OVERVIEW
First Wave BioPharma’s product portfolio is built around its three proprietary technologies – capeserod, a selective 5-HT4 receptor partial agonist which First Wave will pursue for gastrointestinal (GI) indications; the biologic adrulipase, a recombinant lipase enzyme designed to enable the digestion of fats and other nutrients; and niclosamide, an oral small molecule with anti-inflammatory properties.
ADRULIPASE
First Wave is advancing two programs built around adrulipase for the treatment of exocrine pancreatic insufficiency (FW-EPI) in patients with cystic fibrosis (CF) and chronic pancreatitis (CP).
CAPESEROD
First Wave is developing capeserod, a selective 5-HT4 receptor partial agonist, for several gastrointestinal (GI) indications, including gastroparesis and pediatric ulcerative colitis.
NICLOSAMIDE
First Wave’s niclosamide program leverages proprietary formulations to address multiple GI conditions, including ulcerative proctitis/ proctosigmoiditis (FW-UP), and Crohn’s disease (FW-CD).
Adrulipase is a recombinant lipase enzyme for the treatment of exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis (CF) and chronic pancreatitis (CP). Adrulipase, supplied as an oral, non-systemic, biologic capsule, is derived from the Yarrowia lipolytica yeast lipase and breaks up fat molecules in the digestive tract of EPI patients so that they can be absorbed as nutrients.
EPI is a condition characterized by deficiency of the exocrine pancreatic enzymes, resulting in a patient’s inability to digest food properly, or maldigestion. The deficiency in this enzyme can be responsible for greasy diarrhea, fecal urge and weight loss.
The digestive standard of care for both CF and chronic pancreatitis (CP) patients with EPI are commercially-available PERTs. Ideally, a stable daily dose of PERT will enable CF patients to eat a normal to high-fat diet and minimize unpleasant gastrointestinal symptoms. In practice, however, a substantial number of CF patients do not achieve normal absorption of fat with PERTs. Moreover, PERTs require the administration of as many as 40 pills per day and have potential issues with Black Box safety warnings.
In developing adrulipase, First Wave is seeking to provide CF and CP patients with a safe and effective therapy to control EPI that is non-animal derived and offers the potential to dramatically reduce their daily pill burden.
Capeserod is a selective 5-HT4 receptor partial agonist, which First Wave licensed from Sanofi and is repurposing and developing for GI indications. Sanofi previously conducted seven Phase 1 and two Phase 2 trials investigating the potential of capeserod for neurological disorders. In these trials, involving over 600 patients, Capeserod appeared safe and well-tolerated.
Sanofi’s research on capeserod determined the drug’s mechanism of action may directly or indirectly initiate the peristaltic or secretory reflex by releasing neurotransmitters that can decrease colonic transit time and improve bowel movement in constipation. Additionally, capeserod may reduce the likelihood of inflammation and damage of epithelial cells where its partial agonistic effect is expected via stimulation of 5HT4b in intestinal epithelium. Moreover, combination therapy with ADBR3 agonists may provide additive effect and relief in symptoms in ulcerative colitis.
Based on this research and subsequent artificial intelligence (AI)-empowered analyses, First Wave believes capeserod has potential applications for several gastrointestinal disorders in multibillion-dollar markets where there are significant unmet clinical needs. These GI indications include gastroparesis, a disease whereby the movement of food from the stomach to the small intestine is delayed, resulting in severe constipation, and pediatric ulcerative colitis, an inflammatory bowel disease (IBD) that causes irritation, inflammation, and ulcers in the lining of the colon.
Niclosamide is an oral small molecule with anti-viral and anti-inflammatory properties that has been safely used on millions of patients worldwide. It is listed as an essential medicine by the World Health Organization (WHO) and was approved by the U.S. Food and Drug Administration (FDA) in 1982 for the treatment of intestinal tapeworm infections.
Recent discoveries in immune cell metabolism suggest that it is possible to selectively target disease-causing immune cells to treat inflammatory diseases without unwanted side effects such as broad immunosuppression. Research indicates that IBD, including ulcerative colitis, Crohn’s disease, and ulcerative proctitis/ proctosigmoiditis, is driven by pathogenic Th17 cells, which release a cascade of local cytokines that in turn cause inflammation in bowel wall tissues.
Th17 cells rely on a cellular process called oxidative phosphorylation to survive. Niclosamide is known to disrupt the oxidative phosphorylation in the mitochondria of pathogenic Th17 cells in a manner that selectively induces apoptosis of pathogenic Th17 cells, overcoming their inherent resistance to cell death. By killing Th17 cells, niclosamide reduces inflammation and calms the gut, selectively killing pathogenic, inflammatory cells while leaving healthy cells untouched.
First Wave’s suite of proprietary, gut-restricted niclosamide product candidates are designed to target the metabolism of disease-causing Th17 cells to potentially halt or delay the progression of disease, stop flare-ups, and address patient needs at all stages of IBD, from mild to severe, and for cancer patients with checkpoint-induced colitis.
PUBLICATIONS
|
|
ADRULIPASE: |
|
"Formulation Development of Enterically Protected Spray Dried Dispersions of Adrulipase." Desai H, Conlon D, Brown A, Draganov A, Tagliaferri F, Srinivasan D, Brieger M, Stover, T. AAPS 2022 PHarmSCi 360 Conference Poster. “A Phase 2, Open-Label, Multicenter, 2×2 Crossover Trial to Assess the Safety and Efficacy of MS1819-SD in Patients with Exocrine Pancreatic Insufficiency Due to Cystic Fibrosis”. Konstan M, McBennett K, Boas S, Mazurek H, Gangal M, Srinivasan D, Pennington J. 2020 Digestive Disease Week (DDW) Presentation. “Impact of a spray dried recombinant lipase, MS1819, For the treatment of exocrine pancreatic insufficiency in patients with chronic pancreatitis. Results of a multicenter, Phase II, open-label, non-randomized study”. Nguyen, N, Lebreton, L, Smith G, Jais P, Schue M, Spoor, T. 2019 Digestive Disease Week (DDW) Presentation. “Yarrowia lipolytica Lipase 2 is Stable and Highly Active in Test Meals and Increases Fat Absorption in an Animal Model of Pancreatic Exocrine Insuffiency.” Aloulou A, Schué M, Puccinelli D, Milano S, Delchambre C, Leblond Y, Laugier R, Carrière F. Gastroenterology. December 2015. 149(7):1910-1919 |
|
|
NICLOSAMIDE: |
|
Marafini, I, De Crisofaro, E., Salavatori, S, Calabrese, E, Lolli, E, Monteleone, I, Franchi, L, Ciccopcioppo, R, Glick, G, Opipari, A, Monteleone, G. Niclosamide Enema for Active Distal Ulcerative Colitis: A Phase 1, Open-Label Study. Inflamm Bowel Dis. 2023 July 21. Read more. Shin, B., Benavides, G. A., Geng, J., Koralov, S. B., Hu, H., Darley-Usmar, V. M., & Harrington, L. E. (2020). Mitochondrial oxidative phosphorylation regulates the fate decision between pathogenic Th17 and regulatory T cells. Cell Reports, 30(6), 1898-1909. doi:10.1016/j.celrep.2020.01.022. Read more. Fuseini, H., Cephus, J., Wu, P., Davis, J. B., Contreras, D. C., Gandhi, V. D., Rathmell, J. C., & Newcomb, D. C. (2019). ERα signaling increased IL-17A production in Th17 cells by upregulating IL-23R expression, mitochondrial respiration, and proliferation. Frontiers in Immunology, 10. doi:10.3389/fimmu.2019.02740. Read more. Kaufmann, U., Kahlfuss, S., Yang, J., Ivanova, E., Koralov, S. B., & Feske, S. (2019). Calcium Signaling Controls Pathogenic Th17 Cell-Mediated Inflammation by Regulating Mitochondrial Function. Cell Metabolism, 29(5), 1104-1118. doi:10.1016/j.cmet.2019.01.019. Read more. Franchi, L., Monteleone, I., Hao, L., Spahr, M. A., Zhao, W., Liu, X., Demock, K., Kulkarni, A., Lesch, C. A., Sanchez, B., Carter, L., Marafini, I., Hu, X., Mashadova, O., Yuan, M., Asara, J. M., Singh, H., Lyssiotis, C. A., Monteleone, G., Opipari, A. W., & Glick, G. D. (2017). Inhibiting oxidative phosphorylation in vivo restrains Th17 effector responses and ameliorates murine colitis. The Journal of Immunology, 204(2). doi:10.4049/jimmunol.1600810. Read more. Tao, H., Zhang, Y., Zeng, X., Shulman, G. I., & Jin, S. (2014). Niclosamide ethanolamine improves blood glycemic control and reduces hepatic steatosis in mice. Nature Medicine, 20(11), 1263-1269. doi:10.1038/nm.3699. Read more |
