What would you say if someone offered you a safe pill that could lower your blood sugar, help you lose weight, preserve beta cell function, and keep Alzheimer's at bay?
Actually, that's the wrong question. The question isn't what you would say, but what would you pay?
That's likely the question that was on the boardroom table at bio-tech firm Metabolic Solutions Development Company (MSDC), when they bet the $55-million farm on their pair of new pills that they claim can do all that.
In the words of one of the firm's co-founders and scientific head honchos, this new set of pills called called mTOT Modulators could very well "be blockbusters that might change the way we think about type 2 diabetes."
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To find out more about what sounds like a medical mirage, we talked to Dr. Jerry Colca, who not only co-founded the Kalamazoo, Michigan-based startup MSDC, but also serves as president and chief scientific officer. He says since day one in 2006, the company's been single-mindedly focused on developing a new approach to battling insulin resistance, the key mechanism behind type 2 diabetes.
Along the way, the company may have redefined our understanding of how insulin resistance works...
Too good to be true?
That's what we wanted to find out.
Getting to Know Insulin Sensitizers
To understand how these new insulin-sensitizers work and why they might be safer, we have to start with understanding how existing insulin sensitizers — the TZD drugs Actos and Avandia — work.
Back in 1984, when the compound that would later become Actos was first being studied, no one had a clue how it (or any other TZD) worked, Colca tells us. That's not as crazy as it sounds. Historically most drugs were discovered this way — empirically.
Empirical research involved testing a variety of compounds on animals and hoping for something good to happen. If you lucked out, you next tested the compound on a small number of people, a Phase 1 Trial. If all went well, you'd next take your compound into Phase 2 Trials, to determine how effective it is in various doses, and how much any side effect increases with those doses. The last step is a large Phase 3 Trial that leads to government approval.
Though out all of this, there's no requirement to demonstrate how a drug works.
Long after Actos was in the works, researchers postulated that TZDs targeted a nuclear receptor called PPARÎ³ (pronounced Pee-Par Gamma). Pharma companies went full-tilt after this receptor, creating a slew of drugs that never saw the light of day. Why? The more they targeted PPARÎ³, says Colca, the worse the side effects of fluid rendition, weight gain, heart failure, edema, and bone loss got.
What went wrong? According to Colca, it's now widely accepted that PPARÎ³ is the smoking gun in TZD's negative side effects. Pharma executives threw up their hands in defeat, and the quest for new insulin sensitizers was largely abandoned. No new TZD has been approved since 1999.
Like Cookies on a Conveyor Belt
But Colca, one of the fathers of TZDs, had a different view than his colleagues about how TZDs work. For years he felt the industry was barking up the wrong tree. He believed that PPARÎ³ was the wrong target, and felt TZDs were lowering blood glucose via a clandestine effect on something else. If that "something" could be discovered, he believed he could create a TZD-like insulin sensitizer without the side effects.
After a dozen years, Colca and his team finally discovered their quarry and named it mitochondrial target of thiazolidinediones, or mTOT for short. Then they started developing designer drugs specifically to target mTOT— taking into consideration the leaps and bounds in medical knowledge gained during the last several decades.
After evaluating 200 potential recipes, MSDC ultimately designed and built two drugs called mTOT Modulators, code-named 0160 and 0602.
Getting Dr. Colca down to our level is no easy task. Talking about mTOT Modulators involves a lot of phrases like metabolic oxidation, mitochondrial pyruvate carrier, and reactive oxidation cell differentiation.
How would you explain it to your Grandmother, Dr. Colca? "In Italian," he says with a laugh. I'm on the verge of being able to grasp it, but not quite. It has to do with how cells deal with excess calories.
Dumber still, please, Dr. Colca.
OK, says Colca: Let's say we're making cookies. And they're coming down a conveyor belt. At the other end a colleague boxes up the cookies. But the belt starts running too fast, some cookies fall off and get wasted. They pile up on the floor. "But," says Colca, "if you can find a way to slow the conveyor belt back down, everything will be copacetic again."
That's what an mTOT Modulator does. It slows the conveyor belt back down, re-establishing normal metabolism in the cells, thus reducing insulin resistance.
Head-to-Head vs. Actos and Avandia
Colca says his company's meds are safer anti-insulin-resistance drugs because they minimally bind to PPARÎ³, and yet they lower blood glucose as well as the historic TZDs do, supporting his theory that PPARÎ³ has a smaller role in insulin resistance than many believe.
Colca points out that Avandia was a much more "potent activator" of PPARÎ³ than Actos, and that's why the side effects of now-banned Avandia were more aggressive than those with Actos.
Based on the results of the current Phase 2 studies, Colca believes 0602 will be able to drop a patient's A1C from 8.0 down to 6.5 in one year.
And while designed as a type 2 medication, Colca also feels that mTOT meds may help type 1s, as the drugs show promise in preserving beta cell function.
A 12-week Phase 2 trial published in poster form at the recent ADA Scientific Sessions compared one of his meds to Actos and found it had similar glucose-lowering potency, without the typical TZD side effects. Moving forward, rather than compare to placebo, as recent pharma practice has done, Dr. Colca hopes to keep comparing his new drugs to existing drugs in the marketplace — head to head.
What about the ethics of comparison trials using a med under a dark cloud? Colca says Actos' connection to bladder cancer in long-term use is not proven. But for the sake of argument, if it is proven, he sees no ethical issues around using Actos in short-term trials with patients to conduct clinical comparisons.
Trademarking White Breadâ„¢
Of course, this effort isn't just for the benefit of mankind, or PWDs either. Like all firms, MSDC is in the biz to make money, going so far as to take the unusual step of taking out a trademark on the name of the whole new class of meds they are developing: mTOT Modulatorsâ„¢ and on the acronym mTOTâ„¢ itself. Since this is a class of drugs rather than individual products, it seems a bit like trademarking the terms "insulin" or "white bread."
Think of the confusion this will create for doctors, pharmacists, and consumers alike, if future meds in the same class all have to have different class names to avoid lawsuits. Wouldn't that make it almost impossible for others to enter the arena?
"That's the idea," says Colca, defending the approach by saying MSDC must do everything in its power to maximize return for their investors.
As trails on the two agents went forward, 0602 showed a better profile in terms of side effects and efficacy over 0160. Also, 0602 is "more unique" in its recipe, meaning it can be tied down better with patents, maximizing shareholder value again. But, 0160 is far from dead. It's being investigated as an anti-Alzheimer's med, as Alzheimer's research is revealing a connection between brain glucose utilization and dementia.
Will MSDC bring their insulin sensitizers to market themselves? Colca says in the beginning he was "naive enough to believe we could do it ourselves," but now thinks it's unlikely. He says that a Phase 3 Trial costs $22,000 per participant, involving 2-3,000 participants. Plus, the new cardiovascular safety trails the FDA requires in the post-Avandia era will add another $120 million to the price tag.
MSDC will need help from deep pockets to get their pill to your local Rite-Aid. Developing new medicines isn't for the faint of heart or shallow of pocketbook.
To get to where they are today, MSDC has burned though $55 million in venture capital, and is in the process of raising $40 million more to finish the work at hand — getting 0602 through its six-month Phase 2b study of 350-400 people.
So which Big Pharma companies are you talking to, Dr. Colca? He laughs as he says, "All of them."
I bet all of them are interested. More than one Big Pharma company is missing a diabetes blockbuster in its portfolio. And what could be a bigger blockbuster than a safe insulin sensitizer whose only side effects are weight loss, and an old age free from dementia?