NeurAxon Inc. offering more than just pain relief

---

By Tim Bryant

It’s a given a biotech company needs money to get off the ground and be successful. What isn’t a given is how much is needed to make that happen. In the case of Toronto-based NeurAxon Inc., it is abundantly clear the lack of a multi-billion dollar research budget has not hindered its success.

In 2004, NeurAxon was established as on outlet for intellectual property developed by Suman Rakhit’s contract research organization, MCR Research Inc. He took this opportunity to free himself from the constraints of working for someone else.

“Although we were going to make money being a CRO, we had to work for other companies on projects of their choosing,” he says. “We felt that we should devote some time to do our own research that would be stimulating for our young chemists.”

But bringing NeurAxon to life was anything but a solo effort. Lending a hand were colleagues Shawn Maddaford, now NeurAxon’s vice president of discovery chemistry, and John Andrews, now the company’s chief scientific officer.

Maddaford and Rakhit already had a history working together, having co-founded MCR Research in 1999. Andrews gained his foothold as a consultant to one of the venture capital firms that provided funding to get NeurAxon off the ground. Asked to review their proposal on nitric oxide synthase, Andrews was initially skeptical, aware of many previous failures to make a drug addressing this target. The fact he had spent much of his life working in central nervous system drug discovery in both big and small pharma didn’t hurt either.

“So the three of us started the company with a modest amount of VC capital, and slowly we developed compounds that were quite interesting.” That reasonable amount of VC capital has grown to $55 million since 2004, says Rakhit and after two years they had their first product development candidate.
“And I would say that I am very proud of the people here, the way we handle our finances and the projects.”

NeurAxon has managed its money so well that in the six years it has been up and running, it has managed to complete five phase one trials, one phase IIa trial and two phase two trials on NXN-188, its lead drug candidate for the treatment of migraine. A third phase II trial is also ongoing. In addition, a phase one trial has been started on NXN-462, a product candidate for the treatment of neuropathic pain.

“We don’t have a gorgeous laboratory space where we have our own carpet monogrammed with NeurAxon,” Rakhit says. “We spend most of our money on R&D.”

The choice to spend the money primarily on the R&D has had a significant impact on NeurAxon’s success, as having two internally-developed drug candidates undergoing clinical trials within six years will attest.

It is something Rakhit views as nearly unprecedented in the biotech world, as he has never seen a company start trials on two different drug candidates and keep the R&D department intact with only $55 million in capital, more than $20 million of which was still on the company’s balance sheet at the beginning of this year. But he is not resting on his laurels.

“We would like to raise more money, of course, but we can still execute on our business model independently with our current cash for another two years in these tough economic times. You can see how we organize our finances - it is a story of success built on survival.”

But what else is so special about NeurAxon that has created the success it’s had with such a lean budget? Rakhit believes it comes down to a single philosophy: communication to support the mission of doing groundbreaking science.
“Everything that happens in the discovery and development process we communicate it to our people,” he says.

There is a free flow of ideas and information amongst the employees and management. If everything is going well, the news will find its way from the lab to the executive offices and vice versa. When the company encounters challenges as often happens when trying to innovate a new class of drugs, meetings are often held to discuss why that is so and what can be done to fix the situation.

“We don’t believe in keeping problems or ideas secret in science,” says Rakhit. “It doesn’t work that way because we believe very strongly that the path of developing a drug is not very straight forward. Problems only stay problems when they are not communicated. With communication, they become challenges to solve and overcome.”

Rakhit says this philosophy is critical to NeurAxon’s success. Without constant discussion and re-evaluation, it would be very difficult to solve any problems that arise in the process. This is where communication becomes key to solving problems, and drug discovery and development is all about problem solving.

“To be able to solve problems, we have to understand the problems,” he says.

In a way, Rakhit’s work with NeurAxon is the culmination of a life in drug discovery and development. Despite having already been retired when he started MCR Research in 1999, he still enjoys the daily challenges of problem solving.

Rakhit, along with the rest of the management has a long history of drug discovery. Holding a PhD in pharmaceutical chemistry, his career started at Montreal’s Ayerst Research Laboratories in 1965. While there, he helped discover the anti-rejection drug, Rapamycin.

After 18 years with Ayerst, Rakhit moved to Laval, QC, where he was involved in the creation of BioMega Inc., which was eventually taken over by Boehringer Ingelheim.

In 1992 he moved again, this time down Hwy. 401 to Mississauga, ON, and Allelix Biopharmaceuticals.

“Allelix didn’t have any medicinal chemistry, so I came to start the medicinal chemistry department with four people,” he says. “It grew and we had several interesting research projects.”

He stayed at Allelix until 1998, when he retired. But the retirement didn’t last too long, as he became edgy and leapt at the chance to start MCR Research the very next year. Five years later, NeurAxon was born.

Since that time, Rakhit and NeurAxon have focused primarily on pain therapeutics based on their understanding of nitric oxide synthase inhibition. But that choice has been fraught with challenges.

There are three forms of nitric oxide synthase in the body, with each one serving a different purpose. One is present in the central and peripheral nervous systems (nNOS). The second is found in the blood vessels (eNOS). A third is broadly distributed around the human body and is induced as part of the immune and inflammatory system response (iNOS). All three are needed for the human body to remain healthy, Rakhit says. But in certain conditions, the neuronal form is overproduced, which can lower the threshold for perceiving pain. While it may seem straightforward to develop a drug to control the overproduction of nNOS, Rakhit says it’s not that simple.

“The problem is these are three related forms, or isoforms, of the enzymes. They are very close to each other in their structure, and in the past there has been a chemistry challenge to come up with any new chemical structure that will affect only the neuronal form without affecting the form that exists in the cardiovascular system.”

This is critical, because if eNOS is inhibited, the patient’s blood pressure will increase, Rakhit says, resulting in increase cardiovascular risks, including stroke.

“So we thought, oh, that’s an interesting challenge. We have done that in our past lives. We all came from drug discovery, where that was a common challenge,” he says. “We said, OK, let’s do it. And we were able to achieve what we were looking for. We have now a series of compounds that are selective for nNOS over eNOS.”

If inhibiting the nNOS enzyme only wasn’t challenging enough, the company took things a step further by intentionally designing their nNOS inhibitors to bind to other targets relevant to pain. For instance, in addition to nitric oxide, serotonin is important in migraines. The triptan anti-migraine drugs on the market (e.g. Imitrex) work through the serotonin mechanism (5HT1D/1B receptors). While they are the current gold standard of care, these drugs are far from perfect. 30 per cent of patients fail to respond and many suffer from rebound headache. The timing of when you take these medications is crucial for successful headache therapy. Take them too early during the so called “aura phase” of a migraine attack and they don’t work. Wait too long, and again triptans are mostly ineffective, especially once cutaneous allodynia, or hypersensitivity to pain, has set in. About 70 per cent of migraineurs will develop tactile or cutaneous allodynia where a light touch now becomes painful; even combing your hair can be excruciating.

Nitric oxide appears to be an important modulator of pain signals and interacts with many neurotransmitter systems “We felt that having both mechanisms of action in a single drug would potentially treat non-responders and expand the window of intervention.”

The company has a strong focus on dual action drugs or Designed Multiple Ligands, but at the time of NeurAxon’s founding in 2004, there were only seven prior examples of dual action by design small molecules drugs or NCEs in the history of rational drug design, and now the company has increased that number by more than 50 per cent while integrating them with first-in-class selective nNOS inhibitors. It intends to apply its nNOS technology to design other pain therapies such as dual acting nNOS-opioid analgesics which the company has trademarked NOpioid™ or NOpiate™. One of the issues related to the use of opioids for pain management is the development of tolerance. Nitric oxide is known to reduce the effectiveness morphine-like pain medications and inhibiting it appears to reduce tolerance and the dosage required for analgesia.

This success in the pain therapeutics realm has given NeurAxon confidence to attempt to branch out into other therapeutic areas. As such, the company applied for and received a $267,000 grant from the Michael J. Fox Foundation in January 2010. Rakhit says the money will be used to develop a proof of concept for a way to reduce the effects of Parkinson’s disease, which has been linked to an overproduction of nitric oxide.

Nitric oxide can react with free radical oxygen in the body, producing peroxinitrite, which ultimately does most of the damage by attacking the proteins, lipids and DNA in the body. Once that starts, it continues to cascade, causing neural degeneration.
“Nitric oxide is a double-edged sword,” Rakhit says. “If you don’t have enough, then it’s not very good. If you have too much, or in the wrong places, then it’s bad.”

The end goal is to partially inhibit or control the enzyme that produces the nitric oxide, in turn reducing the damage caused by excessive nitric oxide and alleviating the Parkinson’s conditions.

Rakhit also says NeurAxon is leveraging the Michael J. Fox grant to jumpstart an expansion in the work the company does.

“So we felt that we cannot diversify our products into other indications other than pain because it takes a lot of money and we will get defocused,” he says.

The grant gives the company the opportunity to diversify its work without jeopardizing its core mission in pain. This plays directly into the thinking around the company that NeurAxon could be more than simply a pain therapeutics company.

In NeurAxon’s six short years, and with a relatively limited budget, Rakhit and his team has done what is very difficult to do, establish a pipeline that continues to produce new drug candidates. This commitment to performance virtually guarantees that the remainder of NeurAxon’s first decade will be just as exciting, scientifically and financially.