM (range 75-163) in adults; and 89 LPM (45-126) in children. Mean inspired V(DPI) was 1.75 L for all patients; 2.2 L (0.8-3.7) in adults; and 1.2 L (0.5-1.8) in children. At the lowest resistance a minimal flow rate of 30, 45, and 60 LPM was attained in 100%, 99%, and 96% of all patients. Volumes of 1.0, 1.5, and 2.0 L were attained by 85%, 57%, and 30% of the patients. At the highest resistance mean PIF(DPI) was 52 LPM (range 26-70) for all patients; 55 LPM (40-70) in adults; and 47 LPM (26-62) in children. Mean inspired V(DPI) was 1.5 L in all patients; 1.9 L (0.9-3.5) in adults and 1.1 L (0.5-2.3) in children. At the highest resistance, a minimal flow rate of 30, 45, and 60 LPM was attained in 99%, 80%, and 22% of all patients. Volumes of 1, 1.5, and 2 L were attained in 84%, 45%, and 23% of the patients. We defined ranges for inspiratory variables in a diverse CF population for a range of device resistances that bracket those of current DPIs. The recorded inspiratory patterns can be used on the bench to design and test new dry powder formulations and devices to target the largest proportion of the CF population.