DUBLIN – Shares in Polyphor AG dropped as much as 21% Wednesday as the company shut down two phase III trials of its lead drug candidate, murepavadin, a first-in-class intravenous antibiotic in development for hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP).
The decision was not entirely unexpected. It came after an earlier move in May to halt further recruitment onto the two studies, following the emergence of an unexpectedly high frequency of acute kidney injury in study participants. An analysis of the incomplete dataset it had compiled before the clinical hold confirmed the initial observations. Among 41 patients recruited onto the more advanced of the two studies, 63% of those in the drug treatment arm (n=33) developed acute kidney injury, as compared with 38% of those in the control arm (n=8).
Murepavadin is a 14-amino-acid cyclic peptide that targets lipopolysaccharide transport protein D, an outer membrane protein of Pseudomonas aeruginosa, the second most common cause of HABP/VABP. It was being investigated in two phase III trials, Prism-MDR, which was to recruit 150 patients with multidrug-resistant VABP due to confirmed or suspected P. aeruginosa infection, and Prism-UDR, which was to recruit 250 patients with usual-drug-resistant HABP due to confirmed or suspected P. aeruginosa infection.
The UDR study enrolled its first patient less than a month before the clinical hold was imposed, so the clinical data that Polyphor has amassed comes from the MDR study, which had randomized 41 patients to receive, in a 2-to-1 ratio, either murepavadin plus a standard antibiotic or a control regimen of two standard antibiotics. As well as having a higher frequency of acute kidney injury, those in the murepavadin study arm also had greater severity of kidney injury than those in the control arm. Thirteen of 21 patients in the former group had stage II or stage III acute kidney injury. One of the three patients in the control group who developed kidney injury had stage III disease, whereas two other patients had stage I disease.
There was no difference between the two study arms in terms of serious adverse events. The 28-day mortality rates were 30% for the murepavadin arm and 37.5% for the control arm, although that figure was not statistically significant. Even if the protocol could be amended to reduce the kidney problem, Polyphor's management concluded that any resulting drug would not have an attractive commercial profile.
Not dead yet
Murepavadin is not dead by any means, however. The company has opened scientific studies to investigate whether the intravenous formulation can get back on the rails, by developing a different version of the drug with an altered pharmacokinetic profile. It is not disclosing the particular lines of inquiry it is pursuing as the work may lead to new patent filings.
If that initiative does deliver a result, it would still take at least two years to get back into phase III studies, Frank Weber, Polyphor's interim chief medical and development officer, told a conference call audience. "Our current thinking is we probably need to have a couple of preclinical studies before we go back into humans," he said. A phase I bridging study in healthy volunteers would then need to follow.
The company is also working on an inhaled formulation of murepavadin, which is part-funded by the Innovative Medicines Initiative, the research program backed by the European Commission and the pharmaceutical industry. A nebulized version of the drug could have potential in patients with cystic fibrosis and bronchiectasis, a chronic condition arising from illness or injury in which the airways of the lung are excessively widened. The systemic exposure to the drug would be about 10-fold less than that associated with the intravenous version, Weber said.
Although the patient populations involved are smaller than those affected by HABP/VABP, the actual amount of drug use would be greater, Polyphor CEO Giacomo Di Nepi told BioWorld. A clinical study is still more than a year away, however. "We plan to finish the preclinical phase by the first half of next year," he said.
Development of its next-generation of OMPTA antibiotics, which, like murepavadin, target bacterial outer membrane proteins, is on a similar trajectory. The hope is that they will have a radically better safety profile – their specific targets vary. "Most of the chemical scaffolds are different," Di Nepi said. Their specific elimination characteristics are also different.
The company's lead program is now its immuno-oncology play, balixafortide, a CXCR4 antagonist, which recently began a pivotal phase III trial in HER2-negative breast cancer in combination with the tubulin inhibitor Havelen (eribulin).
Polyphor's stock (Zurich:POLN) closed at CHF8 Wednesday, down almost 17% on its previous close. Most of the damage was done in May, when the stock fell 48.5%. It is 79% down on its May 2018 IPO price of CHF38 per share.