Rezpeg tamps down disease activity; fails to meet ISLAND primary goal

The aim of rezpegaldesleukin (NKTR-358) is to promote regulatory T-cell proliferation

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by Margarida Maia |

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A middle dose of rezpegaldesleukin, an experimental medicine being developed by Nektar Therapeutics, led to clinically meaningful gains in measures of disease activity in people with systemic lupus erythematosus (SLE).

That’s according to top-line data from ISLAND (NCT04433585), a Phase 2 clinical study that evaluated how safe and effective rezpegaldesleukin is against a placebo in SLE patients with moderate to severe disease, despite being on medications.

While the study’s primary endpoint — a four-point reduction in the SLE Disease Activity Index 2000 (SLEDAI-2K) score — wasn’t met, “rezpegaldesleukin had a positive impact on disease activity,” Brian L. Kotzin, MD, Nektar’s chief medical officer, said in a company press release.

Even so, Eli Lilly, the study’s sponsor, opted not to proceed with a Phase 3 clinical study of it for SLE and the companies are now discussing studies in other autoimmune diseases.

SLE is an autoimmune disease that occurs when the immune system attacks healthy tissues by mistake, causing inflammation and damage. More common in women than men, its symptoms include fatigue, joint pain, and skin rashes, and can range from mild to severe.

While there’s no cure, many treatments can help ease it and prevent complications. They may not work for everyone or in the same way, however.

Rezpegaldesleukin, also known as rezpeg or NKTR-358, is designed to target a protein complex called interleukin-2 (IL-2) receptor complex to promote the proliferation of regulatory T-cells, a type of immune cell.

These regulatory T-cells act as brakes on the immune system, helping to keep it in check and preventing it from attacking healthy tissues. Having more regulatory T-cells may bring SLE patients’ immune system back into balance, resulting in fewer or less severe symptoms.

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Primary endpoint not met, despite ‘clinically meaningful activity’

A total of 291 people with SLE took part in ISLAND and were assigned to receive one of three doses of rezpegaldesleukin or a placebo, as a subcutaneous (under-the-skin) injection, once every two weeks.

There were 74 patients in the low-dose group (300 micrograms), 70 in the mid-dose group (900 micrograms), 73 in the high-dose group (1,800 micrograms), and 74 in the placebo group. Their mean ages ranged from 40-42 and most were women.

Of those in the mid-dose group who received at least one dose of rezpegaldesleukin, 8.8% achieved a reduction of at least 4 points in the SLEDAI-2K score 24 weeks after the study’s start, compared with the placebo group.

For those who completed the study without major deviations to its protocol (per protocol population), the proportion was 13.9%. These differences didn’t reach statistical significance, however.

“Although the primary endpoint was not met, the study did show that [rezpegaldesleukin] demonstrated clinically meaningful activity as compared to a placebo,” Howard Robin, Nektar’s president and CEO, said in a webcast livestreamed on Feb. 23. An audio-only version of the webcast is available until March 27.

Because no medication for SLE has been approved on the basis of the SLEDAI-2K score, the “primary endpoint (SLEDAI-2K) was not chosen as [a] critical success factor,” the company wrote on a presentation shared during the webcast.

Researchers looked at other (secondary) measures of disease activity, which have been used as the basis for approving Benlysta (belimumab) and Saphnelo (anifrolumab) in the U.S.

These included the SLE Responder Index 4 (SRI-4) and the British Isles Lupus Assessment Group (BILAG)-Based Composite Lupus Assessment (BICLA), among others. The observations were identical.

Researchers also observed that the greater the dose of rezpegaldesleukin, the more regulatory T-cells there were, which was consistent with previous data.

“These data also further support rezpegaldesleukin’s ability to expand regulatory [T-cells] and the potential for this [regulatory T-cell] stimulator to be used as a novel approach in the field of autoimmune disease,” Kotzin said.

Placebo-adjusted responses for the low- and high-dose groups were reduced compared with those in the mid-dose group for all measures of disease activity.

Most side effects reported were mild or moderate. The most common ones were fever, injection site reactions, fatigue, pain, and joint stiffness. Treatment discontinuations were more common with rezpegaldesleukin than a placebo. The highest rate of discontinuations (40%) was observed in the high-dose group and was mainly driven by an increased rate of side effects.