Intellia: Most Advanced In A Tough Field (NASDAQ:NTLA)

I am surprised to see that I have never covered Intellia (NASDAQ:NTLA), among the three pioneers in the gene editing space. Three months ago, NTLA announced positive biomarker data from two of its one-off gene therapies, CRISPR candidates NTLA-2001 and NTLA-2002, targeting transthyretin (ATTR) amyloidosis and hereditary angioedema (HAE), respectively. That was September 16, and on that trading day, there was a huge spike in trading volume, which turned out to be mostly sell because the stock fell markedly thereafter. It appears to be a sale-on-the-news effect, because this was pretty decent news, with transient and manageable reports of liver toxicity being the only safety concern.

Data from NTLA-2001 was from 12 adult patients with ATTR amyloidosis with cardiomyopathy who received single doses of 0.7 mg/kg and 1.0 mg/kg of NTLA-2001. Cut off date for data was July 01. Interim data from this phase 1 trial showed that NTLA-2001 cut the level of transthyretin in the serum, with mean reductions of 93% and 92% at 0.7 mg/kg and 1.0 mg/kg doses at day 28, respectively. Initial data also showed that the therapy was well-tolerated, with only two reported transient infusion reactions, the only treatment-related adverse event.

Data from NTLA-2002 was from six patients in HAE. The trial allowed prophylaxis medications, and two out of three patients in the low-dose cohort did not develop HAE attacks even after the withdrawal of the prophylaxis therapy following the 16-week primary observation period. Reduction in plasma kallikrein, although in just three patients, was higher than competing drugs for HAE. Kallikrein is a protein that is responsible for the often fatal swelling that is seen with HAE patients. A number of therapies exist that try to reduce plasma levels of this protein or otherwise address symptoms of HAE. NTLA-2002 is aiming to be a one-off therapy that works by knocking out the KLKB1 gene in liver cells, which is responsible for the production of kallikrein.

Recently, the company presented very critical durability data from the study. Data showed that:

• All patients treated in the 25 mg and 75 mg cohorts have an ongoing attack-free interval through latest follow-up

• First three patients treated have an ongoing attack-free interval of 5.5 – 10.6 months after a single dose of NTLA-2002

There was a dose-dependent response in mean plasma kallikrein reduction:

Cohort	Mean plasma kallikrein reduction at latest follow-up
25 mg (n=3)	64% (week 32)
50 mg (n=4)	81% (day 22)
75 mg (n=3)	92% (week 16)

Click to enlarge

Here’s a bit of comparative data discussion from Endpts:

The current standard of care for HAE is Takeda’s Takhzyro, a biweekly treatment that offers roughly a 90% reduction in attacks and a 60% inhibition in the activity of kallikrein, the protein dysregulated in the disease.

For Intellia’s treatment, NTLA-2002, average kallikrein levels in the three patients who got the low dose were reduced by 64%, while levels were reduced in the three patients who got the high dose by 92%. At a middle dose of 50 mg, average kallikrein levels fell by 81%.

No attack data were reported on the four patients who got the middle dose; they’d been followed for an average of 22 days as of the cutoff.

So, the differences are, unlike Takhzyro, NTLA-2002 is a one-off treatment, it has shown higher reduction of plasma kallikrein, and reduction in attacks, the most important metric, is roughly comparable. If the treatment is really one-off, this can be considered as a functional cure.

One negative aspect of the high kallikrein reduction is that kallikrein may actually be a useful protein in the human body. People with a rare condition called Fletcher factor deficiency do not produce kallikrein, and a few of them may have high blood pressure and blood clotting problems. However, this is nitpicking; there’s no research that such a situation obtains in the normal population.

Intellia and partner Regeneron (REGN) were the first to produce safety and efficacy data of in vivo gene editing in a clinical study last year. This year, in June, they produced interim data from NTLA-2001 in ATTR amyloidosis patients with polyneuropathy (ATTRv-PN).

Key ATTRv-PN data highlights:

Six patients treated with the highest dose of 1.0 mg/kg demonstrated 93% mean and 98% maximum serum TTR reduction by day 28.

Highlights of the results included three patients in the 1.0 mg/kg cohort who have reached nine-month follow-up with no signs of a loss in TTR reduction after a single dose.

Notably, patients in the 0.1 and 0.3 mg/kg cohorts have now reached 12 months of follow-up with a durable response, the companies said, noting that the patients in the 0.3 mg/kg cohort showed an 89% mean serum TTR reduction at 12 months.

These are biomarker data, but what is more important is clinical data, and here, two patients have remained attack free even after being taken off prophylactic therapies. When a therapy comes to the market, this is the sort of detail on which its success truly depends, not on biomarker improvements alone.

Early signs of data from the cardiomyopathy subtype also showed extreme transthyretin knockdown, see below:

Ph1 NTLA-2001 in ATTR amyloidosis with cardiomyopathy
NTLA-2001 dose	N	NYHA Class	Mean serum TTR reduction by day 28
0.7mg/kg	3	I/II	92%
0.7mg/kg	6	III	94%
Combined 0.7mg/kg dose groups	9	I/II and III	93%
1.0mg/kg	3	I/II	92%

Click to enlarge

Source – Company release, via Evaluate

Two observations here: one, there’s no dose-dependent response; each dose cohort gets more or less the same response. While that would look negative if the response was low, that’s actually a positive when the response is as high as we see here. What this means is, even the minimum dose is good enough.

The other is what we have been hinting at, translation of a biomarker-based response to hard clinical response. The focus of the ensuing phase 3 trial will be just that, with endpoints including hospitalization and mortality.

Financials

NTLA has a market cap of $3bn and a cash balance of $848mn. Research and development expenses were $96.7 million during the third quarter of 2022, while General and administrative expenses were $22.1 million. At that rate, the company has a cash runway for 7 quarters. Just a few weeks ago, NTLA announced a $300mn dilutive public offering, which will add 3 more quarters to its cash runway.

Bottomline

NTLA is working in a novel, exciting field of medicine. The market has remained generally lackluster to gene editing therapies because their later stage data is still years away. Early data here is indicative of treatment effect, which is all that can be said now. There’s no differentiation as well, right now, among the various companies, at least in terms of trial data. NTLA is one to watch, maybe to build a position, but not one to base your retirement against.