SPL84 for Cystic Fibrosis

Recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: SpliSense Ltd.

Must not be taking: Kalydeco, Orkambi, Symdeko, Trikafta

Disqualifiers: Organ transplantation, Liver disease, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 14

Duration: 9 weeks

24 Participants Needed

What You Need to Know Before You Apply

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.

Is 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. ^{1 2 3 4 5}

What 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. ^{1 3 6 7 8}

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. ^{1 3 9 10 11}

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• SPL84

Trial Overview 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.

How Is the Trial Designed?

Group I: SPL84 Active Control 1 Intervention

Group II: Placebo Placebo Group 1 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

Who Is Running the Clinical Trial?

SpliSense Ltd.

Lead Sponsor

Trials

2

Recruited

60+

Published Research Related to This Trial

SPL84, an inhaled antisense oligonucleotide for cystic fibrosis, showed no adverse effects in preclinical safety studies conducted on mice and monkeys, indicating a strong safety profile.

The no observed adverse effect level (NOAEL) was established at the highest doses tested, providing a safety margin of approximately 40 times the proposed starting clinical dose, which supports its progression to clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Friedman, L., Avitzur, OB., Galai, EO., et al.[2023]

SPL84, an inhaled antisense oligonucleotide (ASO) drug for cystic fibrosis, shows broad distribution and effective penetration into lung epithelial cells and nuclei in both mouse and monkey models, indicating its potential efficacy.

The drug demonstrated stability in CF patient-derived mucus and successfully navigated through thick mucus, suggesting it could effectively restore cystic fibrosis transmembrane conductance regulator (CFTR) channel activity, making it a promising treatment option for CF patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delivery Characterization of SPL84 Inhaled Antisense Oligonucleotide Drug for 3849 + 10 kb C- > T Cystic Fibrosis Patients. Ozeri-Galai, E., Friedman, L., Barchad-Avitzur, O., et al.[2023]

A new strategy using a cocktail of antisense oligonucleotides (ASOs) successfully skips exon 23 of the CFTR gene, leading to increased production of a functional CFTR protein in cells with the W1282X mutation, which is associated with severe cystic fibrosis.

This approach enhances CFTR-mediated chloride current in human bronchial epithelial cells, suggesting a promising avenue for developing targeted therapies for patients with the W1282X mutation, overcoming limitations of current treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exon-skipping antisense oligonucleotides for cystic fibrosis therapy. Kim, YJ., Sivetz, N., Layne, J., et al.[2022]

Early diagnosis of cystic fibrosis (CF) in newborns can significantly enhance both the quality and quantity of life for patients.

Interventions such as improved nutrition, management of infections, diabetes care, and early treatment with dornase alfa are crucial for better health outcomes in CF patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence-based medicine in cystic fibrosis: how should practice change? Conway, SP.[2008]

A splice-switching antisense oligonucleotide (ASO) targeting the common CFTR splicing mutation (c.3718-2477C>T) effectively blocks abnormal splicing in primary bronchial epithelial cells from cystic fibrosis patients, leading to long-term improvements in CFTR activity.

The ASO treatment resulted in better recovery of chloride secretion compared to ivacaftor, a current treatment option, suggesting that ASOs could be a promising therapeutic strategy for correcting CFTR function in cystic fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antisense oligonucleotide-mediated correction of CFTR splicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells. Michaels, WE., Bridges, RJ., Hastings, ML.[2020]

In a study involving 19 adults with cystic fibrosis carrying the deltaF508 mutation, the drug 4-Phenylbutyrate (Buphenyl) was found to be safe and well-tolerated, with a maximum tolerated dose established at 20 g due to minimal adverse reactions.

Buphenyl treatment resulted in a statistically significant increase in chloride transport in nasal epithelia, demonstrating its potential to improve the function of the defective CFTR protein in cystic fibrosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence of CFTR function in cystic fibrosis after systemic administration of 4-phenylbutyrate. Zeitlin, PL., Diener-West, M., Rubenstein, RC., et al.[2022]

The triple combination therapy of elexacaftor-tezacaftor-ivacaftor has shown significant efficacy in improving lung function and survival rates in cystic fibrosis patients, particularly those with the p.Phe508del mutation, which is associated with poorer outcomes.

This review highlights the safety and effectiveness of these CFTR modulators, which work by correcting the misfolding of the CFTR protein, and discusses their regulatory approval and potential future research directions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elexacaftor-tezacaftor-ivacaftor: The new paradigm to treat people with cystic fibrosis with at least one p.Phe508del mutation. Gramegna, A., Contarini, M., Bindo, F., et al.[2022]

Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) significantly improves lung function and quality of life in cystic fibrosis patients, as shown in a systematic review of 9 clinical trials and 16 observational studies involving participants aged 6-11 and older with specific genetic mutations.

The treatment has a favorable safety profile, with mostly mild to moderate side effects, although its effects on cystic fibrosis-related diabetes remain unclear and further research is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Elexacaftor-Tezacaftor-Ivacaftor in the Treatment of Cystic Fibrosis: A Systematic Review. Kapouni, N., Moustaki, M., Douros, K., et al.[2023]

The study of 186 cystic fibrosis patients found that specific polymorphisms in the IL8 gene, particularly rs2227307, are linked to the severity and early onset of the disease, suggesting a genetic influence on disease progression.

Pulmonary function markers, such as oxygen saturation and spirometric variables, were associated with IL8 gene polymorphisms, indicating that these genetic variations may contribute to the variability in lung disease severity and overall clinical outcomes in cystic fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL8 gene as modifier of cystic fibrosis: unraveling the factors which influence clinical variability. Furlan, LL., Marson, FA., Ribeiro, JD., et al.[2019]

Mutations in the ATP8B1 gene, which causes Progressive familial intrahepatic cholestasis type 1 (PFIC1), lead to significantly reduced levels of the CFTR protein in the apical membrane of intestinal and pulmonary cells, which is crucial for proper function.

The study demonstrates that ATP8B1 is essential for the correct localization of CFTR, suggesting that the extrahepatic symptoms seen in PFIC1 patients, similar to those in cystic fibrosis, may be due to impaired CFTR function caused by ATP8B1 deficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The phospholipid flippase ATP8B1 mediates apical localization of the cystic fibrosis transmembrane regulator. van der Mark, VA., de Jonge, HR., Chang, JC., et al.[2018]

The study successfully identified and characterized the cystic fibrosis transmembrane conductance regulator (CFTR) protein in T84 colonocyte cells, confirming its presence as a 170-kDa protein that behaves similarly to CFTR found in human pancreas and colon.

CFTR was localized to the apical region of T84 cells, indicating that these cells express sufficient levels of CFTR for further immunochemical studies, which could aid in understanding its role in cystic fibrosis and related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of the cystic fibrosis transmembrane conductance regulator in a colonocyte cell line. Cohn, JA., Nairn, AC., Marino, CR., et al.[2019]

Citations

1. England pubmed.ncbi.nlm.nih.gov

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]

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

Delivery Characterization of SPL84 Inhaled Antisense Oligonucleotide Drug for 3849 + 10 kb C- > T Cystic Fibrosis Patients. [2023]

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

Exon-skipping antisense oligonucleotides for cystic fibrosis therapy. [2022]

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

Evidence-based medicine in cystic fibrosis: how should practice change? [2008]

5. England pubmed.ncbi.nlm.nih.gov

Antisense oligonucleotide-mediated correction of CFTR splicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells. [2020]

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

Evidence of CFTR function in cystic fibrosis after systemic administration of 4-phenylbutyrate. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Elexacaftor-tezacaftor-ivacaftor: The new paradigm to treat people with cystic fibrosis with at least one p.Phe508del mutation. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Elexacaftor-Tezacaftor-Ivacaftor in the Treatment of Cystic Fibrosis: A Systematic Review. [2023]

9. Germany pubmed.ncbi.nlm.nih.gov

IL8 gene as modifier of cystic fibrosis: unraveling the factors which influence clinical variability. [2019]

10. Netherlands pubmed.ncbi.nlm.nih.gov

The phospholipid flippase ATP8B1 mediates apical localization of the cystic fibrosis transmembrane regulator. [2018]

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

Characterization of the cystic fibrosis transmembrane conductance regulator in a colonocyte cell line. [2019]