Interview Transcript- Part 2 of 3
Read Part 1 here
Dr Ramasamy: So what is Natesto?
Dr Ramasamy: Natesto is a nasal testosterone. It delivers 11mg of testosterone per pump per nostril and it's used three times a day. In Canada it's approved bid twice a day, in the US the FDA's approved it three times a day.
Dr Ramasamy: The levels peak in about 40-60 minutes. It's like an on-demand testosterone. This is not a ... this is not a medication wherein testosterone levels are high throughout the day like Androgel. Not a medication wherein, like cypionate or enanthate where testosterone levels are high for about two or three days in a row before it starts to decrease before you start the injections.
Dr Ramasamy: Certainly not like pellets wherein levels are high for weeks together. All of the hormones that we discussed with GnRH, FSH, and LH, they are all pulsatile. They have a peak, they have a trough, they have a peak, they have a trough throughout the day. When you give exogenous testosterone with injections and gels all of that pulsatility goes away. No longer, no more GnRH pulsatility, no more FSH, and LH pulsatility. Certainly not the testosterone from the testes.
Dr Ramasamy: Whereas Natesto, I think what it does ... we certainly don't have the complete trial data but I'm happy to show some preliminary data ... is because it has its peak in 40-60 minutes and it actually washes out in 3-4 hours before you're ready for the next dose. I think ... it because it's pulsatile dosed the GnRH, and so , therefore,the FSH and the LH actually is preserved.
Dr Ramasamy: It decreases, don't get me wrong. It goes down. In the initial ... I'll show some of the data ... FSH and the LH decrease. But it's not 0. It does not go down to become undetectable. I think the little FSH and the LH that is maintained on Natesto is probably sufficient for sperm production to be maintained.
Dr Ramasamy: Again, this is a hypothesis-based investigator-initiated study. We get some partial support from the company but this is certainly not an industry-funded study. Because this is hypotheses-generating we have to wait for the final data to make certain conclusions but I think that's what's happening.
Nelson Vergel: One question. You mentioned Canada has a dose of twice a day.
Dr Ramasamy: Yes.
Nelson Vergel: Is that a bigger dose? Or just a-
Dr Ramasamy: No, it's the same dose that was just approved twice a day as opposed to three times a day. One pump per nostril.
Nelson Vergel: Okay, so that kinda tell us that ... we'll proceed.
Dr Ramasamy: So what did Natesto do?
Dr Ramasamy: In a study that was presented to the AUA last year from the group in Boston, they showed that testosterone increased from a baseline of 200 to 420. I don't think you're going to get levels of 800-900-1000. You're going to at least get to the target range of 400-600 in guys that start off from 200.
Dr Ramasamy: Interestingly, the FSH and the LH levels, as you can see with the bid and the tid ... twice per day was from the Canadian studies and tid was from the US studies ... the FSH and the LH go down from 8 and 6 it goes down to 6 and 3. The LH goes down from 5 to 3 and 2. It certainly decreases, but the nice thing to show is that it certainly does not become undetectable, which happens 95% of the time in men who take injections, Androgel and other gels, and pellets.
Dr Ramasamy: Testosterone increased to normal levels, to at least the target range beyond the 300 levels but the FSH and the LH decreased but certainly remained within normal limits. Now the ... it's nice to say that FSH, LH has decrease but so we should start giving it, but no semen analysis was performed as part of the study. One of the biggest goals of our study was to show that the sperm parameters are actually maintained when you take Natesto.
Dr Ramasamy: Why does Natesto maintain FHS and LH? I think we spoke about a little of this, can you click again, Nelson? I think what happens with GnRH is there are fast pulses and slow pulses. GnRH is actually ... every one hour from the hypothalamus there is a GnRH pulse that is produced. As long as you have fast pulses your LH, it gets produced. If you slow down the frequency and sort of every one hour,and produce one pulse every 4 hours your LH is not produced but the FSH is still produced. Even if you decrease the pulsatility of GnRH, your FSH production is maintained and as long as the FSH production is maintained your sperm production is also maintained.
Dr Ramasamy: This is a nice pharmacokinetic study with Natesto. Very surprising to see ... I mean if you see the three doses that men take over the range of ... over the course of a 24 hours ... on the x-axis that's hours from starting from 0 to 24 hours. On the y-axis you see the serum total concentrations that are reached. You see as soon as time 0 you see the peak is achieved between 30-40 minutes within the one hour and the peaks go up, on average, to about 700-800.
Dr Ramasamy: Then you see by hour 2 to hour 3 the levels are almost back down to where they started. Then you wait for the next peak, and so on and so forth. It's very interesting ... I mean obviously because of testosterone testing variations there are wide standard deviations with testosterone levels that got measured in these guys but it's interesting to note that during the times that testosterone is back down to the baseline I think the FSH and the LH start getting produced from the brain. During the times the testosterone is high the FSH and the LH production has stopped. Because this whole concept of pulsatility is still maintained I think we are able to get away with giving testosterone on-demand.
Dr Ramasamy: It's a very new concept, right? I mean men always say "Doc, I want my levels to be high before I got to the gym." "I want my levels to be high before I have sex." "I want my levels to be high in the evenings." No guy ... if you ask most men, they don't care that their levels are high when they sleep, right? Although there is some research showing that the majority of the muscle building happens during sleep it's tough to know exactly what the levels are when the guys are sleeping.
Dr Ramasamy: This concept is sort of on-demand. It's ... I would equate this to similar to Cialis and Viagra. Where in Cialis was marketed, is marketed as a pill that you could have sex anytime during the 24-36 hours but the best activity is seen at 2 hours, whereas Viagra is on-demand. You've got to use it and have sex between 1-2 hours after you take it. I think Natesto, moving forward, I see it as probably going to be used as a on-demand increase in testosterone rather than guys that say that they want to have increased levels throughout the day.
Dr Ramasamy: What are we doing? We are recruiting men between the age of 18-55. They have to have a decent sperm concentration so they cannot have too much infertility and so their sperm concentration needs to be greater than 5 million and we're looking at changes in testosterone, LH, FSH, both ... and the semen parameters at 3 months because that's how long it takes for one spermatogenesis cycle, and at 6 months.
Dr Ramasamy: As part of the study we're providing the Natesto for 6 months and doing all of the semen analysis free of charge. All of their lab values, of course, get billed to insurance and they need to qualify for the study in order to get involved into the study.
Nelson Vergel: Dr., if they decide not to stay on the drug are they just taken care of and put on TRT, on testosterone replacement.
Dr Ramasamy: Absolutely, yes. I don't leave them alone.
Nelson Vergel: Okay so you are actually ... okay, good.
Dr Ramasamy: Yeah, i actually treat them. If they decide to take the drug, and they want to come off of the trial because either they didn't like it or some guys with sinus infections and allergies can no longer use the drug and want to come off the trial I put them on other modes of TRT, yes, absolutely.
Nelson Vergel: Thank you.
Dr Ramasamy: So this is basically the study timeline. It's 6 month study. It's pretty involved so guys that are out of town ... it is fairly hard to do so we are truly targeting men in the South Florida area who could come visit with us at least for 3 visits during the 6 months to do the semen analyses and to also get testosterone, FSH, and LH levels, along with estrogen during the other visits.
Dr Ramasamy: We've recruited a total of 23 men in the study. So far the average age is around 35. Their starting testosterone level was 227 so these young guys with such a low T level, you know this is definitely worrisome because young men, your levels should be somewhere 350-400 or even higher. We have measured this on the morning before 10:00 on two separate dates so unless you qualify for the study to get less than 350 you can't get enrolled in the trial. They have normal FSH, LH levels and their sperm concentration and their motility is all fairly normal.
Dr Ramasamy: This is the ... sorry, let's go back to the data. This is the data that's at 1 month, 3 months, and 6 months. We obviously don't have all of the 23 patients completed so far. At the 1 month time point, about 93% of patients had levels beyond 300. About 62% at the 3-month time point had levels beyond 300, and 4 out of 5 patients, at 6 months had beyond 300.
Dr Ramasamy: One of the reasons the three-month data doesn't look that great is we learned that you had to draw the levels, like I showed the pharmacokinetic data, that the levels ... the blood has to be drawn within an hour to two after they take their Natesto. If we don't get that within that hour to two we know when you're looking at 4-5 hours after ... your levels go back to baseline to where you started. I think it was just one of the study findings that we found as we did the study along. We were trying to question as to why the levels were low even though the guys were feeling great. It's just that we were not measuring appropriately but we've now fixed that problem with our lab and we're trying to get the levels done within an hour to two after they take the medication.
Dr Ramasamy: Levels do go up, certainly not in everyone. As you can tell, most of the men are fairly happy and satisfied on the trial.
Nelson Vergel: Dr., how do you measure compliance? Adherence to therapy.
Dr Ramasamy: We give them only the amount of canisters that they need from one visit to the other and they are asked, because-
PART 2 OF 3 ENDS [00:26:04]
Dr Ramasamy: Need for that from one visit to the other. And they are asked because this is a controlled substance, they're asked to bring back all of the canisters with them. We can tell if the canisters are empty or not, and whether they have used up the canisters or not unless they are squirting it all outside.
Nelson Vergel: You know there are ways around every study.[crosstalk 00:26:23]
Dr Ramasamy: Hopefully they are not doing it, but that's how we assist compliance with empty canisters.
