NTLA Shows Efficacy for In Vivo Gene Editing
Gene Editing Clinical Trials for Investors (July 2021)
Summary
The first in vivo clinical trial results using in vivo CRISPR gene editing technology were reported yesterday (6/26/21) by Intellia (NASDAQ:NTLA) and its partner Regeneron (NASDAQ:REGN).
The trial is for a rare disease called transthyretin amyloidosis that is treated by decreasing levels of transthyretin (TTR), the causative agent.
The results showed a dose-dependent reduction in serum levels of TTR after a single dose of NTLA-2001, NTLA’s CRISPR therapy targeting inactivation of the TTR gene.
NTLA and other key CRISPR companies are in the BPIQ.com database and have clinical readouts coming this year.
Yesterday, at the annual meeting of the Peripheral Nerve Society (PNS) annual meeting, Intellia (NTLA) reported the first clinical results for in vivo delivery of a CRISPR technology. The CRISPR therapeutic candidate, called NTLA-2001, targets the causative protein, transtheyretin (TTR), or a rare disease called rare disease called transthyretin amyloidosis (ATTR). The results were impressive.
Transthyretin amyloidosis (ATTR) is a progressive and fatal disease that results from the build-up of a misfolded form of the transthyretin (TTR) protein, leading to peripheral neuropathy and cardiomyopathy. It is known that treatments that reduce the levels of TTR in serum can effectively treat the disease (See e.g., Adams et al, NEJM (2018) Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis). The liver is the primary source of circulating tetrameric transthyretin protein (See Adams et al., 2018). So it is a good candidate disease for a proof-of-concept study NTLA-2001, which targets liver cells using this very hyped gene editing technology called CRISPR.
The results of the first two dosing levels of NTLA-2001, appear to establish proof of concept for NTLA-2001 and NTLA’s in vivo CRISPR technology for knocking down a protein produced by liver cells. The results, which were presented at the PNS biomedical meeting, an accompanying investor event (See presentation HERE), and an accompanying New England Journal of Medicine article (Gillmore et al. 2021 “CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis”), showed that NTLA-2001 was able to reduce levels of TTR in serum in a dose-dependent manner and to an extent that should be clinically meaningful. The 80%+ reduction in TTR levels measured at 28 days after administration of the highest dose tested (FIG. 1) compares well with the approx 75% reduction seen with RNAi technology Partisan (ONPATTRO®) (Adams et al. 2018) marketed by Alnylam (See HERE). Safety data for NTLA-2001 looked good thus far too, with only grade 1 (lowest grade) adverse events reported thus far (See slide 11 of this presentation HERE).
FIG. 1
This is an exciting proof of concept for NTLA-2001 and especially for in vivo CRISPR technology. Next up for NTLA-2001 will be a report-out later this year of more data from this Phase 1 study (See HERE). Investors will be looking at whether the reduction in TTR serum levels is sustained over long periods and whether further reduction can be achieved. This is important data when comparing NTLA-2001 to approved RNAi therapeutics for this disorder, which require re-administration every 3 week (See Onpattro label HERE).
Analyzing NTLA-2001 safety data will be very important of course, in this first in vivo human study. As opposed to ex vivo workflows, where a patient's cells are removed from the body, edited, and returned to the patient, in vivo workflows involve injecting a therapeutic genetic construct into a patient and editing the genome of a patient's cells inside the patient's body. That's why, for example, one of the primary endpoints in the NTLA-2001 Phase 1 trial is whether patients develop antibodies against the CAS-9 enzyme, which is delivered indirectly as part of CRISPR therapy (See Clinicaltrials.gov entry for this trial. Most importantly, will be a confirmation that the NTLA-2001 CRISPR genetic therapeutic constructs when delivered in vivo, is not interrupting other genes (off-target) in addition to the target TTR gene (on-target).
CRISPR technology is an example of gene editing technology. It is one of three well-known gene editing technologies that also include Zinc Fingers and TALENs (See e.g., Hirakawa et al. Gene editing and CRISPR in the clinic: current and future perspectives, Biosci Rep. 2020). CRISPR has some advantages in terms of being easier to make specific constructs against a target gene sequence that has brought a lot of excitement to the technology (See e.g., Hirakawa et al. 2020). However, all three technologies are being used in technologies in current clinical trials in indications such as numerous cancers and diseases driven by one or a few known genetic abnormalities.
From an investor perspective, Zinc Fingers and TALENs have been used longer in clinical research but investors have valued CRISPR technology more, probably because of the relative ease at which CRISPR therapeutic candidates can be made and tested (See e.g., Hirakawa et al. 2020). Most/all of the top companies in terms of clinical development using these technologies are biotechnology companies with market caps of around $10 billion or less and are in our BPIQ.com database (Table 1). Of the companies in Table 1, BEAM, CRSP, EDIT, and NTLA utilize CRISPR as a core technology for most/all of their clinical programs (i.e. 1' technology). SGMO uses zinc finger technology and CLLS uses TALENs for some of their clinical programs (i.e. 2' technology). ALLO only uses TALEN's through its partnership with CLLS in the development of some of its allogeneic CAR-T technologies (i.e. 3' technology) (Table 1).
All of the 1' and 2' gene editing companies are involved with partnerships with larger companies, which investors generally view as validation of the promise of the underlying technology. And all but SGMO, went public within the last ~5 years (BEAM (2020), NTLA (2016), EDIT (2016), CRSP (2016), CLLS (2015), and SGMO (2000)). From a market-cap perspective, the valuation of the 3 CRISPR companies is much higher than SGMO (zinc finger) or CLLS (TALEN) despite the fact that SGMO and CLLS have more and/or more advanced clinical programs. This reflects that the market values the CRISPR companies based on potential game-changing technology that could catapult over other technologies, seeing them similar to a Moderna for mRNA vaccine technology. This type of bet is a virtually always a very risky bet for investors. Is CRISPR just a sexy technology, mainly useful for biotech research, or is it an enabling technology that will drive numerous approved billion-dollar revenue therapeutics? This is the fundamental questions for investors.
TABLE 1.
As far as upcoming readouts, keep in mind that by searching the BPIQ.com Catalyst Calendar Mechanism of Action field for "CRISPR", "TALEN", or "Zinc Finger" you can always find the next readouts for these gene editing companies. All three CRISPR companies are planning data readouts in the second half of this year, with EDIT's readout of the Phase 1/2 trial of EDIT-101 in certain rare diseases scheduled for September of this year, as the next CRISPR clinical readout from a smid-cap biotech company. SGMO is planning a readout for its Zinc finger-enabled technology BIVV003 in sickle cell disease later this year.
In the months and years ahead, gene editing companies should remain some Big-Mover stocks to watch. We encourage you to diligence these companies and share your results in our BPIQ.com forum. Are you a CRISPR believer - willing to bet that this is a game-changing, REVENUE GENERATING technology? Or are you more of a value investor, making bearish bets on pullbacks, or waiting for pullbacks like those that CLLS has experienced, to move in to place a bullish bet?
This late-breaking news article may be updated from time to time
Article History:
6/27/21 Created
6/28/21 Added BEAM even though they have no clinical assets yet.
This article is NOT investment, tax, or legal advice. Please use this as a starting point for your detailed diligence and consult professional advisers before making investment decisions.
#NTLA #NTLA2001 #CRISPR