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Caribou Biosciences, Inc. (NASDAQ:CRBU) is a great speculative biotech play to look into. The reason why I state that is because it is developing a CRISPR-edited allogeneic CAR-T known as CB-010, which could possibly change the potential treatment landscape for CAR-T.
I will go into more detail below, but the gist of the approach is to generate longer persistence compared to other CAR-Ts out there. It is advancing CB-010 in a phase 1 study treating patients with relapsed/refractory B-cell non-Hodgkin Lymphoma (NHL). Not only that, but there is a possibility that it could possibly advance this study quickly by having the potential to turn a phase 2 study into a registrational one. It is also advancing other candidates for hematology in that it is developing CB-011 as an allogenic CAR-T targeting BCMA for relapsed/refractory multiple myeloma (MM). In addition, it is developing CB-012 for patients with relapsed/refractory acute myeloid leukemia (AML).
The downside is that both of these candidates are in the very early stages of clinical development. They are each in IND-enabling and discovery stages respectively. Not only that, but it is developing iPSC-derived CAR-NK cell therapies. The reason why is that it has observed in early testing that it may be possible to counter the immunosuppressive tumor microenvironment with the use of CB-020. Additional results from the phase 1 ANTLER study, using CB-010 for the treatment of patients with relapsed/refractory B-cell Lymphoma are expected by the end of 2022. These are the reasons why I believe Caribou Bioscience is a great speculative biotech to look into.
CB-010 For The Treatment Of Patients With Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma
The main clinical program in the pipeline to go over involves the use of CB-010 for the treatment of patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma. B-cell malignancies occur in B-cells (immune system cells) and most are non-Hodgkin Lymphomas. Lymphoma is cancer that develops in the lymphatic system, which is the body’s fighting immune system network. The lymphatic system is composed of: Lymph Nodes, spleen, thymus gland and bone marrow area. This type of cancer affects these organs and several others. There are two main types of lymphomas that you are likely aware of, which are:
- Hodgkin’s Lymphoma
- Non-Hodgkin’s Lymphoma.
These are the two main ones, although there are some other types. Both of these types are lymphomas that have problems with the B-cells in the body, which are responsible for fighting off infections in a person’s body. The main difference is found under a microscope where each of the cells are shown to be different. There is a difference in the 5-year survival rates between Hodgkin’s Lymphoma and Non-Hodgkin’s Lymphoma, which are shown directly below:
- Hodgkin’s Lymphoma – More than 86% of patients diagnosed with this type of cancer survive 5 years or more
- Non-Hodgkin’s Lymphoma – More than 70% of patients diagnosed with this type of cancer survive 5 years or more
The main thing is that a majority of biotechs targeting the large non-Hodgkin’s lymphoma market. That’s because the global Non-Hodgkin’s Lymphoma market is expected to reach $12.5 billion by 2027. This is a large market opportunity for any biotech. One important thing to note is that there is a specific focus for B-cells, which is the targeting of B-cells that express CD19. If you are thinking that the targeting of only CD19 expressed B-cells would limit market potential, then that would be a mistake. That’s because B-cell malignancies express CD19 at normal to high levels as follows:
- 80% of acute lymphoblastic leukemia (ALL)
- 88% of B-cell lymphomas
- 100% of B-cell leukemia.
As you can see, the targeting of CD19 specifically won’t hinder the possible market opportunity.
It dosed the first patient for the phase 1 ANTLER study back in July of 2021. This early-stage study intends to recruit about 50 patients and then evaluate them for safety and efficacy of CB-010 for the treatment of patients with relapsed/refractory B-cell Lymphoma. The primary endpoint for this trial is objective response rate (ORR). Thus far, I believe that this biotech is on the right track. Why do I state that? It is because it had seen excellent data from several patients that were only given one starting dose of CB-010 which is 40×106 CAR-T cells.
It is important to note that this is dose level 1, because it is now in the process of dose level 2. Speaking of dose level 1 for this phase 1 ANTLER study, as I stated before, it was able to obtain impressive results just with one dose given at this level. It was revealed that there was a 100% complete response (CR) rate observed as best response as of the cutoff date of May 13, 2022. At 6 months following a single dose noted above, the CR was 40% (2 of 5 patients). This is not bad for patients only being given a single dose of therapy. Another item to note which I think is great is that 1 patient evaluated after the May 13, 2022, cutoff date maintained CR to 12 months. In addition, these were patients who had relapsed with prior treatments. They relapsed after a median of 3 prior therapies, ranging from 2 to 8 therapies.
They were very sick patients to begin with. What comes next? Well, there is potential to improve efficacy. This can be done if dose level 2, which is 80×106 CAR-T cells, can achieve an improvement in terms of objective response rate over an extended period of time. A risk to be aware of is that dose level 1 consisted of adverse events which were consistent with other allogeneic and autologous CAR-Ts. This means that if adverse events are even worse with the next dose, there is a possibility that Caribou will have to stick with the current dose. I don’t view this as a bad thing, being that one dose of CB-010 at dose level 1 is already strong as it is. Investors/traders wont’ have to wait that long to see data from dose level 2. Additional results from the phase 1 ANTLER study are expected at the end of 2022.
Improvement Of CAR-Ts Through PD-1 Knockout
Why does this biotech hold the potential to change the landscape of CAR-T? The reason all has to do with the technology it has. That is, developing a CRISPR-edited allogeneic CAR-T, which can possibly improve persistence in the patient. More specifically, it is the first allogeneic CAR-T cell therapy to include edits to achieve this function. There are three edits which are done as follows:
- Inserting CD-19 specific CAR into the T-cell genome
- Remove TRAC gene in place to remove T-cell receptor
- Knockout gene encoding PD-1.
The last bullet point above of knocking out PD-1 is especially important. It believes that knocking out PD-1 may lead to persistence of the CAR-T cell itself against the tumor. Other improvements with such an edit could be the ability to reduce CB-010 exhaustion. This makes a lot of sense, because while CAR-Ts are highly effective treatments, one major issue a lot of them lack is the ability to persist for an extended period of time. The first CAR-T CB-010 may possibly be advanced into the clinic quickly. Caribou believes that there is a chance for an eventual phase 2 study to be a registrational one. If the FDA sees compelling data in phase 1, then it’s possible that it may allow a phase 2 study to become a registrational one. This all depends on unmet medical need, how good the data is and rules established by the agency at the time of a meeting.
Additional CAR-Ts With Different Edits And Approaches
As I noted above, CB-010 has 3 CRISPR edits in place to be altered. Well, what I think is interesting about Caribou is the ability to go a different route with its other allogenic CAR-Ts. What do I mean by that? Well, looking at the very next product in the pipeline CB-011, it incorporates 4 edits. The main edit to make note of is the ability to present a minor HLA class I antigen, which is responsible for removing T- and NK-mediated rejection of the CAR-T cell therapy by the patient’s very own immune system. In essence, CB-011 incorporates what is known as immune cloaking to achieve this function. The other CAR-T in the pipeline known as CB-012 is being developed to target CLL-1 (CD371), which is expressed on Acute Myeloid Leukemia (AML) tumor cells and not on normal hematopoietic stem cells. There is a catalyst with respect to this clinical candidate. It is said that an IND application for the use of CB-011 for the treatment of patients with relapsed/refractory multiple myeloma (MM) is expected in the 2nd half of 2022.
The main thing about CB-012 is that is being armored to drive persistence of activity against the tumor, while at the same time reducing the possibility of immunosuppression occurring. Besides targeting only hematological indications, the goal is to expand to targeting solid tumors as well. There is an early-discovery clinical candidate known as CB-020, which is an iNK being derived to treat such tumors. The development of this candidate is overcoming challenges facing immune therapies in the immunosuppressive tumor microenvironment. In other words, generating edits to possibly overcome this environment.
Financials
According to the 10-Q SEC Filing, Caribou Biosciences had cash, cash equivalents and marketable securities of $390.8 million as of March 31, 2022. A big reason for the cash on hand that it has is because it has been able to raise funds to date through sales of its convertible preferred stock, which has allowed it to obtain approximately $150.1 million in net proceeds to date. Its initial IPO helped it obtain about $321 million in net proceeds. In addition, there has been many other ways to raise cash. This is the sale of Intellia common stock in which it received $88.4 million from. Lastly, it made $78 million through March 31, 2022, through several other means like licensing agreements, service agreements, patent assignments and a few other ways. Matter of fact, about $30.2 million of the $78 million was received under an AbbVie (ABBV) agreement.
Based on the current cash on hand, it believes it has enough to fund its operations for at least the next 12 months from the date of the 10-Q SEC Filing, which is May 9, 2022. I don’t believe it will wait the entire 12 months to raise cash. I think that it may choose to raise cash before the end of 2022. More than likely, it could be done if it can release positive results from the phase 1 ANTLER study in the coming months.
Risks To Business
There are several risks that investors should be aware of before investing in this biotech. The biggest risk I think has to do with the pipeline itself. A lot of the CAR-Ts are early in the clinical process. Even though Caribou reported positive results from the phase 1 ANTLER study, using CB-010 to treat patients with relapsed/refractory B-cell Lymphoma, there is no guarantee that additional results in dose level 2 to be released at the end of 2022 will turn out to be better. In addition, you also have to consider that there may or may not be additional safety issues identified with the higher dose. Especially, since there were adverse events noted in dose level 1.
The second risk factor to consider is that there is no guarantee that the additional allogeneic CAR-Ts being developed in the pipeline will advance to phase 1 and further clinical studies.
The final risk to consider involves the financial position. Caribou believes it has enough cash to fund its operations for at least the next 12 months. However, I don’t believe it will wait to raise cash. I think it will likely raise cash before the end of 2022 to make sure it has the necessary funds to keep its trials going.
Conclusion
The final conclusion is that Caribou Biosciences is a great speculative biotech play to look into. It has already established proof of concept with the use of CB-010 for the treatment of patients with relapsed/refractory B-cell Lymphoma in the phase 1 ANTLER study. This was proven with the initial 100% CR rate achieved and then the subsequent 40% CR at 6 months.
Not only that, but it is already gearing up to advance other hematological studies using its other CAR-Ts, which are CB-011 and CB-012. Speaking of which, an IND filing for CB-011 for the treatment of patients with relapsed/refractory multiple myeloma (MM) is expected by the 2nd half of 2022. A major catalyst which investors can look forward to would be the release of additional results from the phase 1 ANTLER study by the end of 2022. It is expected that these results would likely include dose level 2 of the patients being treated. This would give an indication if further efficacy can be achieved with the dose being increased. Hopefully no safety issues are found with the use of a higher dose of CB-010 for patients with r/r B-cell Lymphoma. Lastly, it is already gearing up in the discovery phase towards advancing an iPSC-derived Natural Killer (NK) cell treatment for solid tumors.
Based on proof of concept with CB-010 for patients with r/r B-cell lymphoma, plus a few catalysts expected before the end of 2022, these are the reasons why I believe that Caribou Biosciences is a great speculative biotech play to look into.
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