Welcome to your weekly digest of approaching regulatory and clinical readouts. Top-line data from two phase III trials of Achaogen’s next-generation aminoglycoside plazomicin, designed to combat multidrug-resistant bacteria, are expected by the end of the year. But with competition in the pipeline the results will need to outshine the rest to carve out market share.
And early next year Nektar will release phase III data on its novel mu-opioid agonist NKTR-181 for use in patients with lower back pain. Despite a phase II failure due to a high placebo response the company plodded on with development and needs to prove this was the right decision.
Resistance is futile
Typically carbapenem antibiotics are used as the last line of defence against infections caused by multidrug resistant bacteria, but carbapenem-resistant infections are on the increase. Achaogen’s plazomicin is said to be potent against carbapenem-resistant enterobacteriaceae (CRE) and bacteria that produce beta-lactamase, an enzyme that can break down antibiotics.
Plazomicin is the company’s most advanced pipeline product and was developed by modifying an existing aminoglycoside called sisomicin. It has fast track and qualified infectious disease product (QIDP) designation from the FDA and the programme is in part funded by BARDA under a $124m contract.
Two trials are expected to report before the end of the year: the Care trial in CRE infections and the Epic trial in complicated urinary tract infections (cUTI).
Epic is expected to serve as the basis of the NDA submission, which is due in the second half of next year. The double-blind trial in 609 adult patients compares plazomicin, given once a day intravenously, with meropenem, a member of the carbapenem class. After this treatment there was an option to switch to oral levofloxacin.
The primary endpoint is microbiological eradication and clinical cure at days 5 and 17 in the modified intent-to-treat population. A non-inferiority margin of 15% was agreed with the FDA.
The Care study enrolled 69 adult patients with hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia or bloodstream infection due to CRE. The first cohort compared plazomicin with colistin, in combination with either meropenem or tigecycline. A second cohort tested plazomicin therapy in combination with an adjunctive antibiotic. Colistin, also known as polymyxin E, was developed in the 1950s and is also used to treat multidrug-resistant bacteria although it is rarely used due to kidney toxicities.
The primary endpoint is 28 day mortality and severe disease-related complications. Secondary outcomes include safety and PK parameters.
Achaogen notes that plazomicin is the only aminoglycoside engineered to overcome common resistance mechanisms, and could be used as part of a combination therapy.
The company completed its $72m IPO in 2014 and to date its shares are down 66%. Needham analysts are cautious that as the cUTI trial serves as the basis of approval there is minimal opportunity for differentiation, and the CRE trial may need to reveal a strong trend over standard of care to drive market share. Meanwhile emerging competition from other new antibiotics in development from Merck, Medicines Company, Shionogi and Astrazeneca/Allergan should become apparent as results read out within the next couple of years.
No pain no gain
Three years ago Nektar’s NKTR-181, a mu-opioid receptor agonist, failed a phase II withdrawal study in pain caused by osteoarthritis of the knee. There was no difference in average change in patient’s pain score between placebo and drug arms during the randomisation phase (Nektar’s faith in pain project hurts share price, September 27, 2013). Shares plunged 26% on the news.
At the time the company said that efficacy signals were still strong enough to warrant a move forward, but the barrier would be designing a trial to overcome the placebo signal. Nektar estimated the pivotal study would cost around $100m.
Now the phase III trial is expected to report in the first quarter of next year. The study, called Summit-07, is in patients with chronic lower back pain. At the beginning of 2016 the DSMB recommended increasing the patient size by 200 after approximately 50% of the initially planned 416 patients completed the study. This was done as the powering fell between 50-85%; with the increased sample size it is expected to be between 65-95%.
Janney analysts note a number of differences between this and the failed phase II study. Patients were dose titrated to 50-60% reduction in pain from baseline compared with 40% in the previous trial, this is a 12-week rather than a 3-week study, and lower back pain could deliver a greater effect size as opposed to chronic knee pain.
Patients are being rolled over onto a 52-week safety study, and a pivotal human abuse liabilities trial is expected to start before the end of this year and should complete by mid-2017.
Nektar shares have recovered little since the phase II failure, and are down 25% this year. With the company trudging on with development it needs to prove to both investors and regulators that it really was worth the time and effort.
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