On the horizon: a new wave of rheumatoid arthritis treatments

Research advances in the field of rheumatology have been energized by the search for treatments of severe COVID-19. In particular, rheumatologic agents may help patients with interstitial pneumonia with alveolar damage so dangerous that it leads to severe acute respiratory distress syndrome (ARDS). Intriguingly, cytokine storm plays a role in both ARDS and rheumatologic pathology, according to the experts.

In a fortuitous twofer, with the exception of ianalumab—which is slated to treat Sjӧgren syndrome—all the rheumatology agents highlighted here are being considered for treatment of COVID-19.

hUC-MSC

In June 2020, the FDA gave the green light to an investigational new drug application filed by Balyx Inc., for the treatment of rheumatoid arthritis (RA) with fresh, nonfrozen human umbilical cord tissue mesenchymal stem cells (hUC-MSC).

“Our stem cell product candidates distinguish from others in that the stem cells are harvested shortly before the administration to the recipient, in order to keep the cells fresh, and maintain the optimal viability and biological activities of the cells without the supplement of any cryoprotectant (eg, DMSO). This is in line to our strong belief that the fitness of the cells at the time of administration is an important factor for their therapeutic effects,” said Wenbin Liao, MD, and CEO of Baylx Inc., in a press release. 

"Current interventions do not prevent the progression of injury in RA patients. We believe that BX-U001 has the potential to inhibit the inflammation, diminish or prevent the degenerative process on joints so that patients not only have alleviated symptoms, but also can avoid disabilities that commonly result from the joint deterioration at the late stage of the disease," he added.

Previous research has demonstrated that MSC exhibits potential in treating inflammatory conditions, inflammatory bowel disease, liver cirrhosis, stroke, multiple sclerosis, and more. 

HB-adMSCs

Hope Biosciences has recently completed enrollment for a  Phase 1/2a, open-label, single-dose study involving 15 patients with clinically diagnosed, active RA. In the trial, patients will receive a single IV infusion of autologous adipose-derived mesenchymal stem cells (HB-adMSCs).

“The primary endpoint of this study is to measure the number and frequency of adverse event(s) and/or severe adverse event(s) throughout the study duration,” according to clinicaltrials.gov. “The second endpoint of this study is to evaluate the ability of HB-adMSCs to alter RA-related inflammation via measuring levels of Tumor Necrosis Factor alpha (TNF-a), Interleukin-6 (IL-6), C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR) and Joint Count 66/68 after a single infusion of autologous HB-adMSCs for up to 12-month post-infusion.”

ABX464 

After proving safe and effective in a Phase 2a induction study in patients with moderate-to-severe ulcerative colitis, as well as 12-month maintenance trial, this first-in-class, small molecule is now positioned to tackle RA.

In light of promising results in animal models, Abivax is currently conducting Phase 2a clinical trials to test the safety and tolerability of ABX464 plus methotrexate in patients with moderate-to-severe RA. Patients in the study had previously demonstrated inadequate response to methotrexate with or without one or more antitumor necrosis factor alpha (TNFα) agents, noted the maker of the drug.

“Patients who complete the ABX464-301 trial, have the possibility to roll over into a Phase 2a open-label study, ABX464-302, aiming at the evaluation of the one-year safety and efficacy of ABX464 as maintenance therapy in RA,” according to Abivax.

PF-06650833

PF-06650833 is a potent, selective inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). Reporting results of a phase I trial, authors publishing in Arthritis Research & Therapy concluded that, “PF-06650833, the first IRAK4 inhibitor to enter clinical development, has a favorable safety and pharmacokinetic profile and has shown evidence of pharmacological effect. The data support continued evaluation in human clinical trials for the treatment of rheumatic and autoimmune diseases.”

In the trial, this agent lowered high-sensitivity C-reactive protein (hs-CRP) levels, with only mild adverse reactions including headache, gastrointestinal disorders, and acne. Importantly, the drug did not trigger metabolism via CYP3A.

Pfizer, the maker of the drug, anticipates results of a randomized clinical trial PF-06650833 involving 450 participants to drop in 2022, according to projections proffered on clinicaltrials.gov.

Ianalumab

No approved treatments yet exist for primary Sjӧgren’s syndrome (pSS), which is characterized by B-cell hyperactivity. Prospects for such treatment could change with the introduction of ianalumab (VAY736) , an anti-B-cell activating factor receptor fully human IgG1 monoclonal antibody, which was developed for direct antibody-dependent cellular toxicity-mediated B-cell depletion.

Results from a phase 2b study intended to determine a dose-response relationship over a range of VAY736 doses, with the primary outcome being changes from baseline in the EULAR Sjӧgren’s Syndrome Disease Activity index (ESSDAI) over 24 weeks as the primary endpoint. In the trial, 190 patients with pSS were randomized 1:1:1:1 to monthly subcutaneous injections of either placebo or one of three VAY736 doses: 5 mg, 50 mg and 300 mg.

In an abstract presented at the American College of Rheumatology 2019 annual meeting, authors concluded the following:

“The defined primary endpoint assessing ESSDAI was met, showing statistically significant dose-response for ianalumab with clinically important improvement over placebo at the highest tested dose. The preliminary safety profile was good. Future analysis will focus on PK and immunogenicity, salivary and tear flow parameters and the exploration of ESSDAI domains, and the ongoing-blinded treatment period up to Week 52.”

Of note, ESSDAI is a systemic disease activity index created to assess disease activity in patients with primary Sjӧgren syndrome, and is now the gold standard to measure disease activity in clinical trials, according to authors of a user guide published in BMJ.