Hello, I'm Carlos Prime, a clinical and biochemical geneticist, and I will be talking today about Cerdelga and Liglustad capsules, the only first-line oral therapy for most adults with Gaucher disease type 1, indicated for long-term treatment of both naïve and switched patients. What is Gaucher disease? Gaucher disease is an autosomal recessive disorder caused by deficient activity of the lysosomal enzyme acid beta-glucosidase, GbA1, resulting in progressive accumulation of the substrate, which is glucosyl ceramide, Gl1, mainly in macrophage. This lipid-laden macrophage you can see in the picture, also called Gaucher cells, start accumulating in the bone marrow and spleen, leading to manifestations, visceral, hematological, and skeletal, which are debilitating to patients. This is a progressive, lifelong disease that can go undiagnosed for as long as 10 years. Now let's review the mechanism of action for treatment of Gaucher disease. So ceramide with glucosyl ceramide synthase activity helps build glucosyl ceramide, or Gl1. Patients with Gaucher disease have a deficient activity of acid beta-glucosidase, which leads to accumulation of Gl1. Enzyme replacement provides or replenishes that acid beta-glucosidase activity that is missing in patients, improving degradation of glucosyl ceramide, especially in the cells that are monocyte macrophage lineage. Now substance reduction therapy blocks the activity of glucosyl ceramide synthase, decreasing the accumulation of glucosyl ceramide that we see in patients with Gaucher disease. Now let's review indications and usage. So Cerdoga, a legal stat, is indicated for the long-term treatment of adults, patients with Gaucher disease type 1 who are CYP2D6 extensive, intermediate, and poor metabolizer as detected by an FDA-clear test. Limitations of use include patients who are CYP2D6 ultra-rapid metabolizers because they may not achieve adequate concentrations of Cerdoga to achieve a therapeutic response. A specific dosage cannot be recommended for those patients who CYP2D6 genotype cannot be determined. So we call this indeterminate metabolizers. There are contraindications for Cerdoga based on the CYP2D6 metabolizer status due to a risk for cardiac arrhythmias for prolongation of the PR, QT corrected, and QRS intervals. Patients that are extensive metabolizers who are taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong CYP3A inhibitor, extensive metabolizers with moderate or severe hepatic impairment, or extensive metabolizers with mild hepatic impairment and taking a strong or moderate CYP2D6 inhibitor. Intermediate metabolizers who are taking a strong CYP2D6 inhibitor concomitantly with a CYP3A moderate inhibitor or a strong inhibitor, intermediate metabolizers who are taking a strong CYP3A inhibitor or intermediate metabolizers with any degree of hepatic impairment should not take this medication. Poor metabolizers taking a strong CYP3A inhibitor or any degree of hepatic impairment will also be contraindicated. Now warning and precautions, Serdelga is predicted to cause increases in ECG intervals, PR, QT, and QRS intervals, and substantially elevate plasma concentrations that may increase the risk for arrhythmias. So use of Serdelga is contraindicated or to be avoided or requires those adjustments in patients taking CYP2D6 or CYP3A inhibitors depending on CYP2D6 metabolizer status, type of inhibitor, degree of hepatic impairment, and we should avoid use of Serdelga in patients with pre-existing cardiac disease, such as lung QT syndrome, or combination with other class 1A or class 3 antiarrhythmic medications. Now in this slide we can look at information about Serdelga. This is a small molecule, it's a specific inhibitor of the GL1 synthase, and it acts as a substrate reduction therapy for Gaucher disease type 1 by decreasing the production of glucosylceramide of GL1. The Serdelga has been studied for a long-term use in patients who have never been on ERT and patients that are switching from ERT to oral therapy. Now more than 10% of patients have experienced adverse events including fatigue, nausea, headaches, diarrhea, back pain and extremity pain, and upper abdominal pain. This is a non-invasive oral prescription therapy and patients that can switch to Serdelga can start medication as little as 24 hours after the last infusion dose. Now let's talk about clinical trials. So Serdelga is the largest clinical trial program performing Gaucher disease. About 400 patients participated from 29 different countries. These two studies engage and encourage, engage focus on patients that were treatment naive and encourage patients that were switching from ERT to oral therapy. This presentation will make emphasis on safety and efficacy from these two clinical trials. Let's first review the Engage Treatment Naive trial. So this is a phase 3 study which is multi-centered, double blind, placebo control, 40 patients were enrolled, 20 patients on each arm, patients have a median age of 30 years, and patients on the Serdelga group were primarily extensive metabolizers, but we have some that were intermediate and some that were ultra-rapid metabolizer. Those was based on drug levels in plasma testing. Now the endpoint of this study was at 9 months and the primary endpoint was the spleen volume in multiples of normal from baseline to 9 months. Secondary endpoints include liver volume and hematological parameters, hemoglobin, and platelet counts. Once patients completed this initial analysis phase, they had the option to go into an open-label extension. 39 patients of the 40 patients entered this extension phase and they were on Serdelga and during this open-label phase, at 2 years, we looked at the outcomes of the same organ parameters and visceral parameters and hematological parameters, and some patients contributed up to 4.5 years of data. Now let's look at the spleen volume and liver volume changes in this slide. And also you can see at the bottom that both groups have similar spleen volumes and liver volumes at baseline. We can see on the blue line that Serdelga had a 28% reduction of the spleen size at the 9-month mark compared to increased 2% in the spleen volume for patients in the placebo arm. And in the liver volume, we also see a similar reduction of 5.2% in the Serdelga group compared to an increase of 1.4% in the placebo. These two measurements were statistically significant. Now when we look at other parameters, in this case hematological, the absolute hemoglobin, also in blue, you can see an increase of 0.7 grams per deciliter in the Serdelga group versus reduction in the placebo group, and in platelet counts a similar pattern of increased platelet count, 32% for the treatment arm on Serdelga versus the treatment arm on placebo. Again, the baseline parameters were very similar on these two treatment groups. Now let's look on the open label extension phase. So in two years, which more patients contributed data, we still continue to see a reduction on the spleen volume with 51% reduction from baseline, and you can see this reduction is maintained up to four and a half years, although we should be cautious to interpret this data because there's not as many patients as in the two-year mark. Similarly, we have a 16% reduction in the liver volume in the patients that went into the open extension, and this is maintained at four and a half years. Looking at hematological parameters in this slide, we can also see that there's a sustained increase in the absolute concentration of hemoglobin, an increase of 1.3 grams per deciliter in the Serdelga patients in the open label at two years, and similarly, 65% increase from baseline at two years on the patients on the open label extension phase. Now again, these measurements are maintained through four and a half years, but again, we should be cautious since there is less patients participating or contributing information at this time point. Now let's look at adverse reactions. So this occurred more frequently than in the placebo groups, over 10% of patients, and the most common reactions included arthralgia followed by headaches, migraines, flatulence, nausea, and oropharyngeal pain. Now, serial patients discontinued Serdelga due to adverse reactions during this primary analysis period, and there were no new signals detected during the open label phase of this study. Let's review this phase two open label trial in treatment naive patients. The primary endpoint of this trial was to look at a composite of two out of three efficacy parameters, looking at spleen, hemoglobin, and platelet counts. At 52 weeks, so one year of therapy, we can see at the bottom of this slide, the inclusion criteria that include diagnosis of Gosha disease, adults, patients with splenomegaly over 10 multiples of normal, and thrombocytopenia and anemia. 26 patients entered this first year of analysis phase. Six patients withdraw due to different situations. Two patients have adverse events that were asymptomatic, non-sustained ventricular tachycardia on day one. Three due to pregnancies, one due to an adverse event of a bone lesion that retrospectively was identified at baseline. 20 patients actually entered that trial extension phase, and one patient withdrew because their study site amendment was not approved to extend the trial beyond two years, and 19 patients completed the trial after eight years of therapy. Dosing was done based on plasma levels, 1,500 milligrams of eliglustat, which are equivalent to 42 or 84 milligrams of Celedelga for this study. The characteristics, the demographics of these populations are stated on this table, and we see a similar profile in all patients that participated in the trial versus the patients that completed the trial. Very well distributed in terms of male and female ethnic distributions. Age, very similar, 34 in both groups. Age of diagnosis also very similar, and when we look at severity in terms of hemoglobin, platelets, spleen, and liver volume, these are very comparable groups. And you can also see the CYP2D6 metabolizer status, which for both groups, the most common was extensive. Now, in this study, the treatment naive patients, they continue to look at outcomes over four years and up to four years in some patients to make sure they were meeting the liver, spleen, and hematological parameter outcomes. Now, in this slide, we can look at the analysis of these outcomes at eight years on Celedelga, and we can look on gray baseline data versus blue after seven and a half to eight and a half years of treatment. Again, we should be cautious because the numbers are not as high, but we can see in this slide there is a response in all participants that were on treatment. And also when we stratify the analysis based on spleen size over 15 multiples of normal and also liver over 1.25 multiples of normal. And similarly for hemoglobin and platelets, we stratify them based on severity, moderate and to severe anemia versus no anemia to mild anemia. And again, looking at the absolute change of hemoglobin numbers and similarly for platelet counts when they're also stratified based on less than 60,000 and over 60,000. Let's move now to the NCORE trial, which is the SWITCH study. This was an open-label, multi-center, active control that look at non-inferiority. Basically, we define a set of composite endpoints that include the four domains, hemoglobin, platelets, spleen, and liver volumes. And we look at 12 months if these are maintained in the two groups, Sardelga versus imiglucerase. This study patients were randomized two to Sardelga, one to imiglucerase. And as you can see, there is a good distribution of extensive intermediate and poor metabolizers. And we also know what therapy patients were prior to going into this trial. Most patients were imiglucerase followed by belaglucerase alpha, and then 4% of patients did not report the specific therapy they were on. Now, the endpoints basically were evaluated individually and as a composite score for this primary analysis phase. And when this was completed, patients were offered the opportunity to be in the open-label phase. So 152 patients of those 159 patients were able to participate in the extension phase. And again, we look at the similar outcomes at two years, and some patients contributed data up to four years. Now, let's look at what was the outcome of this NCORE trial. And basically there was no clinically meaningful difference in between patients receiving Sardelga versus patients on imiglucerase based on those predefined endpoints. So what this means is that patients with in the Sardelga group, 85% of them met those pre-specified criteria compared to 94% of the imiglucerase group. And because this difference was less than 25%, this was considered a non-inferior therapy. But let's look at the absolute numbers more in detail. So we can see on this slide, the visceromeganly numbers, so spleen volume and liver volume. And we can see that in Sardelga in blue, you can see a 6.2% reduction in spleen volume at 12 months. And this is very similar to imiglucerase with a reduction of 3% in yellow. And in liver also, the difference is very similar, 1.8% increase in volume for liver in Sardelga, but a 3.6% also increase with imiglucerase. So these numbers are very stable and very comparable in the two therapies. Now for hematological parameters, we have a similar behavior. There's an initial decrease with Sardelga at three months, but at six, nine, and 12 months, this difference is closer to baseline. So the absolute change was 0.2 grams per deciliter in the Sardelga group versus no change with imiglucerase in this parameter. Now, when we look at platelet counts, we see a similar increase in platelet count, 3.8% in Sardelga versus 2.9% increase on imiglucerase. Now, when patients went into the open label phase, we look at two years and four years for the patients we have data. And this in-court trial, we look at this numbers, the spleen and liver volume are maintained at two years. And similarly for the patients that contributed to four years, these numbers are maintained as well. And this points to that goal of non-inferiority for this trial. Similarly for hemoglobin, we can see at two years is maintained. Four years, there's also an increase in the absolute amount of hemoglobin. In platelet count, you can see a similar distribution that is stable at two years, and then a slight increase at four years. So again, the data for years, we have less patients. Now, let's talk about adverse events and reactions during this primary analysis period, comparing Sardelga versus imiglucerase. And they were much more common in the Sardelga group. Over 5% of patients experienced more frequent side effects when they were switching from imiglucerase to Sardelga. Two patients, 2% for this trial, discontinued the medication due to adverse events during this primary analysis, but there were no new safety signals observed during the open-label extension phase. When we look at the adverse reactions, the most common was fatigue, followed by headache, nausea, diarrhea, back pain, extremity pain, and upper abdominal pain. Now, we also have other adverse events, including dizziness, asthenia, cough, dyspepsia, gastroesophageal reflux, constipation, palpitations, and rash. And you can compare the frequency against imiglucerase in this slide. Let's review safety profile and dosing information. Sardelga is contraindicated in the following patients based on their CYP2D6 metabolizer status due to risk of cardiac arrhythmias for prolongation of the PRQT-corrected and QRS cardiac intervals. Now, drug interactions are important. So, illegal stat is a CYP2D6 and a CYP3A substrate. So, drugs that inhibit this CYP2D6 and CYP3A substrates may significantly increase the exposure of illegal stat, and this can increase the risk for cardiac arrhythmias for prolongation of PRQT and QRS cardiac intervals. Sardelga may be contraindicated, or modification of sardelga dose may be needed for those patients that have that specific metabolizer status. Illegal stat is also an inhibitor of P-glycoprotein in addition to CYP2D6. So, co-administration of sardelga with drugs that are substrates for this may result in increased concentration of that specific drug. Now, this table, which you guys can refer to the prescribing information, provides details about drug interactions based on extensive intermediate and pre-metabolizer status. So, I'm gonna highlight that patients that are taking CYP2D6 inhibitors, either strong or moderate, with a strong CYP3A inhibitor, should not be on sardelga regardless of your metabolizer status. Now, in this table, you see a lot of different combinations of when the medication is contraindicated or when it's possible to do, but avoiding co-administration with the sardelga dosing. There are also examples of different inhibitors, such as strong CYP2D6 inhibitors, such as paroxetine, which you have to decrease the dose of extensive metabolizers and intermediate metabolizers to once a day from the original prescription of twice a day. But as you can see for poor metabolizers, you don't have to change your prescription, will continue to be once daily. And we also have CYP3A inhibitors that should be contraindicated for patients that are poor metabolizers and intermediate metabolizers, and drug can be reduced in extensive metabolizers. So, this table, which is available in your prescribing information label, for sardelga will help you make that decision about drug interactions, drug modifications, and if the medication is contraindicated. Now, we should also be aware of the P-glycoprotein and other CYP2D6 interactions. So, digoxin, which is a well-known P-glycoprotein substrate, patients should measure drug concentration for digoxin before starting sardelga and consider reduction at 30% of digoxin and monitor levels if they are taking sardelga to avoid side effects. There are P-glycoprotein substrates I mentioned in this slide, and you should be aware of that. And then we have other CYP2D6 substrates such as metoprolol, tricyclic antidepressant, and other medications, which you should also monitor drug levels and not just dosing based on clinical effect and also preventing potential drug interactions and side effects. Again, you guys can refer to the prescribing information for the sardelga. Now, let's look at preexisting cardiac conditions. So, there are some specific populations that should be aware. So, sardelga is predicted to increase ECG intervals, so can elevate plasma concentration. So, patients that have preexisting cardiac conditions, we should be aware of this. Patients with long QT syndrome and patients that are on class one or class three, eight antiarrhythmics. Pregnancy and lactation, we have some data from the clinical trials and post-marketing case reports, but this is limited to really be able to make any recommendations and to know the risk for fetal outcomes with this medication. Based on animal data, we know sardelga may cause fetal harm and we know it may be present in human milk. So, the decision about this during breastfeeding should be, we should have good consideration of benefits of breast milk for an infant and also decide about benefit of therapy for the mother. So, patients with renal or hepatic impairment, we should be aware of the metabolizer status because based on this, will be contraindicated or not. And also based on other medications they are taking, this could also be modified risk or contraindicated as well. And we don't have a pediatric safety data, so this medication is only approved for adults. And if you suspect a reaction to sardelga, please contact Sanofi Medical Information at the number in this slide and dial option number two. Now, we have learned today that sardelga is prescribed based on the metabolizer status. So, extensive and intermediate metabolizers should be those 84 milligrams twice daily, unless we have a drug interaction or another modifier as we have learned throughout the day. And patients that are poor metabolizers should be those 84 milligrams once daily. Now, sardelga is approved for both treatment naive and patients that want to switch from enzyme therapy. Patients can switch as soon as 24 hours after their last infusion dose. And dosing, again, is based on that metabolizer status, renal or hepatic impairment, pre-existing cardiac disease, and potential drug interactions. Now, recommended administration, so this should be taken as a whole capsule, can be taken with or without food. You should avoid grapefruit or grapefruit juice because this also interacts with the CYP pathway. And patients should avoid, if you miss the dose, you should just wait for the next dose the following day. You should not double the dose of the medication. Now, as we learned from the trials and most of the population is extensive metabolizer, most patients will be eligible for therapy with sardelga based on their metabolizer status, over 90% based on population estimates. Now, this testing is available at no cost to your patients throughout a sponsor-funded program by Genzyme and LabCorp, which has over 1,700 locations throughout the U.S. This is a blood test. Results are available in two weeks. And these are sent to your doctor who actually will communicate this to the patient. Now, if you have any questions about how to access this test, there's information here about Sanofi phone numbers and how to contact for additional information. Now, let's make a summary of this presentation. So, sardelga is the first-line oral therapy for adults with Gaucher disease who are either treatment-naive or they are switching therapy from enzyme therapy. In this presentation, we look at the data from N-GAGE trial, which look at patients that were treatment-naive and look at outcomes of hematological and visceral parameters. And also, we look at data from the NCORE trial to look at disease stability and switching from enzyme therapy to the oral therapy. Now, let's review one more time indications of sardelga usage and limitations. So, sardelga is indicated for patients with Gaucher disease type 1 who are CYP2D6 extensive intermediate and poor metabolizers defined by FDA clear tests. And use is not limited to patients that are ultra-rapid metabolizers for CYP2D6 because they may not achieve adequate levels of sardelga to have a therapeutic effect. In patients that can not be recommended dosage because of the CYP2D6 metabolizer status is indeterminate. Thank you.

Cerdelga

Liglustad

Gaucher disease type 1

enzyme therapy

clinical trials

safety profile