A relatively new technology called CRISPR/Cas9, or CRISPR for short, has the potential to change the way doctors treat genetic diseases, and may even lead to cures. That would be wonderful news for patients, but as with any new technology, the road from idea to reality can be long and fraught with missteps and good luck.

CRISPR Therapeutics (NASDAQ:CRSP), Editas Medicine (NASDAQ:EDIT), and Intellia Therapeutics (NASDAQ:NTLA) make up a cadre of public biotech companies investors can choose from to gain exposure to the burgeoning CRISPR field.

Hand with scissors cutting strands of DNA

Image Source: Getty Images.

CRISPR's stock more than doubled last year while Editas' gained a respectable 27%. Intellia's stock bounced around throughout the year, eventually ending up 7%, which looks comparatively pretty meager. However, that does not mean investors should not take a deeper look at Intellia's prospects.

Intellia's first CRISPR clinical trial to start mid-year

Intellia plans to commence a clinical trial with its first CRISPR product in the middle of 2020. Editas and CRISPR have already initiated clinical trials with their respective lead programs. This lag in timing could be responsible for the wide difference in stock appreciation compared to its peers.

Intellia initially will attempt to use CRISPR as a therapy to treat transthyretin amyloidosis (ATTR). The disease occurs due to an accumulation of misfolded transthyretin protein. That accumulated debris can damage the heart, nerves, kidneys, and eyes. According to Intellia, approximately 50,000 people worldwide have the inherited form of the disease and another 200,000 to 500,000 have the wild-type version.

Intellia's program, dubbed NTLA-2001, aims to correct the incorrect transthyretin gene in the liver, the organ responsible for producing the 95% of transthyretin protein. The company demonstrated in non-human primates that a single administration of NTLA-2001 can knock down the incorrect protein by more than 60% and sustain the effect for 42 weeks. That's quite impressive from a single injection.

While that result is promising, now begins the long road of translating lab work and animal studies into a human therapy. Intellia plans to submit its Investigational New Drug (IND) Application for NTLA-2001 to the Food and Drug Administration in the middle of 2020. Until then, the company is wrapping up IND-enabling toxicology studies and working on manufacturing to support the clinical trial.

Can lessons be learned from Pfizer?

Pfizer (NYSE:PFE) gained FDA approval in May 2019 for Vyndaqel and Vyndamax, two oral medications with the same active substance, tafamidis, as a treatment for transthyretin amyloid cardiomyopathy (ATTR-CM). While these seek to treat cardiomyopathy, a significant and life-threatening component of ATTR, I think investors looking at Intellia today can glean some insights from Pfizer's development program.

The FDA will require a reasonable number of patients be treated with NTLA-2001 to gauge its safety and potential efficacy. Remember, there are likely tens of thousands of patients in the U.S. who could one day receive this treatment.

Pfizer's tafamidis pivotal trial enrolled 441 patients in an international, double-blind, placebo-controlled study. The trial looked at all-cause mortality at 30 months. There are a few important things to understand here.

First, the timeline. A large international study like this for a rare disease can easily take six to 12 months or more to fully enroll. Then, patients need to take the treatment for 30 months to reach the point where their results can be properly evaluated (unless they die during the treatment phase). It can then take three to six months to close out the study to get all the data. Pfizer allowed patients receiving the drugs to continue past the 30-month mark and even submitted data to the FDA for patients at 33 months. Add it all up, and a study like this can take four to five years to complete.

Second, the data included in the drug's final approval shows that there was no difference in survival benefit between the drug and placebo arms of the trial until 17 months after the start of treatment. From that point forward, those patients getting Pfizer's drug lived longer than those on placebo. Could it take a long time to see a benefit from NTLA-2001? Possibly -- but that's why clinical trials are necessary. 

Third, about 80% of the deaths in both the treatment group and the placebo group were cardiovascular-related, according to the FDA-approved package insert for Vyndaqel and Vyndamax. This shows that Pfizer's aim to target the cardiomyopathy with a daily oral treatment makes a lot of sense. If NTLA-2001 can provide a curative benefit, then Pfizer may be out of luck. Patient preference may come into play here. 

CRISPR therapy will take time to get to market

Investors now need to see how that translates into Intellia's timeline. Assume that six months from now, Intellia files an IND. The FDA then has 30 days to comment or request additional information. If the 30 days pass without word from the FDA, then the company can begin its trial. In gene therapy situations, trials begin slowly, often only treating a few patients. Editing genes could have unintended consequences and neither the companies nor the FDA want to subject anyone to undue harm.

Phase 1 first-in-human clinical trials try to determine dosing as well as push the dose to find the level where side effects become unacceptable. Let's fast-forward to summer 2021, and speculate that the trial is hailed as a success in 12 ATTR patients. Will the next trial be a pivotal study, and what size will FDA want? From Pfizer's experience, a pivotal trial could take four to five years to complete.

Intellia's gene editing has the potential to cure patients with this disease. Investors should see the tremendous potential if that can be achieved in humans. I'll be cheering the company on from the sidelines, but I'll hold off on investing in Intellia shares until the phase 1 trial results are available.



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