Intellia’s second CRISPR gene editing therapy reduces swelling attacks by 95% in hereditary angioedema

An experimental CRISPR therapy has dramatically lowered levels of an inflammation-promoting protein and reduced bouts of harmful swelling by 95% in patients with an inherited condition, Intellia Therapeutics announced Sunday at a medical conference in Germany.

A Phase I clinical trial tested three dose levels of a gene editing therapy in 10 patients with hereditary angioedema, a rare, genetic disease that leaves people prone to sudden inflammation and swelling. The attacks can be disfiguring when beneath the skin, painful when they occur in the gut, and deadly when they block breathing in the airways.

Before the study, some patients experienced swelling attacks once a month while one person had them as often as nearly 17 times a month. Intellia’s one-time therapy, dubbed NTLA-2002, aims to reduce those attacks by knocking down production of an enzyme called kallikrein that leads to leaky blood vessels and swelling.

All but one of the patients who got the therapy saw greater than 60% reduction in kallikrein blood levels. By the end of a four-month observation period, those patients stopped having swelling attacks and didn’t have another one through the latest follow ups ranging from an additional two to 10 months later. The one patient who had a smaller kallikrein reduction, implying that the gene editing didn’t work as thoroughly, had only a single mild attack.

Incredibly, even the two patients who suffered 14 and 17 attacks a month stopped having them within four months of the CRISPR infusion, and they have remained attack-free for 11.5 and 7.5 months, respectively.

John Leonard

“This may be resetting the bar in the disease,” Intellia CEO John Leonard told Endpoints News. “In some cases, I think we will be able to say ‘cure’ because we’ll return the patient to a state as if it looks like there was no mutation.”

The Cambridge, MA-based company announced data from the first six people in the study last September. The new data from all 10 patients were presented at the European Academy of Allergy and Clinical Immunology’s meeting in Hamburg over the weekend.

Editing inside the body

The study is Intellia’s second trial testing a CRISPR therapy that’s infused directly into the body. That approach, known as in vivo gene editing, is often considered more challenging than ex vivo editing, in which a patient’s blood or immune cells are removed, edited in a petri dish, and then reinfused.

CRISPR Therapeutics and Vertex Pharmaceuticals are employing the ex vivo approach for their sickle cell disease therapy, which could become the first FDA-approved CRISPR medicine by the end of the year. For that treatment, scientists slip the molecular scissors into a patient’s blood stem cells by electrically zapping them. But delivering CRISPR to cells inside the body requires a more refined approach.

Both of Intellia’s in vivo treatments use bubbles of fat called lipid nanoparticles to shuttle the genetic blueprints for CRISPR-Cas9 into liver cells. Once there, a patient’s own cells make the gene editing machinery and use it to snip a precise sequence of DNA that will stop production of the offending protein in the disease.

Intellia is also testing a CRISPR therapy that reduces levels of a toxic protein that damages the heart and nerves in a condition called ATTR amyloidosis. But the slowly progressing nature of that disease makes seeing the clinical benefits of the lowering the protein a longer process. The new hereditary angioedema trial, in contrast, appears to have generated a faster readout.

“What’s particularly exciting is that not only do we see the biochemical results of the edit, but we see the clinical results really pretty quickly. And tying those two together is what’s been a missing element in the space,” Leonard said. “The drug is doing everything, and frankly more, than what we hoped for.”

Even though the ATTR amyloidosis program has a head start, it’s possible the hereditary angioedema program could pull ahead and finish first, Leonard acknowledged: “This program is moving very quickly.”

Toward a “functional cure”

Hereditary angioedema is caused by mutations in a protein that inhibits kallikrein. With that protein broken or missing, swelling can quickly get out of hand. Intellia believes that reducing kallikrein, which is easier to do than repairing or replacing its inhibitor, will result in a “functional cure.”

Intellia tested three dose levels of its therapy in the trial, with kallikrein reductions of 67%, 84%, and 95% in the low, medium, and high doses at the most recent time points. All doses appeared to reduce swelling attacks equally well.

“What we’ve done is rebalance the system, so it functions as if it were normal,” Leonard said. The ultimate hope is that the treatment proves to be potent and durable enough for patients to no longer need to worry about the possibility of a swelling attack. “These data indicate that we’ve made really very substantial headway to relieving or potentially even eliminating,” those concerns, he added.

The most common side effects reported in the trial were mild or moderate infusion-related reactions and fatigue, with no severe side effects. “It’s been really remarkably well tolerated,” Leonard said. “We’re really excited about where we are so far.”

The company is required to follow the patient’s progress for 15 years, as stipulated in the FDA’s rules for companies developing gene therapies. “We will continue observing these patients essentially indefinitely,” Leonard said, adding the company has already seen what it needs to move onto the next stage of testing.

Leonard said the Phase II study is “underway and progressing very rapidly.” The company expects to finish enrolling all 25 patients in the study before the end of the year — 10 people will get the low dose, 10 will get the medium dose, and five will get a placebo infusion.

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