On June 26, Achaogen’s Zemdri (plazomicin) obtained a bittersweet victory: the FDA approved its use in complicated urinary tract infections (cUTI), but issued a complete response letter with regards to Achaogen’s application for a bloodstream infection (BSI) label, effectively rejecting approval in this indication. 1
These results are not surprising, since the FDA’s Antimicrobial Drugs Advisory Committee (AdCom) that convened on May 3rd, 2018 voted that plazomicin had not provided substantial evidence of efficacy and safety in BSI patients with limited treatment options, while unanimously voting that enough evidence had been submitted for cUTIs.
Here, we discuss the FDA’s decision with regard to the BSI label, and analyze possible implications for the development of new antibiotics.
Antibiotics are not lucrative
Developing antibiotics is not as lucrative as developing treatments for other therapeutic areas, such as oncology or rare diseases – the market is heavily genericized, treatment courses are given over a period of a week or two rather than for months or years, there is a reduced tolerance for high prices, and the best drugs are kept on the shelf and reserved for use as a last resort so as to minimize the emergence of drug resistance. As a consequence, development of novel therapies has not been a priority for most of pharmaceutical companies; major companies such as Merck and AstraZeneca have spun off their early/mid stage assets, while Pfizer and Novartis have a limited presence. More recently, Allergan announced their intention to sell the anti-infective portfolio.
The FDA is helping
In the past years, the FDA has implemented several measures aimed at incentivizing the development of new molecules, particularly for the treatment of antibiotic resistant pathogens, where there is a critical unmet need for satisfactory therapeutics and a limited armamentarium available to manage those infections. One of the measures employed is the limited population antibacterial drug (LPAD) pathway; this approach allows antibiotic developers to evaluate antibiotics that target serious/life threatening infections with high unmet need in small trials and well-defined populations (e.g., in patients with infections due to carbapenem-resistant Enterobacteriaceae (CREs) or MDR Pseudomonas). An eventual label for an indication obtained through this pathway would be narrow, as it would be limited to a population where the benefits outweighed the risks. 2
Achaogen submitted an NDA
In October 2017, Achaogen submitted an NDA for plazomicin through the LPAD pathway, based on data from a small Phase III, pathogen-specific CARE trial to support a BSI label for limited populations. This trial targeted infections due to CREs and enrolled a total of 39 patients, comparing the efficacy of plazomicin in combination with meropenem or tigecycline against colistin in combination with meropenem/tigecycline in patients across multiple indications, of which 29 were BSIs. The company had initially planned to enroll a larger number of patients, but enrollment difficulties forced a change of plans - approximately 2,100 patients were screened, but less than two percent met inclusion criteria and were included in the trial. These enrollment difficulties highlight one of the major challenges seen when running pathogen specific trials, namely the timely identification of patients that meet the FDA requirements.
The AdCom was not convinced by the BSI data
On May 3rd, the Antimicrobial Drugs Advisory Committee voted 4-11 (yes-no) that the data presented by Achaogen for a BSI label did not provide “substantial evidence of the safety and effectiveness of plazomicin for the treatment of BSIs in patients with limited or no treatment options”. Because of the small sample size it was not possible to perform a statistical analysis and the presentation of results was descriptive. However, a lower all-cause mortality at day 28 was reported in the plazomicin arm (7%, n = 1/14) than in the colistin arm (40%, n = 6/15). The plazomicin arm also performed better on safety endpoints, including indicators of renal function (serum creatinine increases ≥ 0.5 mg/dL) – 17% (n = 2/12) in the plazomicin arm and 50% (n = 8/16) in the colistin arm.
Could the FDA have decided differently?
While it is true that no statistical analysis was performed, the results suggest that plazomicin is not inferior to colistin when treating CREs, and that it could, in fact, be superior to colistin. Based on the data from the CARE trial, wouldn’t it have been reasonable for the FDA to grant approval for BSIs, even if conditional to the presentation of new efficacy data in the treatment of CREs?
Achaogen was requesting a label for use in a limited population in line with that laid out in the LPAD description. Isn’t there a suggestion that when plazomicin is combined with meropenem/tigecycline the benefits outweigh the risks, as defined in the guidance for industry outlined by the FDA? Indeed, the FDA recently granted a conditional approval for Sarepta’s Exondys 51 (eteplirsen) for Duchenne muscular dystrophy, which not only did not receive the support of the AdCom, but also presented data arguably less impressive than plazomicin’s; Sarepta is currently running efficacy trials to further demonstrate benefits, and it would not be unreasonable to request the same to Achaogen.
As some members of the AdCom admitted, plazomicin will be used off-label for the treatment of BSIs. While frowned upon in other therapeutic areas, off-label prescribing is common for antibiotics, since many of them have a limited number of approved indications, especially when treating life threatening infections.
Only a limited number of antibiotics has a label for BSIs, and our primary market research indicates that off-label prescribing is widespread in BSIs. However, lack of approval for BSIs may limit formulary inclusion, hindering its uptake. Moreover, the FDA decision can have important repercussions for new antibiotics under development. Some of them (Merck’s imipenem/cilastatin/relebactam and Shionogi’s cefiderocol) are being evaluated/have been evaluated in smaller Phase III clinical trials, that specifically enrolled patients with confirmed infections caused by antibiotic resistant pathogens.
The FDA’s decision may have raised questions among those with interest in the development of antibiotics:
- How will data provided by those smaller trials be evaluated? How valuable will it be for approval of a specific label?
- Will developers continue to invest time and money running smaller pathogen-specific trials?
What’s next for plazomicin?
This decision was a disappointing outcome, considering that the LPAD pathway was created to facilitate the development of new antibiotics, and the FDA could have shown some flexibility and willingness to work together with Achaogen. Instead, the first molecule ever to use this mechanism was criticized for data shortcomings that would be expected for any trial run in such a limited patient population. Achaogen has indicated their intent to initiate conversations with the FDA to determine if there is a way to address the complete response letter it received, but damage may have already been done.
Nuno Antunes is a Senior analyst on Infectious, Niche, & Rare Disease team at DRG, currently covering the hospital antibiotic markets, including Gram-Negative Infection and C. difficile Infection.
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Nuno T. Antunes, Ph.D., is principal business insights analyst on the Infectious, Niche, and Rare Diseases team at Decision Resources Group. Previously, he was a Latin America Market Access senior analyst in the Global Market Access Insights Team, where he developed expertise in market access, pricing and reimbursement, health technology assessment, and health policy.
Nuno holds a Ph.D. in animal health from the Universidad de las Palmas de Gran Canaria, Spain, and a D.V.M. degree from the Universidade de Trás-os-Montes e Alto Douro, Portugal. Prior to joining DRG, he conducted research in antimicrobial resistance and antimicrobial development, and worked in the medical devices industry as a scientist.