Profile: no pain for Xenome

After 17 years at CSL, seven at Millennium Pharmaceuticals in the US and a couple overseeing the merger of the struggling Meditech Research with Alchemia in 2006, it was going to take quite an interesting offer to draw Dr Ian Nisbet out of the consulting world and into another CEO role.

In January this year, it was the venom-derived peptide company Xenome that managed to tempt him back. Since joining the company, Nisbet has had the pleasure of announcing a nice little investment from venture capitalists and good results from a Phase II trial for the relief of chronic pain in cancer patients.

Like Meditech, Xenome has had a bit of chequered history, with internal divisions and long delays in early stage trials due to problems with patient recruitment, but in the last year it has raised over $16 million in equity and investment.

Nisbet has put plans for an IPO on hold until the market rights itself, but in the meantime has raised US$6 million from Melbourne biotech investment group GBS Venture Partners and announced the good trial results at a world congress on pain in Glasgow in late August.

Xenome was founded by well-known scientists Richard Lewis, Paul Alewood and Queensland chief scientist Peter Andrews, all then from the University of Queensland, along with CSIRO’s Roger Drinkwater. Lewis and Drinkwater are still with the company – Lewis is the chief scientific officer and Drinkwater the vice president of R&D – and a chief medical officer, Dr Wendy Martin, was recruited last year and is based in San Diego.

The original concept that started the company was that venoms, particularly venoms from cone snails, also called cone shells, and other venomous creatures were a good starting point for pharmacologically active agents, Nisbet says.

“When you think about it, these are molecules that have over evolutionary time been designed to act at very small doses, by injection,” he says. “They have exquisite activity on fundamental molecular targets to induce paralysis. Conceptually, as a starting point for doing drug discovery, venoms seem a good place to start.”

Cone shell venoms were the original molecules of choice, as unlike spider and snake venoms, which are large peptides and are complex to make synthetically, cone shell venom peptides are quite small.

“They are generally less than 20 amino acids in length,” Nisbet says. “The concept was that we have a cornucopia of venomous creatures on our doorstep, let’s go through and identify smaller molecular-weight peptides, make libraries of these peptides and start screening them against interesting targets.”

Xenome now has a library of more than 2000 synthetic peptides, covering about 50 different species of cone shells. One venom peptide of interest was found to have activity against the norepinephrine transporter (NET), with the inhibition of this transporter found to elevate levels of norepinephrine in the spinal cord, modulating pain signals from the brain.

This native peptide served as a starting point for a synthetic analogue that became Xenome’s lead drug candidate, Xen2174.

“It’s about 1.14 kDA so it is small, 13 amino acids, and has two disulphide bridges,” Nisbet says. “This is a tightly constrained, three dimensional structure and that gives it not only a clear structure for a pharmacophore but it also provides some stability over and above a linear peptide.”

---PB--- Good results in Glasgow

Xen2174 was filed as an IND and then taken into early clinical trials, initially administered by IV, as required by the FDA. The original plan was to deliver it intrathecally, which is the delivery method now being used in the Phase II stage.

The results of the latest trial were presented at the pain congress in Glasgow. The 37 cancer patients enrolled in the trial had a background of chronic pain that was not adequately treated with routine analgesia.

Xen2174 was found to be well tolerated and evidence of pain relief was seen at most dose levels. Encouragingly, pain relief was characterised by rapid onset of action and long-lasting effect.

The company is also planning a Phase II study in the acute pain setting, targeting post-operative pain. “One of the challenges of this, particularly in the US, is that the practice of how you manage pain in the post-surgical setting is changing in real time,” Nisbet says.

“That creates some complications. What we don’t want to do is design the study, start it and then find we can’t enroll patients because all of a sudden it doesn’t fit in with medical practice. Our intention is to start that study in the second half of this year and have it completed sometime in 2009, so it will be a reasonably quick study.”

Nisbet says there are a number of applications in both acute and chronic settings. “For acute, it is surgical pain so hip replacement, knee replacement and that sort of thing. On the chronic side, cancer pain is an obvious one, and neuropathic pain – both are very clear major unmet needs.

“What is still unappreciated is that people think of pain and they generally think of ibuprofen or something like that for headaches and for severe intractable pain they think of opiates and that’s pretty much it.

People say of the severe pain space, why not just use morphine or other opiates? The fact of the matter is that a lot of people can’t tolerate morphine, they become addicted to the drug or they become tolerant to the drug so you have to raise the dose. And people are zonked out. With cancer pain patients, the quality of life in the last period of their life is very important – they don’t want to be zonked out all the time. “

Nisbet points out that the rate of suicide in patients who suffer severe, debilitating pain is 20 times higher than the general population. “Severe pain is really nasty. There is a real need out there. We believe that for a drug like ours, where there is potentially a large therapeutic window and we can treat safely, where potentially there is a long-lasting effect with a single administration, there is a real need there.”

There is already a cone shell-derived peptide on the market, Prialt (ziconotide), marketed by Elan Pharmaceuticals, which is both a good and a bad thing for Xenome, he says. “The good thing is that this is a drug that is approved, it is marketed, and it demonstrates that you can make drugs out of cone shell toxins.

“The bad thing is that it is not a very good drug, the reason being that it’s the unmodified toxin. It has a very narrow therapeutic window. You have to titrate the dose for the patient and it has some very nasty side effects. So why is our drug better? What we can say is it could be a much better drug, if we show it has a larger therapeutic window and it has a better safety profile. It also has a different molecular target.”

---PB--- Pipeline

In addition to Xen2174, Xenome has another conopeptide-derived product in the pipeline. “This candidate is an agonist of the kappa-opioid receptor, an attractive target in inflammatory pain,” Nisbet says.

“The molecules we are investigating are analogues of a toxin isolated from Xenome’s library that is only eight or nine amino acids long and they are currently in animal testing.

“The indications are for things like irritable bowel syndrome and that’s what we are focusing our attention on at the moment.”

The company is also working on in-licensing a candidate from a local academic group. While Xenome has its own library of peptides, it also has a great deal of expertise in developing peptide-based drugs, which it would like to use on other people’s lead peptide molecules.

“We’d like to pick those up, do the analoguing around them and take them forward,” he says. “We have a desire to build out our own development portfolio in the general areas of inflammation and pain, and basically leverage our skill set to get drugs from other people as well.

“We’d like to put ourselves in the position where at the end of next year, we’ve completed our Phase II study in 2174, move on to the next study, and then have one or two other compounds ready to go into clinical studies.”

Xenome has a strong relationship with California-based peptide company Amylin Pharmaceuticals, which is an investor in Xenome. Amylin has two peptide drugs on the market – Symlin (pramlintide acetate) which is derived from the amylin hormone and is a treatment for types 1 and 2 diabetes, and Byetta (exenatide), a synthetic version of extendin-4, a hormone found in the saliva of the Gila monster, also for type 2 diabetes.

“What they want in the relationship with Xenome is to get access to classes of peptides that they don’t have in their own libraries. They’ve taken our library and are screening it against targets in metabolic diseases.

“We are also exploring partnerships with other biotech and pharma companies in other therapeutic areas. Our desire is to have multiple discovery partnerships covering multiple therapeutic areas, so that we exploit our key discovery asset as widely as possible. Hopefully that will allow us to get the maximum value out of the peptide library.”

---PB--- In the clinic

Before returning to Australia at the end of 2004, Nisbet worked for Millennium Pharmaceuticals – which has just been bought by Takeda for the tidy sum of $8.8 billion – for seven years, mainly in mergers and acquisitions and in-licensing. One of his major roles was as project leader for Velcade (bortezomib), Millennium’s proteasome inhibitor aimed at people with relapsing multiple myeloma.

“That looks like it is going to be a billion dollar drug,” Nisbet says. “We got that approved in 2003 and launched it ourselves in the US, partnering with Johnson & Johnson outside the US.”

His time in the US gave him a keen insight into the differing ways our healthcare systems work, clinical trials being a case in point. “It’s not only a problem with the small populations but many local clinicians don’t really think about clinical studies,” he says.

“Australian clinicians tend to be much less commercially focused than in the US. In the US enrolment in a clinical study and getting access to experimental therapies is pretty much an accepted part of clinical practice, whereas here it’s not. It was a bit of a revelation coming back.

“Also in the US you have patient support groups – patients are generally much more aware that here are studies out there and they go chasing after them. In the US, people demand the best and the latest but in Australia, people don’t expect the latest treatment – we accept what we are given, and the clinicians do as well.

“That was something I couldn’t understand when I came back. It has created a mindset in Australia amongst clinicians and patients that is not conducive to recruiting patients into studies.”

Nisbet was also critical of the restrictions placed on access to new and innovative therapies in Australia. “In a lot of ways it is counterproductive. For example, some of the newer therapies available work better when the patients get them earlier.

“Herceptin in breast cancer is a classic. Women have to go through failed multiple lines of treatment before they get access to the drug. The thing is, if they got it earlier they might respond better and have a better quality of life. They’d also probably be a lesser burden on the healthcare system in general, but instead they only get it as a last resort.

“In things like multiple sclerosis, people don’t get access to best in class treatment straight away – they have to go through other treatments before that.

“If you think about the cost to the individual, to their family and the system in general – I’d be really interested to see if anyone’s done an analysis to find out what is the relevant cost benefit of treating people earlier when they are more healthy rather than delaying new treatments until later, just because you want to limit access to them due to cost.”