Amplyx Cleared To Complete Phase II Study Of New Antifungal Class
Executive Summary
Fosmanogepix, with safety and efficacy clearances to continue Phase II, could provide an IV-to-oral option for patients with potentially lethal Candida fungal infections.
Amplyx Pharmaceuticals Inc. grew closer to bringing a new class of antifungal therapy to patients on 16 September after a pair of data review boards monitoring its Phase II trial of fosmanogepix in candidemia infections approved enrolling the second half of the study.
If approved, fosmanogepix (APX001) would be a first-in-class gepix antifungal agent and offer an intravenous-to-oral course of therapy to patients suffering multi-drug-resistant Candida auris and Candida glabrata infections.
Both the Data Review Committee (DRC) and the Data Safety Monitoring Board (DSMB) reviewed data from the first 10 patients dosed with fosmanogepix in an open-label Phase II study and cleared privately held Amplyx to enroll another 10 patients and advance the trial to conclusion. In an interview, Amplyx CEO Ciara Kennedy said the San Diego firm hopes to complete enrollment of the study before the end of 2019.
The DRC determined that the drug has demonstrated a high level of treatment success so far, defined as clearance of Candida from the patient’s blood, the patient’s survival and no other antifungal therapy administered after the patient began receiving the experimental drug. It is being studied in post-surgical patients who are susceptible to infections due to their immunocompromised states – initially patients receiving coronary artery bypass grafts or having tissue such as part of their esophagus removed due to an underlying cancer.
Fosmanogepix is a prodrug of manogepix; both inhibit the fungal enzyme Gwt1, which is highly conserved in Candida-infected cells. Manogepix has demonstrated broad-spectrum activity against common species of Candida and Aspergillus, as well as rare molds including Fusarium, Scedosporium and fungi of the Mucorales order, Amplyx said.
As such, fosmanogepix may offer a broad-based commercial opportunity for Amplyx, Kennedy explained. Backed by a $67m series C financing raised in 2017, the company is conducting four Phase II studies of the agent, including one in South Africa, where 15% of Candida infections are the highly drug-resistant and potentially fatal Candida auris variety. (Also see "Amplyx Raises $67m For Antifungals Against Life-Threatening Pathogens" - Scrip, 2 Aug, 2017.) That and the study just approved for continuation would back a regulatory filing at the US Food and Drug Administration to treat Candida pathogenic infections, Kennedy said.
Other Indications Possible For Fosmanogepix
Beyond that, Amplyx is getting ready to enroll a study of the agent in the three rare mold types it has shown preclinical activity against, which could back a separate new drug application (NDA) filing. Then, with backing from the National Institutes of Health, Amplyx also is studying fosmanogepix in Uganda in patients with cryptococcal meningitis. While such infections are relatively routine to treat in the US and Europe with tericin therapies, Kennedy explained, in sub-Saharan Africa, less access to standard-of-care therapies for these infections has resulted in 150,000-200,000 deaths annually.
This is second only to the mortality caused by HIV in that region, Kennedy said. “We have the potential to offer an all-oral course of treatment, by removing amphotericin B and by including APX001 in the treatment regimen,” she noted, which would be more feasible in those countries and their health care systems.
Thanks to these various potential indications and uses for fosmanogepix, the drug has four qualified infectious disease product (QIDP) designations, orphan drug designation and fast track status for seven indications and Neglected Tropical Disease status for cryptococcal meningitis, which could bring Amplyx a priority review voucher if the drug is approved for that setting. The QIDP designations bring five years of regulatory exclusivity on top of the product’s other exclusivity, which combined with orphan status would mean at least 12 years exclusivity for fosmanogepix in several indications, including Candida, Aspergillus and the rare mold pathogens.
“Those things together really highlight the broad spectrum of activity of this product,” Kennedy said. “The target, an enzyme called Gwt1, is very highly conserved across fungal pathogens, so fosmanogepix has potential to help a lot of different types of patients.”
Amplyx is developing both fosmanogepix and manogepix, the active moiety of the small molecule therapeutic, to enable both intravenous and oral dosing. Of the three approved antifungal classes, only one offers an oral therapy option, seen as ideal for allowing patients to leave the hospital setting as soon as possible to avoid further exposure to pathogens, Kennedy explained.
Development Mirrors Expected Real-World Use
The company designed its Phase I program so that the Phase II studies could occur in a setting as close to what real-world treatment would be like as possible, she continued. In the candidemia study and the others, patients are being transitioned from IV therapy to oral drug as soon as they can tolerate an oral therapy. Patients are infused with two doses of the drug on their first day of treatment, so that steady state can be achieved as quickly as possible with the agent which has a two-and-a-half-day half-life, with patients then receiving the IV or oral version once-daily thereafter for the course of therapy.
Simultaneous to announcing the continuation of the candidemia study, Amplyx also reported that it has licensed the Phase II-ready monoclonal antibody MAU868 from Novartis AG at undisclosed terms. Amplyx intends to launch a pair of Phase II proof-of-concept studies of the antibody to study its ability to inhibit reactivation of the BK virus (BKV), which lies dormant in about 80%-90% of the general population. MAU868 targets the major viral capsid protein of BKV, VP1, essential to the virus’s ability to bind to and infect new cells.
Part of Novartis’s ongoing effort to out-license early-stage infectious disease candidates, MAU is seen by Amplyx as offering protection against BKV reactivation in kidney transplant and hematopoietic stem cell transplant (HSCT) patients. (Also see "BIO 2019 Notebook: Merck; Out-Licensing Deals; RMAT" - Scrip, 3 Jun, 2019.) Reactivation of the virus can cause renal allograft failure and/or shorten the lifespan of an allograft in kidney transplant patients and can lead to hemorrhagic cystitis in HSCT patients, Kennedy said.
For both the fosmanogepix and MAU868 programs, Amplyx eventually will need a new infusion of cash, although Kennedy called her company well-financed for now. Looking ahead, she said the firm will explore all avenues. “We are quite well financed with very supportive, top-quality investors but we will be evaluating other accesses to capital, be that through additional private financing or public financing over the next six-to-nine months,” she said.