Welcome, ladies and gentlemen, to the CRISPR Therapeutics Clinical Update conference call. At this time, I would like to inform you that this call is being recorded and that all participants are in a listen-only mode. At the request of the company, we will open up the call for a question period at the end of the presentation. I would like to introduce Susan Kim, CRISPR Therapeutics' Vice President of Investor Communications. Please go ahead.
Good morning, and thank you for joining us as we report results from our ongoing studies of CTX001 for the treatment of beta and severe sickle cell disease. Joining me this morning are Sam Kulkarni, Chief Executive Officer, and Tony Ho. We recommend that you access the webcast slides on our website as you listen to this call. This call is recorded and a replay will be available on our website. During today's call, we will be making certain forward-looking statements. These statements may include statements regarding, amongst, the efficacy and safety of our product candidates, our research and development plans, regulatory plans, and our report additional data. These forward-looking statements include current information, assumptions, and expectations that are subject to change and involve risks and uncertainties that may cause actual results to differ materially from those contained in the forward-looking statements.
These and other risks are described in filings made with the SEC, including our quarterly and annual reports. You are cautioned not to place undue reliance on these forward-looking statements, which are only made as of today's date. The company disclaims any obligation to update such statements. With that, I'm pleased to turn the call over to Sam Kulkarni, our CEO, who will make some introductory remarks.
Thank you. Good morning, and thank you all for joining us today. Earlier this morning, we reported the first clinical results from two patients with severe hemoglobinopathies, CTX001, a CRISPR-Cas9-based investigational therapy that we are developing together with Pharmaceuticals. This is a significant milestone for our company as well as the entire field, the first report of clinical data from a company-sponsored trial of a CRISPR-Cas9-based therapy. Less than a decade ago, when CRISPR-Cas9 was discovered by our scientific founder, Dr. Emmanuelle Charpentier, it was immediately recognized as a revolutionary technology, it was not known how it would benefit human health. Today, we show that this promise is becoming a reality. The results so far indicate that CTX001 has the potential to be a curative approach for sickle cell disease and beta thalassemia. Our Head of R&D will now go through a brief presentation of the data.
Thank you, Sam. Sickle cell disease and beta thalassemia are severe genetic disorders that affect hemoglobin, a protein in the blood responsible for transporting oxygen throughout the body. Millions of people worldwide have hemoglobinopathies, and they result in significant morbidity, a heavy burden of care throughout life, and reduced life expectancy. There are very few disease-modifying approaches available to treat these disorders, and a functionally curative approach using gene editing could have an enormous impact for these patients. We are aiming at making a single genetic edit in the blood-forming stem cells of the patient using CRISPR-Cas9. We carefully designed this edit to increase levels of fetal hemoglobin, a protein that can substitute hemoglobin that causes both sickle cell disease and thalassemia.
As shown on slide three, this approach is supported by decades of studies of rare patients who have naturally high levels of fetal hemoglobin that prevent disease symptoms without any harmful side effects. In fact, at the level completely asymptomatic. We are using CRISPR-Cas9 to mimic these protective genetics for those who are not so fortunate as to have them occur naturally. Over the past several years in our research labs, we screened numerous ways of using CRISPR-Cas9 to increase levels and finally selected CTX001 as our lead candidate. As shown on slide four, this approach makes a single double-stranded break in a non-coding region of the BCL11A gene, which is known to regulate fetal hemoglobin levels, specifically in red blood cells. In this manner, we enhance fetal hemoglobin production to protect against these diseases.
As slide five shows, we have taken this approach into the clinic at multiple sites worldwide through our Phase I/II CLIMB trials. CLIMB-111 treats adult patients with transfusion-dependent beta thalassemia, and CLIMB-121 treats adult patients with severe sickle cell disease. The primary endpoint for the thalassemia trial is reduction in transfusion burden, whereas the primary endpoint for the sickle cell is the level of fetal hemoglobin produced. Slide six demonstrates the treatment approach, which is similar in the two trials. Both occur in the context of an autologous stem cell transplantation. A patient's stem cells are collected and shipped to our manufacturing facility, where they are edited at the target locus using CRISPR-Cas9. They are then frozen and shipped back to the treatment center for editing before the edited cells are infused.
Once the edited cells engraft successfully and reconstitute the patient's blood system, a process that typically takes three to six weeks, the patient can be discharged with periodic follow-ups. On slide seven, we transition to the clinical data on the first patient treated. The patient had transfusion-dependent beta thalassemia of the beta zero/IVS-I-110 genotype and a significant transfusion burden requiring an average of 16.5 transfusions per year. Following infusion, the patient had successful engraftment at days 33 and 37, respectively. The safety profile for this patient was consistent with busulfan conditioning, and there were no adverse events considered related to CTX001. Serious adverse events occurred during the post-transplantation neutropenia period and were not considered related to CTX001. The patient experienced veno-occlusive disease of the liver that was attributed to busulfan conditioning, both of which subsequently resolved.
On slide eight, you can see that following CTX001 infusion, the patient demonstrated a notable increase. The fetal hemoglobin level began to rise at month two and increased to stable level above 10 gram per deciliter by four months post-infusion. The last blood transfusion for this patient was at one month post-transplant. As expected, the transfused hemoglobin A declined from this point to a level less than one gram per deciliter. The patient has maintained total hemoglobin levels above 11 without transfusions, suggesting that the increase in fetal hemoglobin is sufficient to eliminate the need for transfusions. The patient started phlebotomy and iron chelation at three and six months post-transplant in order to address the residual iron overload caused by the disease. Slide nine shows the red blood cells in this patient demonstrate a highly pan-cellular expression of fetal hemoglobin.
9.8% of cells positive for fetal hemoglobin at 9 months post-transplantation. Overall, these data suggest that this patient, who previously required more than one transfusion per month and is similar to a beta zero, beta zero patient, has now achieved transfusion independence due to the treatment with CTX001. On slide 10, we transition to data on the patient, who at the time of consent was a 33-year-old woman with severe sickle cell anemia and who had a historical rate of seven severe vaso-occlusive crisis, or VOC, per year. The patient successfully achieved engraftment at day 30 after CTX001 infusion. The safety profile for this patient was also consistent with busulfan conditioning. There were three serious adverse events: sepsis, cholelithiasis, and pain. All have resolved and were not considered related to CTX001. Slide 11 shows that this patient also demonstrated a notable hemoglobin in the months following transplantation with CTX001.
Prior to infusion, the patient received exchange transfusion, which reduced the level of sickle hemoglobin from 74% at baseline to 0% post-transplantation. These transfusions were stopped at approximately two weeks, subsequently, the transfused hemoglobin A has decreased steadily. At four months post-transplantation, fetal hemoglobin represented 46.6% of total hemoglobin. The total hemoglobin in this patient significantly from baseline level 7.2 to 11.3 gram per deciliter at four months post-transplantation. There have been no VOCs reported in the four months following transplantation. The percentage of cells expressing fetal hemoglobin has increased steadily post-transplantation to 94.7% at four months and is continuing to increase.
We believe that this pan-cellularity of fetal hemoglobin is highly desirable, since it may ensure that the vast majority of red blood cells are prevented from sickling. To summarize on slide 13, we have reported initial clinical data on the first two patients, one with beta thalassemia and one with sickle cell disease that have been treated with CTX001. The profile we observed is consistent with myeloablative busulfan conditioning, and successful engraftment was achieved in both patients. The patient with beta thalassemia required transfusion prior to treatment and has now been transfusion-free for approximately eight months. This is likely due to the high levels greater than 10 gram per deciliter of fetal hemoglobin being produced due to the CTX001.
Similarly, the patient with sickle cell disease has experienced no VOCs in the first four months after treatment, compared to a baseline rate of seven per year, likely due to the 46.6% fetal hemoglobin being produced due to CTX001 treatment, which is far more than our primary endpoint target of 20%. While early, these data demonstrate that CTX001 is a promising approach to treating these severe hemoglobinopathies. I will now turn the call back to Sam.
Thank you, Tony. We and Vertex Pharmaceuticals are very encouraged by this first set of clinical data for our CTX001 program. While these data are early, they show that this could be a one-time curative therapy for patients suffering from sickle cell disease and beta thalassemia. This is a major landmark for CRISPR and highlights the potential for gene editing to provide cures for serious diseases. We would like to acknowledge our colleagues at Vertex Pharmaceuticals for their close. Above all, we would like to thank the patients, their families, and the investigators who've had the courage to participate in this groundbreaking clinical research. We will now turn to your questions. Operator?
Certainly. We will take our first question from Salveen Richter with Goldman Sachs. Please go ahead.
Great. Thank you for taking the question. Congrats on the data here. For both patients, can you just walk us through the time course of the reported SAEs and how long after the preconditioning treatment was the sepsis reported in the sickle cell disease patient? Even if these events occurred prior to transfusion of CTX001. I have a follow-up.
Thanks for the question. I think, overall, the safety profile that's observed in both the thalassemia and sickle studies have been consistent with what you expect for an autologous stem cell transplant. None of the serious adverse events were considered related to 001. The more important point broadly is from a risk-benefit standpoint, given the tremendous benefits that these therapies offer, there's significant enthusiasm with the risk that you have with autologous transplants. I'll also ask Tony Ho, our Head of R&D, to make comments and answer questions on the AE.
Yeah, the AE we observed is typical for busulfan conditioning, and we're working with centers that will manage these side effects.
Great. Do you guys have any data here on the proportion of biallelic editing that you guys observed, and the % of RBC HbF? Is this correlated with increasing the lifespan of the RBCs?
Yeah. It's a good question. I think we do measure, as we dose these patients, we have to measure the editing rates in the drug product, but also in the periphery over a time course. At this point, we have not disclosed the allelic editing rate. I think what's very encouraging is the level of, or the percent, nearly all of the cells have fetal hemoglobin in there, and the pan-cellular expression of fetal hemoglobin is very important for disease amelioration from a pathophysiology standpoint. That is a very high number in terms of the F cell.
Our next question will come from Ted Tenthoff with Piper Jaffray. Please go ahead.
Great. Thank you. Question on patient numbers. Why two, and maybe you can give us a sense of additional enrollment, where it stands in the two studies. Thanks.
Thank you, Ted, for the question. There has been significant enthusiasm for the studies, and we have enrolled a number of patients in both studies and actually manufactured drug products for a number of patients. At this point, we have data for one patient each in each of these trials. Given how compelling the data are, we thought it was the right thing to do to release the data now for one patient each in each of these trials. We're quite excited by the data. In a few months and a year, we expect to enroll rapidly and dose patients rapidly to get to a reasonable cohort in each of these trials and look forward at a medical conference next year.
Our next question comes from Maury Raycroft with Jefferies.
Hi, everyone. Good morning, and congrats on the update today. Thanks for taking my questions, too. Just wondering if you can contextualize these patients' baseline characteristics, including their VOC and transfusion needs, and potentially how this compares to what we've seen with competitor programs.
Thank you. I think both of these patients that have been dosed with CTX001 had a serious disease. In the thalassemia trial, the significant transfusion burden prior to coming into the trial, nearly 16 transfusions per year on an annualized basis. The mutation that we look at non-beta zero, it's a beta zero IVS-I-110 mutation, which means that they had very low baseline hemoglobin, beta globin that's being produced. Even in this patient with severe disease burden, we saw in terms of fetal hemoglobin being produced, and we see nearly 10 grams per deciliter of fetal hemoglobin and a total hemoglobin level that's above 11. I think that's very encouraging for us to see that in a patient in thalassemia that's suffering from a serious disease type that we've treated.
We obviously disclosed earlier that we have now expanded the trial to beta zero patients and look for patients into the CLIMB-Thal-111 trial. On the sickle cell disease side, the patient again came in with significant disease burden with a number of VOCs, at least seven VOCs per year on an annualized basis before coming into the study. For this patient, what we see, while the data are early at the four-month mark, we see that there is a significant proportion of fetal hemoglobin. Very important ratio to understand in the sense that fetal hemoglobin acts as an anti-sickling globin. With 46% fetal hemoglobin, you're seeing a very high proportion of anti-sickling globin cells and a high pan-cellularity. We've also seen that the patient has not had any VOCs since being infused with CTX001, which is a very encouraging sign.
We obviously hope to follow up on these patients for an extended period of time. At this point, what we see is very encouraging and has the promise of providing a one-time functional cure for these patients.
Our next question will come from Sylvain Tourkian with Oppenheimer. Please go ahead.
Thank you. Congrats on this very early data set, and thanks for taking my question. I just wanted to know in terms of continued trial execution, are there any more DSMB hurdles that you internally have before you dose the next patient or several patients?
I think the way the trials are designed, I think in each of these trials, the idea is to dose the first two patients serially, and once you make sure that these patients have safely engrafted with their drug product, then you can open up for a parallel number of sites. We hope to get to that point soon after dosing two patients in each trial and then expanding in parallel across a number of sites that are all excited about this trial and are well-qualified to undertake a trial like this, such as this.
Great. Could you please quantify the baseline hemoglobin, total hemoglobin levels of these patients? Were they in line with the typical patient or not?
Thalassemia context, the baseline hemoglobin, it's a tricky one to say what the number is because they get continuous transfusions. What you're seeing in the baseline level of hemoglobin is the RBCs from the transfused blood. What we do know is that for the genotype that we've seen here, which is a beta zero/IVS-I-110 genotype, they're producing very low baseline beta globin. They essentially behave like a beta zero patient. In that context, I think what we see in terms of the fetal hemoglobin being produced from our CTX001 drug is quite encouraging, and the fact that every liter at a sort of slow and steady points to a durable effect. I think that's a harder one to quantitate. I think on sickle cell, again, you do produce on a baseline level, a lot of sickling globins that's being produced.
I think what we see is what's important from a disease mechanism standpoint is the ratio again of the sickling to anti-sickling globin. At this point, more anti-sickling globin or fetal hemoglobin than the endogenous sickling globin.
Our next question will come from Gena Wang with Barclays. Please go ahead.
Thank you for taking. First, wanted to congratulate you on the data. It was really impressive. The first question is, Sam, regarding the editing efficiency, it is fair to say that it's still consistent with what we have seen so far with the cell line system, which usually is over 90%?
Yeah, I think, thank you, Gena. We're obviously very pleased and excited about the data. The editing rates, we'll continue to measure for all the drug products we make, then we'll also measure the editing rate that you observe in the periphery as well as the bone marrow, we look forward to updating you on data regarding medical conferences. That said, I think what we observe are relatively high editing rates in our drug product consistent with what we've shown with our preclinical data before we filed our IND and our CTA application. Our platform is very facile and allows for an easy scale-up into manufacturing, you continue to see those sort of consistencies at a patient scale. We run those manufacturing processes over time to make it even better than what we've seen in the past.
As we have more experience with patients, we continue to apply those lessons into our process development and manufacturing.
Next question from Ravi Mehrotra with Evercore ISI. Please go ahead.
Hey, thanks for taking my question. Sam, it was a surprise. I'm going to ask you a pretty big-picture question. Congrats on this in the ex vivo editing setting. Just take us through your thoughts on the transferability of today's data to other settings.
Yeah. Thank you, Ravi. As I opened the remarks, I said it's a landmark moment for us, not just for the hemoglobinopathies program, but for the rest of our portfolio as well. I think if you think about our portfolio at CRISPR Therapeutics, it's been a learning from the CTX001 product in terms of a simple edit and doing ex vivo editing in an autologous setting to then transfer that and learn from that into our immuno-oncology products, where we have more complex edits, like setting and beyond that into Regen Med, where we have a program against type 1 diabetes, where we have even more complex edits.
I think these early data, obviously tremendous promise for hemoglobinopathies, but they in some ways foreshadow what we're trying to see and expect to see with our immuno-oncology and our Regen Med products as well in terms of the manufacturability and ultimately the ability to dose these safely in patients. We're quite excited for the rest of the ex vivo portfolio as well. Overall, I think it does say that this heralds the coming of gene editing and a new type of therapy into medicine, which would apply into in vivo as well in the long run.
Got it. Thank you. Congrats again.
Great. Thank you.
This does conclude today's program. Thank you for your participation. You may now disconnect.