SpliSense Advances Cystic Fibrosis Treatment with Phase IIb Trial of Inhaled Antisense Therapy SPL84

TEL AVIV, ISRAEL – [Current Date] – SpliSense, a clinical-stage biotechnology company dedicated to developing innovative RNA-based therapies for genetic diseases, has announced the commencement of a pivotal Phase IIb clinical trial for its lead candidate, SPL84. This inhaled antisense oligonucleotide (ASO) therapy is specifically designed to address a challenging genetic mutation in cystic fibrosis (CF) patients, the 3849+10 kilobase (Kb) C>T mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The trial marks a significant step forward in precision medicine for CF, particularly for patients who may not achieve optimal benefits from existing modulator therapies alone.

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The ongoing placebo-controlled, double-blind, randomised study, designated SPL84-002, aims to recruit approximately 40 participants globally. These individuals must carry at least one copy of the specific 3849+10kb C>T mutation and already be receiving stable treatment with commercially available CFTR modulator therapies such as Trikafta, Kaftrio, or Alyftrek. The primary objective of this Phase IIb segment is to rigorously assess the safety and tolerability of SPL84, building upon promising earlier data. SpliSense anticipates releasing top-line results from this crucial study in the second half of 2027, a timeline eagerly awaited by the CF community and investors alike.

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Main Facts: A New Horizon for Targeted CF Therapy

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Cystic Fibrosis remains a debilitating, life-shortening genetic disorder primarily affecting the lungs and digestive system. While groundbreaking CFTR modulator therapies have revolutionized treatment for many patients, a significant number still face challenges, either due to their specific genetic mutations rendering modulators ineffective or achieving only partial symptom improvement. SpliSense’s SPL84 represents a novel approach, leveraging antisense oligonucleotide technology to correct a specific splicing defect caused by the 3849+10kb C>T mutation, which affects the production of functional CFTR protein.

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The initiation of the Phase IIb trial is a direct progression from a successful Phase IIa segment, which demonstrated a favorable safety profile and encouraging signs of clinical activity. Notably, the company reported that up to 70% of participants in the earlier phase experienced at least a five-point improvement in lung function from baseline, a clinically meaningful outcome in CF. This next phase is strategically designed to evaluate SPL84’s efficacy as an add-on therapy, examining its potential to provide additional clinical benefit for patients already on standard-of-care CFTR modulators.

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The study protocol involves participants being randomised in a 4:1 ratio to receive either 50mg of SPL84 or a placebo via inhalation once weekly for a duration of 12 weeks. Beyond safety, the trial will delve into a comprehensive array of secondary and exploratory endpoints, including detailed assessments of lung function (ppFEV1 and ppFEF25–75), respiratory symptoms measured by the cystic fibrosis questionnaire–revised (CFQ-R) respiratory domain scores, sputum microbiology, and the Lung Clearance Index. These multifaceted evaluations aim to provide a holistic understanding of SPL84’s impact on patient health and disease progression.

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SpliSense’s commitment to addressing this specific patient population underscores a broader trend in rare disease drug development: the pursuit of highly targeted, mutation-specific therapies that can complement or even supersede existing treatments. With regulatory designations such as Fast Track and Orphan Drug status from the US Food and Drug Administration (FDA), and PRIME designation from the European Medicines Agency (EMA), SPL84 is recognized for its potential to fill a critical unmet medical need, signaling a collaborative effort between industry and regulatory bodies to accelerate promising therapies to patients.

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Chronology: From Concept to Clinical Advancement

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The journey of SPL84 is a testament to the persistent scientific endeavor required to translate complex genetic insights into tangible therapeutic solutions. The development of SPL84 began with a deep understanding of the 3849+10kb C>T mutation. This particular mutation is a "splicing mutation," meaning it disrupts the normal process by which messenger RNA (mRNA) is processed to produce the CFTR protein. Instead of producing a full, functional protein, the mutation leads to the inclusion of a "cryptic exon," resulting in a truncated and non-functional CFTR protein. Antisense oligonucleotides like SPL84 are designed to precisely target this splicing error, guiding the cellular machinery to correctly process the mRNA and restore the production of functional CFTR protein.

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Early Research and Preclinical Development: Years of meticulous laboratory research and preclinical studies laid the groundwork for SPL84. These foundational stages involved identifying the optimal ASO sequence, demonstrating its ability to correct the splicing defect in cellular and animal models, and establishing its safety profile before human trials could commence. The inhaled delivery mechanism was chosen to directly target the lungs, the primary organ affected by CF and where a localized therapeutic effect would be most beneficial.

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Phase I/IIa Clinical Trials: The first-in-human studies, comprising Phase I and Phase IIa segments, were crucial for establishing initial safety and proof-of-concept. The Phase I portion typically focuses on dose escalation and pharmacokinetics in healthy volunteers or a small cohort of patients. The subsequent Phase IIa segment, as referenced by SpliSense, involved a larger group of CF patients with the 3849+10kb C>T mutation. It was during this phase that SPL84 reportedly demonstrated its favorable safety profile and, critically, showed early signs of clinical activity. The observation that up to 70% of participants experienced a five-point improvement in lung function (likely measured by ppFEV1, a standard metric) from baseline was a significant milestone, providing the impetus for advancing to the larger, more definitive Phase IIb trial. These early successes underscored the potential of SPL84 not just as a treatment, but as a potentially transformative add-on therapy.

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Regulatory Designations: Concurrent with clinical development, SpliSense actively pursued regulatory recognition for SPL84, highlighting its potential to address an unmet medical need.

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• US FDA Fast Track Designation: Granted to expedite the development and review of drugs intended to treat serious conditions and fill an unmet medical need. This means more frequent interactions with the FDA and potentially an accelerated approval process.

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• US FDA Orphan Drug Designation: Provides incentives to companies developing drugs for rare diseases (affecting fewer than 200,000 people in the US), including tax credits, fee waivers, and seven years of market exclusivity upon approval.

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• European Medicines Agency (EMA) PRIME Designation (PRIority MEdicines): A similar initiative to the FDA’s Fast Track, designed to enhance support for the development of medicines that address unmet medical needs. It offers early and enhanced dialogue with the EMA, helping to optimize development plans and accelerate assessment.

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These designations collectively underscore the urgent need for new therapies for this specific CF patient population and reflect regulatory confidence in SPL84’s potential.

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Initiation of Phase IIb: The current Phase IIb trial, initiated recently, represents the culmination of these prior efforts. It is designed to confirm the safety profile observed in Phase IIa and, more importantly, to definitively characterize the treatment effect of SPL84 when administered in combination with existing CFTR modulator therapies. This phase is critical for gathering robust data on efficacy and safety that will inform subsequent pivotal Phase III trials, should the results be positive. The targeted completion and top-line results in the second half of 2027 set a clear timeline for the next major data readout for SpliSense and the CF community.

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Supporting Data: Deciphering the Science and Trial Mechanics

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The scientific rationale behind SPL84 and the meticulous design of the Phase IIb trial are crucial to understanding its potential impact. Cystic fibrosis is caused by mutations in the CFTR gene, which provides instructions for making the CFTR protein. This protein functions as a channel that transports chloride ions across cell membranes, a process vital for maintaining the balance of salt and water on many surfaces in the body, including the lungs. A dysfunctional CFTR protein leads to thick, sticky mucus buildup, particularly in the lungs, pancreas, and other organs.

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The 3849+10kb C>T Mutation: This specific mutation is a deep intronic mutation, meaning it occurs within an intron (a non-coding region of a gene) rather than in an exon (a coding region). Its effect is to create a "cryptic splice site," leading to aberrant splicing of the CFTR messenger RNA (mRNA). Instead of correctly removing the intron, the cell’s splicing machinery incorporates a small, non-coding segment into the final mRNA, resulting in a premature stop codon and a truncated, non-functional CFTR protein. This is where SPL84 comes into play.

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Mechanism of Action: Antisense Oligonucleotides (ASOs): SPL84 is an antisense oligonucleotide, a synthetic strand of nucleic acids designed to bind specifically to a target mRNA sequence. In the case of SPL84, it is engineered to bind to the cryptic splice site created by the 3849+10kb C>T mutation. By binding to this site, SPL84 effectively blocks the aberrant splicing event, thereby promoting the correct processing of the CFTR mRNA. This allows the cell to produce a full-length, functional CFTR protein, potentially restoring chloride channel activity and improving the underlying pathology of CF. ASOs represent a highly precise form of gene therapy, correcting defects at the RNA level without altering the DNA sequence itself.

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CFTR Modulators and the Rationale for Combination Therapy: Current CFTR modulator therapies, such as Trikafta (elexacaftor/tezacaftor/ivacaftor), Kaftrio, and Alyftrek, have transformed CF care. These drugs work by improving the function of the defective CFTR protein, either by helping it fold correctly (correctors) or by enhancing its channel activity (potentiators). While incredibly effective for many patients with common mutations like F508del, their efficacy can vary depending on the specific mutation. For patients with splicing mutations like 3849+10kb C>T, modulators may have limited effect if there is insufficient functional CFTR protein being produced in the first place.

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The SPL84-002 Phase IIb trial is therefore designed as an "add-on" study. By administering SPL84 to patients already on stable CFTR modulator therapy, SpliSense aims to determine if correcting the underlying splicing defect with SPL84 can increase the amount of functional CFTR protein, thereby allowing the existing modulators to work more effectively or provide additional benefit. This combination approach holds the promise of achieving a more robust and complete restoration of CFTR function than either therapy alone.

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Trial Design and Endpoints:

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• Participants: Around 40 individuals with at least one copy of the 3849+10kb C>T mutation, already on stable CFTR modulator therapy. This ensures a homogenous patient population where the additional effect of SPL84 can be clearly assessed.

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• Randomisation: 4:1 ratio (SPL84:placebo) ensures more participants receive the active drug, which can be beneficial in rare disease trials while maintaining blinding.

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• Dosage & Duration: 50mg by inhalation once weekly for 12 weeks. This dosing regimen was likely optimized during Phase IIa to balance efficacy and safety, and the 12-week duration is typically sufficient to observe changes in lung function and other clinical parameters in CF trials.
• Primary Objective: Safety and tolerability of SPL84. This includes monitoring for adverse events, vital signs, laboratory parameters, and physical examinations. Given the inhaled route, particular attention will be paid to respiratory adverse events.
• Secondary Objectives:
  • Lung Function: ppFEV1 (percent predicted forced expiratory volume in 1 second) and ppFEF25–75 (percent predicted forced expiratory flow between 25% and 75% of forced vital capacity). FEV1 is a gold standard for assessing lung function in CF, while FEF25-75 can provide insights into small airway obstruction.
  • Respiratory Symptoms: Cystic Fibrosis Questionnaire–Revised (CFQ-R) respiratory domain scores. This patient-reported outcome (PRO) measures the impact of the disease on daily life, providing a crucial subjective perspective on treatment benefit.
• Exploratory Analyses: Sputum microbiology (to assess changes in bacterial load or composition, which can impact lung health) and the Lung Clearance Index (LCI), a sensitive measure of ventilation inhomogeneity that can detect early lung disease changes, even before FEV1. These provide deeper insights into the drug’s physiological effects.

The robust design, coupled with a comprehensive set of endpoints, is intended to provide compelling evidence for SPL84’s potential as a disease-modifying therapy.

Official Responses: A Glimpse into SpliSense’s Vision

The enthusiasm from SpliSense leadership underscores the significance of this trial for both the company and the broader CF community. Gili Hart, CEO of SpliSense, articulated the company’s perspective on the trial’s initiation:

“Following the favorable safety and efficacy profile demonstrated in the Phase IIa study, we are excited to initiate the Phase IIb study, designed to determine whether once-weekly SPL84 can provide additional clinical benefit for people with the 3849+10kb C>T mutation who are already receiving standard-of-care CFTR modulator therapy.”

Hart’s statement highlights several key points:

1. Confidence from Phase IIa: The positive safety and initial efficacy signals from the earlier phase are a strong foundation for moving forward. This confidence is crucial for justifying the investment and patient recruitment for the larger Phase IIb.
2. Focus on "Additional Clinical Benefit": The emphasis is not merely on treating CF, but on improving outcomes for patients who are already receiving the best available care. This addresses a critical unmet need for those whose disease is not fully controlled by modulators alone.
3. Targeted Population: The explicit mention of the 3849+10kb C>T mutation reinforces SpliSense’s commitment to precision medicine and addressing specific genetic defects.
4. Strategic Combination Therapy: The trial’s design to evaluate SPL84 alongside existing modulators demonstrates a pragmatic approach, recognizing the established benefits of current treatments while seeking to enhance them.

Beyond the CEO’s direct quote, the official granting of Fast Track, Orphan Drug, and PRIME designations by major regulatory bodies like the FDA and EMA serves as an indirect but powerful official response. These designations are not given lightly; they represent an acknowledgment by health authorities that SPL84 has the potential to address a serious disease with significant unmet needs. Such recognition lends credibility to the scientific rationale and the potential impact of the therapy, facilitating development and signaling hope to patients and clinicians.

Implications: Reshaping the Landscape of CF Treatment

The successful outcome of SpliSense’s Phase IIb trial for SPL84 could have profound implications across several dimensions: for patients, for the broader CF treatment landscape, for the field of precision medicine, and for SpliSense as a biotechnology innovator.

Implications for Patients with the 3849+10kb C>T Mutation:
For individuals carrying the 3849+10kb C>T mutation, SPL84 offers a new beacon of hope. This specific mutation, while less common than F508del, still affects a significant patient population globally. These patients often experience severe disease and may not respond optimally to current CFTR modulators because the underlying problem is a lack of sufficient CFTR protein production, rather than just a misfolded or less active one. If SPL84 proves effective, it could lead to:

• Enhanced Lung Function: A further improvement in lung function beyond what modulators can achieve, potentially slowing disease progression and reducing the frequency of pulmonary exacerbations.
• Improved Quality of Life: Better respiratory symptoms, fewer hospitalizations, and an overall improvement in the daily lives of patients, as measured by PROs like the CFQ-R.
• A More Complete Therapeutic Solution: For a mutation that has been historically challenging to treat effectively, SPL84 could provide a targeted genetic correction that complements or synergizes with existing therapies, leading to more comprehensive disease management.

Implications for the Broader CF Treatment Landscape:

• Validation of Combination Therapy: The trial’s success would strongly validate the strategy of combining gene-specific therapies (like ASOs) with small-molecule modulators to achieve superior outcomes in CF. This could pave the way for similar combination approaches for other CF mutations or even other genetic diseases.
• Expansion of Treatable Populations: It underscores the continued drive to leave no patient behind in the CF community. While modulators have transformed care for many, there remain groups who benefit less. SPL84 could bring precision medicine to another underserved segment.
• Paradigm Shift in Treatment Philosophy: It reinforces the move towards highly individualized, mutation-specific therapies, emphasizing that a "one-size-fits-all" approach is rarely sufficient for complex genetic disorders.

Implications for Precision Medicine and Antisense Technology:

• Reinforcement of ASO Efficacy: A positive outcome would further bolster the growing success story of antisense oligonucleotides. ASOs have already demonstrated efficacy in other neurological and rare genetic diseases (e.g., spinal muscular atrophy, Duchenne muscular dystrophy). SPL84’s success would expand their utility into pulmonary diseases and genetic splicing defects, showcasing the versatility and precision of this therapeutic platform.
• Advancement in RNA Therapeutics: The field of RNA therapeutics, including ASOs and mRNA therapies, is rapidly evolving. SPL84’s potential success would contribute valuable data and momentum to this innovative area of drug development, encouraging further investment and research into RNA-based approaches for a wider range of diseases.
• Model for Rare Disease Drug Development: The journey of SPL84, from identifying a specific mutation to gaining regulatory designations and progressing through clinical phases, serves as a robust model for developing treatments for other rare and ultra-rare genetic diseases.

Implications for SpliSense:

• Market Leadership in Niche CF: A successful SPL84 could position SpliSense as a leader in treating specific, difficult-to-target CF mutations. This specialized focus could lead to a strong market position, even within the competitive CF landscape.
• Commercial Potential: With Fast Track and Orphan Drug designations, SPL84 would benefit from accelerated review and market exclusivity upon approval. This, coupled with the unmet need, suggests significant commercial potential for a successful therapy.
• Pipeline Validation: Success with SPL84 would validate SpliSense’s underlying scientific platform and drug development capabilities, potentially attracting further investment and enabling the company to expand its pipeline to address other genetic diseases. It could also open doors for partnerships with larger pharmaceutical companies.
• Challenges Ahead: Despite the promise, challenges remain. The clinical trial must successfully demonstrate both safety and efficacy, and the path to market involves regulatory approval, manufacturing scalability, and market access considerations. The high cost of specialized therapies is also a continuous point of discussion within healthcare systems.

In conclusion, the initiation of SpliSense’s Phase IIb trial for SPL84 represents a critical juncture in the ongoing fight against cystic fibrosis. By meticulously targeting a specific genetic splicing defect with an innovative antisense oligonucleotide therapy, and by strategically evaluating its potential as an add-on to existing modulator treatments, SpliSense is poised to potentially offer a new lease on life for a subset of CF patients who are still searching for optimal therapeutic solutions. The anticipated top-line results in late 2027 will be a pivotal moment, not just for SpliSense, but for the entire CF community holding out hope for a future free from the devastating effects of this genetic disease.