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CRISPR Therapeutics: Progress In Treatment Of Blood Disorders Using CRISPR/Cas9 Looks Highly Promising

About: CRISPR Therapeutics AG (CRSP), Includes: BAYRY, VRTX
by: Terry Chrisomalis
Terry Chrisomalis
Long only, biotech, healthcare, short only

CRISPR Therapeutics and its partner Vertex Pharmaceuticals announced positive preliminary results using CTX001 to treat one patient with transfusion dependent beta-thalassemia and one with vaso-occlusive crisis because of sickle-cell disease.

CTX001 is given as a single infusion and has thus far achieved remarkable preliminary data in both treated indications, however, long-term implications of this treatment must be put into perspective.

CRISPR/Cas9 technology by CRISPR Therapeutics is promising in that it has several methods of editing a gene which are: Disrupt, delete and correct/insert.

CRISPR Therapeutics had $629.7 million as of September 30, 2019 which was believed to be enough to last for at least the next 24 months. However, based on a surge in stock after positive data, it chose to raise cash immediately.

CRISPR Therapeutics (CRSP) and its partner Vertex Pharmaceuticals (VRTX) reported a positive update on early-stage studies using a product known as CTX001. Early evidence shows that the mechanism of action for the CRISPR/Cas9 tech works quite well in certain indications. These indications are beta-thalassemia and sickle-cell disease (SCD). The key issue being that positive data was only achieved in one person for each indication. Additional patients will be needed to confirm that the efficacy didn't just happen by chance and that it works for more than a few patients. Still, encouraging results will allow both companies to push forward and recruit the total expected goal of 45 patients.

Early Phase 1/2 Data Promising But Additional Patients Are Needed

The reported preliminary positive results stemmed from two phase 1/2 studies that used CTX001. The technology of CRISPR/Cas9 is quite advanced in nature. Having said that, this looks highly promising based on the release of early data. It is first important to understand the type of technology that was deployed for these two phase 1/2 studies. CTX001 involves an ex-vivo process by which CRISPR/Cas9 is involved. CRISPR Therapeutics uses both ex-vivo and in-vivo technology, but for the purpose of these two studies in particular, the former is the key to the recently released data. CRISPR is a type of tool for gene editing in being able to cut DNA. Cas9 is an enzyme or endonuclease that acts like a pair of scissors that ends up creating a single cut into DNA. The way that the cut is precisely made is with an RNA molecule or guide RNA ((gRNA)) which directs where the cut is to occur. The technology even goes further than that in that it can be broken down into different ways of achieving gene editing of a particular disease. The options for CRISPR/Cas9 are:

  • DISRUPT- This is where a single cut is made and there is either an addition or deletion of the base pairs - causes the gene to deactivate
  • DELETE- Deletion of a large segment of the DNA is deleted using 2 guide RNAs
  • CORRECT OR INSERT- A perfectly working DNA template being added so that the body can either correct the gene that is defective or insert an entirely new one in its place at the CRISPR/Cas9 level

Each of the phase 1/2 studies deal with diseases known as hemoglobinopathies. Each of the studies are to recruit a total of 45 patients and then follow patients for 2 years after an infusion. The first phase 1/2 study evaluated one patient with transfusion dependent beta-thalassemia (also known as TDT). Beta-thalassemia is a blood disorder where the patient had a reduction in the production of hemoglobin. This is very bad, because a hemoglobin is a protein in red blood cells that carries oxygen to cells throughout the body. When such a patient as this has low levels of hemoglobin, many parts of the body lack the oxygen necessary to function. Having said that, this patient recruited into the study was also transfusion dependent. This patient, on average, had to go through 16.5 blood transfusions per year. While this may seem like a good way to treat beta-thalassemia, there are some drawbacks to this. The first that comes to mind involves iron overload. With many blood transfusions necessary, too much iron can start to build up in the body. In turn, this can result in severe damage to organs. The good news to report for this one patient with TDT, is that once given a single infusion of CTX001 they became transfusion independent. The patient became transfusion independent and achieved total hemoglobin level of 11.9 g/dL at least 9 months after a single infusion. Fetal hemoglobin was 10.1 g/dL. What's the significance of hemoglobin levels? That's because it was pretty much near normal range. Normal range of hemoglobin for males is between 13.5 - 17.5 and then in females the range is between 12.5 - 15.5. It is good that hemoglobin started to approach the normal range, but I believe the more pressing finding for this patient is the ability to avoid having to do so many blood transfusions each year. In essence, quality of life was disrupted before the patient entered the study. The second phase 1/2 study incorporated a patient with sickle cell disease (SCD) with vaso-occlusive crisis. SCD involves red blood cells becoming misshapen. In turn, this is another hemoglobinopathy that leads to lower amount of oxygen being circulated in the body. However, about half of these SCD patients experience something known as vaso-occlusive crisis (VOC). VOC occurs with these sticky misshapen red blood cells getting stuck on the inner lining of the blood vessels in the patient's body. That's a major problem, because pain occurs in such a situation. This was another patient that had a terrible quality of life situation. This patient had 7 VOC events per year. Four months after having received one infusion of CTX001, there were no VOC events to note of. Not only that, but hemoglobin levels improved to 11.3 g/DL.

Potential Risks

There are several risk factors involved with a new type of technology such as this one. In addition, there are some other key factors to keep an eye on as these phase 1/2 studies progress. The first risk factor is on the safety front based on a long-term approach. Each of the patients, with their respective indication, had some serious adverse events. The good news is that none of these SAEs occurred because of CTX001. However, in the patients with TDT they had to be conditioned with busulfan before receiving CTX001. With this type of conditioning, the patient experienced pneumonia in presence of neutropenia and veno-occlusive liver disease. They were both resolved, and the patient was fine after that. The other patient with SCD had three SAEs which were: Sepsis in presence of neutropenia, cholelithiasis, and abdominal pain. Again, these SAEs were not caused by CTX001. First and foremost, there was only 1 patient evaluable for each study. It is important to see safety across additional patients, before defining how tolerable the drug is. I believe it is difficult to extrapolate safety based only on a few patients, especially efficacy. However, I bring up the safety front for another reason. The technology of CRISPR/Cas9 is quite new and hasn't been explored on a long-term basis. One major problem is that if a single cut in DNA is made in an inappropriate portion on the DNA it's possible that there could be long-term devastating effects. That's why it is imperative to understand the possible long-term complications of using CRISPR/Cas9 for gene editing. How can I prove this point? It's first important to point out that CRISPR and Vertex Pharmaceuticals are partners for CTX001. Vertex not only partnered with CRISPR, but it also acquired another company developing treatments using CRISPR/Cas9. Vertex had acquired Exonics for its improved CRISPR/Cas9 technology. In essence, Exonics figured out a way in which it could use its technology to avoid errant edits. Such an errant edit would be mistakenly removing a portion of DNA that may result in a serious adverse event or worse than that. This is the long-term impact that must be addressed as I discussed above. This might be a major risk with gene editing technology. In the case of Exonics, it found a way to use its technology to skip over defective DNA as opposed to actually removing it. That means it figured out a way to avoid errant edits. A second issue with single-cut DNA gene editing is that it may not be used for every single disease out there. In essence, there might be limitations. For some diseases, removing a significant amount of protein using CRISPR/Cas9 may not allow for recovery after the edit is done. This is where the limitation of certain indications may occur with single-cut edits. The safety front for CTX001 is remarkable though since no patient had a SAE after having received the treatment. These are just some risks to keep in mind as the months and years progress with these clinical studies.


According to the 10-Q SEC Filing, CRISPR Therapeutics had $629.7 million as of September 30, 2019. As I noted above, the company had signed an agreement with Vertex Pharmaceuticals to develop CTX001 for a few indications. On top of that, another partnership was also established with Bayer AG (OTCPK:BAYRY) based on the CRISPR/Cas9 technology. CRISPR Therapeutics established that it would have enough cash for at least the next 24 months, without any additional cash coming from one of its partnerships. However, it recently chose to raise cash through a public offering. It sold 4,250,000 common shares at a price of $64.50 per share. Despite having enough cash, I believe a big reason for the raise was the massive increase in stock price after the positive preliminary data. Not always, but most of the times when a biotech obtains such a massive gain based on positive data, they tend to raise cash almost immediately.


CRISPR Therapeutics and its partner Vertex Pharmaceuticals appear to be on the right track with a few of the patients treated with CTX001. It appears that a single infusion of the treatment brings about a major change both in terms of quality of life improvements and the primary goal for each respective indication. I highlighted a majority of the risks above. The main ones would be the long-term impact of patients being infused with CRISPR/Cas9 tech and the fact that the positive results obtained were only in a few patients. It is important to see all 45 patients first or close to that amount before establishing whether or not the treatment is safe/tolerable and efficacy has been established. Still, that doesn't take away completely that one beta-thalassemia patient has been transfusion independent for 9 months and that the other SCD patient had seen no VOC events during a 4-month time period. It will be interesting to see if the single infusion continues its momentum for a longer period of time in both patients. Flush with cash, a large pipeline and promising technology with CRISPR/Cas9 I believe CRISPR Therapeutics should continue its momentum higher for the time being.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.