This section is about me taking actual clinical data readouts and breaking them down. I will take screenshots of key sections of the data release and explain what it means. I will use my understanding of the science I focus on to show you how to evaluate data. The key is to then take that data and compare it to other competitors and the current standard of care. Any data read out can look good on its own. Then it has to be put into context to know where the data fits into the competitive landscape. I focus on Oncology and Genetics mostly so that is the kind of data you will learn about here. The key to learning to read any data is to figure out what the key measurements are for any indication. Oncology has its own like Overall Survival and RECIST response rates. In the same way Immunology or CNS indications have their key tests. The other important part is to ensure the trail design is valid. Too many times companies do not create good trails as they try to skew data to make it look better than it really does.
RLY-4008 Phase 1 Data
Link to the original data pdf so you can follow along RLY-4008 Phase 1 Data
Here we will look at the data from RLY-4008. The image below will open in a full window so you can read it and follow along with the data. The first image is the top section of the press release. Most of these press releases start the same. They have a few bullet points to point out key data. I will read them, but too many times companies will put data in the bullet points to make things look great, but when you read the actual data further down, it turns out to be bad. Never just read only the bullet points as many investors do this and get the wrong impression.
After the bullet points, there will be the section that highlights the data along with company comments on the data. This always comes with the quotes to highlight the company comments. I often call this the spin comments. Many times, when data is bad, the company will put spin on it in their comments to try to make it sound better than it really is. For this data read out of RLY-4008, they are pointing out a subset of patients that were treated only at the phase 2 dose. They show 15 of 17 responding for 88% Overall Response Rate. I don't have any problems with this type of data cutout. I still would look over the rest of the patients which showed 66% Overall Response Rates across all dose cohorts. The one word of caution I have is that a really awesome response rate of 88% can be misleading in these small patient populations as they often do not hold up to those high levels as the trials progress and the patient populations get bigger. Most FGFR2 inhibitors have response rates in the 20% to 30% which makes 88% more than 3x the response rates compared to other drugs in this space. That is a game changer if it holds up that level of response or doesn't give up a ton going into larger patient populations.
The very first thing we see in the data section is they treated 195 total patients, of which, 89 of them were treated at the phase 2 dose of 70mg. The actual data is based on only 17 of those patients which reached enough follow up to be included in the data so far. That is only about 19% of the patients in the total trial were included. This still has a long way to go on data. Of the 15 patients that responded 13 remain in response with 1 of them only coming off treatment to get their tumor removed with curative intent. That is very positive as the study drug shrank the tumor enough that they could remove it. The 2 people who did not respond were still in stable disease. They did not progress or get worse. That is another very positive data point. Out of all the patients who were treated in all dose cohorts, the response rate was 63% which is still more than double the historical rate for other FGFR2 inhibitors.
The last section is the Safety Data. They don't provide very in depth data for the safety at this point other than to say that most have been mild to moderate and manageable. This is encouraging as many FGFR2 inhibitors have a ton of toxicity. We will have to wait and see more detailed data on safety.
Overall, I would sum this up as very powerful early data in an indication which typically has low response rates and high toxicity. We still have 80% of the patients to see data on and it could change the response rate. The key now is to see more of the data develop to ensure the response rates stay strong and the safety stays clean.
NTLA-2001 Phase 1 Data
Link to the original data pdf so you can follow along NTLA-2001 Phase 1 Data
This starts out with the standard bullet statements which cover the indication, the biomarker data, and basic safety statement. There are 12 patients for aTTR Cardiomyopathy treated with 2 possible doses of .7 mg/kg and 1.0 mg/kg. This data sets the stage for the study.
Then comes the chart for 28 days after treatment. They break out 3 dose cohorts across different patient demographics. You can see the first dose was tested in patients with 2 different classifications of aTTR. The aTTR serum levels were reduced 92% and 94% in this .7 mg/kg dose. This compares with RNAi therapies like Vultisiran which had 88% serum aTTR reduction. This is slightly better on the biomarker data. They will still have to do a bigger study with key endpoints for Polyneuropathy and Cardiomyopathy indications.
The next section starts out with the company comments about the study. The key data here is the safety section. With RNAi studies, the drugs are taken once every 3 months or 4 times a year. About 15.6% of patients have serious side effects from these chronic therapies. This is where permanent gene editing can compete. There is going to be a percentage of patients who don't want to deal with the side effects they feel every time they have to administer an RNAi injection. Where they might have trouble competing is on acceptance by insurers. The RNAi product in this space costs upward of $460,000 per year to treat a patient. They would have to demonstrate long term efficacy to show insurers they have a cost benefit. I suspect these treatments will be around $2 million per patient.
Overall, this data is very encouraging as it shows biomarker data that is superior to current treatments and a safety profile that is safer than the current treatments. It's going to take a lot more data before we know for sure that this therapy will be competitive with RNAi. It needs to hold efficacy and safety to be competitive.
NTLA-2002 Phase 1 Data
Link to the original data pdf so you can follow along NTLA-2002 Phase 1 Data
As usual, the press release starts with a set of bullet statements that are designed to highlight key data points in the clinical trial. These statements tell us there were robust levels of kallikrein knockdown along with a reduction in HAE attacks. The rate of attacks in these patients were reduced which increased their time they are able to live without experiencing another attack. Some of them went up to 10.6 months without another attack after treatment. It also tells us it was well tolerated. Now we should confirm all these claims by looking at the actual data below.
They use a nice chart to lay out the dose cohorts with a 25 mg, 50 mg and 75 mg cohort. It seems by these numbers the first dose has the longest follow up of 32 weeks while dose 2 has only 22 days and 75 mg had 16 weeks. Based on that timeline, the middle dose of 50 mg was started last. Each dose saw an increase in kallikrein reduction with 64%, 81% and 92% respectively. That is impressive at the higher doses. If they can hold upward of 81% to 92% reduction, I think they got a winner here for this therapy.
The next section of the data is a chart of the HAE attack rates. HAE patients go through attacks that look very much like anaphylaxis attacks, but they don't respond to Epipens. They can be very dangerous and life threatening. Any good level of sustained reduction in these attacks would be a huge win. Ideally, we would like to see them completely eliminate the attacks after treatment. The data is too early to determine that. So far, we have about an 89% reduction in the rate of attack after the treatment. This will be the key data that we need to see a longer term follow up on. If they can continue to get prolonged reduction of attack rates of 89% or more, then they are a big winner.
The last section of the press release is about safety. This therapy looks very clean with mostly grade 1 events which are considered mild. No grade 3 event as to date which would be considered serious. With clean safety and long term durability they provide a strong benefit to patients.
Exa-cel Phase 1/2 Data
Link to the original data word document so you can follow along Exa-cel Phase 1/2 Data
I cut off the bullet statements at the top as I wanted to capture the patient cohorts for this trial in one screen capture. This data was presented at EHA and was a combination of patients from all 3 clinical trials. It covers both Transfusion Dependent Thalassemia and Sickle Cell Disease.
The data included 44 patients with TDT, of which, 26 of them were beta-zero/beta-zero subtypes. This is important as these patients are the worst genotype of the disease. The data from Bluebird helped patients with non beta-zero/beta-zero genotypes. They only worked best in the less severe patients. The Exa-cel data clearly shows that it works equally well across both severe and milder patients. Of the 44 patients, 42 of them were completely transfusion independent. Only 2 did not reach full independence from transfusion, but they were reduced by 75% and 89%. The level of Hemoglobin maintained by these patients was greater than 11 g/dl. That is just below the normal range, but well above the level at which transfusion would be required. Typically below 9 g/dl will require transfusion. This looks like a very effective treatment. I would go as far as calling it a functional cure for TDT.
The data included 31 patients with Sickle Cell Disease. The key is the Vaso-occlusive Crisis. These are sickling attacks that are extremely painful and potentially life threatening. The average was 3.9 attacks per year before the therapy and none after the therapy. They maintained the VOC free state for up to 32.3 months. The level of Fetal Hemoglobin expression was 40%. This is lower than the 50% or more needed to completely avoid the VOC crisis as carriers are 50% and they are relatively disease free. They can have some symptoms under extreme circumstances. This means we could see some relapse of the VOC crisis for these patients over time. There is room here for newer therapies to push across the 50% threshold and offer a sure winner.
This section above looks at the safety across both programs. The SCD data is cut off, but it had no events that were considered linked to Exa-cel. The Beta Thalassemia patients seemed to have the most complications with the conditioning and subsequent treatment. The one place these therapies can improve in future generations are in the conditioning. These therapies require myeloablation of the stem cells by Busulfan which is a very toxic drug and leaves patients without an immune system until it comes back after the transplant. Newer therapies can strive to replace toxic Busulfan with safer therapies or move into in-vivo editing of the stem cells to eliminate it completely.
The last section is the company comments. I think they should be very happy with this data. Many other companies that attempted to copy this approach have failed. CRISPR has a very strong functional cure for Beta Thalassemia and Sickle Cell Disease. There are places in this therapy where there is a ton of room for improvement over time. There were more sections of the press release, but they didn't pertain to the data so I left them out. The link to the full press release is linked at the top of this section if you want to read it all.
CTX-110 Phase 1 Data
Link to the original data word document so you can follow along CTX-110 Phase 1 Data
The first section of the press release was the bullet statements which I cut off to focus on the data. This trial was run in 2 parts with Part A and Part B. In 2021, we saw the readout of part A and some of this data slightly improved in part B. This is probably related to the higher dose cohorts being treated. Here is a link to the first readout from 2021 to compare. First Data Readout
The second section of the press release lays out the cohorts with 4 dosing levels of 30 million to 600 million cells. Everything here is pretty standard for all CD19 CAR-T therapy trials. It even gives you a little background on what patient populations they were treating.
Part A of the data is updated and shows slight improvement in the ORR moving from 58% in the first readout to 67% in this data. That is an improvement, but still short of other programs which are getting 75% ORR or higher. The CR rate improved from 38% to 41% which is still lower than other programs at 50%. The real problem is the durability. They didn't even bother to list it anymore in the second data readout. The first data readout showed only 21% of patients were still in response at 6 months. That is way below the average of 50% for other programs. I suspect this is because they knocked out MHC I but never replaced it with anything to pacify NK cells. That made things worse and not better. It was rejected even faster than if they hadn't even done that edit. That has led CRISPR to come up with a 2nd generation of these CAR-T programs with newer edits. All we can do is hope these edits are better than the last ones.
CB-010 Phase 1 Data
Link to the original data pdf so you can follow along CB-010 Phase 1 Data
I have to say this is one of the most impressive press releases I have ever seen. They include a few slides on the side for the swimmers plot which you can click on and view. It has the standard bullet points to lead off. This data was for the first 6 patients in the first dose of only 30 million cells. That is the first thing I have to point out as the data could always change as they do more doses and more patients.
We can skip the ORR response rate as we compare to CTX-110 because this had a 100% CR rate vs only 41% for CTX-110. A 100% CR rate is astounding. I have seen a few 100% ORR rates which measure complete and partial responses, but this therapy had all 6 of 6 patients achieve a complete response. Their slide shows that 2 of 4 patients had continued response at 6 months. The other 2 patients haven't reached 6 months. This put the 6 month response rate at 50% which is inline with other allogeneic programs in CAR-T. This could even improve with higher doses, but we will need more data.
The last section covers the safety data which is pretty much inline with other programs that use Flu/Cy lymphodepletion. The one note of caution is that Caribou is using a very heavy level of conditioning in these patients. So far, they haven't seen any serious events related to infection, but that would be my biggest concern. Their only serious grade 3 event was 1 case ICANS. I would watch that as doses go higher. As long as the data holds up and the safety stays this clean, this is clearly the best in class allogeneic CAR-T for CD19.
* I am not a doctor. This is not designed to be Medical Advice. Please refer to your doctor for Medical Decisions