They represent one of the most widely used groups of medications in the world, generating billions of dollars annually for pharmaceutical companies. Chances are that if you’ve ever suffered from pain or inflammation, you’ve turned to a nonsteroidal anti-inflammatory drug (or NSAID for short) for relief.
You can get them over-the counter or have them prescribed for a wide range of conditions, such as osteoarthritis, acute pain and rheumatoid arthritis to name a few. However, as widely used and effective as they are, the relief they provide has always come with a cost.
For starters, it has been found that most NSAIDs can cause serious side effects, including gastrointestinal problems such as ulcers and bleeding, and cardiovascular issues. They have had a very volatile 40 years of existence, highlighted of course by major recalls and lawsuits, most notably Vioxx which was pulled off the market after it was linked to heart attacks and strokes. As such, there is need for a better
and more importantly, safer NSAID.
Fast forward to the present, Toronto-based Antibe Therapeutics might be on the verge of finding one. According to the company’s CEO and president Dan Legault, his company’s lead product, ATB-346, is an NSAID that is quite different than its predecessors both in terms of its
composition and safety performance in pre-clinical trials. In terms of its composition, the design of ATB-346 is different in that it involves chemically linking an existing off-patent NSAID, Naproxen, to Antibe’s patented hydrogen sulfide-releasing molecule. The result is a new ‘composition of matter’ molecule that according to Legault has significantly improved properties compared with the base drug. He adds that the choice of Naproxen as the base drug was not accidental.
“If you put traditional NSAIDS on a grid, all have issues of a cardiovascular or a gastrointestinal nature. However, Naproxen is generally regarded as the best of a bad bunch on the cardiovascular side. For example, The American Heart Association recommends it over other NSAIDs. It’s a major prescription NSAID and is available over the counter, which is our goal with ATB-346, first, to be a prescription drug, and subsequently over the counter as well. Because the base drug has a predictable profile in terms of toxicity and its effectiveness, we believe the regulatory process for ATB-346 will not be onerous.”
The development of hydrogen sulfide-releasing molecule portion of ATB-346 stems from the work of Dr. John Wallace, the company’s founder and chief science officer. As one of the most respected NSAID scientists in the world, Wallace’s career has centered on the use of gaseous mediators to treat inflammation, particularly intestinal injury and dysfunction. On these subjects he has published more than 400 peer-reviewed papers and is among the top 0.5 per cent of biomedical scientists worldwide in citations (>28,000).
“In the early 90s, John had this idea of taking a molecule that released one of the gaseous meditators that are naturally produced in the human body, namely nitric oxide, and attaching it to an off patent base molecule — perhaps this could improve the base molecule either by reducing its toxicities or increasing its effectiveness.”
That initial idea led to the creation of a company called NicOx S.A.(still in existence today), but it was also the foundation of Wallace’s work on ATB-346. In 2002, Wallace took the same approach that he had taken with nitric oxide, but this time he chose to use hydrogen sulfide because of its crucial role in mediating inflammation in the body.
How the resulting new molecule has performed in terms of GI data in preclinical trials is astounding says Legault.
“It targets the pain and inflammation of arthritis, without causing the gastrointestinal damage that other NSAIDs cause,” he says.
Specifically, unlike standard Naproxen on its own, the data indicates that ATB-346 does not induce damage to the gastrointestinal tract.
“GI damage is a pervasive problem that affects the quality of life of 100 million people around the world who use NSAIDs, and there’s a correspondingly large amount of money if you can solve it. And our extensive data indicates we might be able to do just that.”
Further validating the preclinical data is the fact that the research was conducted on unhealthy animals in addition to healthy ones.
“We spent four years of work on unhealthy animal models because they are the most indicative of potential success in the human clinic. The fact that most NSAIDs are only tested on healthy ones suggests our data is compelling. For example, Celebrex, the leading NSAID on the market and one of the five fastest ramping drugs to blockbuster status in history was only ever tested on healthy animals. So again, this is another indication that our drug works.”
Legault cites other facts that are clinically relevant to ATB-346’s efficacy and safety such as that it promotes healing of pre-existing ulcers which goes against traditional behavioral patterns of NSAIDs. Moreover, early data also seems to indicate that ATB-346 also performs well on the cardiovascular side.
“It’s a well-known fact that all NSAIDs increase blood pressure, and that the increase of blood pressure is well correlated with other cardiovascular issues with these drugs. Our studies have found that ATB-346 has no effect on blood pressure. It’s something we do want to explore, but perhaps once we get further along on the gastrointestinal side.”
ATB-346 is itself being developed to address osteoarthritis, although Legault adds that Antibe intends to broaden its application to rheumatoid arthritis and other diseases that are currently treated by NSAIDs.
Another benefit to ATB-346 that Legault sees from its preclinical results is that it could address another problem associated with NSAIDs, namely that they are the number one cause of adverse drug reactions in western-world hospitals. This may be partly due to their often being subscribed with a gastro-protective proton pump inhibitor or PPI.
“PPI’s provide some protection to the stomach, but together they make the intestinal damage worse. The PPI is essentially killing bacteria in the stomach, but it’s also killing all the good bacteria in the intestine. There have been four published human studies showing that when you give NSAIDs with PPIs to healthy teenage volunteers, they have 50 to 70 per cent chance of suffering an incident of serious damage in the small intestine. That’s a huge problem.”
It’s also a very large opportunity for anyone who can solve the problem he adds. He believes his company’s drug, if successfully developed like key NSAIDs that came before it, could be a blockbuster.
“We’re talking a global market of over $12 billion annually, and this is a market that will continue to grow in the developed world because of an aging population, and in the developing world where NSAIDs continue to gain in popularity.”
With the pre-clinical work for ATB-346 finished ahead of schedule, the company is now ramping up for human clinical trials. A Phase 1 trial is scheduled this summer. The study will be conducted in Montréal by Algorithme Pharma Inc. Legault calls it a robust, well-designed Phase 1, involving integrated single-ascending and multiple ascending dose studies on 88 healthy volunteers.
“An integrated study is a faster and more intelligent way of study design that most in industry are migrating towards. While we are conducting our Phase 1 trial, we will be performing the important planning and ancillary work required for our Phase 2 trial for ATB-346, anticipated for the next fiscal year. We plan on doing a particularly rigorous Phase 2, it’s Phase 3-like in depth. We’re doing that for two reasons: one, we think it’s prudent to have a very conservative regulatory strategy. We have studied every FDA NSAID filing for the past 30 years. The FDA is on record as saying “The world needs a safer NSAID,” but they are understandably nervous given the challenging history of recent NSAIDs. The second reason is that, like many biotech companies in Canada, we may have to explore the idea of partnering for Phase 3. Our thinking is having a higher quality clinical trial that will enable us to drive a good global partnering deal. We have filed our IP in all major markets around the world and thus far, stage for stage, we’re quite superior to all NSAIDS on the market including the ones that were withdrawn.”
The company isn’t a one-trick-pony either. In addition to ATB-346, it has an additional NSAID in its pipeline, including what Legault calls a short-term, stronger NSAID for severe acute pain.
“ATB-346 is our general purpose NSAID, but there is also a good market for a shorter term, stronger NSAID, like indomethacin, which is strong, and very good for severe pain. Doctors will never prescribe it for more than two or three days because of the bad GI damage it causes. So we’ll be hoping to develop something similar, but again with safer GI results.”
The company is currently performing proof-of-concept studies on this second ‘stronger’ NSAID and the plan is to ready this drug for GLP pre-clinical studies to commence next year.
In terms of financial strategy, the company is now fully capitalized through to the completion of Phase 1 clinical trials for ATB-346, with significant cash reserves thanks in large part to a very successful IPO (initial public offering) last summer, the first Canadian biopharmaceutical company to take the IPO route since 2008. Legault says the choice to go this route was rather simple.
“Put bluntly, venture funding for NSAIDs is virtually non-existent. It wasn’t always this way, but in light of the Vioxx situation, and the long regulatory pathway, the venture community simply view such technologies as risky. What we heard from the VC community was, “the science is amazing, John is incredibly respected and it’s a huge market, but you have a full regulatory path and it’s not 2007 anymore.” So, we felt we’d be able to bootstrap it with friends and family money, followed by an IPO; so far we’ve raised $10 million dollars in a relatively short period of time.”
Legault credits the validity of the science and the business acumen of the management staff for the success of the IPO.
“We have a sound scientific pillar to stand upon, and John is the top of food chain when it comes to inflammation scientists. In addition to John, we have a science advisory board chaired by Lou Ignarro, a Nobel Prize winner in Physiology or Medicine in 1998. The science is rigorous, in depth and our data are extensive. And then on the business side I like to think we have the same calibre of people.”
Legault says he relies heavily on his management team, leveraging insight from all involved.
“Roughly speaking three times a week we’re into brainstorming and project management mode. We sit around the couches and run through all of our business and development issues. It’s a way to keep everyone in sync and on track and we discuss everything.”
He says at times it can be overwhelming to be in the presence of so many PhDs, but at the same time, he feels he brings unique insight to the discussions. He smiles, “I would call what I bring a PhD in Murphy’s Law. As a former Air Force rescue pilot I can ask the tough questions and hopefully discover potential issues before they can fully materialize. What is fascinating about drug design is that it’s not just project management or scheduling studies. Big and small companies alike often make mistakes in drug development and they don’t recognize the poor decisions until years down the road. I make us all take a step back and ask ourselves what mistake are we making today that we’ll only
discover down the road…we then try and spot them before it’s too late.”
The common ground they share though is that they are all adventurous and willing to work together to get to the top of the mountain.
“That’s why I like running companies. Running a biotech, especially one whose lead product is an NSAID is a lot like climbing a difficult mountain. And you’re doing it with colleagues who you respect and admire. We have a Mount Everest-sized challenge, but we all in our gut feel we’re onto something. If it’s not our drug, it will be one that has to do with hydrogen sulfide; it’s just amazing how important this molecule is to the body. The data is compelling and if successful, the payoff will be huge.”