Motley Fool article brings gene editing into focus:
CRSP sports a 16+% short interest position right now. I think that's the highest I've noticed it recently. There's certainly been a down draft in the share price since July so maybe that's part of the reason. I added 12% more shares to inventory this AM.
PRs https://finance.yahoo.com/news/vertex-crispr-therapeutics-present-american-130000205.html https://finance.yahoo.com/news/crispr-therapeutics-provides-ongoing-phase-150000313.html
4629 CTX110 Allogeneic CRISPR-Cas9–Engineered CAR T Cells in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Results from the Phase 1 Dose Escalation Carbon Study https://ash.confex.com/ash/2022/webprogram/Paper166432.html
2137 Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Transfusion-Dependent ß-Thalassemia https://ash.confex.com/ash/2022/webprogram/Paper166881.html
12 Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Severe Sickle Cell Disease https://ash.confex.com/ash/2022/webprogram/Paper162353.html
CTX130 allogeneic CRISPR-Cas9–engineered chimeric antigen receptor (CAR) T cells in patients with advanced clear cell renal cell carcinoma: Results from the Phase 1 COBALT-RCC study
CRISPR/Cas9 gene-edited, allogeneic anti-CD83 CAR-T cells demonstrate potent activity in GvHD and AML tumor models
CRSP continues to expect to move multiple programs utilising in vivo approaches into the clinic in the next 12 to 18 months, including programs in cardiovascular disease. The company’s lead program, CTX310, targeting angiopoietin-related protein 3 (ANGPTL3) is currently in IND-enabling studies. Also, CTX320 (LP(a)) and CTX330 (PCSK9) are at the research stage, but they could combine all three. In addition, they have established CRISPR-X, a dedicated group within that focuses on emerging technologies, including those to allow HDR-independent and/or AAV-free whole gene correction and insertion.
Too bad GNCA NPT with CAR knock in + PD1 will never be tested. ACT with CART targeting multiple neoantigens will be as potent and more durable.
They start with healthy donor fibroblasts, reprogram to create an iPSC pool and engineer using CRISPR (anti-MICA/B CAR, CD38 KO, IL-15RF and hnCD16 KI). After, comes single-cell sorting and screening of individual clones. The latter for extensive characterisation prior to master cell selection.
For that they look at clones with copy number and locus-target verification, maintain pluripotency, free of reprogramming vectors, demonstrate genomic stability, without off-target edits, ideal propensity to become NKs, as well as desired functional activity and specificity.
500 clones from different editing sequences? What gets knock in/out first? Are these trade secrets?
Either they make all the edits at the iPSC stage or make a few foundational edits. If it's the latter there would be at least a second round of engineering, going through the sub-clones and then banking.
As for any DNA mutations/translocation they are detectable in the clonal population and can be screened out. I know FATE had to screen over 500 clones to find just a single one to create FT536.
That is a lot of man made mutations. Hard to believe there is no risk or downside when the T cell genome is cut and paste at will. How do they determine the sequence of the edits?
They haven't publicly disclosed anything (yet), but the route for iPSC-derived NKs could be knockout of the B2M gene and a knock-in encoding SERPINB9, IL-15 fusion, and/or HLA-E. Also, knockout of the CIITA gene and a knock-in encoding the CAR construct. In addition, knockout of ADAM17, FAS, CISH, and/or REGNASE-1.
How many gene edit/inserts will be required in that process?
Ultimately, the company aims to move to iPSC-derived CAR-T cells as well, but its effort in this area is still at an early stage https://www.nature.com/articles/d41587-021-00027-1
They are also working on iPSC-derived CAR-NK cell therapies as well.
I let 5% of my shares go today at $59.95 for a short term gain.
Next -5% Sell Target = $63.12
Next +12% Buy Target = $46.47
The company will host an innovation day focused on early R&D on Tuesday, June 21 at 2:00 PM ET. It will focus on the company's gene engineering platform technologies, novel approach to cell and gene therapy, and emerging discovery programs.
As for edits, knockouts (in addition to CD70) could include TET2 , CD95 , TGFBR2 , regnase-1 , and/or SOCS1 . Also, the knock-in of (inducible) IL-12 [6-8].
They are also working with NKTX on three different products. One will combine CAR-NK plus CAR-T (both could target two different antigens), as well as two CAR-NK cell products, one of which will target CD70 https://crisprtx.gcs-web.com/static-files/83035e80-926a-4e61-b167-bfcde6392ee6
The company has expanded the CTX110 trial to incorporate consolidation dosing and begun treating patients in a pivotal arm. Also, top-line data is expected to be reported this half for the ongoing CTX120 and CTX130 (in ccRCC and T/B-cell malignancies) trials.
In addition, they have locked in the design and edits (four or five) for next-gen. Now, are designing third-gen, which will have seven or eight edits. Beyond that, with their own facility, have automated parts of manufacturing, are using machine learning plus translational data, as well as CRISPR screens. Preclinical data from last year https://aacrjournals.org/cancerres/article-abstract/81/13_Supplement/1537/667455/Abstract-1537-CD70-knockout-A-novel-approach-to
Based on CTX110's data. I view it as positive, and based on the profile, the company plans to expand into a potential registrational trial that incorporates consolidation dosing in Q1 2022.
Title: CRISPR/Cas9 gene-edited allogeneic CAR-T cells targeting CD33 show high preclinical efficacy against AML without long-term hematopoietic toxicity
Abstract Number and Type: 133, poster
Date and Time: Friday, November 12, 2021, 7:00 a.m. – 8:30 p.m. ET
Presented jointly with NKTX:
Title: A combined strategy of CD70 CAR co-expression with membrane-bound IL-15 and CISH knockout results in enhanced NK cytotoxicity and persistence
Abstract Number and Type: 16439, oral
Date and Time: Wednesday, November 10, 2021, 2:40 p.m. ET
Title: CISH gene-knockout anti-CD70-CAR NK cells demonstrate potent anti-tumor activity against solid tumor cell lines and provide partial resistance to tumor microenvironment inhibition
Abstract Number and Type: 113, poster
Date and Time: Friday, November 12, 2021, 7:00 a.m. – 8:30 p.m. ET
CRISPR Therapeutics to Participate in the Chardan's 5th Annual Genetic Medicines Conference
BusinessWire, GlobeNewswire and PR Newswire News
8:00 AM ET
CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, today announced that members of its senior management team are scheduled to participate in the Chardan's 5th Annual Genetic Medicines Conference on Monday, October 4, 2021 at 2:00 p.m. ET.
A live webcast of the event will be available on the "Events & Presentations" page in the Investors section of the Company's website at https://crisprtx.gcs-web.com/events. A replay of the webcast will be archived on the Company's website for 14 days following each presentation.
The company anticipates filing of lead candidate CTX-001 in 18 to 24 months. More than 45 patients have been dosed across two trials and enrollment should be completed by the end of the year (we might get more data at ASH).
In addition, the company plans to report additional PhI data this year on CTX-110. Also, top-line PhI data from three trials by the end of the year on CTX-120 and CTX-130 (being tested in two trials).
Head n shoulders pattern back then
You were compelling. You influenced me to sell! DAMN
They also have a number of collaboration, one of which is with Stride Bio, whose platform allows them to modify AAV surfaces which are no longer recognized by pre-existing neutralising antibodies, modify binding sites to alter the tissue specificity, and engineer capsids to enhance potency as well as transduction efficiency.
In addition, they have in-licensed novel (AAV) vectors from Duke Uni and an IgG-degrading enzyme to clear neutralising antibodies https://insight.jci.org/articles/view/139881
This publication includes information on the company's development of proprietary small Cas9 variants which may allow for more efficient delivery in vivo using viral delivery vehicles. They expect to move multiple programs (a number of which are partnered) utilising in vivo approaches (both viral and non-viral) into the clinic in the next 18 to 24 months https://www.nature.com/articles/s41467-021-24454-5
Covered at $121 from $155.
For full discloser, are you short CRSP?
And at what price will you cover.
Bail while you have a prayer.
Crispr Therapeutics: Get Ready To Bail Out
Jul. 05, 2021
The company is lagging behind established pharmaceutical companies.
Other cheaper alternatives are on the way.
The company’s valuation is excessive.
CRISPR Therapeutics (NASDAQ:CRSP) is a company that has the kind of valuation that investors in pets.com could only have dreamed about, even at the peak of the “dot.com” hysteria. For many owners of CRSP stock, the rich valuation for the company is more than justified since they believe that CRISPR has the “silver bullet” for malignant tumors and will therefore turn stock holders into gazillionaires in due course. I’m afraid, I’m not so sure. My primary reason for being doubtful is that there are already established companies providing CAR-T treatments and there is a plethora of equally effective and relatively low-cost remedies on the horizon. Whilst it is true that CRISPR is developing treatments for a number of disease areas, my focus in this article is their anti-cancer product line.
An overview of current cancer research
To fully explain my perspective, I believe it would be helpful to give a brief synopsis of the state-of-the-art advances. Broadly speaking, investigators in cancer research are developing therapies that can be categorized as small molecules, large molecules or CAR-T treatments.
Over decades of research, many of the cellular mechanisms that lead to cancer have become understood and drugs that target these processes have been made available. For instance, it has been known for quite some time that tyrosine kinase, an enzyme necessary for cell division, cannot switch off in some cancers due to a faulty structure. In recent years, a number of novel compounds have been approved that can inhibit these defective enzymes. One such compound is gilteritinib, which sells under the trade name Xospata and is produced by the Japanese biotechnology company Astellas Pharma (OTCPK:ALPMF). This product would be called a small molecule since it can enter a cancerous cell to perform its action. As you may imagine, the problem with small molecules is that they can enter healthy as well as abnormal cells, and this is the primary reason for the side effects often associated with cancer treatments. Additionally, these small molecules cannot cure the underlying problem, but merely slow its progress, and so must be taken for an extended period of time; often for life. For those unfortunates that have to be prescribed this medication, the cost is quite steep at around $25,000 a month.
The mode of action of large molecules is quite different, they attempt to activate a person’s own immune system to destroy the cancer. These large molecules consist of two parts, a component that locks onto the malignant cell and another that activates the immune response.
The majority of readers may be familiar with the idea that cancer is caused by flawed genes that then leads to uncontrolled reproduction of cells. Coincidentally, each flaw is often represented by a unique lipid or protein or polysaccharide on the surface of a cancerous cell known as a tumor-specific antigen. In fact, researchers can typically determine which gene is defective according to the antigen on the outside of a cell.
So, scientists are trying to produce large molecules (antibodies) that can bind to these specific antigens and then cause the immune system to destroy those cells. There are several methods being explored to introduce these tumor-specific antibodies into patients.
One such method is by the use of mRNA that is coded to enable cells within the patient to manufacture the antibody. I guess by now many readers have heard of mRNA given the extensive coverage that has been given to mRNA-based COVID 19 vaccines. For those who are unsure of the mechanism of action, put simply, mRNA vaccines induce cells to produce the “spike” protein of the virus and so coax an effective immune response to the actual virus. One company investigating the use of mRNA to fight cancer is BioNTech (NASDAQ:BNTX), the COVID 19 vaccine partner of Pfizer (NYSE:PFE). Initial results are more than encouraging; fewer adverse reactions and impressive improvements in patient outcomes. According to the company, it is envisaged that the costs associated with the treatment are expected to be relatively low, although this is difficult to tell given the company do not, as yet, have a product on the market.
Other biotech companies are synthesizing specific antibodies directly and then administering them to patients. There is a “penny stock” British biotechnology company called Scancell (OTC:SCNLF) that has demonstrated extremely encouraging conclusions following their phase 1/2 study for their lead melanoma product, SCIB1. Using their proprietary technology, “T cell responses were induced in nearly 90% of patients with no serious adverse events or dose limiting toxicities." Even though patients had stage III and IV cancer, around half were still breathing 5 years after the study had started.
Finally, there is CAR-T research that involves editing the genes of cells within the immune system so that these cells can recognize cancer cells and then attack them. You might be forgiven for thinking that this research is so sophisticated that very few companies have the capability to employ such technology to develop this kind of treatment. However, in actual fact there are around a hundred such companies around the world doing similar work to CRISPR.
On a recent conference call, CEO Samarth Kulkarni described progress thus far with their lead immuno oncology products. At the time of writing, the company’s principal oncology products are only in phase 1 testing. Needless to say, it will be several years before these products will be generating any income for the company.
Competitive CAR-T products
Let us consider one of CRISPR's blockbuster hopes, CTX110, which, as I mentioned, is several years away from being available for doctors to recommend to their patients. This is assuming that efficacy and safety can be confirmed, which is not a forgone conclusion. For those who are unfamiliar with CTX110, it is envisaged that it will be a one-treatment-only fix for B-cell blood plasma cell cancer.
Sounds great, right? A once-only treatment for blood cancer a few short years away. The only problem is that there are already two enormous companies manufacturing approved CAR-T therapies for B-cell blood cancer; Novartis (NYSE:NVS) and Gilead (NASDAQ:GILD). Furthermore, way back in 2018, it was reported that there were more than 200 ongoing clinical trials on CAR-T therapies, chiefly to tackle hematological cancers (lymphoma, leukemia, and myeloma).
It was announced in June 2020 that Gilead had received the European Medicines Agency approval for their CAR-T product, Yescarta. Since then, they have built treatment and production centers all around the world. On the market for only a short period of time, growth for the Gilead therapy has been an impressive 36% Y-O-Y. Originally brought to market by Novartis in 2018, Kymriah is now manufactured in across 5 sites globally, including Japan.
Compared to mRNA cancer vaccines and directly administered antibodies, the cost of manufacturing CAR-T cells is huge. For instance, a single treatment with Kymriah can cost around half a million dollars, then there may be further costs associated with continuing care.
To sum up
CRISPR Therapeutics is a company researching in the field of CAR-T medication with around $2 billion in the bank and almost zero revenue. On top of that, the company is burning through approximately $400 million a year in research costs. Despite this, its market cap is at $12.5 bn.
Competition for the company’s lead oncology target is already established globally in the shape of recognized pharmaceutical giants. If this were not bad enough, alternatives to the pricey CAR-T treatments are under development.