SPL84 for Cystic Fibrosis
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: SpliSense Ltd.
Must not be taking: Kalydeco, Orkambi, Symdeko, Trikafta
Disqualifiers: Organ transplantation, Liver disease, others
Prior Safety Data
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?The goal of this clinical trial is to learn if drug SPL84 is safe for adult patients with cystic fibrosis (CF). It will also learn if the drug works to treat works to treat CF with a specific mutation.
The purpose of this research study is to:
* test the safety and effectiveness of multiple doses of the study drug, SPL84
* test how multiple doses of the drug are processed by the body
Researchers will compare drug SPL84 to a placebo (a look-alike substance that contains no drug) to see if drug SPL84 is safe and if it works to treat CF.
Participants will:
Take drug SPL84 or a placebo by inhalation every week for 9 weeks months Visit the clinic approximately 14 times over 17.5 weeks for checkups and tests
Will I have to stop taking my current medications?
You may need to stop taking certain medications like Kalydeco, Orkambi, Symdeko/Symkevi, or Trikafta/Kaftrio at least 30 days before starting the trial. Other CF medications should be on a stable regimen for at least 28 days before screening, and inhaled antibiotics for prophylaxis should be stable for at least 90 days before the trial.
What data supports the effectiveness of the drug SPL84 for cystic fibrosis?
Research shows that SPL84, an inhaled antisense oligonucleotide, effectively reaches the lungs and penetrates cells, improving the function of the CFTR channel, which is crucial for treating cystic fibrosis. Studies in cells from cystic fibrosis patients demonstrate that SPL84 can restore chloride secretion better than some existing treatments.
12345Is SPL84 safe for humans?
SPL84 has undergone a full set of safety and toxicology studies, which support its use in a Phase 1/2 clinical study for cystic fibrosis, indicating it is generally safe for humans.
12678What makes the drug SPL84 unique for treating cystic fibrosis?
SPL84 is unique because it is an inhaled antisense oligonucleotide (a type of genetic material that can block specific genetic instructions) designed specifically for cystic fibrosis patients with the 3849 + 10kb C->T mutation, allowing it to target the disease at a genetic level. This approach is different from traditional treatments that often focus on managing symptoms rather than addressing the underlying genetic cause.
1291011Eligibility Criteria
Adults with cystic fibrosis can join this trial. They'll use an inhaler to take SPL84 or a placebo weekly for over two months and visit the clinic about 14 times in that period. The study will check if they have a specific CF mutation.Inclusion Criteria
FEV1 40-90% predicted at screening.
I have cystic fibrosis with a specific genetic mutation.
Body mass index (BMI) of ≥ 17 kg/m2.
+1 more
Exclusion Criteria
I have not taken Kalydeco, Orkambi, Symdeko/Symkevi, or Trikafta/Kaftrio in the last 30 days.
I have been on a stable CF treatment plan for at least 28 days.
I have not coughed up more than 30 mL of blood in the last 3 months or been hospitalized for coughing up blood in the last 6 months.
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive SPL84 or placebo by inhalation every week for 9 weeks
9 weeks
14 visits (in-person) over 17.5 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial is testing SPL84, a new drug for cystic fibrosis, against a placebo (a substance with no active drug). It aims to determine the safety of multiple doses and how well it treats CF when taken by inhalation.
2Treatment groups
Active Control
Placebo Group
Group I: SPL84Active Control1 Intervention
Group II: PlaceboPlacebo Group1 Intervention
SPL84 is already approved in United States for the following indications:
🇺🇸 Approved in United States as SPL84 for:
- Cystic fibrosis with the 3849+10 kilobase (Kb) C->T splicing mutation
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Alabama at BirminghamBirmingham, AL
Boston Children'S HospitalBoston, MA
Nationwide Children'S HospitalColumbus, OH
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Who Is Running the Clinical Trial?
SpliSense Ltd.Lead Sponsor
References
The safety and toxicity profile of SPL84, an inhaled antisense oligonucleotide for treatment of cystic fibrosis patients with the 3849 +10kb C->T mutation, supports a Phase 1/2 clinical study. [2023]SPL84 is an inhaled antisense oligonucleotide (ASO) in development for the treatment of cystic fibrosis (CF) patients carrying the 3849 + 10kb C->T (3849) mutation. To support the initiation of the first clinical study, a full battery of safety and toxicology studies were performed.
Delivery Characterization of SPL84 Inhaled Antisense Oligonucleotide Drug for 3849 + 10 kb C- > T Cystic Fibrosis Patients. [2023]Recent advances in the therapeutic potential of RNA-related treatments, specifically for antisense oligonucleotide (ASO)-based drugs, have led to increased numbers of ASO regulatory approvals. In this study, we focus on SPL84, an inhaled ASO-based drug, developed for the treatment of the pulmonary disease cystic fibrosis (CF). Pulmonary drug delivery is challenging, due to a variety of biological, physical, chemical, and structural barriers, especially when targeting the cell nucleus. The distribution of SPL84 throughout the lungs, penetration into the epithelial cells and nucleus, and structural stability are critical parameters that will impact drug efficacy in a clinical setting. In this study, we demonstrate broad distribution, as well as cell and nucleus penetration of SPL84 in mouse and monkey lungs. In vivo and in vitro studies confirmed the stability of our inhaled drug in CF patient-derived mucus and in lung lysosomal extracts. The mobility of SPL84 through hyperconcentrated mucus was also demonstrated. Our results, supported by a promising preclinical pharmacological effect of full restoration of cystic fibrosis transmembrane conductance regulator channel activity, emphasize the high potential of SPL84 as an effective drug for the treatment of CF patients. In addition, successfully tackling the lung distribution of SPL84 offers immense opportunities for further development of SpliSense's inhaled ASO-based drugs for unmet needs in pulmonary diseases.
Exon-skipping antisense oligonucleotides for cystic fibrosis therapy. [2022]Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), and the CFTR-W1282X nonsense mutation causes a severe form of CF. Although Trikafta and other CFTR-modulation therapies benefit most CF patients, targeted therapy for patients with the W1282X mutation is lacking. The CFTR-W1282X protein has residual activity but is expressed at a very low level due to nonsense-mediated messenger RNA (mRNA) decay (NMD). NMD-suppression therapy and read-through therapy are actively being researched for CFTR nonsense mutants. NMD suppression could increase the mutant CFTR mRNA, and read-through therapies may increase the levels of full-length CFTR protein. However, these approaches have limitations and potential side effects: because the NMD machinery also regulates the expression of many normal mRNAs, broad inhibition of the pathway is not desirable, and read-through drugs are inefficient partly because the mutant mRNA template is subject to NMD. To bypass these issues, we pursued an exon-skipping antisense oligonucleotide (ASO) strategy to achieve gene-specific NMD evasion. A cocktail of two splice-site-targeting ASOs induced the expression of CFTR mRNA without the premature-termination-codon-containing exon 23 (CFTR-Δex23), which is an in-frame exon. Treatment of human bronchial epithelial cells with this cocktail of ASOs that target the splice sites flanking exon 23 results in efficient skipping of exon 23 and an increase in CFTR-Δex23 protein. The splice-switching ASO cocktail increases the CFTR-mediated chloride current in human bronchial epithelial cells. Our results set the stage for developing an allele-specific therapy for CF caused by the W1282X mutation.
Evidence-based medicine in cystic fibrosis: how should practice change? [2008]This critical review of current practice and research in some aspects of cystic fibrosis (CF) concludes that, despite recent success in prolonging life expectancy, there is still room for improvement in terms of earlier diagnosis and earlier intervention in some of its complications. Specifically, the body of evidence implies that neonatal diagnosis; early attention to nutrition, staphylococcal and pseudomonal infection, and diabetes mellitus; and early treatment with dornase alfa can all be expected to improve patients' quality and quantity of life.
Antisense oligonucleotide-mediated correction of CFTR splicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells. [2020]Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, encoding an anion channel that conducts chloride and bicarbonate across epithelial membranes. Mutations that disrupt pre-mRNA splicing occur in >15% of CF cases. One common CFTR splicing mutation is CFTR c.3718-2477C>T (3849+10 kb C>T), which creates a new 5' splice site, resulting in splicing to a cryptic exon with a premature termination codon. Splice-switching antisense oligonucleotides (ASOs) have emerged as an effective therapeutic strategy to block aberrant splicing. We test an ASO targeting the CFTR c.3718-2477C>T mutation and show that it effectively blocks aberrant splicing in primary bronchial epithelial (hBE) cells from CF patients with the mutation. ASO treatment results in long-term improvement in CFTR activity in hBE cells, as demonstrated by a recovery of chloride secretion and apical membrane conductance. We also show that the ASO is more effective at recovering chloride secretion in our assay than ivacaftor, the potentiator treatment currently available to these patients. Our findings demonstrate the utility of ASOs in correcting CFTR expression and channel activity in a manner expected to be therapeutic in patients.
Evidence of CFTR function in cystic fibrosis after systemic administration of 4-phenylbutyrate. [2022]Most individuals with cystic fibrosis (CF) carry one or two mutations that result in a maturation defect of the full-length protein. One such mutation, deltaF508, results in a mutant membrane glycoprotein that fails to progress to the apical membrane, where the wild-type protein normally functions as a cyclic AMP-regulated chloride channel. 4-Phenylbutyrate (Buphenyl), an orally bioavailable short chain fatty acid, modulates heat shock protein expression and restores maturation of the deltaF508 protein in vitro and in vivo. We performed a randomized, double-blind, placebo-controlled, dose-escalation and safety study of Buphenyl in 19 adults with CF (homozygous deltaF508) to test the hypothesis that Buphenyl would be safe, well-tolerated, and associated with an increase in chloride transport in nasal epithelia. Three dose levels (20, 30, or 40 g divided t.i.d.) of drug or placebo were given for 1 week. Serial measurements of chloride transport by nasal potential difference (NPD) testing and metabolic safety testing were performed. A maximum tolerated dose of 20 g was defined based on minimal adverse reactions, the safety profile, and a statistically significant induction of chloride transport that was maximal by day 3. This short-term phase I/II study demonstrates proof of principle that modulation of deltaF508 CFTR biosynthesis and trafficking is a viable therapeutic approach for cystic fibrosis.
Elexacaftor-tezacaftor-ivacaftor: The new paradigm to treat people with cystic fibrosis with at least one p.Phe508del mutation. [2022]Cystic fibrosis is the most common life-limiting genetic disease in the Caucasian population, with median predicted survival progressively improving up to 50 years, thanks to highly standardized multidisciplinary approach. Patients with p.Phe508del homozygosity usually have poorer lung function and higher mortality rates per year than other groups. By reason of that, this population has been among the most eligible target of the cystic fibrosis transmembrane conductance regulator (CFTR) modulators, a new class of drugs that can partially restore CFTR function by the correction of CFTR misfolding and trafficking to the cell surface. This narrative review summarizes the current preclinical and clinical evidence of the triple combination of elexacaftor-tezacaftor-ivacaftor, the new benchmark among highly effective CFTR modulators. It provides details on the efficacy and safety that led to drug regulation and approval and discusses future developments in clinical and translational research.
Efficacy and Safety of Elexacaftor-Tezacaftor-Ivacaftor in the Treatment of Cystic Fibrosis: A Systematic Review. [2023]Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) is a new CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) modulator treatment, used over the last few years, which has shown an improvement in different clinical outcomes in patients with cystic fibrosis (CF). The objective of this study was a systematic research of the literature on the efficacy and safety of this CFTR modulator on patients with CF. A search of Pubmed was conducted for randomized clinical trials and observational studies published from 2012 to September 2022. The included full manuscripts comprised nine clinical trials and 16 observational studies, whose participants were aged ≥12 years or were children 6-11 years old with at least one Phe508del mutation and/or advanced lung disease (ALD). These studies reported that ELX/TEZ/IVA has a significant positive effect on the lung function of patients with CF, by ameliorating parameters such as FEV1, LCI, pulmonary exacerbations or sweat chloride concentration, increasing BMI and improving quality of their life. Its role in cystic fibrosis-related diabetes (CFRD) is not yet clear. It was found that this new CFTR modulator has an overall favorable safety profile, with mild to moderate adverse events. Further studies are needed for a deeper understanding of the impact of CFTR modulators on other CF manifestations, or the possibility of treating with ELX/TEZ/IVA CF patients with rare CFTR mutations.
IL8 gene as modifier of cystic fibrosis: unraveling the factors which influence clinical variability. [2019]The severity of cystic fibrosis (CF) is associated with classes of mutations in the CFTR gene (cystic fibrosis transmembrane regulator), physical environment and modifier genes interaction. The IL8 gene (interleukin 8), according to its respective polymorphisms, influences inflammatory responses. This study analyzed IL8 gene polymorphisms (rs4073, rs2227306 and rs2227307), by means of PCR/RFLP, and their association with pulmonary function markers and clinical severity scores in 186 patients with CF, considering the CFTR genotype. There was an association between rs2227307 and precocity of the disease. The severity of lung disease was associated with the following markers: transcutaneous arterial hemoglobin oxygen saturation (SaO2) (regardless of CFTR genotype, for the polymorphisms rs4073, rs2227306 and rs2227307); mucoid Pseudomonas aeruginosa (regardless of CFTR genotype, for the polymorphisms rs2227306 and rs2227307). Pulmonary function markers (SaO2 and spirometric variables) and clinical severity scores were also associated with IL8 gene polymorphisms. This study identified the IL8 gene, represented by rs4073 and rs2227306 polymorphisms, and particularly the rs2227307 polymorphism, as potentiating factors for the degree of variability in the severity of CF, especially in pulmonary clinical manifestation correlated with increased morbidity and mortality.
The phospholipid flippase ATP8B1 mediates apical localization of the cystic fibrosis transmembrane regulator. [2018]Progressive familial intrahepatic cholestasis type 1 (PFIC1) is caused by mutations in the gene encoding the phospholipid flippase ATP8B1. Apart from severe cholestatic liver disease, many PFIC1 patients develop extrahepatic symptoms characteristic of cystic fibrosis (CF), such as pulmonary infection, sweat gland dysfunction and failure to thrive. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel essential for epithelial fluid transport. Previously it was shown that CFTR transcript levels were strongly reduced in livers of PFIC1 patients. Here we have investigated the hypothesis that ATP8B1 is important for proper CFTR expression and function. We analyzed CFTR expression in ATP8B1-depleted intestinal and pulmonary epithelial cell lines and assessed CFTR function by measuring short-circuit currents across transwell-grown ATP8B1-depleted intestinal T84 cells and by a genetically-encoded fluorescent chloride sensor. In addition, we studied CFTR surface expression upon induction of CFTR transcription. We show that CFTR protein levels are strongly reduced in the apical membrane of human ATP8B1-depleted intestinal and pulmonary epithelial cell lines, a phenotype that coincided with reduced CFTR activity. Apical membrane insertion upon induction of ectopically-expressed CFTR was strongly impaired in ATP8B1-depleted cells. We conclude that ATP8B1 is essential for correct apical localization of CFTR in human intestinal and pulmonary epithelial cells, and that impaired CFTR localization underlies some of the extrahepatic phenotypes observed in ATP8B1 deficiency.
Characterization of the cystic fibrosis transmembrane conductance regulator in a colonocyte cell line. [2019]An anti-peptide antibody raised to the C-terminal sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) was used to examine CFTR immunoreactivity in the T84 colonocyte cell line. Immunoblots of T84 cell lysates detected CFTR as a 170-kDa protein that appeared as a broad band or doublet in SDS/PAGE. This protein comigrated with the predominant immunoblot signal detected in human pancreas and colon. An equivalent protein was detected as a prominent substrate for protein kinase A and for protein kinase C in T84 cell immunoprecipitates with this antibody. The immunoprecipitated protein resembled the protein detected by immunoblot in that both proteins showed the same change in electrophoretic mobility after digestion by N-Glycanase. The precipitated protein was indentified as CFTR by two criteria. First, the same protein was immunoprecipitated with an antibody to a different CFTR peptide, [Lys102]CFTR-(102-116). Second, two-dimensional phosphopeptide mapping was used to compare the immunoprecipitated protein with a bacterially expressed protein known to contain most of the predicted protein kinase A phosphorylation sites in CFTR. Because the six most prominent peptides in each map were equivalent, these maps confirm that the precipitated protein is CFTR. By using these antibodies for immunofluorescence and immunoperoxidase staining, CFTR was localized to the apical region of T84 cells grown in tumors and in monolayers. Thus, T84 cells express CFTR at sufficient levels to permit identification and immunochemical studies of this protein in its endogenously occurring form.