This week, we continue our exclusive short interview series with NuSirt CEO, JC, in which he talks about some of the groundbreaking work his company is doing to increase the effectiveness of metformin.
Steve Freed, Publisher, Diabetes in Control: What actually brought you to taking this compound and combining it with metformin? You could have tried thousands of other drugs. Is it because of your background?
Joe Cook, Jr: It was probably a combination of several backgrounds. With just having studied the space at Amylin and at Lilly, I knew that we were close here, so I asked the team to do all the research they could on diabetes and figure out the drugs that worked for the same pathway. It wasn’t my hunch alone. There was a group of us who were working in the same area of the company. When I saw the results from the human study, I knew we had to take a closer look. We put leucine into the animal models, and those were the two studies that were released at the ADA that showed that, in fact, we did substantially narrow the effects of full-dose metformin in these animals, with a dose, in some cases, as low as 84% reduction….
SF: How many people with diabetes cannot take metformin due to the intestinal and other side effects?
JC: The literature varies, Steve, but the submission that Bristol-Myers Squibb did to get Glucophage, or metformin, approved suggested that between 30 to 50 percent of patients reported some degree of GI adverse events associated with use of metformin. In terms of those who actually have serious vomiting or diarrhea, it’s probably in mid-single digit numbers, however, six to eight percent is frequently quoted. No one has actually done a rigorous analysis on the side effects, but I would suspect that the number of people who experience some bloating, discomfort, or pain is somewhere in that original number that Bristol-Myers reported. I do not want you to misinterpret my comments. I do not think this is a product that half of the people currently taking metformin should take if it’s approved, but there are a considerable number of people who struggle with taking metformin and maybe this will give them some relief without compromising their glucose control.
There is an additional element to this that I think is interesting. That is the current metformin label suggests that physicians start a patient at 500 mg BID and titrate to 850 mg BID after two weeks to get the body used to taking the drug. This involves a physician interaction at least two times. Frequently, there are additional adjustments to the dose. We hear physicians talk about the need to titrate it down or up, and vary it from BID to TID, and all kinds of things to try to get the patient’s GI distress reduced. A principal reason for that, which we hear from a lot of folks, is that when people suffer GI distress with metformin, they occasionally will skip a dose, or skip a day. Obviously, this results in less than the ideal amount of glucose control they might achieve if they were able to fully tolerate it. In fact, there was an article published recently that suggested that, on an annual basis, 17 percent of those who take metformin go to another drug. This was surprising to me. I think about it in two ways. One, they either have lost control, or two, they cannot tolerate it.
SF: There have been a number of articles recently reporting that metformin has other capabilities besides lower blood sugar, such as preventing cancer, which makes what you are doing even more important, because it opens up the door to a couple million more people.
JC: Yes. In fact, if our hypothesis is right, Steve, and if the clinical trials prove our hypothesis, and the FDA approves NuSirt’s technology, we can offer practicing physicians a chance to prescribe a dose that does not require titration. By lowering the impact of adverse side effects, perhaps patients could stay on the medicine and achieve better glucose control, and stay on it longer. We think that would be a good thing all the way around.
SF: If it does get as far as submitting to the FDA, your one indication is, basically, to help reduce blood sugars with fewer side effects. Would that be correct?
JC: Yes, that’s right. Our initial trial design will be to show what’s called non-inferiority to metformin, but with a lower dose.
SF: OK. What do you see the impact as for physicians treating those who have diabetes, because patients do not want to hear that if they are given metformin, the doctor then will need to give them another pill to prevent the side effects. The patients will ask why they need to take another pill to prevent side effects. Just give them a pill that doesn’t have any bad side effects.
JC: Yeah. “Just give me a pill that doesn’t give me side effects, doc.” We hear from physicians that they are comfortable with metformin. They’ve used it so many times and it is the first drug of choice and will continue to be the first drug of choice. I think what we will provide physicians is an alternative for those patients who the clinicians already know are super sensitive to drugs and do not tolerate medicines well. There are groups of people who simply are sensitive to all medicines. Many are known to be less than 100% compliant when asked to take meds. If we give them a medicine that does not cause them to feel uncomfortable, they do not have a reason not to take their meds. We think NuSirt technology will be a way for some patients to get better control of their glucose.
SF: We know with some of the other products, similar products that came out much earlier like DBI, phenformin, etc., there were some serious side effects with lactic acidosis. Now, you are bringing out a product that is going to make metformin more effective, which means it’s going to be, possibly, stronger. Do you have any information about that side effect? is this going to be an issue? It is certainly something the FDA is going to want to look at.
JC: Yes, we talked with a number of physicians. First of all, it’s very, very rare for lactic acidosis to actually occur. In fact, the physicians who we consult have frequently said that they have never seen it. Now, they may not remember that they’ve seen it, but I would suspect, with a true condition, they would remember it. Lactic acidosis often requires hospitalizations and is serious.
Metformin acts on an AMPK signaling pathway, which is upstream of the SIRT1 pathway. This is down in the cellular mechanics. I’m not a molecular biologist, here, but this is my understanding. We are not actually potentiating metformin. We are simply making the cells more sensitive to the presence of metformin, so that they can do their work with less. You think of it as potentially reducing resistance to the work of metformin; however, we do not anticipate that, a) the drug is going to stay in the blood stream any longer and have any higher peak value concentrations in circulating plasma concentration, or b) the drug is going to be active in any organs or cells in the body that it now is not. It is simply going to be more efficient when it’s working at the cellular level.
SF: What have your studies shown, to date, about the potential for the technology?
JC: To date, we have animal studies completed and are enrolling our first human subjects in a phase 2A clinical trial. There are eight sites across the country enrolling patients. We are very pleased with the response we have received from the sites so far.
As I mentioned earlier, the animal studies suggest that the required dose of metformin could be substantially reduced. Those studies were based on animal models that have been frequently used to study diabetes medicines, including metformin. We are reasonably confident that the results we have seen in the animal models will be informative as we go into humans. We took the data from those animal studies to establish the doses that we are now testing in the first clinical trial.
SF: You have four arms in the clinical trials.
JC: That is correct.
SF: What are the dosages? What are you looking for? Are we talking about reducing it by 50 percent? What are the arms showing?
JC: Let’s start with the active control arm, which is metformin at 500 mg BID for two weeks, titrating to 850 mg for the final two weeks of the 28-day study portion.
SF: What about the other three arms?
JC: The other three arms all have lowered doses of metformin. The lowest dose arm is 125 mg metformin BID, plus leucine. The others are 250 BID and 500 BID.
SF: What are you hoping to find? That the 125 mg dose would be as effective as the 500mg dose?
JC: In animals, we saw that 125 mg was effective. What we have found from a lot of literature is that there is very infrequent intolerance to 500 mg BID metformin, but it does not provide very good glucose control at 500 mg. You need to get to at least 1500 mg or higher to get the beginnings of good glucose control with metformin. If we see activity of our combination at 125 mg that is similar to metformin alone at 500 mg, which is our suggested dose response, we could see actual improvement in glucose at the 500 mg BID metformin plus leucine arm. Our initial, primary outcome is to show non-inferiority, which means that the glucose control that we exhibit at any of the lower dosage arms will be statistically indistinguishable from the glucose control achieved by the metformin active control arm.
Next Week, we’ll find out how soon NuSirt will be submitting to the FDA.