Ionis’ HAE Therapy Greatly Reduced Monthly Swelling Attacks During Trial

The experimental therapy IONIS-PKK-LRx can significantly lower the number of monthly swelling attacks in patients with hereditary angioedema (HAE) type 1 and 2, according to top-line data from an ongoing Phase 2 trial.

Newly announced data show the study (NCT04030598), sponsored by therapy developer Ionis Pharmaceuticals, met its primary goal, with IONIS-PKK-LRx reducing the number of monthly HAE attacks by 90% over the course of 17 weeks (around four months), compared to a placebo, and by 97% between weeks 5–17.

Findings also demonstrate the therapy was superior to a placebo at preventing these attacks, with 92% of treated patients remaining attack-free in weeks 5–17.

The treatment was able to reduce the number of moderate or severe HAE attacks, and the number of attacks requiring acute treatment in weeks 5–17, data show. The company is planning to present a full analysis of study data at a medical conference later this year.

“These results highlight the potential benefits and advantages of IONIS-PKK-LRx for the treatment of hereditary angioedema and more broadly underscore the power of Ionis’ antisense technology to target the root causes of rare diseases like HAE,” Kenneth Newman, MD, vice president of clinical development and leader of the pulmonology and immunology franchise at Ionis, said in a press release.

HAE type 1 and 2 result from genetic mutations that cause the C1 inhibitor protein (C1-INH) to malfunction or cease being produced. Low levels of functional C1-INH trigger a cascade of dysregulated inflammatory factors, including the overactivation of the enzyme plasma kallikrein followed by the increased production of bradykinin, culminating in sudden bouts of swelling.

Most available HAE treatments work by replacing C1-INH or suppressing plasma kallikrein or bradykinin to prevent these swelling attacks.

IONIS-PKK-LRx is an antisense oligonucleotide that is designed to target and block the production of prekallikrein (PKK), a precursor of plasma kallikrein. The therapy does so by binding and inactivating the messenger RNA that cells use as a template for producing PKK. By doing so, the treatment is thought to lower the levels of plasma kallikrein, and thereby the risks of swelling attacks.

A previous Phase 1 trial (NCT03263507) showed IONIS-PKK-LRx was safe when given to healthy volunteers, and a more recent study showed the therapy was effective at reducing the frequency of attacks in two women with HAE. 

The Phase 2 study was designed to assess the safety and efficacy of the therapy in a larger group of adults with HAE type 1 or 2.

A total of 20 patients were recruited and assigned randomly to receive monthly subcutaneous (under-the-skin) injections containing 40 mg of IONIS-PKK-LRx (14 patients) or a placebo (6 patients), for a total of 17 weeks. 

Top-line data from the study now announced by Ionis showed the trial met its main goal, as well as all key secondary goals.

Most reported adverse effects were mild and similar between the two groups. Headache and nausea, the most common adverse events to emerge during treatment, were more frequent in the placebo group. 

“These topline Phase 2 study results support a profile for IONIS-PKK-LRx as a potential best-in-class prophylactic treatment for patients with HAE, with excellent efficacy, safety and tolerability along with the convenience of once per month low volume subcutaneous injections,” said Newman.