Revisiting Old Favorites
The production of b-lactamases to destroy b-lactam-based antibiotics has long been used by bacteria to survive antibiotic attack. Two companies, both spin-offs from big pharma, France’s Novexel (www.novexel.com), a sanofi-Aventis spin-off, and Swiss biotech Basilea Pharmaceutica (www.basilea.com), spun off from Roche, discussed their compounds to target b-lactamases.
Christine Miossec, Ph.D., a senior scientist at Novexel said, “We identified NXL104, a small molecule that inhibits serine b-lactamases. This compound has shown good activity in mouse and rabbit models infected with gram negatives including klebsiella that produce Class A and C b-lactamases.” NXL104 had a good safety profile in its Phase I trial.
“We have also used NXL104 in a Phase I study in combination with ceftazidime, a third generation cephalosporin often compromised by b-lactamases activity,” Dr. Miossec continued. “The data demonstrates a high plasmatic bactericidal activity against enterobacter and klebsiella producing b-lactamases, so we now plan to initiate Phase II studies with the NXL104/ceftazidime combination to treat complicated urinary tract infections. The ceftazidime/NXL104 combination could be used as a front-line therapy for treating a broad spectrum of gram-negative bacterial infections.”
Like Novexel, Basilea is developing b-lactamase inhibitors to target gram-negative bacteria. Malcolm Page, Ph.D., head of biology at Basilea explained why they are targeting gram negatives. “In cancer patients the incidence of gram-negative and -positive infections is about the same. In this patient group, around 50 percent die from P. aeruginosa infections because about 20 percent of the patients are multidrug resistant.”
The company is developing the antibiotic BAL30376, which is a combination of three compounds with both b-lactamase Class A and B inhibitory activity. Dr. Page presented in vitro data that demonstrated that BAL30376 has potent activity against acinetobacter, P. aeruginosa and K. pneumoniae strains that were not susceptible to any other antibiotics tested. “The promising activity of BAL30376 against resistant stains shows that it is one of the few new drugs in development that could overcome established resistance mechanisms,” said Dr. Page.
Montreal-based, Biophage Pharma (www.biophagepharma.com) and Ipsat Therapies presented two additional approaches to treating bacterial infections in the form of phage and enzyme therapies.
Prevention Rather Than Cure
Beatrice Allain, Ph.D., director of phage technologies at Biophage explained, “We identified lytic phages specific to pathogenic bacteria. Lytic phages did not integrate into the host DNA and lyze only bacterial cells, not mammalian cells. When targeted pathogenic bacteria are not present in the body, lytic phages are rapidly eliminated without toxic effects, thus they could be safely used as antibacterial therapies or as disinfectants.”
There have been no negative effects reported with the use of lytic phages over the past 80 years, according to Dr. Allain, and the FDA and EU have approved the use of phages as food additives as well as the use of E. coli and Salmonella phages on live animals.
The company was initially concentrating on E. coli and Salmonella infections in swine and poultry and is now also focusing on nosocomial infections and has phages for MRSA. “We have a codevelopment program with Montreal Sacre Coeur Hospital where we hope to break the transmission chain of MRSA. Several phages, that infect and destroy MRSA strains found at the hospital yet do not infect nonpathogenic gut E.coli have been identified.
“We will conduct proof of concept studies using phages for equipment decontamination. We also believe phages have massive potential as natural and ecological treatments against superbugs,” said Dr. Allain.
Another novel strategy to combat resistant infections is Ipsat Therapies’ idea of using a b-lactamase enzyme in conjunction with a b-lactam-based antibiotic.
Kaarela explained that “taking an antibiotic always changes patients’ gut microflora and can lead to acquiring an additional infection or acting as a reservoir to infect others. If we give b-lactamases at the same time as a b-lactam antibiotic, it will inactivate any unused antibiotic in the gastrointestinal tract, thus maintaining the gut microflora and helping to prevent colonization by resistant or pathogenic bacteria.”
To prove this theory, Kaarela presented data on five clinical studies of its lead b-lactamase product, P1A, which showed that of 99 patients treated with P1A and ampicillin, P1A did not produce serious adverse events and did not change the clinical effectiveness of ampicillin.
In a Phase IIb study of 112 patients treated with ampicillin for serious respiratory infections, the 54 patients treated with ampicillin and P1A had a 20% change in gut flora compared to 50% in those treated with ampicillin alone.
There was also a 12% increase in ampicillin-resistant coliforms in those treated with P1A and ampicillin compared to an 80% increase in ampicillin resistant coliforms in those treated with only ampicillin. “If we can reduce the number of secondary infections from 10 to 3 percent using P1A with piperacillin/tazobactam antibiotic, which the Phase II study is now targeting, we could potentially reduce treatment costs of secondary infections by 50 percent,” concluded Kaarela.
Time to Invest Again?
Speakers at the “Superbugs and Superdrugs” conference agreed that the lack of investment in antibiotic development is a cause for concern, which has led to the unchecked rise of many resistant bacterial strains during the 90s, both in hospitals and in the wider community.
“Big pharma is producing less and less antibacterial therapies, so much so that most real work in this area is now being done by underfunded biotechs,” stated Dr. Page.
“Funding is being driven away from antibiotics into areas such as obesity, erectile dysfunction, and male pattern baldness,” Dr. Alder added. “Governments and investors are favoring lifestyle drugs rather than those to treat desperately ill people and as a result we have seen only two novel compounds come to market since the 1970s.
“In nosocomial bacteria tested, over 50 percent of S.aureus are methicillin resistant, almost 30 percent of Enterococci are vancomycin resistant, and over 30 percent of gram negatives have quinolone resistance,” he warns. “The problem is that we don’t have a lot in our bag of tricks to counter this, and it is imperative that we start developing new drugs now. The alternative is that we won’t be able to fight back the rising tide of bacterial resistance.”