Editas Medicine (EDIT) is one of the 3 CRISPR/Cas9 gene editing companies that includes Intellia (NTLA) and Crispr Therapeutics (CRSP). These are related companies in terms of the science they use to develop genomic medicine. However, CRSP is a $9bn company while the other two range below $2bn.

In its Corporate Presentation, Editas says that it has become the first company to begin dosing of an in vivo CRISPR medicine to cure genetic blindness. This is Leber Congenital Amaurosis, a family of congenital retinal dystrophies that results in early onset severe vision loss.

A number of mutant genes are implicated in this disease. A total of 17 phenotypes (LCA1 to LCA17) with 25 genotypes have been identified that account for 70-80% of cases. “Genes with known mutations are GUCY2D, RPE65, SPATA7, AIPL1, LCA5, RPGRIP1, CRX, CRB1, NMNAT1, CEP290, IMPDH1, RD3, RDH12, LRAT, TULP1, KCNJ13, GDF6, CABP4, CNGA3, ALMS1, IQCB1, MYO7A. The other genes causing LCA are unknown. CEP290 (15%), GUCY2D (12%), and CRB1 (10%) and RPE65 (8%) are the most frequently mutated LCA genes.”

LCA is a rare disease with estimated birth prevalence of two to three per 100,000 births. However, it is still the “most common cause of inherited blindness in childhood and constitutes more than 5% of all retinal dystrophies. LCA accounts for blindness in more than 20% of children attending schools for the blind.” There are no good treatment options for LCA, let alone cure. Current methods of treatment include “correction of refractive error, use of low-vision aids when possible, and optimal access to educational and work-related opportunities.”

In 2017, however, the FDA approved Spark Therapeutics’ Luxturna for the treatment of biallelic RPE65 mutation-associated- LCA2. This was the first FDA–approved gene therapy product for the eye. However, this targets a very small subset of LCA because the RPE65 mutation accounts for only a minority of patients with LCA.

This approval was based on success with a dog with a similar disease, and then a clinical trial which demonstrated significant vision improvement. However, “Multiyear follow-up evaluation of the patients from two other trials (ClinicalTrials.gov NCT00481546 and NCT00643747), however, revealed progressive decline of clinical benefits including retinal sensitivity, visual acuity, and functional gain following an initial peak seen at 6– 12 months after the treatment. “

What the EDIT101 trial is targeting is the CEP290 gene, which, the company claims, has 2-5k patients in the US and Europe.

In mouse models, preclinical data showed positive results from administering the editing method

In the EDIT-101 trial, an open-label, dose escalation study to evaluate safety, tolerability, and efficacy of EDIT-101 in patients with CEP290 IVS26 mutation, there are 18 patients aged 3 years and above. A single dose of EDIT-101 is administered via subretinal injection. The measures are as follows:

Primary: Safety including frequency and number of adverse events related to drug, procedure, and dose limiting toxicities

Secondary: Efficacy including visual acuity, mobility course, macula thickness, pupillometry, and electroretinogram

Patient follow up will include core measurements every 3 months for the 1st year. Next steps will include adult dosing. By 2020, they plan to enroll in the adult low dose cohort and begin dosing in the mid dose cohort. They also plan to begin working on other in vivo medicines in neurological diseases.

Other developments

The company plans to file IND for sickle cell disease treatment by year end. This is claimed to be a more precise genomic therapy than lentiviral therapy, and will use proprietary Cas12a to edit beta-globin locus to safely, robustly, and durably increase fetal hemoglobin. Other features of the SCD therapy are:

  • Reduces sickle globin, in contrast to lentiviral gene therapy

  • Editing beta-globin locus provides level of inherent safety,in contrast to BCL11Ae

  • More robustly repopulates red blood cell lineage than BCL11Ae

  • Demonstration of no measurable off-targets

SCD is a group of inherited blood disorders that result in abnormality in the oxygen-transporting haemoglobin in red blood cells. Hydroxyurea is a widely used medication, which “induces fetal hemoglobin expression and thereby reduces sickling.” However, response may be variable, and modest. The second approved drug, L-glutamine, fares worse. These are not curative drugs. In contrast, “allogeneic hematopoietic stem cell (HSC) transplantation with a matched sibling donor can be curative for both pediatric and adult SCD patients.” However, compatible donors are only available in about 10% cases, and GvHD is a major concern. A good workaround is “HSC-targeted gene therapy, in which autologous HSCs from SCD patients are modified by adding a normal or therapeutic β-globin gene (or γ-globin gene) using lentiviral vector gene transfer.” However, although early data looks promising, there are a number of technical hurdles that reduce the efficacy of lentiviral vector based HSC therapy. Editas is trying to address these.There are over 100,000 patients in the US alone, and more in RoW.

According to Editas, the competitive differences of the EDIT-301 therapy is as follows:

In preclinical trials using healthy human donors on mice models, the company say signs of efficacy and safety.

Besides these, the company has plans to begin IND-enabling studies in solid tumors using Natural Killer (NASDAQ:NK) cells.

Financials

Editas has a market cap of $1.94bn as of this writing. The stock is trading about 20% below its 52-week high. The company has about $495mn in cash and ST equivalents, and that is enough runway for at least two years at current pace.

Editas as a major development and marketing collaboration with Bristol Myers Squibb, which has provided $100mn in payments till date, with future milestone and royalty payments. It has technology collaborations with other companies.

Editas is mostly held by funds and insiders - nearly 85% of the company. The bad thing is that insiders share is only about 1% of that; insiders almost never purchase shares. In the last two years, there’s been a single such purchase in the open market last year.

Source - openinsider.org

The company has “Exclusive foundational IP for CRISPR/ Cas9 and Cas 12 (Cpf1) editing in human therapeutics,” with over 70 issued patents and 600 pending applications.

Risks

George Church, Harvard professor and co-founder of Editas, has called the technology used at the company he co-founded a "blunt ax" and "genome vandalism". I have not been able to access the specific talk where this was said, however, professor Church has published widely on the topic - here’s a sample and here are further resources for the adventurous.

There are other concerns centering around the p53 gene, also known as the “guardian of the genome” because of its stabilizing effect on the DNA. Some CRISPR techniques may overactivate the p53 gene, which kills off the edited cells. Anything used to suppress the p53 gene may also remove an important obstacle to cancer formation. Much more research is needed in the area; my aim in providing these brief details is to affirm that there are voices questioning some aspects of the technology that is central to the success of companies like Editas.

Bottomline

Editas is working in the cutting edge of medicine and is years away from approval. I feel what it - and other companies working in the area - lacks is urgency. These treatments are years away, and while they may be superlatively curative therapies, the diseases they target are here and now, and are killing people. Therefore, medicine cannot wait. Other therapies are being developed which have lesser goals, but they deliver quicker. So, until the CRISPR therapy matures into something we can see in a phase 3 trial or any trial aimed at FDA approval, nothing is certain. We have seen other such “promising” therapies go to waste. So a cautious approach works best. I would work with a basket of stocks from all 3 CRISPR companies, and then slowly add to or reduce my position as things unravel. Since the insiders are not buying their stock, I think they aren't thinking too differently.

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