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InCarda Therapeutics Announces Results From the RESTORE-1 Phase 3 Trial and Plans for Continued Development
InCarda Therapeutics Press Release
SAN FRANCISCO -- InCarda Therapeutics, Inc.:
• Analysis of the results of the RESTORE-1 Phase 3 trial following its premature termination demonstrated statistically significant cardioversion of PAF with orally inhaled flecainide, providing compelling rationale for the continued development of FlecIH-103 in the target population of PAF patients.
— The RESTORE-1 trial was stopped prematurely due to lower-than-expected efficacy and plasma flecainide levels during a blinded review of the data
— There were no safety concerns associated with the administration of FlecIH-103
• A novel drug delivery platform has shown the potential to enable efficient and reliable delivery of flecainide to the heart through the lung, appropriate for both hospital and home use
• Bridging Phase 1 study data to date establishes a path for future registration trials
Today, InCarda, a privately held biopharmaceutical company developing an inhaled flecainide acetate inhalation solution (FlecIH-103) for the acute conversion of paroxysmal atrial fibrillation (PAF) to sinus rhythm (SR), announced significant progress made on several fronts:
1) Results of the RESTORE-1 Phase 3 trial were presented at the 2024 European Society of Cardiology meeting in London1 on September 2, 2024, and demonstrated strong “patient proof of concept” data for the safe and effective cardioversion of patients with PAF who were administered inhaled flecainide. These results were particularly striking in light of the fact that the trial was stopped prematurely.
2) Transition to a novel and more efficient drug-delivery platform is supported by recent in vitro and Phase 1 clinical data.
3) Preliminary interim results from a Phase 1 clinical study designed to establish the dose and dosing regimen with the new drug delivery platform warrant continuation of the study for the potential advancement of FlecIH-103 into registrational trials.
RESTORE-1 Phase 3 results
RESTORE-1 was a randomized, placebo-controlled, Phase 3 trial, employing a commercially available jet nebulizer, to assess the efficacy and safety of FlecIH-103 for the treatment of patients with PAF. The trial was stopped prematurely after 54 of the planned 400 patients had been enrolled due to an unexpectedly low rate of blinded cardioversion compared to the experience in the Phase 2 study (INSTANT). The rate of cardioversion in RESTORE-1 was 31% in the treated group versus 47% in the Phase 2 INSTANT study. This outcome was caused by lower-than-expected flecainide plasma levels and unexpected drug-device incompatibility not previously observed in the Phase 2 clinical trial. The premature halting of the trial was not due to any safety concerns.
Despite the early termination of the trial and a small sample size (n=54), an analysis showed that the 31% cardioversion rate was statistically significant in FlecIH-103-treated patients compared to placebo (p=0.04), with a median time to restoration of normal sinus rhythm (NSR) of approximately 13 minutes from the start of dosing.
The study captured statistically significant pharmacoeconomic benefits from early restoration of SR following administration of FlecIH-103:
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80% of patients whose AF converted to sinus rhythm were eligible for discharge from the hospital within 2 hours of dose administration, compared to only 30% of patients whose PAF did not convert (p=0.002) |
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83% of patients who converted from PAF to NSR within 90 min of dosing were symptom-free, while only 28% of patients whose PAF did not convert to SR were symptom-free (p<0.0001) |
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The need for electrical cardioversion to restore sinus rhythm was 49% in the active arm vs. 83% in the placebo arm (p<0.05). |
There were no safety concerns or SAEs associated with the administration of FlecIH-103 in this study and no patients discontinued the study due to an adverse event (AE) or had an AE that required treatment.
In summary, these results indicate that orally inhaled flecainide can provide safe and rapid restoration of sinus rhythm in patients presenting to the emergency room with symptomatic acute PAF. We believe FlecIH-103 delivered via oral inhalation has the potential to be clinically meaningful and address the important unmet medical need for the estimated one million U.S. patients who visit ERs with PAF each year.
Improved drug-delivery platform
The lower-than-expected flecainide plasma levels observed in RESTORE-1 using a jet nebulizer motivated the transition to Aerogen’s novel, high-performance drug-delivery platform that enables more efficient and reliable inhaled delivery of FlecIH-103.
This platform includes:
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A novel vibrating-mesh aerosol generation engine proven to deliver drugs to the deep lungs for rapid systemic absorption, provided by Aerogen Ltd., a world leader in acute care aerosol drug delivery located in Galway, Ireland, and |
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A unique patient-facing breath-synchronized dosing system that helps optimize the patient’s breathing for the inhalation of FlecIH-103. |
The Aerogen drug-delivery platform employs the PDAP (Photo Defined Aperture Plate) technology, a breakthrough patented vibrating mesh for medical aerosol delivery developed by Aerogen Ltd. The PDAP technology effectively aerosolizes our flecainide formulation (FlecIH-103) into a fine-mist aerosol. In addition, the patient is guided by the dosing system to synchronize their breathing with the generation of the aerosol. We believe this increases the efficiency of the delivery of FlecIH-103 to the heart and may enable a low nominal dose needed for rapid and safe cardioversion.
Bridging Phase 1 clinical data
Preliminary interim results from a Phase 1 study being conducted in Australia with FlecIH-103 administered with this new delivery platform show encouraging results:
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Peak flecainide plasma concentrations (Cmax) similar to those achieved in the Phase 2 (INSTANT) clinical trial, which showed a conversion rate of ~ 50% |
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One-third of the amount of FlecIH-103 was needed in the inhaler to achieve similar Cmax when compared to the amount needed with the commercial jet nebulizer used in RESTORE-1, and |
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Electrocardiographic (ECG) changes that are transient and consistent with the pharmacokinetics (PK) of the inhaled flecainide and are within a safe range [Max ΔQRS duration < 30 msec] |
No new safety signals have been observed, no SAEs reported and all AEs resolved without sequelae; the FlecIH-103 safety profile is consistent with that observed in prior studies.
We believe the novel delivery platform will easily be adaptable in all patient care settings including the hospital and at-home settings.
Future plans
InCarda plans to complete the ongoing Phase 1 study, including the investigation of additional dose regimens such as administration of a booster dose similar to current approved products for treating cardiac arrhythmias.
Inhaled flecainide is being developed for use in both a medically supervised setting (e.g., in-hospital, emergency rooms and clinics) and as a portable treatment for self-administration outside the hospital. InCarda plans to reinitiate safety and efficacy trials in patients with PAF in 2025.
Dr. Luiz Belardinelli, MD, InCarda’s Chief Medical Officer, said, “We believe that inhaled flecainide has the potential to be a valuable treatment for patients with recent-onset episodes of PAF. While RESTORE-1 did not achieve the level of efficacy desired and the trial was terminated early, the analysis showed a statistically significant higher conversion rate in the active arm compared to the placebo for the 54 patients evaluated, and the continued encouraging safety and tolerability profile of FlecIH-103 suggest that this treatment could become an important option for patients with acute episodes of recent-onset of PAF. The trial also indicated that patients whose PAF converted to NSR had their symptoms relieved, required fewer interventions, and were discharged earlier from the ER, thus suggesting attractive pharmacoeconomic benefits of orally inhaled flecainide.”
Carlos Schuler, Ph.D., co-founder and CEO of InCarda, said, “I am very excited by the ability of the new drug-delivery platform to deliver flecainide reliably. Given the positive Phase 1 results to date, I am optimistic that we will be able to achieve commercially attractive efficacy and safety and demonstrate pharmacoeconomic benefits in the registrational studies currently being planned.”
About Atrial Fibrillation (AF)
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia (abnormal heart rhythm) and is characterized by rapid and irregular heartbeats often resulting in palpitations and other symptoms that can be debilitating. A chronic, progressive condition, AF is estimated to affect six million people in the U.S., with that number expected to double by 20502. This expected increase is partially due to the correlation between AF prevalence and an aging population, with approximately 9% of those aged 65 and older affected by the condition2. AF is associated with significant morbidity and a substantial reduction in quality of life, with the condition potentially resulting in exercise intolerance, congestive heart failure, tachycardia-induced cardiomyopathy, and stroke. The annual cost of AF to the U.S. healthcare system is estimated at more than $26 billion2.
Paroxysmal AF (PAF) is a self-terminating type of AF in which episodes occur intermittently and resolve spontaneously in fewer than seven days. Approximately 25% of PAF patients progress to the permanent form of AF within five years3. Common symptoms of PAF can include a racing heartbeat, chest pain or pressure, a fluttering feeling in the chest, weakness, fatigue, dizziness, sweating, and lightheadedness. Current treatments for patients with PAF rely upon either chronic administration of oral antiarrhythmic drugs or acute hospital-based procedures such as intravenous drug administration of rate-control medicines and electrical cardioversion, neither of which adequately address the unmet need of patients for a rapid-acting treatment that can be administered whenever an episode of PAF occurs. There are currently no approved treatments that can be self-administered by patients whenever or wherever an episode of PAF occurs.
About Inhaled Flecainide
Inhaled Flecainide is a novel inhaled therapeutic candidate designed to rapidly deliver flecainide, a well-established oral antiarrhythmic agent, to the heart via the lungs to restore normal sinus rhythm and relieve the patient’s symptoms following the onset of new or recurrent episodes of paroxysmal AF (PAF). Previously completed Phase 1 clinical studies in healthy volunteers demonstrated that orally inhaled flecainide can rapidly and safely deliver the drug and result in ECG changes consistent with the potential to restore sinus rhythm in patients with PAF. A previously completed Phase 2 trial (INSTANT) in patients with recent-onset PAF showed that inhaled flecainide with an administration regimen of approximately eight minutes can safely and rapidly convert recent-onset PAF to normal sinus rhythm. InCarda started RESTORE-1, a Phase 3 clinical trial, but halted the study as mentioned above. With intellectual property protection now potentially extendable through 2045 with the inclusion of the new delivery system, orally inhaled flecainide continues to have potential as a first-in-class treatment for acute management of PAF. We estimate over a billion-dollar market potential for this product, in addressing this significant unmet medical need.
About InCarda Therapeutics
InCarda Therapeutics, Inc. is a privately held, clinical-stage biopharmaceutical company developing first-of-their-kind inhaled therapies for acute cardiovascular diseases and conditions. The company is leveraging the ability of inhaled therapy to deliver medicine in the “first pass” to cardiac tissue, presenting a ‘small,’ but effective dose of the drug directly to affected regions of the heart. This permits rapid-onset, lower off-target tissue exposure of the drug, lower exposure to cardiac tissue, and has the potential to be patient self-administered in an ambulatory care setting (e.g., at home care). InCarda employs a de-risked approach by using approved drugs as candidates for the new dosing paradigm via inhalation. The company’s lead development product, orally inhaled flecainide, is in development to treat acute episodes of symptomatic PAF, a prevalent cardiac arrhythmia. For more information, please visit: www.incardatherapeutics.com.
LinkedIn: https://www.linkedin.com/company/incarda-therapeutics/
Twitter: @InCardaThera
References:
- RESTORE-1 abstract, Dr. M. Rienstra, MD (Netherlands), ESC, London, Sep 02, 2024
- J Am Coll Cardiol. 2014 Dec 2;64(21):2305-7
- Am Heart J. 2005 Mar; 149(3):489-96
