Introduction

CRISPR Therapeutics is a gene-editing company focused on the development of CRISPR (Clustered Regulatory Interspaced Short Palindromic Repeats)/CAS9(CRISPR-associated protein 9)-based therapeutics. The company is focused on translating revolutionary CRISPR/Cas9 technology into transformative therapies in therapeutics areas such as hemoglobinopathies, immuno-oncology, regenerative medicine and in vivo applications.

The Need for Gene Editing

Aberrant DNA sequences cause thousands of diseases that have not been treated by traditional small molecule and biologics as such treatments do not address the underlying genetics causes. Gene editing has the potential to provide curative therapies to many genetic diseases by precisely altering DNA sequences within the genomes of cells, which is done with the aid of enzymes cutting the DNA at specific locations. After a cut is made, natural cellular processes repair the DNA to either silence or correct undesirable sequences, potentially reversing their negative effects. As the genome itself is modified in this process, the change is permanent in the patient.

Gene editing also has other applications beyond treating genetically-defined diseases. It can also be applied to the engineering of genomes of cell therapies to make them more efficacious and safer. Cell therapies have been making a meaningful impact in certain therapeutics areas, such as oncology. An example of that is the approval of the CAR-Ts by Novartis (NVS) and Gilead (GILD).

The CRISPR/Cas9 Technology

As its name suggests, the company is utilizing CRISPR/Cas9 as its method of gene editing. Their technology is based on the work of their co-founder, Dr. Emmanuelle Charpentier, who is acknowledged as one of the key inventors of CRISPR-Cas9, and her collaborators.

Figure 1 Applications of CRISPR/Cas9 (Source)

The CRISPR/Cas9 technology is a versatile technology that can be used to disrupt, delete, correct or inset genes. It is used to make cuts in DNA at specific sites of targeted genes, and once the DNA is cut, the cell uses naturally occurring DNA repair mechanisms to rejoin the cut ends. If a single cut is made, a process called non-homologous end joining can result in the addition or deletion of base pairs, disrupting the original DNA sequence and causing gene inactivation. A larger fragment of DNA can also be deleted by using two guide RNAs that target separate sites. After cleavage at each site, non-homologous end joining unites the separate ends, deleting the intervening sequence. Alternatively, if a DNA template is added alongside the CRISPR/Cas9 machinery, the cell can correct a gene or even insert a new gene through a process called homology-directed repair.

Clinical Pipeline

CRISPRs lead product candidate is CTX001 which is being evaluated in -thalassemia and Sickle-Cell Disease (SCD). Both -thalassemia and SCD result from mutations in a gene that encodes a key component of hemoglobin, the molecule that carries oxygen in the blood. Both diseases require lifetime treatment that can result in the need for regular transfusion, painful symptoms and ultimately reduced life expectancy.

The companys approach to treat both diseases is to increase the levels of fetal hemoglobin (HbF), which is a naturally-occurring form of hemoglobin present in all people before birth. The company believes that HbF can substitute for the diseased hemoglobin in -thalassemia and SCD patients, therefore reducing or eliminating symptoms.

CTX001 first isolates a patients own blood stem cells, which is then edited with CRISPR/Cas9 to increase HbF expression, and then returned to the patient. The company believes that over time these edited blood stem cells will generate red blood cells that have increased levels of HbF, which may reduce or eliminate patients symptoms. CTX001 is co-developed and co-commercialized in an agreement with Vertex Pharmaceuticals (VRTX).

In November 2019, both companies announced interim data from the first 2 patients treated in CTX001. 1 patient with transfusion-dependent -thalassemia (TBT) received the treatment in the first quarter of 2019 and the other patient was treated for SCD in mid-2019. The safety and efficacy follow-up of both patients was 9 months and 4 months approximately.

The patient with TDT required 16.5 transfusions per year before enrolling in the clinical study. At nine months after the CTX001 infusion, the patient was transfusion independent. There were 2 serious adverse events (SAEs), although they were assessed to be not related to the administration of CTX001.The patient with SCD experienced seven vaso-occlusive crises (VOCs) per year before enrolling in the clinical study. Three SAEs occurred, none of which were considered related to CTX001. At four months after CTX001 infusion, the patient was free of VOCs. Both the TDT and SCD studies are ongoing and all patients will be followed for approximately two years following the infusion of CTX001. The Company has also mentioned that several additional patients have been enrolled in both trials.

The company is also working on allogeneic CAR-Ts with its gene-editing technology. Current generations of CAR-Ts such as Kymirah from Novartis (NVS) and Yescarta from Gilead (GILD) are autologous and derived from the patients own immune cells. Such treatments have several limitations and healthy-donor based allogeneic CAR-Ts have the potential to improve on the current generation of CAR-Ts.

CRISPR believes that CRISPR-edited allogeneic CAR-Ts has the potential to improve cell persistence as well as overall safety and potency. Its first 2 programs target well-validated targets with the potential to be best-in-class. CTX100 is an anti-CD19 CAR T targeting B-cell malignancies while CTX120 is an anti-B-Cell Maturation Antigen (BCMA) targeting multiple myeloma. Both trials are currently enrolling patients, although no interim data has been released.

A third allogeneic CAR-T, CTX130 is planned to eventually be advanced to clinical trials. CTX130 targets CD70 and will be used to treat both solid tumors, such as renal cell carcinoma, as well as T-cell and B-cell hematologic malignancies. Beyond immunology-oncology, the company also plans to utilize CRISPR/Cas9 in both Regenerative Medicines and In Vivo applications, although such efforts are still limited to preclinical development. Figure 2 illustrates the full clinical pipeline of the company.

Figure 2 CRISPR Therapeutics Clinical Pipeline (Source)

Financials and Competition

As of 31 Dec 2019, cash and equivalents were $943.8M, compared to $435.6 a year prior. The increase in cash was driven by several public offerings, as well as cash received from Vertex for milestone and option payments. The healthy cash pile should take them well into 2021 at the very least.

As the company is working in the gene therapy and cell therapy space, there are several notable competitors. They are often compared to Bluebird Bio (BLUE) who has received the approval of Zynteglo to treat TDT in Europe and in the process of filing a BLA with the FDA for US approval. Bluebird is also evaluating Lentiglobin in SCD. As both of Bluebirds product candidates are more advanced in terms of clinical development, they currently hold a competitive advantage unless CRISPR can prove that their treatments are best-in-class. Notably, Bluebird has faced several challenges with its pricing of Zynteglo as well as regulatory delays due to complex manufacturing and it remains to be seen whether CRISPR can overcome such challenges. Bluebird is also partnering with Bristol-Meyers Squibb (BMY) to develop bb2121 and bb21217 which are both autologous anti-BCMA CAR-T against multiple myeloma.

In the Allogeneic CAR-T space, there also several prominent names that include but are not limited to Allogene Therapeutics (ALLO), Cellectis (CLLS) and Precision Biosciences (DTIL). The main difference among these companies is primarily the choice of gene-editing tools with Allogene and Cellectis using TALEN while Precision is using ARCUS. All these companies are currently in a similar stage of clinical development, with multiple programs in Phase 1 and it remains to be seen who will emerge as a clear frontrunner, even though interestingly, Allogene is trading at a premium market cap compared to the other 2 companies.

In addition to healthy donors derived allogeneic therapies, Fate Therapeutics (FATE) is developing allogeneic therapies from induced pluripotent stem cells (iPSCs) as a renewable cell source. The advantage of this is that product consistency and potency will be improved, and the manufacturing process will be akin to the well-established biologics where they are produced from a single cell line. It is notable to note that Allogene is also investigating using iPSCs as a renewable cell source.

Also, Atara Biotherapeutics (ATRA) is developing an Epstein-Barr Virus (EBV)-based allogeneic T cell therapy platform. Their lead program is in Phase 3 and a BLA filing is expected by the second half of the year. That should put them in the lead position of commercializing an allogeneic T cell therapy and the company is gradually moving into CAR T space as well.

Lastly, there are also other companies such as Editas Medicine (EDIT) and Intellia Therapeutics (NTLA) which are focused on using CRISPR/Cas9 as a gene-editing tool. While both companies are also working on treatments for TDT and SCD, these are not their lead programs and CRISPR is further along than both companies in both therapeutics areas.

Conclusion

CRISPR Therapeutics is a gene-editing company utilizing CRISPR/cas9 to develop therapies in hemoglobinopathies, immuno-oncology, regenerative medicine and in vivo applications. While I consider the company to be a pioneer in CRISPR/Cas9, its market cap of around $3B seems generous for a company that has so far reported only interim data from 2 patients.

Also, there is a long ongoing-argument over the patents of CRISPR/Cas9 between the University of California, which CRISPR license their technology from, and the Broad Institute and Harvard College, of which Editass technology is based on.

With the uncertainty over the patent claims as well as the limited clinical data available, I am inclined to avoid investing in the company for now, although I would be keeping a keen eye on further clinical data, especially on allogeneic CAR-Ts.

As always, investors should do their due diligence before taking up any positions and consider their risk profiles and time horizon. I have covered several companies working on cell therapies and will continue to do so in the coming weeks and months.

Disclosure: I am/we are long ATRA, BLUE. 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.

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CRISPR Therapeutics: A Review Of Its Clinical Pipeline And Progress - Seeking Alpha