Hi, everybody. Thanks for joining us today. We're here to talk about the Fazirsiran SEQUOIA top-line results and give an outline for what the phase III looks like. Thanks, all, for joining us this early in the morning. Next slide, please.
Just before we start, I want to make sure everybody knows that we will be making forward-looking statements, so please refer to our SEC filings for the risk factors. Next slide.
Today on the panel, we have Dr. Virginia Clark from the University of Florida, who's gonna talk about AAT and natural history of the disease, as well as some of the significance of the findings from the SEQUOIA study. Myself, I'm Vince Anzalone, the Vice President of Investor Relations, and Javier San Martin, our Chief Medical Officer. Slide.
Today we, as I mentioned, Javier is gonna speak about the Fazirsiran SEQUOIA top-line results. Dr. Clark will then provide some context about why this is important. Javier will go back into the phase III design, and then we'll give some concluding remarks. We know it's a busy day and a busy week, so we'll try to get through this as quickly as possible. Next slide.
I will turn it over to Javier.
Thank you, Vince. Slide. In alpha-1 antitrypsin deficiency, homozygous PiZ mutations in the SERPINA1 gene produces mutant Z protein that aggregate in hepatocyte as globules, leading to progressive liver disease and fibrosis. Fazirsiran, an investigational RNAi therapeutic, was designed to specifically degrade liver Z-AAT messenger RNA and reduce synthesis of the mutant protein. This mechanism allows the cellular machinery to clear existing Z protein, reduce global burden, halt liver disease, and reverse fibrosis. This next slide, I'll show you the SEQUOIA study design. Here is the study design for SEQUOIA, also known as the 2001 study. Patients with homozygous PiZ mutations were enrolled in a 2-to-1 ratio to receive Fazirsiran at either 25 mg, 100 mg or 200 mg or placebo.
At screening, 15 patients were assessed as having no liver fibrosis, and 25 were assessed as having fibrosis based on local reader evaluation. Patients without fibrosis received two doses of Fazirsiran at baseline and at week four and were followed for up to week 64. Patients with fibrosis received Fazirsiran at baseline, week four, and every 12 weeks thereafter. Among the 25 patients with fibrosis, a second liver biopsy was collected at week 48, 72 or 96. Most patients had their second biopsy at week 48. Paired liver biopsies for all 25 patients were centrally read and analyzed. Patients with fibrosis could then opt to continue open label Fazirsiran treatment for up to week 160. The primary input was change in serum Z protein at week 16 in order to select the dose.
We selected the 200 mg dose for the open label period and subsequent safety study. Here we report the results for our study week 48. Baseline characteristics show patients in their 50s and 60s with approximately 1/2 of them men. For inclusion criteria, all patients were homozygous for the PZZ mutation. Patients with fibrosis had paired biopsies that were subsequently reviewed and adjudicated by three central readers blinded to treatment, subject ID, and time point of the biopsy. Three patients initially deemed to have fibrosis, one each in the placebo, 25 mg and 200 mg treatment groups, were later assessed as having no fibrosis based on central grade. This show how variable assessment of fibrosis can be.
Fazirsiran treatment significantly reduced serum Z-AAT concentration in a dose-dependent manner with robust reduction after the first dose, ranging 62%-92% that was sustained over a year. At week 48, Fazirsiran re-reduced serum Z-AAT concentration by up to 94% compared with essentially no changes in the placebo group. Now we present the effect of Fazirsiran versus placebo on key histological feature of PAS-D global burden, inflammation, and fibrosis. Liver Z-AAT was reduced in the Fazirsiran group by a median reduction of 94% at week 48. In contrast, the placebo group had a median increase of 26%. PAS-D global, a hallmark feature of this disease, was reduced by 68% in the Fazirsiran group versus visually no changes in the placebo group.
Histological assessment of portal inflammation and fibrosis were characterized into one of three categories, at least one point improvement from baseline, no change from baseline, or at least one point worsening from baseline. The denominator for each category will vary based on each patient's baseline value. For example, patients with baseline score of zero will be ineligible for assessment for improvement. In the combined Fazirsiran treatment group, 5 of 12 or 42% of patients achieved an improvement of one or more point in portal inflammation versus 0% in patients on placebo group. 1 of 15 or 7% of Fazirsiran-treated patients experienced worsening in portal inflammation versus 5 of 9 or 56% in the placebo group that showed worsening in portal inflammation. Finally, 7 of 14 or 50% of patients in the Fazirsiran group experienced an improvement in METAVIR fibrosis score.
In the placebo group, three of eight patients, or 38%, had one point or greater improvement in METAVIR fibrosis. Improvement in fibrosis in the placebo group was higher than expected based on natural history data that approximately 15% of patients improve over a three-year period. Worsening in fibrosis was similar between groups, 25% and 22% in the Fazirsiran and placebo group, respectively. In this next slide, I wanted to show you side by side the active treatment group of the SEQUOIA study next to the 2002 study results that was published last year in The Journal. SEQUOIA and the 2002 study delivered consistency efficacy across all histological parameters. Liver Z-AAT was similarly reduced by 94% and 83% at week 48 in the SEQUOIA and 2002 study respectively.
At week 48, total global burden decreased similarly in both study active groups, 68% and 71% respectively. Portal inflammation also improved similarly in both studies, 42% in SEQUOIA and 69% in 2002. Importantly, the improvement in at least one point in METAVIR fibrosis was observed in 7 out of 14 or 50% of patients in both studies, confirming a substantial fibrosis regression in two different studies. Now let me summarize the safety findings. Safety results did not show any new safety signals from the previous study, with COVID-19 being the most frequently reported TEAE. There were no TEAE-related studies or discontinuation, dose interruption, or premature study withdrawals. Two serious TEAE were reported both in 200 million cohort, compared with three serious TEAE in the placebo group.
The two serious TEAE reported in the 200 group were exacerbation of bronchiectasis.
Slide. In summary, Fazirsiran reduced serum liver Z-AAT and histological global burden in all treated subjects consistent with previous studies. This was in contrast to placebo, which showed no change or a slight increase in all three measures of Z-AAT burden. At week 48, this results in improvement in portal inflammation in 42% of the active versus 0% of the placebo. Improvement in liver fibrosis in 50% of the active group versus 38% placebo. Placebo rate for improvement in fibrosis was higher than expected from natural history data, approximately 16% over a three-year period. Fazirsiran was well-tolerated. Pulmonary function test was stable and similar to placebo throughout the study.
With that, I'd like to pass the call over to Dr. Virginia Clark, who will talk to us about the natural history data and the significance of these results for patients with alpha-1 antitrypsin deficiency. Dr. Clark.
Thank you very much, Javier. It's my pleasure to talk to you guys today. Next slide.
First, I'd like to start by setting the stage for the natural history, studying natural history in alpha-1 antitrypsin deficiency. Alpha-1 antitrypsin deficiency is considered a rare disorder. This means that less than 200,000 individuals in the U.S. are actually diagnosed with alpha-1 antitrypsin disease, and that makes it a challenge to study when we're looking for to explain the natural history. It's a clear population with an unmet need for liver disease treatment. I show you a picture of the liver biopsy with the globules, with the accumulation of the toxic protein here. There are many undiagnosed but individuals who are affected in the excuse me. In the...
There are many individuals who are undiagnosed, the reasons for this are varied, likely because there is no treatment or therapy for individuals with alpha-1 antitrypsin deficiency liver disease. The other challenge in studying natural history in alpha-1 antitrypsin deficiency is that the data that we have comes from studies with small sample sizes, or selected patient populations, or from registry data without liver biopsies or complete data to use. Next slide.
What do we know about liver disease in individuals who are who have alpha-1? It's prevalent, the presentation is quite heterogeneous. Individuals who are affected with alpha-1 antitrypsin can be completely asymptomatic or can present with liver cirrhosis.
We sometimes will see an elevation in liver enzymes in this patient population, but our work and others have shown that this may or may not correlate with the severity of liver disease that is present. The best way to really de-define and determine what is, if liver disease is present, is with the use of a liver biopsy. There are three things that we look for on the liver biopsy to help us determine the severity of liver disease in alpha-1. The degree of portal inflammation, the accumulation of the toxic protein, in the polymer form, which can be measured directly or visually characterized by the globule, percent globules, and then the spectrum and the severity of liver fibrosis. As you've heard described previously. Using a liver biopsy obviously is an invasive procedure.
It puts a patient through a procedure that has some risk of complications, but it gives us the most data and the most relevant to understanding completely what is happening in the liver and in the response to therapy. The challenge that we have with liver biopsies is interpretation. Largely is interpretation of the liver fibrosis. There can be some variability in the reads between pathologists and inherently, the way I think of it is that individuals you're taking a, you're trying to categorize something into a single category that's likely on a continuous spectrum. Even within a single stage of F2, there may be someone who has an early F2 versus someone who is still an F2 but has more, a little bit more advanced fibrosis.
I think that can help explain a little bit of the variability in the fibrosis in the, in the individual reads. And that also can be overcome by having techniques in trials where you have pathologists read or adjudicate the presence of the fibrosis stage. Next slide.
What do we know? There have been several liver biopsy studies to look and define what the prevalence of liver disease is in alpha-1 antitrypsin deficiency, ZZ adults. We published a study in 2008 that biopsied 94 individuals with Z, ZZ alpha-1 and found that the prevalence of fibrosis was around two or greater in 35% of these individuals. Across multiple other studies, smaller or larger, you can see there's some variability in the prevalence, which is likely reflects the underlying patient population.
I think when I look at these numbers, I see consistently a prevalence in between 20% and 30% of what we would expect if we biopsied individuals, suggesting that these individuals with fibrosis are the patients who may progress to cirrhosis and are the appropriate patient population for therapeutic intervention. Fortunately, more advanced fibrosis was even a lower prevalence, but it was even up to stage three, and these were individuals that were completely asymptomatic and not known to have liver disease. That is the concern in individuals with ZZ alpha-1 antitrypsin, is that fibrosis will just silently progress and ultimately present with cirrhosis. Next slide.
What do we know about fibrosis progression? In our study where we biopsied a cross-section of 94 patients, we ended up re-biopsying 52 patients, so we had paired biopsies, and that let us give a clear understanding of what would... Of progression rates. What we found is over a period of three years, about 38% progressed by one stage or more. 46% had no change in fibrosis at three years. At, and we described about 15% that improved by one fibrosis stage. Now, this is the number, we you heard Javier mention about changes for improvement in fibrosis and in the SEQUOIA study, is that 38% had improvement.
Now, I can explain this. I think if you think about essentially what this data is showing you is that this is what a placebo arm would look like. This is a large number of patients. It's the best described kind of natural history data that is out there. When you compare this large group of patients with a much smaller group of only eight patients, I think that variability in the small number explains the difference in what was observed and what was expected in the study. Next slide.
Why do we, why do we, are we concerned about the natural history? Well, we understand that the natural progression in alpha-1, it's a, it's a bimodal distribution, the disease presents in childhood and then if it's not, if you're not affected then will present in adults.
Liver-related mortality is only second to pulmonary disease in terms of causes of death from alpha-1 antitrypsin deficiency affected individuals. What we know is that progression, there's very limited data looking at progression from fibrosis to cirrhosis. The most often quoted natural history study is a birth cohort in Sweden that was identified over 40 years ago that had been followed annually. In this cohort, no patient after childhood has been identified with clinical cirrhosis to date. They've reported that out to age 40. However, it's limited by no biopsies and not, and cirrhosis can often be asymptomatic. We still don't. There's to be determined on that data.
From our own data, at repeat biopsy, we saw that about 7% over a period of three years progressed from biopsy that were not cirrhotic on their initial biopsy that progressed. That's a fairly rapid rate of progression, at least in our cohort. What a therapeutic needs to do, a therapeutic intervention for alpha-1 is we want to interrupt this natural progression to prevent the complications related to liver disease. Next slide.
What are the overall significance of the Fazirsiran results? I think to me, highlights three things. The first is the consistency between the two studies of the overall reduction of that toxic accumulation of the Z protein in the liver.
The reason that this is so important is because multiple lines of data have shown that the accumulation of that toxic protein is the key to liver injury. In the pathogenesis, it sets off a series of events that cause progression of liver disease. If this type, if this drug can reduce the alpha-1 in the liver and reduce accumulation, then we can see what will happen. The second thing I'd like to highlight is that that Javier presented, is that there was a significant improvement in portal inflammation. The reason I think this is important is in our own natural history study, we showed that if portal inflammation, those who had worsening portal inflammation, their risk of fibrosis progression was much higher than those who did not.
The fact that the reduction of the accumulation of the Z protein translates into a reduction of portal inflammation, you can anticipate that we're gonna see improvement in liver histology overall. The final thing is that, although these studies were small and aren't really powered to look for improvements in liver histology, it was there. We saw that there was 50% in each study showed improvements in fibrosis stage. The limitations are we know that we have to have larger numbers of patients to really clarify this. We're gonna be stuck. We're gonna have to have a liver biopsy to look at the right outcome.
I think ideally what you see is that we're gonna. It needs to be targeted towards the individuals who have fibrosis so that we can identify improvement. Thank you very much.
Thank you, Dr. Clark. I'd like now to finish the presentation presenting high level the Takeda Fazirsiran registration phase III study design. This is going to be a randomized, double-blind, placebo-controlled, parallel-arm, multicenter study. The indication will be patient with PiZ alpha-1 antitrypsin deficiency associated liver disease. They aim to enroll about 160 subjects with F2, F3, and F4 METAVIR fibrosis at baseline. The primary endpoint will be the decrease from baseline of at least one stage in histological fibrosis METAVIR staging in the central liver biopsy F2 and F3 done at week 106. The dosing regimen will be a baseline of day one, week four, week 16, and then every 12 weeks thereafter, up to week 196 or four years, with liver biopsies at week 106 and 2,002.
The interim analysis, the first one or the first interim analysis is safety assessment at week 52 for safety to allow possible pulmonary inclusion and safety monitoring adjustment. Second, the interim analysis is the primary analysis after all F2 and F3 reach week 106 for safety and efficacy. With that, we conclude this part of the presentation. I will turn the call over back to Vince Anzalone . Thanks.
Thank you, Javier San Martin. Thank you, Dr. Clark, for joining us today, and everybody at home. We are really excited about these results and so are our partners at Takeda. What was really heartening here is that all of these results are consistent with what we saw in the open label study, which was really exciting for us. Thanks to the patients and the investigators that participated. Also I wanted to just flag that our CEO, Chris Anzalone, will be speaking later this morning at J.P. Morgan Healthcare Conference. I hope you all can take a look at that on our website. Thanks very much, and we'll talk to you soon. Have a great week, everybody.