An estimated 20% of Americans suffer from laryngopharyngeal reflux (LPR) with no effective medical therapy currently available. This condition causes gastric juice to travel up from the stomach, through the esophagus, and into the throat. Symptoms of LPR include chronic cough, hoarseness, difficulty swallowing, and the feeling of something stuck in your throat. LPR can also contribute to life-threatening illness including reactive airway disease and laryngeal cancer. While acid suppression, Proton Pump Inhibitor (PPI), therapy is a mainstay in the treatment of gastro-esophageal reflux disease (GERD; commonly known as heartburn), it is not effective for LPR. $26 billion/year is spent on PPIs for LPR, but placebo-controlled trials have shown they are not effective for this disease. The American Gastroenterology Association (AGA) now advise against their use for LPR in the absence of heartburn. A medical therapy for LPR is desperately needed. Pepsin (the major digestive enzyme in the stomach) is the key therapeutic target. Pepsin is present in all gastric juice and is frequently detected in airway tissue and secretions from patients with LPR, absent in reflux-free control subjects. Non-acid reflux of pepsin into the throat is associated with symptoms and clinical findings, and physiologically relevant concentrations of pepsin cause laryngeal inflammation and damage in in vitro and in vivo studies, including pathological changes consistent with those observed in LPR patients. There’s compelling evidence that a pepsin inhibitor will be an effective treatment for LPR.
Fosamprenavir, an existing protease inhibitor used to treat HIV, was found to bind to and inactivate pepsin, preventing pepsin-mediated laryngeal inflammation and damage in preclinical studies. In support, patients taking HIV inhibitors have a significantly lower incidence of LPR compared to that reported for the general population. The Cohort Discovery Tool of the Medical College of Wisconsin Clinical Data Warehouse was used to estimate the incidence of LPR in adult patients with HIV. Only 5/2062 (0.2%) patients taking a HIV protease inhibitor had LPR reported in their medical record, whereas the incidence of LPR in both an age/sex matched population and in the general population is 10 – 34.4%, supporting its use as a treatment for LPR.
Fosamprenavir has a good safety and tolerability profile, and targets a foreign virus, which is otherwise not present, making it an ideal drug to repurpose allowing safe assessment in a clinical trial. This repurposing approach allows for a more expeditious assessment in a clinical trial compared to a new molecule.
N-Zyme Biomedical has engaged LGM Pharma to create a new prolonged release formulation of oral fosamprenavir. This new formulation contains a sodium alginate to increase mucoadhesion, prolonging drug delivery to the esophagus when swallowed. Local esophageal treatment of reflux has been an area of interest for several decades, however drug delivery to the esophagus is challenging due to the exceedingly short esophageal transit time of orally administered drugs. Local esophageal delivery of a pepsin inhibitor such as fosamprenavir would be expected to benefit to the ~50% of LPR patients that have GERD and potentially the ~40% GERD patients that have symptoms despite maximal acid suppression therapy.
The U.S Food and Drug Administration (FDA) approved a 12-week randomized, double-blind, placebo-controlled phase III clinical trial to assess the efficacy of oral fosamprenavir for the treatment of LPR.
In addition to developing a new oral formulation of fosamprenavir, N-Zyme is also developing a dry powder inhaler as local delivery to the throat is likely to be more effective and efficient for LPR. A Falk Catalyst Award funded preclinical assessment of local delivery of fosamprenavir to the throat for the treatment of LPR. The throat is readily accessible, allowing a higher concentration at the disease site and lower systemic concentration. This will likely increase efficacy and decrease side effects. Preliminary studies demonstrated efficacy and safety of inhaled fosamprenavir. A Falk Transformational Award is now funding Good Lab Practice (GLP) inhalation toxicology studies required by the FDA to assess this Investigational New Drug (IND) in a phase I clinical trial. N-Zyme’s dry powder inhaler, providing a low dose fosamprenavir direct to the throat, could be life-changing for those suffering with LPR.
Dr. Nikki Johnston and Franco Vigile co-founded N-Zyme Biomedical (www.nzymebio.com) in 2021. Venture Capital investment in N-Zyme is funding development of both the prolonged release formulation of fosamprenavir and dry powder inhaler, by LGM Pharma, and the clinical trials to assess their efficacy for LPR. Nikki Johnston, Chief Scientific Officer N-Zyme and Associate Professor at the Medical College of Wisconsin, is an internationally recognized expert on reflux and pepsin. She has been working on the development of this drug for over 10 years. Franco Vigile, a successful entrepreneur who co-founded HaluGen (a leading genetic-based pre-screening platform), is Chief Executive Officer of N-Zyme. In addition to Franco’s business expertise, he has first-hand experience dealing with this disease which is what led him to co-founding the company. Together, they are Revolutionizing the Reflux Industry through N-Zyme Biomedical and are committed to helping the millions of people around the globe that are without effective medical treatment options.
LGM Pharma is the leading outsourcing CDMO partner for innovative new drug development. LGM specializes in supporting startup companies with comprehensive outsourcing drug development and commercialization services. LGM Pharma manages all phases of the drug product development process, from sourcing and supply of API through drug product manufacturing. LGM Pharma’s services include analytical testing, analytical methods development, formulation development, clinical trial drug product manufacturing, commercial manufacturing, stability studies, and ANDA / NDA product submission. LGM is focused on customer-centric solutions, providing clients with a comprehensive, one-stop manufacturing solution that reduces risk, increases efficiency, and accelerates the path to commercialization.
To learn more about LPR, the upcoming clinical trials and the new LPR therapeutic under development, please visit: https://www.nzymebio.com/