Intellia Therapeutics Inc (NTLA) Options

NTLA new 52 week low

NTLA still trending south

NTLA that awful Cathie Wood bought more shares

NTLA was added Friday to Cathie Wood’s ARKK fund
This stock has made a round trip priced back to where it was four years ago

(OT): A new AI paper from Princeton and Stanford https://www.biorxiv.org/content/10.1101/2024.04.25.591003v2.full

CRISPR-GPT demonstrated a marked improvement in gene-editing experiments, increasing the accuracy of target gene modifications by up to 30% compared to conventional methods. In validation tests, it achieved a specificity rate exceeding 95%, with a significant reduction in off-targets. The system also reduced the time required to design and plan experiments by approximately 40%, streamlining the workflow for researchers.

NTLA new 52 week low

Found it

NTLA new 52 lo

NTLA new 52 lo

Is NTLA-3001 over before it even starts? https://crisprmedicinenews.com/news/genome-editing-with-cas9-and-aav-generates-frequent-insertion-of-viral-vectors-that-are-difficult-to/

Slides https://recodetx.com/wp-content/uploads/2024/01/ReCode-Non-Confidential-Overview_Jan-2024.pdf

They are opting out of an agreement with REGN to co-develop a factor IX gene editing therapy for haemophilia A and B. The agreement, which was signed in 2020, will terminate 180 days after NTLA provide written notice to REGN. They will continue to have obligations related to the co-development of gene-editing products directed to factor IX until the effective date of termination. Upon termination, NTLA will no longer be obligated for sharing 35% of the development costs, or be entitled to receive 35% of the profits, for gene-editing products directed to factor IX under the agreement.

Separately, the company would continue to support REGN with the development of gene-editing products directed to factor IX, as applicable, pursuant to a 2016 license and collaboration agreement between the companies. NTLA may be eligible to receive up to $320M in milestone payments and royalties in the high-single digits to low teens if REGN develops and commercialises gene-editing products under the terms of this license and collaboration deal.

I assume (rightly or wrongly) the DNA writer is likely a prime editor https://www.businesswire.com/news/home/20240215392146/en/Intellia-Therapeutics-and-ReCode-Therapeutics-Announce-Strategic-Collaboration-to-Develop-Novel-Gene-Editing-Therapies-for-Cystic-Fibrosis

I'm glad I didn't take a (long) position. I expect an offering soon. CRSP did one, and now PRME. NTLA has not only underperformed, but they are now going to dilute their shareholders more!

Gene editing companies can be hit and miss

Good research from Nanolyze

Looks like they cleaned almost all of the ex vivo programs. They also pivoted one in vivo program and changed it to DNA based writing. Now, they are pretty much left with 2001, 2002 and 3001. This on top of a 15% cut of the workforce (that extends cash runway into mid-2026). Let's hope there are no hiccups! https://www.globenewswire.com/news-release/2024/01/04/2804303/0/en/Intellia-Therapeutics-Highlights-its-Three-Year-Strategic-Priorities-and-Anticipated-2024-Key-Milestones.html

New preclinical data, but for some reason they won't upload the poster(s) https://jitc.bmj.com/content/11/Suppl_1/A391

They also focused on CD8+ T-cells, but we know CD4+ T-cells are important https://www.sciencedirect.com/science/article/pii/S0952791521001230

For example, in this the authors showed that SOCS1-inactivation improved the intrinsic and extrinsic antitumour effect of adoptively transferred CD4+ T-cells. In addition, inactivation not only restored CD4+ T-cell expansion but it boosted CD8+ T-cell efficacy as well https://www.science.org/doi/10.1126/sciimmunol.abe8219

NTLA new 52 week low

First time I had heard about Intellia's proprietary Nme2 CRISPR/Cas9 (Nme2Cas9). A quick search brings back the following: ''Nme2Cas9 combines all-in-one AAV compatibility, exceptional editing accuracy within cells, and high target site density for in vivo genome editing applications.'' https://www.cell.com/molecular-cell/fulltext/S1097-2765(18)31033-5

Regeneron Pharmaceuticals and Intellia announced they expanded their existing research collaboration for gene editing therapies to focus on additional targets in neurological and muscular diseases https://finance.yahoo.com/news/regeneron-intellia-announce-expanded-research-110000224.html

The expanded deal combines Regeneron viral vector delivery technologies and Intellia gene modification technologies. Per the terms, the duo will initially research two in vivo non-liver targets, and each company will have the chance to lead potential development and commercialisation for candidates aimed at one target. The company that doesn't lead the program can enter a co-development and co-commercialisation agreement for the target.

That awful Cathie Wood bought more
Intellia Therapeutics Inc NASDAQ: NTLA

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Health Care : Biotechnology | Small Cap BlendCompany profile
Intellia Therapeutics, Inc. is a clinical-stage genome editing company, which is focused on developing curative therapeutics using Clustered, Regularly Interspaced Short Palindromic Repeats/CRISPR associated 9 (CRISPR/Cas9) technology. CRISPR/Cas9 is a technology for genome editing, the process of altering selected sequences of genomic deoxyribonucleic acid. It is focused on leveraging its modular platform to advance in vivo and ex vivo therapies for diseases with high unmet need. Its lead in vivo candidate, NTLA-2001, is for the treatment of transthyretin (ATTR) amyloidosis, as well as NTLA-2002 for the treatment of hereditary angioedema (HAE). It is developing ex vivo applications to address immuno-oncology and autoimmune diseases. Its advanced ex vivo programs include a wholly owned chimeric antigen receptor T (CAR-T) cell candidate, NTLA-6001 targeting CD30 for the treatment of CD30-expressing hematologic cancers, including relapsed or refractory classical Hodgkin's lymphoma.

Holding long for 300 plus easy money

New preclinical data https://www.globenewswire.com/news-release/2022/05/02/2433370/0/en/Intellia-Therapeutics-Presents-Preclinical-Data-Demonstrating-Advancements-in-its-CRISPR-Engineered-Allogeneic-Platform-at-the-2022-Keystone-Symposia-s-Precision-Genome-Engineering.html

Slides https://3o5c4w3neipl16yvhj3nfqam-wpengine.netdna-ssl.com/wp-content/uploads/2022-05-01_Schultes_Keystone-2022.pdf

Also, https://jitc.bmj.com/content/8/Suppl_3/A103.2

https://www.fiercebiotech.com/research/engineered-tcr-t-cells-by-fred-hutch-san-raffaele-intellia-fend-off-evasive-leukemia-solid

ASH abstracts

A Novel Strategy for Off-the-Shelf T Cell Therapy Which Evades Allogeneic T Cell and NK Cell Rejection https://ash.confex.com/ash/2021/webprogram/Paper152999.html

Clinical-Scale Production and Characterization of Ntla-5001 - a Novel Approach to Manufacturing CRISPR/Cas9 Engineered T Cell Therapies https://ash.confex.com/ash/2021/webprogram/Paper153775.html

PR https://www.globenewswire.com/news-release/2021/10/20/2317270/0/en/Intellia-Therapeutics-Presents-Preclinical-Data-Demonstrating-Advancements-in-its-Broad-Genome-Editing-Capabilities-at-the-2021-European-Society-of-Gene-Cell-Therapy-Annual-Congres.html

Consecutive Genome Editing in Non Human Primate Achieves Durable Production of Human Alpha-1 Antitrypsin and Reduction of the Native Protein https://3o5c4w3neipl16yvhj3nfqam-wpengine.netdna-ssl.com/wp-content/uploads/AATD-2021-ESGCT-Final.pdf

A Novel Strategy for Off the shelf T Cell Therapies Evading Host T Cell and NK Cell Rejection https://3o5c4w3neipl16yvhj3nfqam-wpengine.netdna-ssl.com/wp-content/uploads/Allo-2021-ESGCT-Final.pdf

Lipid Nanoparticles (LNPs) as a Superior CRISPR/Cas9 Delivery Modality for Highly Efficient Multiplex Gene Editing of T Cells for Adoptive Cell Therapy https://3o5c4w3neipl16yvhj3nfqam-wpengine.netdna-ssl.com/wp-content/uploads/LNP-2021-ESGCT-Final.pdf

The company will present new data at the 29th Annual Congress of the European Society of Gene & Cell Therapy meeting, taking place virtually from October 19-21.

Oral Presentations:

Title: A Novel Strategy for Off-the-shelf T Cell Therapies Evading Host T Cell and NK Cell Rejection
Abstract number: OR18
Date/Time: Wednesday, October 20, 2021, 10:45 a.m. CEST
Location: Session 2c: Immunotherapy for cancer & CAR T cells
Presenting Author: Yong Zhang, Ph.D., associate director, Cell Therapy

Title: Consecutive Genome Editing in Non-Human Primate Achieves Durable Production of Human Alpha-1 Antitrypsin at Physiologic Levels and Reduction of the Homologous Native Protein
Abstract number: OR12
Date/Time: Wednesday, October 20, 2021, 10:15 a.m. CEST
Location: Session 2b: Gene editing I
Presenting Author: Sean Burns, M.D., vice president of Intellia’s Disease Biology and Pharmacology group

Invited Talk:
Title: Advances in CRISPR/Cas9 Therapeutic Genome Editing for In Vivo and Ex Vivo Applications
Date/Time: Friday, October 22, 2021, 11:30 a.m. CEST
Location: Session 7b: Liver and metabolic diseases II
Presenting Author: Laura Sepp-Lorenzino. Ph.D., chief scientific officer

Poster Presentation:
Title: Lipid Nanoparticles (LNPs) as a Superior CRISPR/Cas9 Delivery Modality for Highly Efficient Multiplex Gene Editing of T Cells for Adoptive Cell Therapy
Abstract number: P205
Date/Time: Tuesday, October 19, 2021, 8:00 a.m. CEST
Presenting Author: Aaron Prodeus, Ph.D., principal scientist, Cell Therapy

The company has announced that it has submitted its first CTA to the UK's MHRA for NTLA-5001 (an auto TCR-T cell therapy targeting WT1) to initiate a PhI trial. The company expects to initiate screening by year-end. This first-in-human trial is expected to evaluate the safety and activity in patients with persistent or recurrent AML who have previously received first-line therapies.

Also, last month they submitted an application to the New Zealand's MMDS to begin a PhI trial for NTLA-2002. Additional applications with other countries are following. It utilises the company's modular in vivo lipid nanoparticle delivery technology to knock out the KLKB1 gene in the liver with the potential to permanently reduce plasma kallikrein protein and activity, a key mediator of HAE.

And BEAM

Sudden burst in genomic stocks. NTLA, EDIT, CRSP moving together. What happened?

Big gap and lot of money to be spent on continuation of just for hope. Hope everything comes to fruition in the long but like you said it a ways away.

You do understand that this is a biotech startup that does not yet generate revenue yet? They have a pipeline of products that aren't set to make it to the market until at least next year? They've proven that the CRISPR-Cas9 technology can be effective - now it's time to finish the clinicals and get approval from the FDA to market the products. Geez!!

Large negatives across the board. Revenue Per Share $0.86

Profitability
Profit Margin -288.47%
Operating Margin (ttm) -291.05%

Management Effectiveness
Return on Assets (ttm) -18.17%
Return on Equity (ttm) -37.46%

Income Statement
Revenue (ttm) 51.52M
Revenue Per Share (ttm) 0.86
Quarterly Revenue Growth (yoy) -50.10%
Gross Profit (ttm) -92.41M
EBITDA -143.6M
Net Income Avi to Common (ttm) -148.63M
Diluted EPS (ttm) -2.47

Balance Sheet
Total Cash (mrq) 584.06M
Total Cash Per Share (mrq) 8.57
Total Debt (mrq) 72.74M
Total Debt/Equity (mrq) 13.33
Current Ratio (mrq) 9.90
Book Value Per Share (mrq) 8.04

Cash Flow Statement
Operating Cash Flow (ttm) -63.74M
Levered Free Cash Flow (ttm) -45.03M

Blackstone Life Sciences, Cellex Cell Professionals, and Intellia Therapeutics have teamed to create a CAR-T therapy start-up https://ir.intelliatx.com/static-files/fca9b71d-739f-4d79-863d-f1c4dc27bcf1

Adding CD8 coreceptors may enhance CD4+ T-cell responses (for MHC Class I-restricted antigens) by stabilising TCR-pMHC interactions. Also, it serves to enhance avidity from low affinity TCRs, while enhancing activation https://www.tandfonline.com/doi/full/10.4161/onci.22590

Another way would be to target MHC Class II-restricted antigens https://www.jci.org/articles/view/120391

Knock-ins, knockdowns and/or overexpression are other ways to improve activity. For example, in this, knockdown enhanced CD8+ and CD4+ T-cell accumulation in the tumour, increased proliferation and increased cytokine production https://www.nature.com/articles/nature12988

In the setting of established and (rapidly) proliferating disease, there is a need to enhance and sustain T-cell function, activity, and persistence. However, too many inhibitory and not enough costimulatory signals are a major hurdle. But one way to overcome this is with immunomodulatory fusion proteins, such as this https://ashpublications.org/blood/article/130/22/2410/36564/A-CD200R-CD28-fusion-protein-appropriates-an

So I hope the company explore it.

This was presented at SITC last year https://jitc.bmj.com/content/8/Suppl_3/A103.2

This trial showed that donor-derived, CD8+ T-cells engineered (using a viral vector) to express a WT1 TCR could prevent relapse of patients at high risk (post HCT) [1].

Based on it, a PhI/II trial is ongoing testing central memory vs. naive CD8+ T-cells for the treatment of high-risk AML patients post-induction chemo (over 80% will relapse within the first year [2]). As of Dec '19, seven had been treated. Four are NED (one out to over 500 days), one relapsed (but declined further treatment), and two had overt disease (one due to WT1 negative leukaemia cells).

I think the product (5001) produced by NTLA should show even better results due to a number of factors.

Refs:
1 https://www.nature.com/articles/s41591-019-0472-9
2 https://ascopubs.org/doi/full/10.1200/JCO.2014.58.3518

https://www.businesswire.com/news/home/20210107005234/en/ArsenalBio-Announces-Multi-Program-Discovery-Collaboration-with-Bristol-Myers-Squibb-to-Advance-Next-Generation-T-cell-Therapies-for-Solid-Tumors

Cathie Wood likes some cutting edge Gene editing stocks including NTLA.



Genome Stocks-Gene Editing.
$BEAM 5 billion market cap ARKG ETF
$EDIT 5.1 billion market cap ARKG ETF
$SGMO 2.3 billion market cap
$NTLA 4.4 billion market cap ARK ETF
$BLUE 3 billion market cap
$BNGO 850 million market cap
$EVGN 180 million market cap 35 million shares 45% owned by institutions & insiders ARKG ETF


$NTLA

NTLA 5001, a T Cell Product Candidate with CRISPR Based Targeted Insertion of a High Avidity, Natural, WT1 Specific TCR, Shows Efficacy in In Vivo Models of AML and ALL https://3o5c4w3neipl16yvhj3nfqam-wpengine.netdna-ssl.com/wp-content/uploads/Intellia-ASH-Poster-Presentation_12.05.2020.pdf

Arsenal Bio [1] is also using it for screening [2] and editing [3]. Different TCRs and CARs [4] will be used for solid tumours, and they are working on ways to overcome exhaustion [5].

Refs:
1 https://www.businesswire.com/news/home/20191017005246/en/ArsenalBio-Launches-With-85-Million-Series-A-Financing-to-Advance-New-Paradigm-to-Discover-and-Develop-Immune-Cell-Therapies
2 https://www.sciencedirect.com/science/article/abs/pii/S0092867420303329
3 https://www.nature.com/articles/s41587-019-0325-6
4 https://www.globenewswire.com/news-release/2020/10/21/2111794/0/en/Teneobio-Announces-a-Research-Collaboration-and-License-Agreement-With-ArsenalBio.html
5 https://www.nature.com/articles/s41586-019-1325-x

Currently, the company is using CRISPR/Cas9 screening to identify edits that can improve infiltration, expansion, potency, and persistence, while also prevent exhaustion of T-cells. Using T-cells with these properties should help in their development of more effective TCR-T cell therapies in a range of solid tumours. They identified both known and novel regulators, and importantly, a number of knock-out targets that accumulate in multiple, distinct TMEs and other targets that are specific.

Data from other groups have shown that deletion of a ribonuclease augmented the capacity of T-cells to control tumour growth by enhancing their ability to infiltrate and persist within the TME [1]. Similarly, a knockout of a transcription factor lead to the improvement in the cytolytic properties of T-cells [2].

They could go further and use TCRs that target both MHC Class-I and II antigens [3], along with delivering 'payloads' to modulate TMEs [4-9].

Refs:
1 https://www.nature.com/articles/s41586-019-1821-z
2 https://www.cell.com/cell/fulltext/S0092-8674(16)31149-7
3 https://www.jci.org/articles/view/120391
4 https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30101-1
5 https://www.nature.com/articles/s41590-020-0676-7
6 https://cancerimmunolres.aacrjournals.org/content/8/6/743
7 https://cancerimmunolres.aacrjournals.org/content/8/4/518
8 https://cancerres.aacrjournals.org/content/71/17/5697.long
9 https://www.jci.org/articles/view/58814

Preclinical data (at ASH) https://ashpublications.org/blood/article/136/Supplement%201/32/471155/NTLA5001-a-T-Cell-Product-Candidate-with-CRISPR

Bought more at $18.30 before selling all @ $19.85. Took profits, but watching to re-enter if pulls back again.

NTLA

CRISPR hits a snag: Our immune systems may attack the treatment

By ANDREW JOSEPH @DrewQJoseph JANUARY 8, 2018

The CRISPR-Cas9 gene editing complex from Streptococcus pyogenes.

A new paper points to a previously unknown hurdle for scientists racing to develop therapies using the revolutionary genome-editing tool CRISPR-Cas9: the human immune system.

In a study posted Friday on the preprint site bioRxiv, researchers reported that many people have existing immune proteins and cells primed to target the Cas9 proteins included in CRISPR complexes. That means those patients might be immune to CRISPR-based therapies or vulnerable to dangerous side effects — the latter being especially concerning as CRISPR treatments move closer to clinical trials.

But researchers not involved with the study said its findings, if substantiated, could be worked around. (Papers are posted to bioRxiv before being peer-reviewed.) Many of the first planned CRISPR clinical trials, for example, involve removing cells from patients, fixing their DNA, and then returning them to patients. In that case, it’s possible that there will be few or no CRISPR proteins remaining for the immune system to detect.

They also noted that scientists are already studying other types of CRISPR that use different proteins, which could stave off the immune responses.

“At the end of the day, I’m not that concerned about it,” said Daniel Anderson of the Massachusetts Institute of Technology, who has studied the delivery of CRISPR therapies and who was not involved with the new study. “But we want to do some experiments to learn more.”

Related Story: Using CRISPR, scientists efficiently edit genome of viable human embryos
The new study should not put the brakes on developing CRISPR therapies, agreed Dr. Matthew Porteus of Stanford, a senior author of the paper and who is himself at work on a CRISPR-based therapy for sickle cell disease. But he said he and his colleagues investigated the immune issues because he felt they were being overlooked as the excitement around CRISPR grew.

“Like any new technology, you want to identify potential problems and engineer solutions for them,” Porteus said. “And I think that’s where we’re at. This is an issue that should be addressed.”

(Porteus and Anderson are both scientific founders of CRISPR Therapeutics, one of the most prominent companies exploring CRISPR-based therapies.)

Immune survey
CRISPR has gained fame in recent years as researchers have deployed it to correct an array of disease-causing mutations in cells in the lab and in animal models, with hopes that the same results can be achieved in people. There are different types of CRISPR systems, but the most well known is dubbed CRISPR-Cas9; it includes Cas9 proteins that cut DNA so that it can be edited. Cas9 proteins come from bacteria.

For the study, the researchers decided to check for immune signals against two of the most common types of Cas9 proteins used, those from the bacteria S. aureus (called SaCas9) and those from S. pyogenes (called SpCas9). In their samples of blood from 22 newborns and 12 adults, the scientists found that 79 percent of donors had immune proteins, called antibodies, against SaCas9, and 65 percent had antibodies against SpCas9.

The researchers then searched for immune cells called T cells. They discovered that about half of the donors had T cells that specifically targeted SaCas9, so that if the immune cells detected that protein on the surface of a cell, they would rally a response to try to destroy it. The researchers did not find anti-SpCas9 T cells, though they said the cells might still have been present.

It’s not surprising so many of the donors had antibodies and T cells against the Cas9 proteins, experts said. That simply means that those people had been exposed to the bacteria containing the proteins in the past, and other studies have found that, at any given time, 40 percent of people are “colonized” by S. aureus and 20 percent of schoolchildren have S. pyogenes. The bacteria only sometimes cause disease.
_______________________________________________
https://www.statnews.com/2018/01/08/immunity-crispr-cas9/

NTLA

In at $18.90. Got to believe the drop is over-reaction to the article.

RATINGS

Today
Consensus Rating: Buy
Consensus Rating Score: 2.67

Ratings Breakdown: 0 Sell Rating(s)
3 Hold Rating(s)
6 Buy Rating(s)
0 Strong Buy Rating(s)
0 Sell Rating(s)

Consensus Price Target: $30.00
Price Target Upside: 63.31% upside

https://www.marketbeat.com/stocks/NASDAQ/NTLA/

PTLA

I don't have enough understanding on how the FDA will view Gene editing methods to put any substantial risk money down, but the reward potential for such a disruptive biotech is quite intriguing! I recently took my gains, but keeping an eye on this.