And chronic disorders. Doctor. Patel, Doctor. Bruno, very good to have you with us. Please go ahead with
your presentation. Thanks, Thomas. Thanks for the invitation. Good afternoon to all. I'm Mahesh Patel.
I'm the President, CEO and Co Founder of the company. I'm here to introduce you to the company and give you an update on our pipeline. And then I'll be passing over to Doctor. Ben Bruno, who is our Director of Financial Development and he will fill you in on the details on our lever asset programs in our pipeline. Before we do that, some disclaimers on the forward looking statement.
I'll give you a few seconds to go over and dive straight into our pipeline. So LipoCiti is a clinical stage biopharmaceutical company a focus on developing innovative products for metabolic and endocrine disorders. Very recently, we have launched and looked into opportunities in the neuroendocrine arena. And I'll be sharing a little bit of that with our new asset that we added to the pipeline LTCN-eleven fifty four. But all of our pipeline candidates are based on our proprietary drug delivery technology that is to effectively deliver highly volatile molecules to get appreciable and relevant levels blood levels.
Our lead asset is Pelando, it's twice a day oral pill for testosterone replacement therapy. We're very excited that we have received a tentative approval and are closing in on getting a final approval, which for which we can apply in January, a couple of months before the or actually after the expiration, which is on March 27, 2020 when the exclusivity of our competing product expires. So, then we will be eligible for a final approval. It's a convenient dosage form, an option that's badly nearly in the marketplace that's dominated by non convenient, non oral products that require titration. We are actively in discussions with business for commercialization partner.
And all I could say is the products will be progressing very well, converging. And as soon as the deal is consummated, if and when it happens, we'll announce to the stream. Our next non opulator for TRT is Sertilando XR. It's a differentiated program, different molecule than the lead asset. It's once a day oral pill.
And we have advanced it all the way to pretty much Phase 3 ready status, but we do have to do a food effect study to start in the approval trial. Again, with Zelando and Zelando XR, we believe we can gain and retain market leadership in the testosterone replacement therapy area, which is a huge opportunity, roughly 7,8,000,000 scripts were written last year for GLP. I think if you liver disease programs and Doctor. Bruno will talk a little bit more on that, but on LTCL-eleven forty four, just a little while ago, we released our top line data for biopsy confirmed NASH patients. The data really striking.
And the next step there would be to meet with the FDA and their clarity on design for the Phase 3 trial and what would be required for the pivotal study. On the next asset, we have LTC1148, that's oral testosterone for cirrhosis management. We're not going to reverse cirrhosis but helping patients to have a better quality of life or decreased decompensation events while they're waiting for a liver. Also, one of the objective would be to improve their post transplant survival outcomes, so rehab outcomes. So, 1144 and 1148 are programs that Doctor.
Bruno will be talking in details. Next on the bucket is Vision Health assets, LTCM-eleven fifty four that's a new foray into neuropsychiatric disorders. Here we have an active that's an oral neurosteroid for depression disorder, in particular for postpartum depression. It's a serious unmet need and there's only one approved drug that's a in hospital ID infusion. And we believe that an oral, which is a user unmet need would be a significant advancement for women badly in need of in home treatment option.
So, we are currently conducting a PK study. We have completed the study. We are analyzing the data and we'll decide on the next step thereafter. Last on our doc, the result is in 1107, that's oral headrestic suggestion for prevention of preterm birth. There's only one product approved for prevention of reedomberg, that's an intramuscular injection.
So we're going after the same indication with the same molecule, but through a oral route. We are the first ones to enable a total delivery of that highly soluble molecule. We have advanced that asset all the way to close to Peru study status. We can see we're doing a food effect study and that will help us to define the dosing originally in the Peru study. Stay tuned for the results from that study as well as interactions with the FDA on the Peru study.
This particular asset has not an orphan drug designation and has a potential to be the standard of care should Makena be withdrawn from the market that's an injectable product. So now we have a robust pipeline and we are diligently advancing R and D assets as well as engage in advanced business development discussion on our lead asset, Chelan. With this, I will pass it on to Doctor. Ben Bruno, and he will talk more about our NASH program as well as the candidate for cirrhosis management. Ben?
Thanks Mahesh. I'm really excited today to share with you some of the results from our recently completed Phase 2 study in men with NASH. First, top line take home messages. We did meet the primary endpoint change in liver fat measured by MRI PDFF at week 12 as well as a key secondary endpoint NASH resolution with no worsening of fibrosis, which is a FDA approvable endpoint for accelerated approval subpartase pathogen. The magnitude of the treatment effect was really striking if you compare the results of our study in terms of mass resolution as well as fat reduction compared to other oral agents that are being developed.
While we observe positive trends in fibrosis improvement in 2 of the 3 methods to investigate the changes in fibrosis, the treatment effect observed on fibrosis needs confirmation in a larger study. Changes in key liver enzymes and body composition both support beneficial treatment effects of LPCN1144. Most importantly, LPCN1144 was well tolerated with an overall safety profile profile comparable to placebo. Changes in cardiovascular markers, androgenic markers and GIS adverse events were comparable between the two arms. These positive top line results strongly support LTPN-eleven forty four development for regulatory approval.
I'd now like to talk a little bit about the study design and endpoints. So, the LIP study, short for liver fat intervention with oral testosterone, was a Phase 2 paired biopsy study in men with NASH. Men were eligible for the study with NASH and F1 to F3 fibrosis. Subjects were randomly assigned 1 to 1 to 1 to 3 treatment arms. Treatment A was oral testosterone twice daily.
Treatment B was oral testosterone plus B alpha cycloprol twice daily, and the 3rd arm was a matching placebo twice daily. Subjects were treated for a duration of 36 weeks. The primary endpoint in the study was change in hepatic fat fraction measured by MRI PFS at week 12. The key secondary endpoints that we'll be discussing today were change in NASH activity and fibrosis measured on liver biopsy and change in body composition and liver injury markers. Let's talk a bit about the baseline characteristics of this study.
In general, these baseline characteristics were comparable to other Phase 2 studies. I'd like to just draw your attention to a few notable differences. The mean ALT and AST values are on the slightly lower end compared to some of the other NASH studies. While mean NAFLD activity score was well balanced between the 3 groups, the subjects in the placebo arm did have a higher stage of fibrosis compared to the two treatment arms. Here we present data that was released in January of this year on MRI PDFF measured reductions in liver fat at week 12.
We see that both treatment arms met with statistical significance, absolute liver fat reduction. Both treatment arms had about an 8% to 9% liver fat reduction compared to 1.5% in the placebo arm. Now for the key secondary endpoint, NASH resolution with no worsening of fibrosis on liver biopsy. We see that we have a set here that
I haven't described yet, which
is the NASH resolution set. We had 44 subjects complete the end of study biopsy. However, not all of these 44 met the FDA's Phase 3 definition of NASH at baseline. So, in order to be eligible to be analyzed for NASH resolution, you must have had NASH at baseline. So, this subset includes 37 total subjects that had baseline and end of study biopsy data.
In the placebo arm, none of the subjects, 0% had NASH resolution with no worsening of fibrosis. In treatment A, 6 subjects, 46% and in treatment B, 9 subjects, 59% at the FDA endpoint of NASH resolution with no worsening of fibrosis. Now, given that this is a subset of our overall data, we did a sensitivity analysis where we categorized anybody who had either missing biopsy data or who did not meet the FDA's definition of NASH at baseline as non responders. So in here, the safety set, the placebo group still had 0 subjects who had NASH resolution with no worsening of fibrosis. Treatment A had 33% of subjects and treatment B had 47% of subjects.
So even in this conservative analysis, nearly half of the subjects in treatment G get the endpoint of NASH resolution with no worsening of fibrosis. This chart this slide shows a breakdown of the individual components of the NAS and the changes from baseline. In the pie charts, a color of red indicates that the score worsened by at least one grade. Yellow means that there was no change between the baseline and end of study biopsy. And green means that there was an improvement, a decrease of at least one grade from baseline to end of study.
We see that both treatment arms led to significant improvement across all of the NASH components.
Moving on to some other markers.
For key reminder markers, ALT and AST, we saw early, sustained and significant reductions in both treatments starting at week 4 and continuing through the end of the study. For ALT, the mean group absolute reduction in treatment B was as large as 23.4 units at the end of the study and ASC reduction was 13.3 units at the end of the study. There are also positive effects in terms of changes in body composition. Both treatment A and treatment B increased appendicular lean mass and decreased whole body fat mass. In terms of appendicular lean mass, the increase was about 2% to 3% and the whole body fat mass reduced about 4% to 7%.
Given the high overlap in comorbidities of metabolic disease and NASH, these body composition changes could be clinically meaningful. Here, we show a side by side comparison of our list study results of other oral drugs under development for NASH. On the top, we see the endpoint of NASH resolution with no worsening of fibrosis and in the bottom, we see absolute changes of liver care from baseline. By comparing these, we can get a better idea of how remarkable these changes were, these improvements were with both of our treatment targets in terms of liver fat reduction and mix of mass resolution. Please note these data are derived from published reports from different clinical trials at different points in time.
These trials are differences in design, size and patient population. No head to head trial has been completed. Now, moving on to the changes in fibrosis. We have pre specified in this study 3 different analytical techniques to investigate the change in fibrosis on liver biopsy. All three of these techniques read the same slide sets.
So, as we see here, we have 2, the paired reads and the digital reads. Both of those did show that our 2 treatments had a beneficial effect over placebo. However, the standard NASH CRM scoring had a placebo improvement rate of 40%, 6 subjects in the placebo and in the treatment A, 4 subjects, 27% treatment B, 2 subjects, 14%. We're still looking into how what is responsible for the disparity between these reading methodologies as well as this high placebo rate. It could possibly one explanation is the fibrosis severity was unequally weighted in the study.
That is the placebo group had more F2, F3 subjects, which are more prone to show improvement even without study drug treatment. In terms of the safety overview, LPT-eleven forty four was well tolerated with an overall safety profile comparable to placebo. The frequency and severity of treatment emergent adverse events in both treatment arms are comparable. In terms of discontinuous of study drugs due to key EAEs, 4 subjects in the placebo arm and 1 subject in the combined treatment arms discontinued the study drug. Cardiovascular events were balanced among the groups.
There were no reports of hepatocellular carcinoma or drug induced liver injury. The gains from baseline were comparable among all groups as were changes in lipids. Here's the rates of some AEs of special interest. And in terms of interest, we mean either the androgenic effects known of testosterone as well as AEs that are common of drugs under development for NASH. Here, we see that the rates are again comparable to placebo and low throughout all study treatment arms.
In summary, we did see significantly reduced liver fat compared to placebo. We met with significance of prespecified histology based regulatory endpoint of NASH resolution with no worsening of fibrosis. Key changes in liver enzymes and body composition support beneficial treatment effects. And we had a well tolerated safety profile comparable to placebo. Now, I'd like to shift gears and talk about our LTCN-eleven forty eight project, oral testosterone for the management of liver cirrhosis, the end stage liver disease.
Little information about cirrhosis, there are over 2,000,000 cases in the United States, and NASH is the most rapidly increasing indication for liver transplant in the U. S. There are over 500,000 people in the United States living with decompensated cirrhosis, and 62% of all those on the liver transplant waitlist are males. There's an extremely high economic cost to liver transplant at about $800,000 per transplant. And 40% to 70% of all men on the liver transplant list have sarcopenia.
And sarcopenia is pretty much another word for muscle wasting low muscle mass. So what's the importance of sarcopenia in cirrhosis? Well, first, a progressive drop in testosterone worsens sarcopenia throughout the progression of cirrhosis. But the presence of cirrhosis in men on the liver transplant list is associated with a 2 fold increase in weightless mortality, and that association is stronger with men than it is with women. The men men and women with sarcopenia have increased risks of hospitalization and prolonged hospitalization to report poor quality of life and higher medical costs at transplants, prolonged hospitalizations at the transplant as well as requiring more time spent in the intensive care units, and they have more post transplant outcomes, including lower survival rates and higher infection rates.
Finally, having sarcopenia increases your risk of decompensation. So, having either an initial first decompensation event, a core initial decompensation events or even your risk of acute on chronic liver failure. Now, about our proof of concept study. It is a Phase 2, multicenter, double blind, placebo controlled study of male subjects with cirrhosis of the liver and sarcopenia on the liver transplant list. This is really a 2 phase study.
It really has a built in open label extension. Stage 1 is week 124. There are 2 arms, placebo controlled is oral LTCM1148 or placebo. 1148 is actually testosterone bone definitely. So, it is a different testosterone ester than has been studied in NASH or in any of our testosterone replacement therapy indications.
After that Stage 1 is complete, we will move into Stage 2, which is an open label expression where all subjects are going to have access to 1148. All subjects from the placebo arm will be switched to the active drug LPCN1148. The primary endpoint for this study is change in skeletal muscle index at week 24. Key veterinary endpoints include change from baseline in liver frailty index. So that is a functional outcome.
The skeletal muscle index is really an imaging based outcome looking for changes in muscle mass, but the liver frailty index is looking at functional capacity. We're also looking at changing number of wait list events, so hard clinical outcomes, including all heart cause mortality, hospitalizations as well as further decompensation events and rate of breakthrough hepatic encephalopathy. This is really our first foray into these end stage diseases. And this study, while it is designed to look for improvement in muscle mass, and we believe that will have beneficial effects not only on patient reported outcomes, but also the clinical outcomes. But really we're going to obtain a lot of information about the role in testosterone and its effects in these end stage patients.
Some of the clinical outcomes we're looking at are of course overall survival and new decompensation events, including hepatic encephalopathy and ascites, survival to and through transplants. So there's a good number of subjects and patients who die either at the liver transplant or shortly after the liver transplant and low muscle mass really puts you at increased risk for poor outcomes surrounding the transplant. And finally, rates of hospitalizations and infections. In terms of the sarcopenia and cache endpoints, we are looking at a handful of functional capacity endpoints, including liver frailty index, which I mentioned on the previous slide, a 6 minute walk test on how far the subjects can walk in 6 minutes and time it up and go, kind of time it takes them to get out of the chair and walk a little bit. Besides the functional capacity, we are looking at the muscle mass and quality.
For sarcopenia, which is really just muscle mass, we're just going to look and see how much muscle they have in a specific region of the body, the L3 region, the MARCAR TAVR III, it correlates well with the overall muscle mass throughout the body. But muscle mass isn't the only thing that is of interest to us. You can have high muscle mass, but it can be loaded with fat. So that's called myosteatosis. And so you got regular muscle mass, but your muscle quality is much lower because of all this fat in your muscle.
And biosteatosis, along with sarcopenia, correlates with poor clinical outcomes. We'll be measuring whole body composition by DEXA and also a handful of patient reported outcomes regarding quality of life and sexual lives. Finally, in terms of biochemical measurements, we're going to be looking at anemia status in these patients. There's a possibility that testosterone may aid in production of red blood cells and clotting factors. We may increase albumin levels in these subjects and albumin is extremely important in these cirrhotic patients in terms of their overall health and really robustness and associated with low albumin associated with higher infection rates.
Ammonia levels will be measured and that correlates with hepatic encephalopathy. Possibly, we're increasing muscle mass. There is a there's at least a mechanistic reason why we believe that ammonia levels may drop and we may see improvements in hepatic encephalopathy. The MELD and Child's Use scores, those are used to clinically stage patients in order to get them on the transplant list and also decide where they are in terms of priority on the liver transplant list. And finally, we'll be looking at creatinine and calculating kidney function as that is a common comorbidity in this disease.
In terms of next steps, first for our LTCM-eleven forty four or NASH. Our next step is really meeting with the FDA to find a path forward for our Phase 3 study, discussing primary endpoints. We're thinking, of course, NASH resolution with no worsening of fibrosis. And we're going to be seeking recommendations on key elements of the Phase 3 design, including treatment, arm size and the duration of treatment. We want to understand the FDA's current stance regarding digital imaging analyses of biopsy slides.
And understand FDA's expectation on exposure requirements as it relates to cardiovascular risk for a serious condition with no approved therapy. For LPCN-eleven forty eight in cirrhosis, we do expect our first subject in that trial to be dosed in the Q1 of 2021. And that is our presentation for today. I appreciate your attention and look forward to your questions.
Thank you very much, Doctor. Patel and Doctor. Bruno, for the presentation. Perhaps a couple of quick questions for me. As we can see here, 1144, and as she outlined earlier, 1144 led to improvements in multiple aspects in NASH patients.
And it definitely has a unique mechanism of action relative to other NASH therapeutic development. So have you considered any potential in 1144 and perhaps medications and perhaps other patient populations that are closely correlated with NASH?
Dan, do you want to take that? Sure. That's a great thought. And it's really hitting at our underlining theory here that naturally the metabolic disease, there's a lot of inputs here. And our treatment is really pleiotropic in attacking many of these different inputs into what eventually leads to liver disease.
There have been a handful of studies looking at the types of testosterone in epigramidal men with diabetes, and they show improvement in insulin sensitivity. However, those are always interesting questions to look at down the line in terms of other possible indications. For the time being, for this 1144 asset, we are going to be focusing on NASH and liver disease.
Sounds good. And then perhaps one question for 1148. You mentioned survival headcount, obviously, that's a primary endpoint. You also found out liver therapy impacts as a key secondary endpoint. What are your expectations for this endpoint?
And can you just outline why it would say significant secondary endpoint?
Sure. I'll just correct you on one thing. The primary endpoint for this proof of concept study is actually change in muscle mass. So, a key secondary was overall survival. But as we said, another key secondary is this liver frailty index, which is made up of a 3 functional tests.
Let's this is one, for example, is the hand grip strength. So we'll be tracking the subject hand grip strength from the beginning week 1 through week 2 of the study and looking for changes in hand grip strength and the other 2 metrics as well to see if we're seeing an improvement in their functional status. I've got to rely on UCSF has done some really interesting work looking at what is really the best predictor in terms of clinical outcomes. Is it the whole mass measured by imaging or is it the functional capacity of the patients of the subjects? So with the imaging by CT scan, we're going to be looking directly at muscle mass, but we're also looking at a number of these functional outcomes to see if the muscle mass increase or muscle mass change correlates to changes in functional capacity.
Sounds good. Thank you again, Doctor. Patel and Doctor. Bruno for your presentation today. And we look forward to 1144 FDM severe Phase III design to be finalized with the FDA at the next really key endpoint and then 11.40 gs file progress throughout next year.
Thank you again. Thanks, Thomas.
Appreciate it. Thank you, Thomas. Appreciate it. Thank you, Thomas. Appreciate it.
Thank you,