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 the U.S., Germany, Italy, Switzerland, and Austria, and is marketed in the UK, Spain, Portugall, Israel, Greece, Cyprus, Ecuador, and certain Middle Eastern countries 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.
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.
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®.
OLPRUVA™ (SODIUM PHENYLBUTYRATE) ACER-001 IN UREA CYCLE DISORDERS (UCDS)
OLPRUVA™ (sodium phenylbutyrate) for oral suspension is a prescription medicine used along with certain therapy, including changes in diet, for the long-term management of adults and children weighing 44 pounds (20 kg) or greater and with a body surface area (BSA) of 1.2 m2 or greater, with urea cycle disorders (UCDs), involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC) or argininosuccinic acid synthetase (AS). OLPRUVA™ is not used to treat rapid increase of ammonia in the blood (acute hyperammonemia), which can be life-threatening and requires emergency medical treatment.
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.
On Dec. 22, 2022, the U.S. Food and Drug Administration (FDA) approved OLPRUVA™ (sodium phenylbutyrate) for oral suspension in the U.S. for the treatment of certain patients living with UCDs involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS). Full U.S. Prescribing Information and Product Website .
OLPRUVA™ (SODIUM PHENYLBUTYRATE) 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 OLPRUVA. The recent approval of U.S. patent 11,202,767 covers methods of use claims related to OLPRUVA’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 OLPRUVA. 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 OLPRUVA. Specifically, the patent covers dosage form claims related to OLPRUVA’s polymer coated formulation for oral administration as a potential treatment for UCDs and MSUD. This patent has an expiration date of Aug. 24, 2031 and provides protection for OLPRUVA 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 OLPRUVA 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.
RaRE Pulmonary DISEASES
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
CHECKPOINT INHIBITOR-INDUCED PNEUMONITIS (CIP)
BERYLLIOSIS / CHRONIC BERYLLIUM DISEASE (CBD)
INFECTIOUS ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS)
Infectious acute respiratory distress syndrome (ARDS) is a potentially life-threatening condition in which the lungs become severely inflamed, leading to buildup of fluid in the lungs, preventing oxygen from getting to the bloodstream and the rest of the body. Infectious ARDS results from an injury or an infection (such as pneumonia, severe flu, sepsis, etc.) of the air sacs in the lung.
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 NeuroRx, Inc., Relief’s former clinical development partner for RLF-100. 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. While regulatory approval in COVID-19-induced ARDS has not been granted in the U.S., aviptadil was approved in this indication in India in early 2022, substantiating Relief’s original hypothesis.
The European investigator sponsored trial initiated in 2021 for the evaluation of inhaled RLF-100 in the prevention of ARDS associated with COVID-19 (the Leuppi Study) was terminated in January 2024 before completion due to difficulties in enrolling eligible patients
As the pandemic has evolved, leading to a reduced need for new treatments, we continue to closely monitor the situation. Despite challenges and setbacks in COVID-19 indications, our belief in the aviptadil potential remains unaffected.
RARE Connective Tissue DISORDERS
Nexodyn® 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.
LEGACY ROYALTY STREAM PRODUCTS
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.
CAMBIA (DICLOFENAC POTASSIUM)
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, authorized generic versions of CAMBIA became available in the U.S. in 2023.
Voltadol (DICLOFENAC DIETHYLAMINE)
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.
1 Iacopi E. et al. The Use of a Novel Super-Oxidized Solution on Top of Standard Treatment in the Home Care Management of Postsurgical Lesions of the Diabetic Foot Reduces Reinfections and Shortens Healing Time. Int J Low Extrem Wounds. 2018 Dec; 17(4):268-274.
2 Strohal R, et al. The management of critically colonized and locally infected leg ulcers with an Acid-Oxidizing
Solution: A pilot study. Adv Skin Wound Care 31(4):163-171, 2018.
3 Ricci E, et al. The management of chronic ulcers with an AcidOxidizing Solution. J Wound Care 25(8):443-50, 2016.
- Hits: 1627