Antibiotics With Bacteria-Specific, Rather Than Site-Specific, Indication Headed To US FDA
Executive Summary
Entasis is seeking a pathogen-specific approval for its antibiotic/beta lactamase inhibitor candidate rather than an indication specific the site of an infection. Achaogen’s earlier failure to do the same may have helped set a path.
Entasis Therapeutics Holdings Inc. hopes to be the first company to obtain a pathogen-specific indication from the US Food and Drug Administration with a broad claim for its antibacterial combination product SUL-DUR to treat carbapenem-resistant Acinetobacter baumannii infections, and it is relying on the agency’s flexibility regarding challenging disease areas with unmet medical need to get that done.
For its combination of the generic polymyxin antibiotic sulbactam with its novel beta-lactamase inhibitor durlobactam (SUL-DUR), the AstraZeneca PLC spinout appears to be working under a hybrid model based on two FDA guidance documents – and with advice from regulators.
SUL-DUR is being developed for carbapenem-resistant Acinetobacter baumannii infections and demonstrated non-inferiority to colistin for 28-day, all-cause mortality in the Phase III ATTACK trial, for which Entasis unveiled top-line data on 18 October. In addition, the combination product demonstrated superiority compared to colistin for reducing nephrotoxicity, a side effect that plagues the polymyxin antibiotic class.
Entasis CEO Manos Perros said his company may succeed where now-defunct Achaogen, Inc. failed years earlier with the aminoglycoside Zemdri (plazomicin) because it worked out a feasible Phase III study design with the FDA and European Medicines Agency to show SUL-DUR could be effective against carbapenem-resistant Acinetobacter infections regardless of where in the body they occur.
Achaogen had hoped to obtain a pathogen-focused indication for Zemdri against carbapenem-resistant Enterobacteriaceae pathogens under the limited population pathway for antibacterial drugs, but was unable to enroll a study for that indication.
The firm later switched tracks to a study sufficient to earn approval for complicated urinary tract infections (cUTI) in 2018, but the product yielded meager sales and Achaogen filed for bankruptcy the following year. (Also see "Achaogen Questioning Whether Others Will Pursue LPAD Pathway After Zemdri Misses Out " - Pink Sheet, 26 Jun, 2018.)
To develop the protocol for the ATTACK study, Entasis seems to have worked out with the FDA an approach based on two guidance documents – the 2018 Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) guidance, which was updated in August 2020; and the Antibacterial Therapies for Patients With an Unmet Medical Need for the Treatment of Serious Bacterial Diseases guidance issued in August 2017 – an industry expert told the Pink Sheet. (Also see "US FDA Fulfills Annual Antibiotic Guidance Goal With Three Women’s Health Guidances" - Pink Sheet, 13 Oct, 2019.)
The idea of species-specific indications came up during the FDA’s efforts to modernize its anti-infective drug guidances several years ago, when the agency proposed five different development and regulatory pathways for antibacterial drugs targeting a single species of bacteria: non-inferiority trials; superiority trials; accelerated approval using surrogate endpoints; approval based on the animal rule; and the limited population pathway. (Also see "Antibacterial Drugs: FDA Panel To Explore Approval Path For Single-Species Agents" - Pink Sheet, 11 Apr, 2017.)
FDA’s Antimicrobial Drugs Advisory Committee urged the agency to consider allowing sponsors targeting a single species of pathogen to use a wider, flexible set of evidence given the difficulties of such trials. The possibilities of species-specific indications have come up throughout discussions of the LPAD pathway, as they would likely mean a small, targeted population. (Also see "Flexible 'Menu' Of Antibacterial Development Options Suggested By US FDA Panel" - Pink Sheet, 18 Apr, 2017.)
“I think the FDA is doing what they have said they will do and what we've seen them do, which is using their maximal regulatory flexibility, where they recognize that finding a new drug for Acinetobacter is hard, and finding new antibiotics is hard,” the industry expert said.
“So they said here's a compound that looks like it probably works, here's a company that is willing to do a hard study, and if they come even close to the mark” that could be enough for approval.
The data Entasis has reported from the ATTACK study appears to be well beyond the mark the sponsor would need to hit to get its approval, the source added.
“We went to the FDA with a design that was looking to develop a product, not for pneumonia or bloodstream infections or UTI, but for carbapenem-resistant Acinetobacter,” Entasis’ Perros said. “They were very receptive and they engaged, we had several conversations to refine the design, and to come up with what eventually became ATTACK. We also worked on that with European regulators.”
Achaogen Precedent May Have Helped Entasis With FDA
The FDA was supportive when Entasis presented its plan to seek a pathogen-specific indication, Perros noted, because the agency understands that’s the way antibacterials are being used in practice today and because of the precedent set by Achaogen’s unsuccessful attempt to do the same.
While Achaogen was unable to enroll its planned Phase III trial for a variety of technical reasons, Perros said Zemdri also struggled to get clinical adoption because it was from an established class and carried a warning level about safe exposure levels that did not differentiate it within the aminoglycoside class, which already had a leading therapy in AbbVie Inc.’s Avycaz (ceftazidime and avibactam).
“Our product will launch with data in the right patients,” he said. “We, of course, will work with the FDA and we hope that [efficacy] data will be reflected in the label as well as the safety data which clearly shows superiority to other treatment options.”
“Most Gram-negative antibiotic trials will go after a body site indication. It will be pneumonia or a urinary tract infection, and if you look at ... the labels, they will all reflect that,” Perros said in an interview. “We had patients with pneumonia and bloodstream infections in part A of our study. We also opened the part B to body-site infections that were carbapenem-resistant.”
“The focus of this trial was on the pathogen and the patients, which we evaluated as a primary efficacy population where patients have carbapenem-resistant Acinetobacter infections,” he explained. “We got both the bug and the resistance mechanism confirmed before including those patients in our analysis. So, this [data] is unique and landmark.”
Global Filing Strategy
The Phase III ATTACK study also was the first pivotal antibacterial study to enroll Chinese patients at the same time as patients in other geographies such as the US and Europe, Perros noted.
As such, Entasis and its Asia-Pacific development and commercial partner Zai Lab Ltd. should be able to file the combination product for approval on the basis of the ATTACK data in the US, EU and China, he said. (Also see "Deal Watch: Gilead’s Immunology Collaboration With Verily Continues Pivot Away From Virology" - Scrip, 2 May, 2018.)
Entasis expects to submit an NDA to FDA in mid 2022.
Non-Inferior For Mortality; Superior On Reducing Kidney Tox
In top-line data from part A of the ATTACK trial, 125 intent-to-treat patients were randomized either to four-times daily intravenous infusion of SUL-DUR or colistin, a polymyxin antibiotic commonly used to treat Acinetobacter infections. For the endpoint of 28-day, all-cause mortality, SUL-DUR achieved non-inferiority with a mortality rate of 19% (12/63) compared with 32.3% (20/62) in the control arm. All patients received background therapy of imipenem/cilastatin.
Similar trends were observed for 14-day, all-cause mortality, Entasis reported. The 28-day mortality endpoint was not powered to show significance, but the company noted that the SUL-DUR arm posted a treatment difference of 13.2% with a 95% confidence interval.
The original trial enrollment was 207 Acinetobacter-infected patients and all received one dose of study drug or the comparator regimen, but the efficacy data are based on an intent-to-treat population that met more specific disease criteria. Part A – which treated patients with carbapenem-resistant Acinetobacter infections such as hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia or bacteremia – yielded a statistically significant difference for test of cure; 61.9% for SUL-DUR and 40.3% for the colistin arm.
Part B was an open-label, study drug-only portion for patients with Acinetobacter infections resistant to or which failed treatment on colistin or another polymyxin antibiotic therapy. Here, 28-day, all-cause mortality was 17.9% (5/28), which Entasis claimed is consistent with the results seen in part A.
Entasis also conducted safety analyses for all 207 patients enrolled at the start and found that SUL-DUR demonstrated superiority compared with colistin for reduction of nephrotoxicity as measured by the Risk-Injury-Failure-Loss-End-stage renal disease (RIFLE) classification, which measures creatinine level or glomerular filtration rate.
Nephrotoxicity was seen in 13.2% (12/91) of patients who received study drug compared with 37.6%(32/85) for the control arm, (p=0.0002). In part A, drug-related adverse events were reported for 12.1% of patients receiving SUL-DUR (11/91) and 30.2% of patients receiving colistin (26/86); the treatment-related AE in the open-label part B portion was 10.7% (3/28).