Next we’re going to look at dose setting for phase one, but I hope that now you have an appreciation for how difficult at pre-clinical phase is. It’s not an easy phase of development and it does take a long time. It takes, on average, four to five years to get through this pre-clinical phase. It takes a lot of money too, in addition to taking a lot of time. And it’s very nice having the guidelines and parameters that I presented to you for conducting the pre-clinical program, but as you can see from the case study, it’s much more time consuming and involved than what I’ve presented to you.

Now, let’s look at dose setting for phase one, and this is going to be the last part of the lecture for this week. This is one of the most different decisions that has to be made in drug development. In this phase we are going from having animal data and in vitro data for a molecule and taking this investigational molecule into the clinic. So it’s an extremely critical phase of drug development, and how one translates that pre-clinical data into setting a dose to be used for the administration of this investigational product in a clinical setting is difficult and something that needs to be thought well through.

Now, there’s different ways that one can set this starting dose. It can be based on the NOEL, the no-observed-effect level that we saw in the animal studies, or it can be based on the MABEL, which is the minimal anticipated biological effect level. This is something that we see mostly with the biologics is this MABEL approach. Now, there is an FDA guidance for industry on estimating the maximum safe starting dose and initial clinical trials for therapies in healthy adult volunteers. That’s where the information comes from in these next couple of slides. If you’d like more information, you can go to the FDA site and find this guidance document.

Now, this schematic goes through the thinking process that one follows for selection of the maximal recommended starting dose for administration of an investigational drug in a health volunteer. It’s not in a patient. It’s in a healthy volunteer. Usually, our phase one studies are done in healthy volunteers.

In order to set this dose, one uses an algorithmic manner. This is from the FDA guidance document, which uses the NOAEL and which recommends the use of the NOAEL. When one sets the maximal recommended starting dose, one needs to ensure that a toxicity is avoided because we are going into a normal volunteer here, and it is unethical to induce toxicity in a normal volunteer; however, you don’t want the dose to be set too low, and you need to set a dose that’s high enough to meet the objectives of your clinical trial. That’s a fine line that one needs to walk. The dose can’t be too high, or you’ll introduce toxicity. It can’t be too low, or you’re not going to meet your end points, you’re not going to meet your trial objectives.

Now, the NOAEL is the highest-dose level that does not produce a significant increase in adverse events in comparison to the control group, so when you design these studies, you have a group getting investigational drug, you’ll have a group getting control drug.

The first step that one must take it to determine the NOAEL in the toxicology studies. If you remember when we went through the case study from Aranesp, the NOAEL was determined for each toxicology study. Now, the next step is a decision on if the reason to believe that toxic doses do not scale by body surface area because one needs to take into consideration that the animal models that we use are different in size, in shape than a human. If there is reason to believe that these doses do not scale, if one answers yes to this question, then one determines the human equivalent dose to be equal to the NOAEL.

Now, if one answers no to this question, if there is not any reason to believe that the toxic doses do not scale by body surface areas, then one dose a conversion where one converts each animal NOAEL to the human equivalent dose. The human equivalent dose is then determined for the most appropriate species, and the most appropriate species for a biologic is the relevant species. This is selected as we discussed based on in vitro binding, and functional assays. A safety factor is applied to this HUD and usually, it’s a factor of at least 10. The use of the safety factor is based on the possibility that humans may be more sensitive to the toxic effects of a therapeutic agent than predicted by the animal models. Also, bioavailability may vary across species, and that the models that were tested, the animals that were used do not valuate all possible human toxicities just because we’re different.

Now, while many NOAELs will be determined and any solace for Aranesp, every study that was conducted had a NOAEL determined. Only one should be used in the calculation, and that is the most appropriate NOAEL that should be selected, and for biologics, that is usually selected based on the most appropriate species.

Now this is a graph taken from the guidance document on the conversion of animal doses to human equivalent dose based on body surface area. I’m just showing it to you as an example. For example, let’s look at primates. If you go down … the way this is sorted is that the left-hand column are species. These are the most common species that are used for toxicology. If one dose toxicology, say in monkeys, which is something that we usually do for our protein products, we use non-human primates, then the animal dose is divided by 3.1 in order to convert that dose to the human equivalent dose, or you can multiply it by 0.32.

If, say, you didn’t use non-human primates, let’s say you used dogs, which is something you typically use for a small molecule, then the animal dose is divided by 1.8 to come up with the human equivalent dose. This is the manner that one converts and takes into consideration the differences in the body surface area between an animal and a human when setting that starting dose.

The MABEL, or the Minimum Anticipated Biological Effect Level, is used in certain conditions, mostly for the biologics. And in order to use the MABEL, one looks at the NOEL and the lowest dose where a pharmacological response was seen. So one does not look at the No Observed Adverse Effect Level, one looks at the lowest dose where a pharmacological response was seen. So you’re looking at a different factor. A safety factor is then applied and sometimes the calculation is based on micro-dosing, which means the safety factor that is applied is less than 1/100th the dose calculated to yield a pharmacologic effect.

So the lecture today covered a lot of material. We covered C and C, we covered preclinical from an in vitro and an in vivo perspective, and we looked at setting the maximum safe starting dose for our first-in-human study. Next week we’re going to look at phase one studies, we’re going to look at clinical trials in general, and get more into a clinical development. And please don’t hesitate to contact me, either by email or by phone, if you have any questions. Thank you.