CRISPR Gene Editing: Intellia Vs CRISPR Therapeutics

In my last article, CRISPR-Cas9 Gene Editing Is On The Cusp Of Something Big, I gave an overview of CRISPR-Cas9 and how exactly the science works.

At the end of the article, I briefly mentioned the major players in the CRISPR space, including Intellia (NASDAQ:NTLA), CRISPR Therapeutics (NASDAQ:CRSP), Beam Therapeutics (BEAM), Editas Medicine (EDIT), Caribou (CRBU), and Prime Medicine (PRME).

In this article, I want to cover what I deem to be the top two players in the near term in this space (i.e., the next 1 to 3 years). The two that I believe fit this bill are NTLA and CRSP.

Intellia Therapeutics

1. Mission and Approach: Intellia is dedicated to harnessing CRISPR-based genome editing technologies for human therapeutic use. They aim to transform the lives of people with severe diseases by developing potentially curative genome editing treatments​​​​.
2. Scope of Work:
   • Intellia employs a modular genome editing platform to create diverse in vivo (within the body) and ex vivo (outside the body) therapeutics, covering a range of disease indications​​. I consider NTLA to be a much more flexible company that is open to various forms of gene editing.
   • Their work spans developing treatments for genetic diseases as well as novel engineered cell therapies for various cancers and autoimmune diseases​​. Their primary focus is on gene editing in the liver.
   • One of Intellia’s co-founders, Jennifer Doudna, along with Emmanuelle Charpentier, was awarded the 2020 Nobel Prize in Chemistry for her pioneering work in CRISPR technology, highlighting the company’s strong foundation in CRISPR research​​.
3. Key Partners: Novartis (NVS): New CRISPR-Cas9-based therapies using chimeric antigen receptor T cells (“CAR T cells”) and Regeneron (REGN) for CRISPR-Cas9 based therapies primarily for the liver.

NTLA Pipeline

Intellia has a comprehensive drug development pipeline focusing on in vivo and ex vivo CRISPR therapies for various genetic diseases and conditions related to immuno-oncology and autoimmune diseases.

Its lead candidate is NTLA-2001, which they have partnered with REGN on, and which focuses on ATTR amyloidosis – a rare progressive and fatal disease where the protein starts folding incorrectly. This therapy uses a non-viral lipid nanoparticle to knock out a gene in the liver and is a single injection treatment.

Below is their full pipeline.

In Vivo Program

1. NTLA-2001 Transthyretin (ATTR) Amyloidosis: Early-stage clinical development for treating ATTR amyloidosis.
2. NTLA-2002 Hereditary Angioedema: Also in early-stage clinical development.
3. NTLA-2003 AATD-Liver Disease: Currently in the IND-enabling stage, this program has pivoted to a DNA writing-based AATD research program.
4. NTLA-3001 AATD-Lung Disease: This is in the IND-enabling stage.
5. Hemophilia B: At the IND-enabling stage of development.
6. Hemophilia A: Currently under research.
7. Additional Research Programs: In the research stage for various genetic diseases​​.

Ex Vivo Program

1. NTLA-6001 CD30+ Lymphomas: In the IND-enabling stage, this program targets CD30+ lymphomas.
2. Acute Myeloid Leukemia / Solid Tumors: This is under research for treatment options.
3. Further Research Programs: Intellia is conducting research for additional immuno-oncology and autoimmune disease therapies.
4. Novartis Programs: There are undisclosed research programs in collaboration with Novartis​​.

CRISPR Therapeutics

1. Mission and Focus: CRISPR Therapeutics aims to develop transformative gene-based medicines for serious human diseases, leveraging the potential of CRISPR/Cas9 technology. Their work involves translating this revolutionary technology into breakthrough therapies​​.
2. Locations and Facilities:
   • The company’s R&D headquarters are in Boston, Massachusetts, where they focus on innovation and advancing the science and technology of gene editing​​.
   • They also have a state-of-the-art manufacturing facility in Framingham, Massachusetts, and a growing R&D hub in San Francisco, California, focusing on advanced gene editing and delivery technologies​​.
   • Their global headquarters is located in Zug, Switzerland, marking their origins as a cutting-edge biotech company​​.
3. Key Partner: Vertex (VRTX) – strategic research collaboration agreement and also a partner in their first drug approved using CRISPR-Cas9, exa-cel. VRTX stands to get 60% of profits from that drug.

Vertex is nearing this launch thanks to its 2015 research collaboration with CRISPR Therapeutics. Under that deal, Vertex is leading global development, manufacturing and commercialization of the therapy, splitting costs and profits 60/40 with its partner.

Source: Fiece Pharma

CRISPR Pipeline

As of 2023, CRISPR Therapeutics has a diverse pipeline of drug candidates in various stages of development, spanning multiple therapeutic areas. Its lead candidate is exa-cel for Sickle Cell Disease and for β-thalassemia. This is the most advanced candidate in the entire gene editing field.

Below is the full pipeline for CRSP.

Hemoglobinopathies

1. Exagamglogene Autotemcel (exa-cel) for Sickle Cell Disease (aka SCD) and β-thalassemia: An ex vivo CRISPR/Cas9 gene-edited therapy aimed at editing a patient’s own hematopoietic stem cells to produce fetal hemoglobin. It’s approved in the UK under the name Casgevy for eligible patients with SCD or transfusion-dependent beta-thalassemia​​. It is up for potential FDA approval in the USA on December 8th.
2. Next-generation conditioning: A targeted conditioning agent to improve the safety of hematopoietic stem cell transplant​​.
3. In vivo editing of HSCs: This involves delivering CRISPR/Cas9 to hematopoietic stem cells in vivo to bypass the need for ex vivo gene editing and hematopoietic stem cell transplant​​.

Immuno-Oncology

1. CTX110 (Anti-CD19 allogeneic CAR T): A gene-edited CAR T cell therapy for CD19+ malignancies​​.
2. CTX112 (Anti-CD19 allogeneic CAR T): Similar to CTX110, with additional edits to enhance CAR T potency and reduce exhaustion​​.
3. CTX130 (Anti-CD70 allogeneic CAR T): For treating hematologic malignancies​​.
4. CTX131 (Anti-CD70 allogeneic CAR T): Aimed at treating solid tumors with enhanced CAR T potency​​.
5. Anti-CD70 allogeneic CAR-NK: A gene-edited CAR-NK cell therapy in collaboration with Nkarta​​.
6. CTX121 (Anti-BCMA allogeneic CAR-T): For multiple myeloma, with additional edits for enhanced CAR T potency​​.

Regenerative Medicine

1. VCTX210 for Type I diabetes mellitus: An allogeneic, gene-edited, immune-evasive, stem cell-derived beta-cell replacement therapy​​.
2. VCTX211 for Type I diabetes mellitus: Similar to VCTX210 but with additional gene edits to enhance cell fitness​​.
3. VCTX212 for Type I/II diabetes mellitus: Another version of the beta-cell replacement therapy with additional gene edits​​.

In Vivo Approaches

1. CTX310 for cardiovascular disease: Targets ANGPTL3 using in vivo gene-editing therapy​​.
2. CTX320 for cardiovascular disease: Aims to reduce expression of Lp(a) through in vivo gene-editing​​.
3. CTX330 for cardiovascular disease: Targets PCSK9 for in vivo gene-editing​​.
4. Hemophilia A: A therapy to insert a corrected factor VIII gene, in collaboration with Bayer​​.
5. Undisclosed deletion and insertion programs: Various in vivo gene-editing therapies using lipid nanoparticles or adeno-associated viral vectors​​.
6. Friedreich’s ataxia (FA): In vivo gene-editing therapy in development, in collaboration with Capsida Biotherapeutics​​.
7. Amyotrophic lateral sclerosis (ALS): An in vivo therapy for familial ALS, also in collaboration with Capsida Biotherapeutics​​.

CRISPR Therapeutics’ pipeline reflects a broad range of innovative gene-editing therapies targeting various diseases. The company continues to push the boundaries of CRISPR-Cas9 technology, exploring its potential across different medical conditions.

Importantly, it has the first drug that has partial approval in the field of gene editing and so it tends to garner a lot of media coverage and likely more institutional investment because some investment funds prefer to invest in companies with approved drugs.

Pros and Cons

Assessing this field is hard for any of us without a background in science. However, there are what I think to be some simple tenets that we can use to determine the best approach to investing in this space and picking the winners.

1. Tenant 1: In Vivo vs Ex Vivo

One key tenet is the company’s approach to gene editing using in vivo and ex vivo approaches.

In Vivo Gene Editing

• Definition: “In vivo” means “within the living”. In vivo gene editing involves directly editing the genes inside the body of the organism.
• Process: The editing tools (like CRISPR-Cas9 along with guide RNA) are delivered directly into the body, often using vectors like viruses or lipid nanoparticles.
• Applications: Used for conditions where targeted cells are not easily removed and replaced, such as neurological disorders or certain genetic diseases affecting the liver or heart.

Ex Vivo Gene Editing

• Definition: “Ex vivo” means “outside the living”. This approach involves editing cells outside the body and then reintroducing them.
• Process: Cells (often stem cells or specific types of blood cells) are extracted from the patient, genetically edited in a lab setting, and then reinfused into the patient.
• Applications: Commonly used in blood disorders, cancers (like CAR-T cell therapy for leukemia), and certain genetic diseases where targeted cells can be easily extracted and reintroduced.

Key Differences

• Complexity and Safety: In vivo editing is more complex and carries a higher risk of off-target effects since it’s performed inside the body. Ex vivo editing offers more control and potentially lower risks since the cells are modified outside the body.
• Scope of Diseases Treated: Ex vivo is often preferred for diseases where targeted cells can be easily extracted and reintroduced, while in vivo is more suitable for conditions where this is not feasible.
• Technological and Delivery Challenges: In vivo editing requires sophisticated delivery systems to reach target cells efficiently without affecting other cells, whereas ex vivo editing can utilize more straightforward laboratory techniques.

CRSP’s lead candidate uses ex vivo. While it is much safer, it is significantly more expensive to do ex vivo than in vivo. Ex Vivo Gene Editing involves costs associated with cell extraction, manipulation in a controlled lab environment, and then reinfusion into the patient. This process can be labor-intensive and requires extensive quality control, adding to the costs.

We will have to see the economics of their drug after it is approved, but given the 40/60 split and likely high cost of the therapy, the market opportunity may be more limited and less profitable.

For this reason, I prefer NTLA which has a larger focus on in vivo. CRSP does have a pipeline of in vivo therapies, though, so they cannot be ruled out. I personally own shares in NTLA but I think a basket approach makes sense.

Tenet 2: Balance Sheet Risks

CRSP cash burn: $400-$500M per year

CRSP cash: $1.7 Billion

CRSP cash runway: 3+ years

NTLA cash burn: ~$400M per year

NTLA cash: $800M

NTLA cash runway: ~2 years

Both companies are not at risk of dilution in the near term (although NTLA did just do a shelf offering, which grants them the right to raise money in the future) so I’m not terribly concerned about this. But even if they do need to raise capital, they will likely do it when good news hits and the stocks make a run-up. And given their enormous potential, this wouldn’t kill the investment thesis (see more below in Conclusion).

Conclusion:

It is still quite early to pick winners in this space. I do hope to take a position in CRSP on a pullback. For now, I have a position in NTLA as I view in vivo editing and their flexible approach to utilizing future gene editing techniques like base editing (more on this in a future article) as the better long term, more profitable approach to doing gene editing.

CRISPR therapies are one-time injections, which are preferable to repeat treatments that other therapies employ. Yet, it is a new technology with a lot of unknowns. Some key questions we need to ask include:

1.) Could there be long-term side effects from hidden off-target edits that come about 5 years down the road?

2.) Are competing therapies viewed in a better light by consumers? For example, there is a competing FDA approved therapy from Alnylam (ALNY) for ATTR (NTLA’s lead drug candidate) that has similar results as NTLA’s therapy with dosing done every 3 months that may be perceived as safer than the more novel gene editing approach by NTLA.

I think taking a basket approach with small positions is the better approach to investing in this space. I think it’s too early for us to know for sure if gene editing will revolutionize science AND make investors wealthy. There will likely be skepticism around gene editing, likely exacerbated by fear-mongering on social media.

So it’s likely that gene editing doesn’t really kick into gear until the 2030s because of the reasons above. That doesn’t mean that these will be bad investments.

Considering that these therapies could be truly life altering, the potential is for these companies to become giants (is $500B market cap potential possible?) and even if it takes 10 years with a couple of rounds of dilutive capital raising along the way, you’re talking about the potential for 30-100X returns (key word is potential as it is far from guaranteed). The CAGR of 30X over 10 years is >40%.