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In the fight against superbugs, research laboratories are looking into the past, not the future. "We cannot develop a drug that will be used again and again without the risk of resistance occurring," says Thomas Vorup-Jensen from the department of biomedicine at Aarhus University. "But, if we use old drugs in the right way, we could solve some of the problem."
The latest breakthrough has been found in a drug that’s been treating multiple sclerosis for 20 years. It turns out that the drug, known as Glatiramer Acetate or Copaxone, can kill gram-negative bacteria within minutes. In the fight against antibiotic resistance, it’s an intriguing new tool.
Infections caused by gram-negative bacteria are often resistant to antibiotics; including the commonly used penicillin. They have a unique outer membrane that surrounds their cell wall, a complex structure that a lot of drugs struggle to penetrate.
“We realised the chemical properties of Copaxone’s proteins are highly similar to antimicrobial peptides,” says Vorup-Jensen, who worked on the study published in Nature. “The drug’s immune supporting formulation is very similar to what frogs do to protect themselves from infection; we are mimicking something which happens in nature.” The researchers found that GA easily killed E-coli and Pseudomonas Aeruginosa (both gram-negative bacteria), but had trouble targeting Staphylococcus Aureus (gram-positive).
“That’s interesting because the first two are gram-negative bacteria and we don't have a lot of antibiotics capable of effectively killing that kind of bacteria,” Vorup-Jensen says. When the researchers realised that it had this property, they wondered if it could treat cystic fibrosis.
"Many people suffering from cystic fibrosis die, and we have very poor means of helping them – one drug that helps also gives them extreme kidney problems,” says Vorup-Jensen. Cystic fibrosis patients have a problem with clearing mucus in their lungs because they become infested with bacteria, particularly Pseudomonas. In this study, the researchers were given access to bacteria taken from the lungs of patients suffering with cystic fibrosis. At least 50 per cent of the bacteria were killed by Copaxone.
In the frantic fight against antibiotic-resistance, it can help to look for new life in old, forgotten drugs. Developing new drugs is hugely expensive, and it can take a decade to get them through the safety processes. "Part of the solution of microbial-resistance is developing new drugs – there's no doubt about that," Vorup-Jensen says. But researchers are also looking at old drugs for new treatments.
When the researchers realised they had potentially found a new treatment, they knew they needed help getting it to market. “If you have an invention or idea like we had, you need to go to a company which specialises,” Vorup-Jensen says. “There's a lot of practical aspects with bringing the drug further on, such as understanding regulatory affairs, that we don't have.” And so the team called in Cambridge based startup, Cycle Pharma.
Founded by James Harrison in 2012, Cycle Pharma focuses on improving drugs, reducing the price of generic drugs and repurposing old compounds for new targets.
In the early years, the Cycle Pharma team thought that improving drugs would be its forte. But with this project, they looked at how to change a drug to make it easier to take. This can be as simple as tweaking a drug so it no longer has to be stored in the fridge. They also work with generic drugs that only have one person marketing it, because this hikes the price up. "Competition is really important for the patient's benefit to bring the price down and improve supply,” says Steve Fuller, Cycle Pharma’s regulatory affairs director.
But repurposing remains the hot topic. “Repurposing is taking an existing molecule which has been approved for a certain indication and looking at its use for a different indication,” Fuller says. “So maybe it’s something like a cold medicine having an application in cancer.” Unfortunately, repurposing isn’t the biggest moneymaker. “Big pharmaceutical companies are looking for new molecules for new treatments – this is because you can get patent protection and control the market for a bit longer as the only drug available to treat a certain thing,” Fuller says.
To get around this, you can change the formulation of a drug slightly. Once a drug is approved for a new treatment, Cycle Pharma can gain some intellectual property, and this helps it fund the development of the drug. In the case of this study, the team is researching whether cystic fibrosis patients could inhale the drug rather than inject it. “The next step, ideally in the next year or so, is to get them in the patient to see if they work,” Fuller says. “If that patient has no option and there's a chance our drug could work, you're allowed to do safety studies in patients a bit earlier.”
Cycle Pharma essentially acts as a financial bridge between academics and the market. “In an ideal world there might be government funding for repurposing drugs so you wouldn't need this economy associated with it,” Fuller says. “The government generally look at short-term cost structures, whereas to invest in researching old drugs for new indications you're looking at millions of pounds and then you may only start to pay it back in five to ten years.”
Disrupting the economics of drug discovery gives Cycle Pharma access to discoveries in universities across the globe. “I think being a smaller company gives us an advantage because we find that academics are more likely to talk to us - if a big pharmaceutical company approaches them then it's always scary that they might want to take their idea away,” Fuller says.
Once a university has done the research, it’s Fuller’s job to contact drug regulatory agencies such as the FDA (Food and Drug Administration) and the MHRA (Medicines & Healthcare products Regulatory Agency) to get the drug approved again. Repurposing drugs significantly shortens the development path. For new drugs, you need a proof of principle that a molecule might treat something. Next you need safety studies – in humans, not just animals.
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Often only one out of ten candidates makes it through safety trials. “There's a huge amount of risk and funnelling down which is why drug development costs are so big,” Fuller says. “Repurposing allows us to take a drug where we understand the safety profile. We know how it’s absorbed by the body and what side effects it may have and its dose limits.”
Using already-approved drugs is also much better for patient safety. “We have a good idea about the safety problems of Glatiramer Acetate. You can inject it in large amounts and in general it performs well,” Vorup-Jensen says. "With new drugs there's a chance of side effects you didn't see in clinical trials,” Fuller adds. “When you repurpose a drug you may take one that's been used for 20 years in million people so you understand the safety profile much more.”
Repurposing drugs could be key to fighting antibiotic resistance when funding for new drug development dwindles. Vorup-Jensen, who used to work in new drug discovery, is all too aware of the need for urgency. “Taking it to the market is extremely expensive and at best it takes about ten years. With the treatment of resistant bacteria you simply don't have ten years to wait.”
This article was originally published by WIRED UK
