Late-Breaking Studies at EULAR Paint Rosy Picture of Rheumatology’s Future

LONDON — Late-breaking abstracts presented at the European Alliance of Associations for Rheumatology’s (EULAR) annual meeting, held here last week, addressed a wide range of clinical concerns and suggested that patients and clinicians have much to look forward to in coming months and years. Following are brief highlights from the presentations. (A fuller treatment of one presentation, on baricitinib [Olumiant] safety, can be seen here.)

Psoriatic Arthritis Drugs Go Head to Head

Two of the drugs most heavily advertised to U.S. consumers are risankizumab (Skyrizi) and bimekizumab (Bimzelx), both approved for plaque psoriasis and psoriatic arthritis. The latter’s manufacturer, UCB, now may have the jump on its competitor for the latter indication with a randomized, head-to-head trial showing better efficacy, albeit with some extra risk we probably won’t see on TV.

With 553 patients randomized to the two biologics — risankizumab targets interleukin (IL)-17A while the other inhibits it and also IL-17F — and an ACR50 response (50% symptom reduction by American College of Rheumatology criteria) as the primary endpoint, bimekizumab was the winner. Joseph Merola, MD, MMSc, of the University of Texas Southwestern Medical Center in Dallas, reported that 49.1% of patients given the latter achieved this milestone at week 16, versus 38.0% of the risankizumab group (P=0.0058). This gap remained when treatment continued for another 8 weeks.

Secondary endpoints such minimal disease activity numerically favored bimekizumab but without statistical significance, Merola said. Safety findings were generally similar, but with one exception: Candida fungal infections were more common “as anticipated by the mechanism of action.” The trial is still ongoing and more data will be reported later, he promised.

Semi-Small Molecule IL-17A/F Drug Wins in Spondyloarthritis

Phase II data for a so-called nanobody drug called sonelokimab showed most patients with axial spondyloarthritis achieving at least 40% symptom reduction in the first month of treatment and continuing out to 12 weeks. The agent is basically a monoclonal antibody pared down to its essentials, with a molecular weight of about 40 kDa versus 150 kDa for a standard antibody drug, which, according to Xenofon Baraliakos, MD, PhD, of Ruhr University in Bochum, Germany, can better penetrate deep tissues.

In the single-arm, 24-patient study, 77% of patients achieved ASAS40 responses at week 4 and 81% at week 12. “Partial remission” was seen in more than half at week 12. Moreover, MRI and PET scans both showed marked reductions in inflammatory joint lesions with the treatment, given in biweekly injections for 8 weeks. Only one patient in the study experienced a serious adverse event, but it was not considered severe (the patient did stop treatment, though).

A 600-patient phase III study is now underway.

Off-the-Shelf CAR-T Alternative Shows Promise

Chimeric antigen receptor (CAR) T-cell therapy is all the rage in rheumatology right now, but it has many drawbacks: it’s expensive and time-consuming (patients’ own cells have to be shipped somewhere for in-vitro engineering and then returned for reinfusion), and comes with a range of adverse effects. Now, a company called Artiva Biotherapeutics has developed what it bills as an off-the-shelf, outpatient-administered alternative called AB-101 based on natural killer (NK) cells from donated cord blood.

Its mechanism is similar to CAR T-cell therapy, with the same goal of obliterating pathogenic B cells and achieving “immune reset.” NK cells are selected for a high-affinity CD16 variant that, when given along with rituximab (Rituxan) and low doses of a conditioning regimen, prompt a greater and longer-lasting B-cell depletion than can be achieved with rituximab alone.

Data were reported at EULAR by Norman Gaylis, MD, of Arthritis and Rheumatic Disease Specialists in Aventura, Florida, with AB-101 given to 15 patients with refractory rheumatoid arthritis, 11 with Sjögren’s disease, and five with systemic sclerosis.

These patients all showed successful B-cell depletion and, encouragingly, major clinical improvements lasting 6 months. Gaylis unfortunately ran out of time and was unable to report safety data (moderators strictly enforced a 10-minute limit on speakers), but the study abstract indicated that no cases of cytokine release syndrome (CRS) — a nearly universal inflammatory condition with CAR T-cell therapy — or more severe neurotoxic effects seen more rarely.

Artiva has launched a series of additional trials, some also targeting B-cell malignancies.

Meet a Trispecific T-Cell Engager

Drug molecules with two different binding sites meant to mobilize T cells to destroy rogue B cells may not be good enough, Chinese researchers decided, so they developed one with three sites — simultaneously binding CD19 on B cells, CD28 on T cells, and, for good measure, CD3 — the latter intended to prevent immune overactivity that CD28 can stimulate. Their company, Shanghai-based CytoCares, has conducted a 48-week study with this agent in systemic lupus erythematosus (SLE), hoping to duplicate the efficacy seen thus far with CAR T-cell therapy.

Reported at EULAR by the company’s CEO, Yingfeng Huang, the product — called CC312 — was tested in 10 SLE patients, with follow-up of 12 to 52 weeks. So-called SRI-4 response was the primary endpoint; it was achieved in all but one. That one withdrew shortly after falling short of that goal by week 8, the point at which the other nine had all reached SRI-4. One of those lost it at week 36 and quit the study; and one more withdrew despite still maintaining SRI-4. Two patients so far have had 52 weeks of follow-up, Huang said, and they both have remained at SRI-4.

Huang also presented biomarker data supporting the clinical responses. He pointed out that these analyses indicated that T-cell “exhaustion,” a problem that has plagued some bispecific T-cell engagers, has not occurred thus far. Huang noted as well that CRS hasn’t been an issue. However, both his oral presentation and the abstract omitted discussion of other adverse effects.

JAK Inhibitor May Come Available for Polymyalgia Rheumatica

At the moment, the only targeted agent with a specific indication for polymyalgia rheumatica (PMR) is a biologic drug. Could an oral JAK inhibitor also fill the bill? Phase III data presented here by Helga Lechner-Radner, MD, of the Medical University of Vienna in Austria, indicates that baricitinib could soon get there.

Forty-six PMR patients from Austria, Italy, and Czechia were randomized in equal numbers to baricitinib or placebo, with the trial conducted in three phases. The first lasted 16 weeks and provided the primary outcome (steroid-free remission). The placebo group was then switched to baricitinib for 12 weeks while the active-drug group continued as before. Finally, all patients were re-randomized with half maintained on the original 4-mg baricitinib dose while the other had it stepped down to 2 mg for 8 weeks and then stopped, with a final assessment at study week 44. Patients’ steroid doses were tapered to zero over the first 11 weeks but could be continued or restarted to control symptoms.

Remission at 16 weeks was achieved by 65% of those on baricitinib versus just 17% of the placebo group. After the crossover, the former placebo group also reached 65%, while a few more of the original baricitinib patients gained remission. In the final phase, those who had baricitinib withdrawn saw a return of symptoms — thus suggesting that the benefit was not especially durable without the drug on board.

Safety findings were unremarkable, Lechner-Radner indicated.

Sirolimus for SLE? Really?

The potent immunosuppressant sirolimus is approved for organ transplant rejection, and is used in some vascular stents to prevent restenosis, but it’s mostly been too powerful to consider for rheumatologic diseases. Indeed, there are reports of inflammatory syndromes among transplant patients receiving the drug. They have not dissuaded some Chinese academic researchers, however, from mounting a good-sized randomized trial with sirolimus in patients with treatment-resistant SLE.

As reported by Liying Peng, MD, of Peking Union Medical College in Beijing, 146 SLE patients were randomized to low-dose sirolimus (1.5 mg/day) or placebo for 24 weeks, at which point the primary endpoint of SRI-4 was evaluated. The placebo group was then switched to sirolimus and the original sirolimus group maintained on the drug for another 24 weeks. Patients were kept on their previous regimens of steroids and medications such as antimalarials, mycophenolate mofetil, and/or methotrexate.

At week 24, 53% of those on sirolimus achieved SRI-4, versus 23% of the placebo group (P<0.001), and a host of other efficacy measures followed suit. All fine -- but what about safety?

Adverse events as reported by Peng were almost a nothingburger. Rates of infections, the chief concern, were nearly identical in the two groups at 26-27%. This despite much larger rates of leukopenia and neutropenia with sirolimus. On the other hand, lymphocytopenia was actually more common with placebo (43% vs 32%). Blood lipid elevations were also substantially more common with sirolimus, but these would not be immediately life-threatening. Three patients treated with sirolimus and one in the placebo group had events rated as serious; there were two deaths, one in each group. Also, 17% of the sirolimus patients experienced menstrual irregularities while none occurred with placebo (all study participants were women).

Now the question, unanswered in this study, is what happens with longer treatment. Peng did not suggest that sirolimus would ever be a one-and-d0ne treatment.

Myasthenia Gravis Drug Might Also Treat Lupus

The FcRn blocker nipocalimab (Imaavy) performed well in a “proof-of-concept” phase II trial, according to data reported by Richard Furie, MD, of Northwell Health in Great Neck, New York. The idea, he explained, is that the drug’s effect to diminish immunoglobulin G production would therefore limit the autoantibodies that drive SLE — just as it limits the autoantibodies responsible for myasthenia gravis, for which nipocalimab was approved last year.

In the new study, 221 were randomized 1:1:1 to placebo or nipocalimab at either 5 or 15 mg/kg/day, each given every 2 weeks. Patients had relatively long disease duration and high disease activity despite standard therapy. Treatment continued for 52 weeks, and SRI-4 was again the primary endpoint.

Nipocalimab looked very effective, with 54% and 52% of patients on the high and low doses, respectively, hitting the mark. There was a strong placebo effect, with 40% of patients achieving SRI-4, but the difference between the placebo and high-dose drug groups was statistically significant.

Furie also reported that a small subset of patients with especially strong autoantibody signatures appeared especially responsive to nipocalimab, with SRI-4 rates of 76% and 66% for the high and low doses, as opposed to 11% with placebo. However, this subset accounted for only 15% of the whole sample.

Safety findings held no surprises and Furie called the drug well tolerated. A phase III trial is now underway.

Improving on Febuxostat for Urate Control

Febuxostat (Uloric) is pretty well established as a go-to drug for patients with gout, or at risk for it because of high serum urate. Still, as Yu Xue, MD, PhD, of Huashan Hospital in Shanghai, explained at EULAR, its pharmacokinetics are not ideal. It’s an immediate-release drug whose FDA-approved label recommends once-daily dosing, but blood levels can drop below the effective range before the next day’s dose. Her team tested an extended release oral version of febuxostat, developed by Jiangsu Hengrui Pharmaceuticals and called HR091506, with the goal of keeping serum urate under steadier control.

It was a large trial, with 442 patients randomized to HR091506 or regular febuxostat. Patients had active, poorly controlled gout and above-normal serum urate levels. Dosing started at 20 mg/day with escalations to 80 mg/day over the 36-week study. Serum urate was the primary outcome measure.

The extended-release product did do a better job of reducing urate levels. At week 36, 64% had achieved the target level of <300 μmol/L, versus 41% of the febuxostat group (P<0.0001). Because the sample was so big, Xue's team was able to perform subgroup analyses, and all but one also benefited from the extended-release version. The exception was patients with moderate renal impairment, defined as an estimated glomerular filtration rate of 30-59 mL/min/1.73 m², in whom both versions performed equally.

Adverse event rates were similar; serious events and those leading to dose reductions were slightly more common with HR091506 though still rare, but events leading to temporary stoppage were more common with regular febuxostat.

She had little to say about clinical outcomes, except that gout flare rates were similar in the two groups.