Can you go into the specifics of the North Star trial, in terms of trial design, rationale, and what you were trying to assess as far as DTE-based treatment, including patients’ self-reported outcomes as well as FDA regulatory criteria for thyroid replacement in persons with hypothyroidism?
It's very important and probably I will go a bit on the nitty gritty of the entire regulatory process, which I think it's important for colleagues and patients alike. So, uh, the question, uh, uh, is related, uh, how to move, uh, one drug. To the state of being FDA approved, FDA requires for drugs to be efficacy efficacious for the treatment of the disease state and more important, safe, safe whereby every, uh, there, there is an inherent safety of the drug per se. And, uh, um, and the, the, uh, and the identification of uh potential side effects. Even before we get to this stage, the company needs to prove that, uh, the drug per se is stable, is reproducible, and, uh, the, um, distribution within the organism is, uh, uh, predictable. So in essence, first off, uh, can we make a drug? Does this drug. Remains the same over time, is it the same between batches? Is it the same between doses and uh they seem very simple questions, so they're not uh and that requires uh uh lots of experimental on one side and on the uh um on the front end requires lots of investment uh and uh. Accurate development of the industrial process. Those are all things that we do not see as physicians, but those are the building blocks in the development of a drug. Something that it's a bit technical is that some drugs that have been around for much longer than FDA existed have been so-called grandfathered in, so they are recognized although they are not approved. And uh uh all the thyroid medications were in this framework. Some levothyroxine products have undergone an accelerated process of FDA approval simply because they've been around for so long. Uh, DT, the, the secret thyroid extracts were not, uh, uh, processed in this manner. So in essence, uh, the next step from uh the regulatory pers uh perspective in order to have a Desiccated thyroid extracts such as North Star been approved need to be measured. Against the benchmark that there will be levothyroxine. So, uh, in the phase of uh uh development of a drug, as I said, the pre-clinical component is the stability, processing, uh, uh, presence or absence of uh contaminants, and all of this have been already done. Next step is looking at the pharmacokinetics of the drug, in essence. How much drug or when you give some some amount of drug, what happens on the distribution of drug? These are those are experiments usually done in healthy volunteers with high dose of drugs looking at how much it how long it takes to get to peak level and how long it takes to go back to normal and uh uh with this information we can have some degree of uh um. Some degree of modeling on the amount of drugs we need to do, we need to provide to achieve a clinical effect. Next step, and this is the study I've been mostly involved with, it's uh looking at the uh establishment of dose. In this case, uh, we cannot have patients starting from scratch because uh it would be unethical having patients stopping their medication and becoming hypothyroid, feeling bad and then starting a medication. So for this reason, uh, we use the a crossover. Uh, type of experiment or rather um parallel design, sorry, uh, in which uh we uh enrolled the patients who were already treated with levothyroxine but uh we assigned them 2 to 1 to Northstar versus levothyroxine with the goal of so-called dose finding. So we had a pretty decent idea where to start with, meaning how to convert. From levothyroxine to desiccated thyroid excess, but we needed to have a good kind of ironclad conversion so that then we can move on a larger study. So what we did, uh, uh, as I said, we enrolled the patients that had virtually no endogenous thyroid hormone production, so they had bad hypothyroidism. Uh, we knew that uh uh we used the uh the amount of levothyroxine that they were taking, so they were taking relative to their body weight, quite a bit of uh levothyroxine, and that indicates that uh. They were, they had very little to no endogenous production of thyroid hormone. And uh that makes the study a bit more complicated uh but we knew in advance and uh and then uh from other uh studies in the literature we estimated uh that uh. 100 mcg of levothyroxine would be equivalent to 68 mg of of Norstar, and that was an approximation. The goal of the study was establishing what is at the individual level the conversion from levothyroxine to leotyronine, and that means that we adjusted the uh the doses both for levothyroxine and leotyronine every 6 weeks for a total of 30 weeks and uh uh the study I'm not going. To go too much in details on the statistics to Uh, to definition of what, uh, uh, um, what the exact conversion, uh, how it, uh, how it came out with, but, uh, in essence, uh. At the end of the study we were able to have a very reliable conversion factor, so that means on On North Star we know how much. Northstar we need to give for individual starting from the levothyroxine dose. This is important. As important, we looked for adverse events and we found no significant difference in adverse events between individuals treated with levothyroxine versus individuals treated with Norstar.
