 Dr. Diana Blyth is the Chief of the Contraceptive Development Program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. She is also the Director of the Conceptive Clinical Trials Network, which conducts clinical development of new contraceptive products for both women and men. She earned her Bachelors of Arts in Chemistry from Douglas College of Rutgers University and her PhD from the University of Pennsylvania. For post-doctoral training, Dr. Blyth was a National Research Service Award fellow in the Laboratory of Molecular Biology at the National Cancer Institute. Dr. Blyth's research has led to products on the market for the treatment of uterine fibroids and emergency contraception. She is a leading expert on contraception with a focus on the development of effective and reversible forms of male contraception. She has published prolifically in the fields of contraception, endocrinology, and glycobiology, and has organized several international meetings. She will be speaking to us today about the current state of development of male contraceptives. Please join me in welcoming Dr. Diana Blyth. I want to thank the organizers for inviting me. I'm not sure I want to thank them for putting me after Dr. Murdoch's brilliant talk, but it gives me an opportunity to say, now for something completely different. So I want to talk to you about the prospects and pipeline for male contraception. And I'll start out by just mentioning that men already do a fair amount of participation in the contraceptive process. This is the methods of contraceptive usage in the United States. Men already account for about 28% of that usage. Primarily, male condoms at about 15%, withdrawal at 5%, both of those are not very effective, and vasectomy at 8%. Now, this is all the suite of methods that are available to men and women. And you can see at the top part, let's see if this little arrow part works, we have greater than 99% effectiveness. We have continuation rates in the fairly high amount of what may seem low to you, but it's actually incredibly high, 78% to 84%. Vasectomy is up here, but it's not reversible. In the next group, we have pills. They're all familiar with that. It's only effective at about 91%, and has a continuation rate only of 67%. And then in the lowest tier, we have male condoms and withdrawal. These are methods. All of these methods in this lower tier depend on usage at each active intercourse. And the failure rate here is between 18 and 22 pregnancies per 100 women per year. So it's not easy to develop a drug. This whole bench-to-bedside thing has this huge valley of death that you can see right about here. And this is where most of the drugs end up. They don't ever get to the bedside. And those who actually get there, many of them don't make it to a product. But fortunately, there's a pipeline for female methods, and we know what that includes, and it includes about 20,000 cycles of research demonstrating safety in women, along with efficacy, to get all of these products. The road to a male contraceptive is a little less straightforward. And it involves basic research to identify a target in drug. The toxicology is extreme because you have a very high bar of safety for a long-term use in healthy subjects. Not no disease here that we have to cure. So tolerance for side effects is very low. And the clinical research in normal volunteers, it's unclear how many subjects, how long. They don't have cycles. How long is it going to take us to get to where the FDA is happy? So the goals of male contraception, of course, are that it should be really effective, reversible with minimal side effects. And we can talk about risk-benefit calculations for men who don't get pregnant, but acceptable to both partners. Now I'm going to tell you about sperm numbers. This is going to surprise many of you. The first one is men make 1,000 sperm per heartbeat. That's a lot. The average volume of an ejaculate is about 4 milliliters. A teaspoon is 5 milliliters, so a little bit less. The number of sperm that is considered normal for men is between 15 million and 200 million per milliliter, or 60 million to 800 million sperm per ejaculate. That's a lot of sperm. Here's the really important feature of this talk. Less than one out of every 10 million of those sperm reach the fallopian tube. When they get there, they have to be able to bind to the wall, undergo capacitation, which means they undergo changes to be able to fertilize the egg. Otherwise, they can't. And in the absence of doing that, they won't be effective. Just take a moment. This is a lot of sperm carnage. Where are these other sperm going? What's happening to them? Why do we need so many? But doing the math, we have between 10 and 100 sperm per fallopian tube. So when they always say, show you pictures of millions of sperm floating around an egg, that's an IVF situation. But in natural fertilization, this is what happens. And then there's going to be communication when the egg comes in the other end of the fallopian tube to bring those sperm to the site where fertilization can occur. It only takes one. That's what everybody says. But in our contraceptive studies, when men reach less than 1 million sperm per milliliter, they are considered fully contraceptive. So it may only take one. But even if there are 4 million little helpers, it doesn't mean that that one is going to get up there and get to the goal. So it's a numbers game, but the egg has the advantage here. OK, so intervention points for male contraceptives. There must be about 1,000 places along here that we can intervene. I'm going to talk to you mostly at the beginning about hormones, because that's something we understand a lot based on what we know from women. Now, this is a picture of a man. You'll recognize all the important parts. We have the hypothalamus, the pituitary, and the testis. OK, this is the blood, which feeds back to the hypothalamus. And what we know is that if we give a high amount of testosterone in the blood, if it gets too high, it will feed back and it will stop the production of these hormones here that cause the testis to make testosterone. The amount of testosterone that is in the testis is between 50 to 100 times higher than what is circulating in the blood. And it needs to be that high in order to stimulate spermatogenesis. If we add progestin, which is very similar in structure, I'll show you later, to testosterone, despite the fact that they have very different functions, progestin will do that same feedback and it will inhibit the hypothalamus from making GnRH and LH and Fsh, LH being the most important one. And that will inhibit the testis from making a high amount of testosterone. So that decreases to very low levels and it stops spermatogenesis and that's the good thing. But what also happens is the blood level now goes way down and it also stops libido and muscle mass maintenance and things that you don't really want to impact. So you have to add back testosterone in a sufficient level that it restores these functions, libido and muscle mass, but you never get that huge amount back in the testis so you don't make spermatogenesis again. So keep in mind that when we're looking for an effective method, we're trying to lower the LH so that we lower the testicular testosterone below a certain threshold and we won't get sperm production and everything else should be maintained normally. Okay, so why isn't there a male pill? You've all asked that in your mind right now. You've said, what is wrong with you people? Why haven't you made a male pill? Challenges for the male pill are to deliver an oral dose of that testosterone that we need to give back because you can give the progestin in any sorts of ways. We can give it as a pill, as an injection, as a gel, as an implant. But testosterone has been incredibly challenging and if there was a way to make an oral pill of testosterone, believe me, it would have been done by now. Donald Trump always says, believe me, I have to find a different way of saying that. So it's very difficult to make an oral pill. It's cleared too rapidly from the blood. It requires multiple doses per day. Longer acting forms of oral testosterone have been made but they've caused hepatic toxicity, liver toxicity and that's not good. So that's been the challenge. So we've tried to overcome that by delivering testosterone in other ways. Now, you've all seen the commercial for low T and you go get this gel and it's wonderful and it replaces your testosterone and here it is, right here. But we also have a really potent progestin called Nestorone, which I can tell you later if you ask me questions makes you smarter. The progestin and the androgen working together, the men use the gel. They applied it to the shoulders or the abdomen every day for six months. The result of that is this is the placebo. They took the testosterone gel but the gel in the other canister was a placebo and you can see down here that it takes a while for, after you stop sperm production it takes a few months or weeks for the rest of the sperm that are already past that point to clear out. So by eight weeks you start seeing a few men who become azospermic here, meaning no sperm. The blue is less than one million which I said is fully contraceptive and less than three million is actually pretty contraceptive as well. We usually try to get down below one. So anything that's white is considered not contraceptive enough even if it's still fairly infertile. So you can see that in the control we're not getting too much effectiveness but in the preparation that had an esterone in it now you can see that we're getting by 12 weeks pretty much 90% of the men are at a contraceptive range. A little bit higher at 16 weeks. And they all recover, that's important. So this is just to show you the individual men. So they all start over here with 15 to 200 million of sperm per milliliter. By four weeks a couple of them are starting to suppress right away. By eight weeks almost everybody is suppressed. By 12 weeks everybody who's gonna suppress has pretty much done so. This person here probably down here is not necessarily being fully compliant which is always a problem with a user controlled method. This person here probably was compliant and they started out with a really huge amount of sperm greater than 200 million per milliliter and eventually probably would have gotten all the way down if they could have continued treatment but the study stopped here and they had to go into recovery. Everybody recovered. So now the next step is that was men who were using the product to show that they could suppress sperm but their partners weren't at risk of pregnancy. Now we wanna go into evaluation of this combination and we put both esterone and testosterone in the same gel. Again, it's gonna be about a half a teaspoon for each shoulder every day and 420 couples will be using the method. They will go into a suppression phase and when they reach suppression at eight to 12 weeks maybe a little bit longer if necessary. When they've been cleared at one million per mill or less they'll go into an effectiveness phase for one year and the couple will agree to not use another method. This will be their method of birth control. After that year they will go into a recovery phase. The primary efficacy phase endpoint is pregnancy rate and the secondary endpoints are safety and side effects and acceptability of the method to both partners. This study will be done at our main sites at UCLA and the University of Washington but also at our partner sites with them in Sweden, Chile, Kansas which is not really another country I just may seem that. England, Italy, Scotland and Kenya. So I've told you about hormones. Now I wanna take shift gear a little bit and tell you about a couple of non-hormonal methods that are in development. They're not in clinical trials yet but they're in development. So the first one, bromodomain inhibitors. This is a family of proteins including a test of specific isoform called BRDT. These proteins regulate apoptosis or program cell death as well as migration and invasion. Now that's normal functions that they are actually stimulating expression of cancer drivers but when overexpressed it can lead to cancer which is not a good thing. So bromodomain inhibitors such as JQ1 and IBET have anti-tumor effects and have been shown to have promising outcomes in patients with cancer. The test of specific BRDT is essential for spermatogenesis and BRDT inhibitors could be effective at male contraception. So this is the pipeline. This is what we go through for every drug we need to develop. We have a discovery period where we identify the target and we have a gene that we identify. We have to prove that it's contraceptive effectiveness which JQ1 has been able to show. Once that happens it moves up into what we call an optimization scheme where we do medicinal chemistry and lead optimization then hopefully into early development and IND and eventually into the clinic. And we're very encouraged that JQ1 is already in clinical trials for cancer treatment because it indicates that it's not going to be harmful in itself to individual when we get there. But our goal is to make this inhibitor very specific for the testicular form. And this is a picture of what's going on and this is actually being done, led by Gunta Gayorg who's at the University of Minnesota, not far from here. And you can see that the test of specific active site, this is a crystallized enzyme and the active site here has a molecule bound. Same molecule is bound to the non-testicular specific BRD4. But you can see that the molecule is in a slightly different configuration in these two active sites. And a low number here is an indication that it's a really strong inhibitor. So 35 is three times better for this one than it is for that one. But by changing structural parts of this molecule you can create one that is twice as good for this site as for here. And that work is ongoing to try to make a very specific and potent molecule that can go into the clinic someday. Now another one called incidentally and coincidentally B-dads. Not, it should be not B-dads if it works, but for the moment it's B-dads. And back in 1961, it was shown that this reversibly suppressed permanogenesis in a clinical trial in men. Now these men were in prison, they were prison population. And that I think is in the days before IRBs because that would not happen now. But 60 men took the drug for up to one year with no significant adverse events. And their sperm concentrations were less than one million per mil. Then one of the inmates managed to get a bottle of alcohol into the prison. And there were side effects when it was co-administered with alcohol, cause severe nausea and vomiting, similar to the medication that's used for trying to treat alcoholics through aversion therapy. So this was abandoned. And again, this is a challenge because this side effect would not have shown up in any of the preclinical studies we did. Even in primates, we're not gonna give them alcohol. We wouldn't have known that this was gonna happen. So frustrating, but this was abandoned. Now many decades later, John Amary at the University of Washington, recognizing that this enzyme is working through testicular synthesis of retinoic acid, which is essential for sperm production. Also recognizing there's a similar enzyme in the liver that was accounting for this alcohol reaction, proposed to use molecular modeling to separate the testis activity from liver activity. Now these are orally active drugs. There's no effect on serum testosterone levels, but we need to enhance the specificity. So similarly to what I showed you before, here we have 100% activity of the enzyme. And with more increasing amount of the inhibitor down here, we can get down to 0% of the activity. But they're all overlapping. So with chemistry and structural biology, similarly changing around the active site, we can create a molecule that will have inhibitory activity that's fully separated from activity at the other enzyme. And that's the goal and this is in progress. Now, I mentioned before to you that progesterone and testosterone are incredibly similar. They're identical in every part of the structure except for this addition right here on R5. But using that theory and making additional substitutions at other places around the molecule, we can retain the testosterone function of the molecule but add progestin activity to it. And that's what we've done with these analogs down here. And then we add these little or long chain acid, aldehyde groups that will cause the molecule to stay in the blood for longer that's the key is it's a pro drug, it's not active but as this gets clipped off, it releases the active drug to the body. So what does this look like in the clinic? Now, we have two here, a dotted line is the drug taken without food. And this is a log scale. So a hundred times more is absorbed if it's taken with food. We're, these are first in man's studies. So you complete the 200 milligram dose before you start the 400 milligram dose. And so forth before you start the 800 milligram dose, you're going slowly because you want to make sure nothing bad's happening. This is a single dose. Importantly though, you can see that the DMAU is lasting for 24 hours. That's good. And remember I said we wanted to reduce LH. Well, this is only at 12 hours which was a very short period of time but you can already see there's a reduction in LH and there's a reduction in testosterone. So this is good, this is showing that it's active. So could DMAU become the male pill or capsule? The next step is daily dosing for 28 days with increasing amounts of DMAU. Again, it's a slow process. So if you hear something happening in a mouse and they say five years we'll have a product on the market, they are lying, they have no idea what they're talking about. Evaluate safety and side effects and will DMAU suppress LH and testosterone? So now we're in 28 days. This is the first 24 hours. Again, you'll see an effect at 12 hours. We're looking at placebo and yellow here. We're looking at then increasing doses at 100 and then 200 in castor oil, 200 in powder, 400 in powder and 400 in castor oil. And as you can see, when we get down to the higher level, these square teal dots are covering up the round green dots but both the 400 formulations are fully suppressing LH. And good news is they're fully suppressing testosterone. This is very encouraging and they all recover. So could DMAU become a male pill or capsule? Maybe. Now the men had very low testosterone but they had no symptoms of low T, which is good because that meant the drug was doing the androgen stuff it needed to do to make them all feel good. There are no safety concerns identified at any of the doses tested. So now we need longer study to establish safety for longer periods and sperm suppressive activity because that's where it's at. Now many of you may have been asking will men take a male contraceptive? Well, there was study done just in this college and an amazing number said yes. Yesterday I asked a whole bunch of students and almost all of them because I was there to intimidate them said yes, they would try it. Importantly, the women said they'd rather date somebody who was using a male contraceptive. I offered them twins equally attractive and they had one with the male contraceptive. It was really wonderful. More than half of the men are willing to use a male contraceptive. There are country specific differences but generally speaking everywhere, it's pretty high. And for the mode of delivery, most men would like to have a pill. They think they would anyway. But a very high in number of them actually would prefer an injection or would be willing to use an injection or an implant or a gel. So could DMAU become a long-acting injectable? Well, when DMAU is delivered as an injection in castor oil, does it lower LH or testosterone? This is done in primates and we gave a very high single dose in primates. We knew it was safe but we didn't think, we didn't know how long it was gonna last. It was extremely high dose but we didn't expect it to last this long, about a year or two. And then they all recovered, which is good. So now we are in first in man studies and the first doses have been delivered either subcutaneously or intramuscularly. And after this single dose subcutaneously of 50 milligrams, you can see there is some, this is a very low dose and we weren't expecting much activity but we were happy to see there seems to be an effect by day 14. Day one, two, four, seven, 14, 21. And then it comes back up to normal. And the testosterone again is very low, which is good. It doesn't last too long but this is a low dose. The intramuscular dose is 80 milligrams. It's lasting longer and the testosterone all the way down and it's doing well. And so far the men seem to be feeling fine. This is great. We're excited. So I've shown you where things are in the clinical network. The nest test gel is out in front, DMAU oral is it and DMAU injectable and we are also 11 beta methyl but time is short. Oh and then there are all these other things that are in the pipeline but they're not in clinic yet. There hopefully will be but there's a lot going on here and it's very exciting but it's way back in the pipeline. So these things are all along the pathway for both production of sperm and function of sperm. One of them may end up being even better. I suspect and predict that hormones will get there first. Now I was asked to talk a little bit about contraceptive funding. If you are interested in contraceptive funding, the way to do that is through an investigator initiated grant. Or periodically there are funding opportunities announced for specific programs that one could submit a grant application to. So keep an eye on the NICHD website for those funding opportunities. Once you get funded then we have this medicinal chemistry facility in University of Minnesota and some other facilities that can help to get things to the clinic. That's our goals to get things into the clinic. And then we can do the work once we get the product there. Also pharmaceutical or small business. Small business grants are really much easier to get than regular grants. So if you have a small business or want to form one that's a good place to go. Ultimately we want partnerships and we want product approval. And we want unhappy sperm. Thank you. So we're actually spot on on time and so I invite you to just take a little stretch and we'll reconvene in about 10 minutes.