Closely-held Appili Therapeutics plans to begin late in the current quarter a Phase 1 bridging, or bioequivalence, study of its lead anti-infective, ATI-1501, a reformulated, taste-masked liquid suspension of metronidazole, targeting anaerobic bacterial infections, including Clostridium difficile.
“Our product has the potential to overcome the very bitter taste of metronidazole when it is crushed and administered to many pediatric and geriatric patients who have difficulty swallowing and must take the medication three times a day for up to two weeks,” Kevin Sullivan, CEO, says in an interview with BioTuesdays.
“Making metronidazole more palatable is a significant market opportunity,” he contends.
Metronidazole has been on the market as a tablet in North America for more than 50 years and has been a workhorse in the field, with some 9.5 million annual prescriptions in the U.S. alone. Metronidazole also is on the WHO list of essential medicines. And despite its widespread use, relatively low levels of resistance have developed against it over the years, Mr. Sullivan points out.
“Our initial focus is on the more than one million pediatric and/or geriatric patients who have difficulty swallowing and are afflicted with diseases where metronidazole is the first line of therapy,” he says. “This is where we expect adoption to be the highest.”
Appili, which was founded in May 2015 by investment banker, Bloom Burton, also is in early research for a second anti-infective drug, ATI-1503, a negamycin analogue development program that continues work started at AstraZeneca after it exited the antibiotic sector in 2014.
According to Mr. Sullivan, negamycin analogues have broad activity against Gram-negative bacteria, including three of the CDC’s most urgent threats: Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa.
“Our goal at the outset was to build a balanced risk portfolio, with potentially faster-to-revenue compounds, like ATI-1501, which would give us the flexibility to take on a higher risk but truly transformational compound, like ATI-1503,” he adds. “We are looking to grow our pipeline substantially over the next few years with faster-to-revenue programs.”
Mr. Sullivan says Appili met with the FDA in February to discuss the clinical program for ATI-1501 and has begun GMP manufacturing clinical batches for its 40-patient Phase 1 study. A subset of patients will advance into a tasting component in order to obtain subjective feedback from ATI-1501 and the standard of care, he adds.
Appili hopes to file a NDA, using the 505(b)(2) pathway, in the first quarter of 2018, with possible market approval in early 2019, he adds. “We will be able to advance our filing with all publicly available scientific data associated with metronidazole.”
In addition, the company has retained Torreya Partners to seek an out-licensing agreement for ATI-1501 and has a data room available for potential partners to evaluate its full commercial potential.
According to a 2014 study by the Review on Antimicrobial Resistance, there are more than two million people afflicted with drug resistant infections, with forecasts of 10 million deaths annual by 2050. The WHO considers antibiotic resistance one of the three greatest threats to mankind.
Mr. Sullivan also notes that the FDA has adopted a number of R&D and regulatory incentives to foster development of anti-infectives, including additional market exclusivity, priority review, fast track approval and priority review vouchers. “This is also a priority research area for NIH, CDC and U.S. military funding,” he adds.
To gauge physician interest in ATI-1501 and build a business case for the company, Appili and Market Street Research conducted a study of 263 physicians treating geriatric patients. The research found 94% of physicians treating the elderly were interested in a taste-masked liquid oral formulation of metronidazole, with 63% of long-term care physicians very interested.
“A pricing strategy is very important with our potential product because metronidazole is relatively inexpensive for a 10-to-14 day regimen,” Mr. Sullivan points out. “If there are issues with metronidazole in hospitals and institutions treating C. difficile, for example, physicians typically switch patients to Vancomycin, which costs more than $300 per regimen.”
Appili and QuintilesIMS surveyed 11 insurance payers, representing 56 million lives and a broad cross-section of managed care facilities, finding that payers considered ATI-1501 good value in the $200-to-$250 range per regimen.
Citing a more than one million target population of seniors with difficulty swallowing metronidazole, Mr. Sullivan figures ATI-1501 has an annual market opportunity of $75-million to $200 million, depending on market penetration.
On the other hand, the market potential for Appili’s ATI-1503 exceeds $1-billion, as it represents a “starting point for a new class of Gram-negative targeting agents,” he contends.
The company has attracted Dr. Sridhar Narayan, who managed the negamycin program at AstraZeneca, to its scientific advisory board. Mr. Sullivan says the major advancement at AstraZeneca was to improve the compound’s potency so that less drug was needed to kill the bacteria.
Appili hopes to identify a clinical lead and establish animal proof-of-concept for ATI-1503 in 2018.
“Gram-negative bacteria has become a global threat because its surrounding molecular structure makes entry of antibiotics difficult,” he adds. “Our ATI-1503 naturally enters Gram-negative bacteria, so our goal now is enhancing that entry. A lot of pharma companies in the infectious disease space are watching our program.”