RARE METABOLIC DISORDERS
PKU GOLIKE® is being commercialized for the dietary management of phenylketonuria ("PKU"), a rare inherited disorder affecting approximately 350'000 patients in the world's key markets. PKU is caused by a defect of the enzyme needed to break down phenylalanine, leading to a toxic buildup of phenylalanine from the consumption of foods containing protein or aspartame. Excessive levels of phenylalanine in the blood results in its accumulation in the brain, which hinders brain development and results in neurophysiological dysfunction. To avoid these serious consequences, people with PKU must comply with a strict diet that limits intake of phenylalanine from infancy onwards.
Patients with PKU require supplementation of amino acids formulated as foods for special medical purposes ("FSMP") to prevent protein deficiency. Currently available FSMPs lead to poor or suboptimal clinical outcomes and compliance because they are rapidly absorbed and are characterized by an unpleasant odor and aftertaste. Such factors contribute to barriers to social interaction for PKU patients, further limiting FSMP compliance and exposing patients to the risks of poor disease control.
PKU GOLIKE®, engineered with the patent protected, proprietary drug delivery technology named “Physiomimic,” is the first prolonged-release amino acid mix product that (i) mimics the absorption profile of dietary proteins while (ii) offering effective taste and odor masking. With these characteristics, PKU GOLIKE® is a uniquely differentiated product, offering improved metabolic management and the opportunity for better compliance for PKU patients of all age groups.
PKU GOLIKE® is currently sold by a direct sales and marketing organization in Germany, Italy, Switzerland, and Austria, and is marketed in the UK, Spain and Portugal by local distributors. PKU GOLIKE® is a fully reimbursed treatment option for PKU patients and is considered a life-saving option for PKU patients. Relief plans to expand the PKU GOLIKE® commercial infrastructure beyond the current countries to increase and accelerate future growth. This will be supported by newer formulations, such as fruit flavored protein bars. In addition, Relief is planning the launch of the PKU GOLIKE® family of products in the U.S., where it has fully assembled its commercial infrastructure and team. PKU GOLIKE® is slated to become commercially available in the U.S. in October of 2022.
The Company has received a Notice of Allowance from the U.S. Patent and Trademark Office (“USPTO”) for Patent Application No. 15/303,121, which covers certain formulations of PKU GOLIKE® and supplements the PKU GOLIKE® intellectual property portfolio, which includes U.S. Patent No. 10,500,180. The patents will expire no earlier than September 27, 2036.
In the U.S., PKU GOLIKE® (code named APR-OD031) has been granted Orphan Drug Designation ("ODD") and is undergoing regulatory and clinical review to assess its potential to be a prescription product.
In March 2021, Relief signed a collaboration and license agreement with Acer Therapeutics Inc. (“Acer”) for the worldwide development and commercialization of ACER-001.
ACER-001 is a proprietary powder formulation of sodium phenylbutyrate (“NaPB”). The formulation is designed to be both taste-masked and immediate release. ACER-001 is being developed using a microencapsulation process for the treatment of various inborn errors of metabolism, including Urea Cycle Disorders (“UCDs”) and Maple Syrup Urine Disease (“MSUD”). ACER-001 microparticles consist of a core center, a layer of active drug, and a taste-masking coating that quickly dissolves in the stomach to avoid a bitter taste while still allowing for rapid systemic absorption. ACER-001’s taste-masked formulation is designed to improve the palatability of NaPB and could make it a compelling alternative to existing NaPB-based treatments, as the unpleasant taste associated with NaPB is cited as a major impediment to patient compliance with those treatments. Additionally, bioequivalence trials have shown ACER-001 to have similar relative bioavailability to BUPHENYL® under both fasted and fed conditions, along with significantly lower projected pricing compared to RAVICTI®.
ACER-001 IN UREA CYCLE DISORDERS (UCDs)
UCDs are a group of disorders caused by genetic mutations that result in a deficiency in any one of the six enzymes that catalyze the urea cycle, which can lead to an excess accumulation of ammonia in the bloodstream, a condition known as hyperammonemia. Acute hyperammonemia can cause lethargy, somnolence, coma, and multi-organ failure. Chronic hyperammonemia can lead to headaches, confusion, lethargy, failure to thrive, behavioral changes and learning and cognitive deficits. Common symptoms of both acute and chronic hyperammonemia also include seizures and psychiatric symptoms.
The current treatment of UCDs consists of dietary management to limit ammonia production in conjunction with medications that provide alternative pathways for removing ammonia from the bloodstream. Some patients may also require individual branched-chain amino acid supplementation.
Current medical treatments for UCDs include nitrogen scavengers, RAVICTI® and BUPHENYL®, in which the active pharmaceutical ingredients are glycerol phenylbutyrate (“GPB”) and NaPB, respectively. Their role is to provide an alternative way to excrete excessive nitrogen. According to a 2016 study by Shchelochkov et al., published in Molecular Genetics and Metabolism Reports, while nitrogen scavenging medications have been shown to be effective in helping to manage ammonia levels in some patients with UCDs, non-compliance with treatment is common. Reasons referenced for non-compliance associated with some available medications include unpleasant taste, the frequency with which medication must be taken, the number of pills, and the high cost of the medication.
The FDA has accepted for review Acer’s New Drug Application (“NDA”) resubmission under the 505(b)(2) pathway for ACER-001, for oral suspension, for the treatment of patients with UCDs. The FDA designated the NDA as a Class 2 resubmission and set a PDUFA target action date of January 15, 2023. Relief anticipates commercialization of ACER-001 for UCDs in the U.S. in the first half of 2023, pursuant to FDA approval in early 2023, after which Relief, in accordance with its collaboration agreement with Acer, intends to submit a Marketing Authorization Application for approval of ACER-001 for the treatment of UCDs in the U.K. and EU. There can be no assurance, however, that ACER-001 will be approved for commercialization in the U.K. or the EU.
ACER-001 IN MAPLE SYRUP URINE DISEASE (MSUD)
MSUD is a rare inherited disorder caused by defects in the mitochondrial branched-chain ketoacid dehydrogenase complex, which results in elevated blood levels of the branched-chain amino acids (“BCAA”), leucine, valine and isoleucine, as well as the associated branched-chain ketoacids (“BCKA”) in a patient’s blood. Left untreated, this can result in neurological damage, mental disability, coma, or death.
There are currently no approved pharmacologic therapies in the U.S. or the European Union for MSUD. Treatment of MSUD consists primarily of a severely restricted diet to limit the intake of BCAA, with aggressive medical interventions when blood levels of BCAA or BCKA become elevated. NaPB is approved for people with UCDs to control their ammonia levels in conjunction with a restricted diet. People with UCDs who are treated with NaPB have been found to have a BCAA deficiency, despite adequate dietary protein intake. Based on this clinical observation, NaPB is being explored as a treatment to lower BCAA and their corresponding BCKA in patients with MSUD.
The FDA and EMA have granted Orphan Drug Designation for the MSUD indication.
Acer has also been issued several patents protecting the usage of and composition of ACER-001. The recent approval of U.S. patent 11,202,767 covers methods of use claims related to ACER-001’s multi-particulate dosage formulation for oral administration for the potential treatment of UCDs and MSUD and supplements previous issuance of U.S. patent 11,154,521 which covers pharmaceutical composition claims of ACER-001. Both patents have an expiration date in 2036. In addition, the China National Intellectual Property Administration (CNIPA) has issued Electronic Patent Certificate ZL202122004991.9 for the Utility Model patent directed to ACER-001. Specifically, the patent covers dosage form claims related to ACER-001’s polymer coated formulation for oral administration as a potential treatment for UCDs and MSUD. This patent has an expiration date of August 24, 2031 and provides protection for ACER-001 in the context of potential commercialization in the China market. Acer has submitted an Investigational New Drug (“IND”) application to the FDA to evaluate the safety and efficacy of ACER-001 for the potential treatment of MSUD. Clinical studies are expected to begin in the fourth quarter of 2022. It is expected that the data from these studies would be suitable for product registration in the U.S. and Europe.
* RAVICTI® and BUPHENYL® are registered trademarks owned by or licensed to Horizon Therapeutics plc.
Ah Mew N, et al. Urea cycle disorders overview. Gene Reviews. Seattle, Washington: University of Washington, Seattle; 1993.
Häberle J, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases. 2012;7(32).
Shchelochkov OA, et al. Barriers to drug adherence in the treatment of urea cycle disorders: Assessment of patient, caregiver and provider perspectives. Mol Genet Metab. 2016;8:43-47.
In July 2022, APR entered into a definitive agreement with the UK based company Meta Healthcare Ltd. (“Meta”). Pursuant to the agreement, the Company has acquired the worldwide rights, title, and interest, except in the UK, for a novel dosage form of a prescription drug already approved by the FDA and intended for the treatment of patients with PKU. This improved product is expected to increase patient acceptance and compliance as well as enable easier, self or caregiver administered metered dosing and dispensing. Meta shall transfer to Relief all data, know-how, as well as any intellectual property as developed or generated so far by Meta, related to APR-OD032. Relief shall only be responsible for independently performing and funding the remaining development activities without additional obligations to Meta, as well as for filing and obtaining a new drug application in all countries, worldwide, except for the UK, where Relief shall grant a license back to Meta, enabling Meta to market the product in such country. Other than low double-digit royalty payments on net profit of the product in the various countries, Relief shall be under no obligation to fund or pay any other amount to Meta.
Relief anticipates the filing of the 505(b)(2) NDA during 2023.
RaRE Pulmonary DISEASES
RLF-100® (aviptadil) is a synthetic form of Vasoactive Intestinal Peptide (VIP) consisting of 28 amino acids, which was first discovered in 1970. Although initially identified in the intestinal tract, human VIP is now known to be produced throughout the body and to be primarily concentrated in the lungs. Here, VIP has shown a multimodal mechanism of action: decrease of inflammatory cytokines release leading to prevention of cytokine storm syndrome and viral replication, immunomodulating effect, vasodilating and bronchodilating effects, and prevention of surfactant depletion. Seventy percent of VIP in the body is bound to a less common type of cell in the lung, the alveolar type 2 cell, which is critical to the absorption of oxygen into the body.
RLF-100® has a 20-year history of safe use in humans in multiple human trials for sarcoidosis, idiopathic pulmonary fibrosis, asthma, pulmonary arterial hypertension, and sepsis-induced acute respiratory distress syndrome. A combination of aviptadil with phentolamine is approved for the treatment of erectile dysfunction by intra-cavernous injections in countries outside the U.S.
Relief recently announced promising three-month stability data on a new formulation of RLF-100® and is evaluating the opportunity to file for additional patent protection for RLF-100®.
RLF-100™ Multimodal mechanism of action
Vasoactive Intestinal Peptide (VIP or RLF-100)
- Produced throughout the body
- Primarily concentrated in the lungs
- 70% of VIP bound to AT2
- Human peptide consisting of 28 amino acids
- Exogenously applied RLF-100 accumulates in the lung with extended half-life (half-life ~19 minutes)
- 20-year history of safety in humans
Binding to G protein-coupled receptors VPAC1, VPAC2 and PACAP-R1 triggers intracellular signaling
- Highest density of receptors VPAC1 found in AT2
- Significant modulation of the immune cell response (macrophages, CD4-T cells and tolerogenic dendritic cells) mediated by activation of the VPAC1 and VPAC2 receptors.
Anti-inflammatory and immunomodulatory roles → immune cells
- Decreases pro-inflammatory cytokines (TNF-α, IL-6, INF-g, …)
- Increase expression of IL-10 and TGF-β
Vasodilatory and inotropic effects → vascular system
- Decreases vascular resistance
- Significantly increases arterial blood flow
- Primary positive ionotropic effect on cardiac muscle
Maintenance of bronchial system → lung
- Upregulates the production of surfactant
- Prevents cell death
- VIP mice display airway hyper-responsiveness to noxious stimulus
- Reduce replication of SARS-CoV-2 virus in AT2 and monocytes s
Clinical development of RLF-100®
A phase 2b/3 clinical study with intravenous RLF-100® in patients with COVID-19 induced acute respiratory distress syndrome ("ARDS") was completed in the U.S. by the parent company, NRx Pharmaceuticals, Inc. (Nasdaq: NRXP) ("NRx"), of Relief’s clinical development partner for RLF-100®, NeuroRx, Inc. ("NeuroRx"). The trial met the primary endpoint for successful recovery from respiratory failure at days 28 and 60 and revealed significant survival benefit after controlling for ventilation status and treatment site.
RLF-100® was also included in a National Institute of Health sponsored phase 3 ACTIV-3b/TESICO clinical trial in severely ill patients with COVID-19, which was discontinued for futility. Relief intends to obtain and review the data from the NIH-sponsored trial in order to better understand the results observed, up to and including the point at which the study was discontinued. While regulatory approval in COVID-19-induced ARDS has not been granted in the U.S., RLF-100® was approved in this indication in India in early 2022, substantiating Relief’s original hypothesis.
Inhaled RLF-100® is presently being studied in a European investigator sponsored trial for the prevention of ARDS associated with COVID-19 (The Leuppi Study), which is at an advanced stage of recruitment and slated to report top-line data later this year (subject to enrollment of eligible patients).
RLF-100® ADDITIONAL OPPORTUNITIES:
RLF-100® is under development in both inhaled and intravenous formulations for other acute and chronic lung diseases, including pulmonary sarcoidosis, for which it was granted an Orphan Drug Designation ("ODD") by the FDA.
An open-label proof-of-concept trial (Avisarco II) in 20 patients with pulmonary sarcoidosis demonstrated clinically significant suppression of inflammatory processes in the lung, as well as amelioration of dry cough and exertional dyspnea (shortness of breath). It was found that RLF-100® significantly restored immune tolerance by promoting regulatory T-lymphocytes, improved CD4/CD8 ratio and normalized TNF-α production. Improvements could also be seen in sarcoidosis-relevant biomarkers. RLF-100® showed excellent safety and compliance, indicating that the drug could potentially suppress sarcoidosis-associated cough with limited side effects. Relief has been granted an ODD by the FDA for the treatment of pulmonary sarcoidosis.
Relief intends to initiate a phase 2b dose-ranging study in 72 patients with pulmonary sarcoidosis using inhaled RLF-100® administered over a 12-week period, following which patients will have the option to participate in the extension phase. A pre-IND meeting with the FDA is planned to confirm the efficacy and safety endpoints as well as the proposed dosing regimen and, based on a positive outcome, the trial is expected to begin in 2023.
RLF-100® is under development in both inhaled and intravenous formulations for other acute and chronic lung diseases, including as a treatment for checkpoint inhibitor-induced pneumonitis (“CIP”), an indication in which Relief received a Swiss method-of-use patent protection related to the inhaled formulation of RLF-100® into at least 2039. RLF-100® will also be tested in treating non-COVID-19-related ARDS with a particular focus on infectious ARDS. There are also plans to conduct European proof-of-concept clinical development of RLF-100® in the treatment of chronic berylliosis, an orphan lung disease for which there are no treatments approved and which is characterized by severe inflammation of the lungs, persistent cough and increasing breathlessness (dyspnea).
Sentinox, a novel nasal spray, is an EU-cleared Class III medical device intended to offer additional protection against airborne viruses and bacteria and their transmission, including, but not limited to, SARS-CoV-2. Sentinox was evaluated in a randomized, controlled clinical trial to establish the efficacy and safety of the product in reducing viral load in the upper respiratory airways in recently COVID-19 infected individuals. The final results were reported in March 2022. Although the primary endpoint was not reached probably due to the small sample size, the results suggest the potential efficacy of Sentinox in the reduction of the nasal viral load, negativization and infectivity and confirmed its safety and tolerability.
The Company is expected to start a confirmatory, controlled clinical trial in the prevention of viral and bacterial airborne infections in the fourth quarter of 2022.
RARE Connective Tissue DISORDERS
Nexodyn® Acid-Oxidizing Solution (“AOS”) is a TEHCLO®-based product proven to restart healing in chronic wounds by creating an ideal microenvironment to sustain the physiological healing process. A wealth of evidence and real-world experience has consistently shown accelerated wound closure with reduced infection rates and less wound-associated pain.
The three main features of Nexodyn® are: highly pure and stabilized hypochlorous acid (HClO >95% of free chlorine species), acidic pH (2.5 - 3.0), and high Reduction-Oxidation Potential (ORP 1.000 – 1.200 mV). The product is a self-administered sprayable solution with ancillary antimicrobial properties intended for use in the debridement, irrigation, cleansing and moistening of acute and chronic wounds (e.g., diabetic foot ulcers, pressure ulcers and vascular ulcers), post-surgical wounds, burns and other lesions. The product is certified in the EU as a Class III medical device and is certified as a 510(k) medical device in the U.S.
APR-TD011 has potential for the treatment of wounds in epidermolysis bullosa ("EB"), a group of rare, genetic, life-threatening connective tissue disorders characterized by fragile skin and mucous membrane with severe blistering throughout the body. There are an estimated 250'000 patients with EB worldwide, with an estimated 30'000 patients in the European Union and 20'000 patients in the U.S.
APR-TD011 is a differentiated acid oxidizing solution of hypochlorous acid. The TEHCLO® proprietary technology, upon which the drug has been developed, allows for a sprayable solution that combines strong antimicrobial action with anti-inflammatory properties, thereby allowing for infection control, reduction of wound colonization, alleviation of pain and itching and improved wound healing. The spray formulation permits wound application while avoiding skin contact and cross-contamination. APR-TD011 could represent the first product specifically indicated for EB patients that provides a comprehensive solution to prevent or reduce wound colonization and infection. This, along with its anti-inflammatory action, could provide symptom relief and wound healing.
APR-TD011 has been granted Orphan Drug Designation by the FDA for the treatment of EB, which provides for a seven-year market exclusivity period in the U.S. Relief intends to seek Qualified Infectious Disease Product (“QIDP”) status for APR-TD011 as well, which may confer up to an additional five years of market exclusivity regardless of patent protection status.
In a preliminary clinical trial, EB patients administered APR-TD011 demonstrated improvement in skin blistering and tissue repair within just two weeks of treatment, and the product candidate was shown to be well tolerated with a favorable safety profile. GMP grade product is being prepared for clinical development under an FDA-authorized IND, which is expected to start in the second quarter of 2023.
APR TM-011 is currently approved in the EU as a Class III Medical Device for the treatment of skin lesions and toxicities induced by cancer treatments, including anti-Epidermal Growth Factor Receptors (anti-EGFR) Monoclonal Antibodies, such as Cetuximab. The use of anti-EGFR inhibitors causes papulopustular manifestations due to their interference of epidermal growth factor receptor (“EGFR”) signaling in the skin with a high risk of secondary infections. Following commercial assessment, the company is planning to conduct a follow-on clinical study for product approval in Europe as a Class III Medical Device beyond 2024, when the new EU device regulations will apply. This clinical study would be a multi-center, post-market, double-blinded, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of APR TM-011 in the management of skin lesions and reactions resulting from anti-EGFR Monoclonal Antibodies and/or radiotherapy treatments in oncology patients.
LEGACY ROYALTY STREAM PRODUCTS
Legacy royalty generating products were originally developed by APR and licensed for commercialization. The rights were acquired by Relief as part of the 2021 acquisition of APR.
SETOFILM is the first prescription-only, orodispersable film (“ODF”) medicine approved in Europe and Canada. The product is indicated for radiotherapy-induced nausea and vomiting ("RINV"), chemotherapy-induced nausea and vomiting ("CINV"), as well as post-operative-induced nausea and vomiting ("PONV") in both adults and children of 6 months of age or older. The product has been formulated and developed using the RapidFilm drug delivery technology in the form of a soluble film and is available in 4mg and 8mg doses. Once placed on the tongue, it dissolves in a few seconds and is swallowed with saliva, without the need for water. The convenience provided by the innovative ODF formulation reduces patient pill burden, enhances compliance, and avoids risks of suffocation in children.
The product is marketed in Europe by Norgine B.V. and in Canada by Takeda Pharmaceuticals, under license from APR.
Diclofenac potassium is an off-patent, potent non-steroidal anti-inflammatory drug ("NSAID") widely used for treating inflammatory conditions and pain management. By applying its patented dynamic buffering technology ("DBT"), APR developed the first and only NSAID approved by the FDA for the treatment of acute migraine attacks in adults. The product is currently marketed as CAMBIA by Assertio Therapeutics Inc. (Nasdaq: ASRT) in the U.S. and Miravo Healthcare (formerly Nuvo Pharmaceuticals Inc.) in Canada, under an exclusive, royalty-bearing license agreement with APR.
APR received a Notice of Allowance from the U.S. Patent and Trademark Office for Patent Application No. 16/713,052 entitled, "Ready to Use Diclofenac Packs” in January 2022, with an expiration date in 2039. CAMBIA is protected by a patent family owned by APR and listed in the FDA Orange Book having expiration in 2026; however, the Company is expecting first authorized generic entrance to start sometime in 2023.
Developed with APR’s patented matrix patch technology, Voltadol is a topical, locally applied and locally acting patch containing and delivering diclofenac sodium, an off-patent, potent NSAID for the local treatment of painful, acute conditions such as muscle and joint strains. The product is marketed in various countries as an over-the-counter medicine by GlaxoSmithKline (GSK) which recently spun-off the rights to Haleon.
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