‘A great step forward’: The next wave of rheum therapies offers ‘tantalizing’ approaches
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In rheumatology, the next generation of new therapies always seems to be just out of reach, or perpetually “only a few years” away. However, several novel, and not-so-novel, approaches are giving hope that the future may finally soon arrive.
Such approaches include the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, as well as agents that target the neonatal fragment crystallizable receptor or blood dendritic cell antigen 2, or stimulate the human programmed cell death protein 1.
Source: Massimo Gadina, PhD
Specifically, according to experts, multiple approved molecules and a robust armamentarium showing efficacy across several disease states position JAK/STAT as both the present and the future of rheumatology care.
“So many of the cytokines that use the JAK/STAT pathway are involved in the pathophysiology of our diseases,” Massimo Gadina, PhD, chief of the Translational Immunology Section in the Office of Science and Technology, at the NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases, told Healio Rheumatology. “There are more possibilities to interfere with the signaling of pro-inflammatory cytokines. It is the natural evolution in our search for molecules to treat chronic inflammation.”
The complement system, on the other hand, is just now emerging as a therapeutic target, with one landmark trial in ANCA-associated vasculitis — and some potential in lupus — to its credit.
“The complement system has checks and balances, on and off switches,” Jane Salmon, MD, Collette Kean research chair and senior scientist at the Hospital for Special Surgery, and professor of medicine at Weill Cornell Medicine, said in an interview. “It is extremely potent at killing invaders but it also has to protect innocent bystanders.”
Deeper in the pipeline is a strategy targeting the neonatal fragment crystallizable receptor (FcRn). It is not yet on the radar for most rheumatologists, but some experts believe this approach could be paradigm-shifting if harnessed correctly.
“Over the last 20 years, there has been progress in understanding how we control IgG levels in the blood,” Leonard Calabrese, DO, RJ Fasenmyer chair of clinical immunology at the Cleveland Clinic, and chief medical editor of Healio Rheumatology, said in an interview. “There appears to be a critical receptor, the FcRn, that helps confer stability in maintaining concentrations of all IgG molecules in the peripheral blood.”
Recent research has shown that this receptor can be targeted therapeutically, the result of which is to “drive down levels of all antibodies,” according to Calabrese.
Also on the bench is peresolimab (Eli Lilly & Co.), a humanized immunoglobulin G1 monoclonal antibody that stimulates human programmed cell death protein 1 (PD-1). Findings presented by Paul Emery, MD, FMedSci, FRCP, FRCPE, MACR, of the University of Leeds, at the American College of Rheumatology Convergence meeting in 2022 demonstrated efficacy with an attractive safety profile in rheumatoid arthritis.
Similarly, a molecule targeting blood dendritic cell antigen 2 (BDCA2) is moving into phase 2 in systemic lupus erythematosus, with a focus on patients with cutaneous manifestations.
“All of this is exciting because there are many new approaches in development that go across different diseases,” Vibeke Strand, FACP, MACR, a biopharmaceutical consultant and adjunct clinical professor in the division of immunology/rheumatology at Stanford University, in Palo Alto, California, told Healio Rheumatology.
That said, many of these emerging therapies come with one notable qualification — they fall short of being fully curative.
“When we talk about cure, we are talking about approaches like stem cell transplantation and CAR T-cell replacement,” Grace C. Wright, MD, PhD, president of the Association of Women in Rheumatology and owner and president of Grace C. Wright, MD, PC, said in an interview. “What we are looking for is to get patients into sustained remission and get off-drug.”
‘Distinguish and Stratify’
Perhaps the most encouraging aspect for researchers exploring JAK/STAT is that there are four JAKs and seven STATs along the pathway. Furthermore, not all have them have been explored therapeutically, meaning there is still room to grow.
The next step in that evolution may come in the form of targeting specific components of the pathway as opposed to the entire system.
In a paper published in Dermatology & Therapy (Heidelberg), Chimalakonda and colleagues investigated the impact of various concentrations of deucravacitinib (Sotyktu, Bristol Myers Squibb), a novel, oral, selective inhibitor of tyrosine kinase 2 (TYK2) signaling.
“At clinically relevant doses and exposures, deucravacitinib demonstrates highly selective inhibition of TYK2 and not JAK 1/2/3,” the researchers wrote.
These findings highlight the burning question in the field, which pertains to whether JAK/STAT selectivity is indeed the future.
“That is a very difficult question to answer,” Gadina said. “Clearly, pharma have gone after selectivity.”
The difficulty lies in matching a component of the pathway with an individual disease state. For example, given the importance of type 1 interferons in the pathogenesis of lupus, Gadina said TYK2 inhibition may be the likely option for those patients.
“There is a scientific rational to go with TYK2 in SLE, but type I interferons also activate JAK1 and so inhibiting both could, potentially, be even better,” he said.
However, matching a part of the pathway with a disease state raises new challenges.
“In the future, it could be that we will have a way to distinguish and stratify patients to determine whether they might benefit from JAK1 or JAK2 inhibition, and so on,” Gadina said. “But we need to have better tools to understand what is driving the pathology in one patient or another to determine which patients would respond better to which therapy.”
In addition, Gadina described a “huge number” of ongoing studies with currently approved JAK inhibitors.
“Companies are trying to find their own niche market,” he said.
Some are looking at the dermatology side, with atopic dermatitis, psoriasis, alopecia areata and vitiligo representing viable targets for JAK/STAT inhibition.
It is in these dermatologic applications that Wright sees another potential avenue for the JAK/STAT class.
“For years, we have been talking about combination therapy in rheumatology,” she said. “Early data indicate that this may be a possibility, but we need more information.”
Specifically, Wright suggested that a TYK2/JAK1 combination could potentially have utility in a disorder like dermatomyositis.
“This could fit the profile of diseases where you see activity with both TYK2 or JAK1 inhibition, or another inhibitor within that class,” she said.
However, as experts explore JAK inhibitors in a wider range of indications, they will also need to keep a close eye on the adverse event profile.
Lacking a ‘Complete Explanation’
If there is a reason pharmaceutical companies should pursue selectivity in the JAK/STAT class, it lies in limiting adverse events, according to Gadina.
“The idea behind that is that if you limit yourself to one specific JAK, you limit the number of cytokines you are blocking and, therefore, you can limit the side effects,” he said. “Most of these drugs can cause anemia, which is something you do not want in these patients.”
However, anemia is just one complication reported in the JAK/STAT class.
“What we did not know, early on, was that they could have side effects in lipids,” Gadina said. “We were not expecting the thromboembolic events, and we still do not completely understand why they arise.”
One theory is that thrombopoietin is a cytokine that uses the JAK/STAT pathway and in particular utilizes JAK2 in its signaling cascade, according to Gadina.
“This is the scientific basis for these events, but it is not a complete explanation,” he said.
Gadina additionally cited the complexity surrounding the safety data from ORAL Surveillance, a post-marketing safety clinical trial that evaluated tofacitinib (Xeljanz, Pfizer) vs. TNF inhibitors in patients with active RA despite methotrexate therapy. The initial results, which have since triggered multiple FDA warnings, some post-hoc analyses and scores of commentaries, suggested that MACE and malignancy risks were increased in the tofacitinib arm.
“Of course, the findings from the ORAL Surveillance study showed that tofacitinib might increase risk of cardiovascular events and cancer,” Gadina added. “TNF inhibitors did not carry the same risks.”
According to Strand, there are two ways to interpret the results from ORAL Surveillance.
“Some believe there is a relationship between JAK inhibition and MACE and malignancy,” she said. “But there is also the chance that TNF inhibition is protective of those events. It may be impossible to prove.”
However, Gadina noted “hundreds of thousands of patients” in WHO and CORONNA registries who have been treated with JAK inhibitors but did not experience these events. Moreover, additional recent studies, such as the German RABBIT register study, showed that MACE did not occur more frequently in patients with RA treated with JAK inhibitors vs. those who received conventional DMARDs or biologics, even in patients with higher risk profiles.
“So, the reality is really complicated and may depend on many other factors,” he said.
Nonetheless, in older patients and those with preexisting risk factors for cardiovascular outcomes or malignancy, caution should be used, according to Gadina.
“For younger and healthier populations, they may be safe,” he added.
Meanwhile, first- and second-generation JAK inhibitors are “not that different” in terms of thromboembolic events, according to Gadina. It remains to be seen whether either selectivity or novel medications may improve on these events, he said.
“It is likely, but we still have to look at more data from more patients before we can make any call,” said Gadina.
As researchers wrestle with questions pertaining to the large number of medications in the JAK/STAT class, investigation into the complement system features fewer drugs but equally significant potential.
Cascade of Proteases
The key challenge with targeting the complement system is that when it is activated, there is a cascade of proteases that is delicately balanced. It is often difficult to determine how and where dysregulation has occurred in this cascade, and even more difficult to intervene appropriately and effectively.
Despite these challenges, many experts view findings from the ADVOCATE trial, conducted by Jayne and colleagues and published in the New England Journal of Medicine, as a beacon of hope for rheumatology.
The researchers assigned 166 patients with ANCA-associated vasculitis to avacopan, while 165 were treated with prednisone. Eligible participants also received either cyclophosphamide followed by azathioprine or rituximab (Rituxan, Genentech). Results demonstrated that 72.3% of patients in the avacopan arm, and 70.1% of those who received prednisone, achieved the primary endpoint of remission at 26 weeks, which the researchers noted met non-inferiority criteria. Moreover, 65.7% of patients in the avacopan arm, and 54.9% of those receiving prednisone, remained in remission through week 52.
“The C5a receptor is expressed on neutrophils, and ANCA vasculitis neutrophils get recruited and activated by C5a, and increase their expression of ANCA on the cell surface,” Salmon said. “If you block the C5a receptor, you can block ex-pression of the ANCA antigen on neutrophils and the result is less damage.”
According to Strand, the safety of the approach is also worth considering.
“An impressive point from this study is that patients who got avacopan with rituximab induction had less renal disease in the end — and they reported improved health-related quality of life compared with the prednisone arm,” she said. “That is a big plus in lupus nephritis.”
However, there is more work to be done to understand the complement mechanism completely.
In a paper published in Nature Reviews Rheumatology, Holers raised several questions for ANCA-associated vasculitis. One is whether avacopan, or complement inhibition in general, can be effective in other forms of vasculitis, including eosinophilic granulomatosis with polyangiitis or IgA vasculitis.
“It is also uncertain whether the major effect of complement activation is on the neutrophil surface, NETs, platelets, vascular endothelium and/or renal glomerular cells,” Holers and colleagues wrote.
Moreover, the researchers expressed concern about whether complement activation can cause injury to the upper airways, muscle and skin.
“Finally, in this condition, as well as in nearly all of the indications for which complement inhibitors are approved, it is not clear when a complement inhibitor could be safely stopped,” they wrote.
This is a critical part of the discussion regarding, for example, avacopan, for one important reason, according to Salmon.
“Avacopan has the potential to be quite effective for steroid sparing,” she said. “We as rheumatologists are always looking for ways to get our patients off of high dose steroids, especially those with ANCA-associated vasculitis.”
Although there is no complement therapy approved in lupus yet, Salmon said she believes that the possibility of therapeutic intervention still exists.
“It is easy to imagine that if you block C5a or some other neutrophil activation or inflammatory pathway, it is conceivable that you can prevent organ damage,” she said.
However, there are limits to C5a blockade in lupus. Specifically, it will not prevent autoimmunity, according to Salmon.
That said, there may be scientific rationale to target other components of the complement system in lupus, which could influence autoimmunity as well as inflammatory damage, she added.
“We measure C3 and C4 in lupus,” Salmon said. “When they go down, we see an increase in lupus activity, and that has been hinting at what we should consider.”
‘Very Close to Approvals’
Regarding other conditions, Salmon argued there is also a rationale for C5a blockade in antiphospholipid syndrome.
“Animal models have shown that if you block C5a-C5a receptor interactions, you can prevent APS-associated pregnancy complications,” she said.
However, whether pharmaceutical companies will pursue this approach in humans remains to be seen.
The complement system has additionally been implicated in conditions ranging from dermatomyositis to osteoarthritis, according to Salmon.
“After acute injury like ACL rupture, complement activation can lead to secondary trauma,” she said.
According to Salmon, rheumatologists should pay attention to the approval of pegcetacoplan (Syfovre, Appellis) for complement blockade in paroxysmal nocturnal hemoglobinuria.
“We are very close to approvals in autoimmune conditions,” she said. “Rheumatologists may then consider off label uses.”
Strand acknowledged that the average rheumatologist may not be intimately familiar with complement-based therapies. However, that shouldn’t stop them from learning about these agents sooner rather than later.
“The problem is that the complement system is very complicated,” Strand said. “It is difficult to keep up with, but we should try, because we could be treating our patients with this approach in the future.”
According to Salmon, rheumatologists hoping to treat a patient with complement inhibition should follow a few crucial steps before jumping in.
“It is essential to vaccinate patients to encapsulated microbes, including pneumococcus and meningococcus, prior to initiating therapy,” she said. “Infections are the main concern.”
Medications targeting the complement system are “unlikely to be used broadly in rheumatology practice,” according to Salmon. However, she suggested that they may have roles in acute injury or flares in OA.
“They might also have a role in RA, as has been suggested in experimental models, but translation to patients would need a lot more research,” Salmon said.
As complement inhibition moves closer to the clinic, a look into the pipeline may help rheumatologists understand how they may be treating patients in the next decade.
‘Tantalizing’ Approach
In a presentation at the 2023 Association of Women in Rheumatology annual meeting, Wright noted that FcRn can accelerate the destruction of IgG and reduce the associated pathogenic processes without impacting IgA, IgM, IgE, the complement system or B cells, as the innate and adaptive immune systems mount a response.
“Because it is a recycling mechanism and a sorting mechanism, it is kind of tantalizing to think about as a therapeutic approach,” Wright told Healio Rheumatology.
Essentially, targeting the FcRn can prolong the life of necessary antibodies living in serum “without interfering with the rest of the immune system,” according to Wright.
However, this approach comes with an obvious concern.
“If I block the binding of this receptor, it may lead to degradation of helpful antibodies,” Wright said.
This may be one reason why no approvals of an FcRn product have come through the rheumatology space at this time. However, Calabrese said he foresees broad applicability if researchers and clinicians can work out the details.
“The beauty of this compared with more specific therapies is that this can be used in diseases where we are not sure which antibody is contributing to pathogenesis,” he said. “In autoimmune diseases, we generate immunoglobulins against a wide variety of targets. For a generation, there have been efforts to target these antibodies with very broad therapies like plasmapheresis or IVIG.”
That said, Calabrese described those approaches as “nonspecific, cumbersome and extraordinarily expensive.” He suggested that FcRn is “IVIG or plasmapheresis in a bottle.”
However, this is not the only potential positive impact.
“So far, research has shown that the safety signal is extraordinary,” Calabrese said.
Some of the rheumatic conditions in which FcRn may theoretically be useful include lupus, Sjogren’s syndrome, RA, ANCA-associated vasculitis or even fibromyalgia, according to Calabrese.
“It is also being studied in POTS in patients who developed it after COVID-19,” he said.
Calabrese added that he believes strongly that trials of FcRn inhibitors “make a great deal of sense” and are “urgently needed” in long COVID, as well as in dysautonomic states accompanied by features of autoimmunity.
The key potential benefit is that a broad base of autoantibodies may be driven down using FcRn, according to Calabrese.
“This may represent a treatment that is effective against a broad array of autoimmune diseases, in the best-case scenario,” he said.
As researchers continue to explore this mechanism, other approaches highlighted by Wright and Strand, such as targeting BDCA2 and PD-1, could further bolster the rheumatology armamentarium.
‘A Great Step Forward’
According to Wright, lupus is the first and most attractive target for the BDCA2 approach.
“In lupus, we are always worried about the interferon that is activated,” she said. “BDCA2 is a molecule that is only found on plasmacytoid dendritic cells. By disrupting that pathway, we can disrupt the interferon pathways.”
Phase 1 trials of litifilimab (BIIB059, Biogen), a humanized monoclonal antibody that binds to BDCA2, have demonstrated encouraging results in both cutaneous and other types of lupus, according to Wright, who noted improvements in both tender and swollen joint counts have been observed.
However, data from phase 2 trials assessing at BDCA2 remain “limited,” she added. Nonetheless, Wright said there is still some hope in this approach.
“We are starting to see a separation between active therapy and placebo, with an acceptable safety profile,” she said.
Wright additionally suggested that BDCA2 may be useful in combination with other therapies to target both arthritis and skin disease. However, more research is necessary to explore these options.
Meanwhile, the main data set for PD-1 inhibition is a phase 2 trial in rheumatoid arthritis for peresolimab. The hypothesis is that binding peresolimab to PD-1 could stimulate physiological immune inhibitory pathways to restore immune homeostasis.
Results of the study — a double-blind, placebo-controlled, randomized clinical trial of 101 patients with RA — demonstrated significant improvements from baseline to week 12 in DAS28-CRP score in both the peresolimab 700 mg (P < .001) and 300 mg (P = .017) groups, compared with placebo.
“The peresolimab trial is very exciting,” Strand said. “The safety profile is very good, not like what we worry about with more extreme approaches like CAR T cells.”
Calabrese acknowledged that although such “extreme approaches” have the alure of potentially being curative, many of the other strategies in the rheumatology pipeline are geared toward minimizing disease activity, reducing steroid use and helping patients reach remission.
“We do not cure immune mediated diseases, period,” he said. “That unfortunately has not been our business. What we have is a lot of poorly understood diseases. If we can find a new class of drugs that are broadly suppressive of disease activity for a period of time, and with a tolerable safety signal, that is a great step forward.”
- References:
- Chimalakonda A, et al. Dermatol Ther (Heidelb). 2021;doi: 10.1007/s13555-021-00596-8.
- Emery P. Abstract L03. Presented at: ACR Convergence 2022; Nov. 11-14, 2022; Philadelphia (hybrid meeting).
- Holers VM. Nat Rev Rheum. 2023;doi:10.1038/s41584-023-00981-x.
- Jayne DRW, et al. N Engl J Med. 2021;doi: 10.1056/NEJMoa2023386.
- For more information:
- Leonard Calabrese, DO, can be reached at 9500 Euclid Ave., Cleveland, OH 44195; email: calabrl@ccf.org.
- Massimo Gadina, PhD, can be reached at National Institutes of Health Building 10, Room 10N311-G, Bethesda, MD 20892-1560; email: gadinama@mail.nih.gov; reynoldsp2@mail.nih.gov.
- Jane Salmon, MD, can be reached at 535 E 70th St. 6th floor, New York, NY 10021; email: salmonj@hss.edu.
- Vibeke Strand, FACP, MACR, can be reached at 300 Pasteur Dr., Stanford, CA 94305; email: vibekestrand@me.com.
- Grace C. Wright, MD, PhD, can be reached at 345 E 37th St., Suite 303C, New York, NY 10016; email: grace.wright@awirgroup.org.
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