Arrevus’s focus is to develop superior treatments that are meaningful to patients for orphan diseases
- Diseases with serious outcomes
- Few treatment options
- High treatment failure rates with currently available therapies
The active component of ARV-1801 is fusidic acid. Fusidic acid has been in clinical use outside the United States for over 50 years and has an excellent safety profile supported by decades of clinical use.1 Fusidic acid is used in multiple approved indications ex-US including cystic fibrosis,2,3 skin infections,4 osteomyelitis,5 pneumonia,6 sepsis, and endocarditis.7 Arrevus’ ARV-1801 is a proprietary oral dosing regimen and formulation of fusidic acid.
ARV-1801 is being developed as a therapeutic to treat cystic fibrosis pulmonary exacerbations. Cystic fibrosis is a progressive, genetic disease that causes persistent lung infections and declining lung function over time. There are approximately 30,000 patients affected by cystic fibrosis in the United States, and patients only live to their mid- to late 30s on average. 70% of cystic fibrosis patients are infected with Staphylococcus aureus,8 and the presence of methicillin-resistant S. aureus (MRSA) has been linked to greater than 6 years shorter lifespan.9 The driving force of lung function decline are “pulmonary exacerbations”, episodes of acute worsening of symptoms that result in decreased lung function. Cystic fibrosis patients that have greater than two episodes of pulmonary exacerbations per year have 8 times increased risk of death compared to those that have ≤ 1.10 There are currently no approved therapies to treat pulmonary exacerbations in cystic fibrosis patients.
Fusidic acid is one of the most potent S. aureus and MRSA drugs ex-US.11,12 Also it is anti-inflammatory, 13,14 has mucolytic properties, and active against biofilms,15 which are communities of bacteria that are commonly resistant to antibiotics and often found in the lung of cystic fibrosis patients. Fusidic acid is already in cystic fibrosis treatment guidelines in the United Kingdom2 and Australia.3 Also, fusidic acid treatment has been shown to be safe and effective in numerous cystic fibrosis clinical studies.16,17,18,19,20,21 Given all this, Arrevus is currently committed to developing ARV-1801 to help cystic fibrosis patients in the United States.
ARV-1907 is an inhaled formulation of fusidic acid and is being developed for the treatment of persistent Staphylococcus aureus lung infections in cystic fibrosis patients. A vast majority of cystic fibrosis patients are infected with Staphylococcus aureus, 8 and the presence of methicillin-resistant S. aureus (MRSA) has been linked to greater than 6 years shorter lifespan, increased rate of pulmonary exacerbations and hospitalizations.9 There is no approved standard of care to address S. aureus infections.
ARV-1502 is an engineered inhibitor of bacterial DnaK and has a novel structure that is inspired by insect host defense peptides. Specifically, through millions of years of evolution, insects have evolved proline-rich antimicrobial peptides as a key element of their innate immune response. ARV-1502 is an optimized peptide monomer that is engineered from multiple insect proline-rich antimicrobial peptides and includes an N-terminal non-native amino acid (amino-cyclohexyl carboxylic acid moiety; Chex) that allows ARV-1502 to avoid aminopeptidase cleavage and improve its activity spectrum while also eliminating nonspecific binding to the substrate-binding pocket of DnaK.22,23,24
DnaK is a heat-shock protein that is essential for stress tolerance and allowing organisms to survive conditions that cause protein unfolding or misfolding. Furthermore, DnaK is one of the most highly conserved bacterial protein-coding genes in prokaryotes, making it an especially attractive target.25 Several studies have described the involvement of DnaK in antibiotic resistance and have shown that, in the absence of functional DnaK, MDR bacteria are sensitive to several classes of antibiotics, including fluoroquinolones and β-lactam antibiotics.26,27 Furthermore, DnaK has also been shown to be associated with oncogenic properties of certain bacteria such as mycoplasma.28
Arrevus has been awarded over ~$3,000,000 through six NIH grants to develop ARV-1502 as a novel therapeutic to target drug resistant bacteria.
ARV-1802 is a leptin receptor antagonist that represents a new paradigm in cancer treatment. Current disease-modifying solid tumor cancer treatments include chemotherapy, radiation and immunotherapy. While there have been numerous advances in each type of treatment, there are still significant limitations. A new paradigm in cancer treatment is metabolic therapy. Metabolic therapy targets the energy production of cancer cells to shut down their growth and prevent them from spreading. A key metabolic target that has not been previously targeted is leptin, which is a regulator of energy balance and is known as “the energy expenditure hormone.”29 Numerous studies have shown that leptin stimulates cancer development, growth, and progression.30,31,32 Furthermore, leptin and its receptor are present in numerous cancer tumors cells but not present in surrounding normal tissue.33 Moreover, the presence of leptin and its receptor is associated with increased tumor malignancy and decreased patient survival.34 These studies highlight that leptin could be a revolutionary new metabolic target for cancer treatment.
To address this, Arrevus is developing ARV-1802 as a novel inhibitor of leptin signaling. ARV-1802 is an innovative new chemical entity that 1) has a novel mechanism of action and displays selective antagonistic activity for the leptin receptor with a Kd of 2 pM;35 2) is effective in suppressing the growth promoting effect of leptin in numerous cancer cell lines;30 3) successfully inhibited cancer tumor growth, progression, and increased survival in numerous cancer models in animals; 4) is not toxic, even when used at 50 times the amount needed for efficacy;36 and 5) uniquely crosses the brain-blood barrier.37 Arrevus is developing ARV-1802 as a novel metabolic therapy to improve cancer patient outcomes and survival.