Two steps forward, one step back: Hunting for a game-changer in scleroderma
Click Here to Manage Email Alerts
The last 3 years of drug development in scleroderma have come to represent everything that ails the current pipeline for that disease.
Within that time, rheumatologists have seen two FDA approvals and one high-profile phase 3 failure — two steps forward, one step back. Now, armed with lessons learned, the hunt for a game-changing drug in scleroderma continues.
Scleroderma, or systemic sclerosis, has the highest disease-specific mortality of all autoimmune diseases for one primary reason, according to Elizabeth R. Volkmann, MD, MS, Scleroderma Program director, and co-director of the Connective Tissue Disease - Interstitial Lung Disease Program, at the University of California, Los Angeles.
“The pathogenesis is complicated,” she said. “In some patients there is a strong component of inflammation, but in others there is also fibrosis. There can be vasculopathy, neuropathy, there is skin involvement, GI involvement, pulmonary disease and renal disease.”
In short, the multi-systemic nature of SSc has made it difficult to find a game-changing drug. The research community has therefore begun to pursue more targeted therapies to mitigate the individual manifestations of the disease. However, in pursuing the twin goals of an all-purpose drug and more precision treatments, researchers have had to rely on trial and error and, in some cases, post-hoc analyses to find drugs that work.
For example, tocilizumab (Actemra, Genentech) for SSc-associated interstitial lung disease (SSc-ILD), one of the most severe and potentially deadly complications of scleroderma, gained FDA approval in March 2021 not from a study testing the drug in SSc-ILD, but from one designed to assess cutaneous manifestations. The drug failed to show improvement in the skin, and it was only in a post-hoc analysis that the signal of efficacy in lung disease emerged.
In contrast, the tyrosine kinase inhibitor nintedanib (Ofev, Boehringer Ingelheim) followed a more traditional path, gaining FDA approval in 2019 for SSc-ILD after a dedicated study looking at that target.
Meanwhile, the aforementioned phase 3 failure occurred in the RESOLVE-1 study of lenabasum (Corbus Pharmaceuticals), an oral, small-molecule, cannabinoid-receptor-type-2 (CB2) agonist, in patients with diffuse cutaneous SSc and dermatomyositis with active skin involvement. The trial failed to meet its primary endpoint, but some experts remain optimistic.
“In the case of lenabasum, it might not be so simple as saying that the drug does not work,” Peter A. Merkel, MD, MPH, chief of the division of rheumatology and director of the Penn Scleroderma Center at the University of Pennsylvania, in Philadelphia, said in an interview. “I still think more evidence is required to draw that conclusion across the board. That pathway may have efficacy, it just may not be for those particular manifestations.”
Experts have no illusions that an all-purpose scleroderma drug will emerge in the near future, or that the movement toward more targeted therapies will allow for each individual patient to get the exact therapy they need. However, efforts are underway to reach both of these goals. To get there, it will be important to understand the SSc landscape as it stands today.
‘A Paradigm Shift’
Arguably the most important factor to understand in the race to develop treatments for SSc is its unpredictable, heterogenetic nature. According to Robert Spiera, MD, director of the Scleroderma, Vasculitis & Myositis Center at Weill Cornell Medical College, disease manifestations and speed of progression can vary across patients.
“Scleroderma is a heterogeneous disease, and although there are a few relatively distinct phenotypes, it is not always possible to predict which manifestation will declare itself or progress in any given patient, and what the tempo of progression in any individual patient might be,” Spiera told Healio Rheumatology.
Source: University of California, Los Angeles.
In some patients, SSc starts in the lungs, while others experience skin involvement first.
“Others do not have any skin or lung involvement at all, but start with gastrointestinal complications,” Volkmann said. “How you treat the patient depends on the stage at which it presents.”
This type of thinking — attacking the disease based on progression stage — is a hallmark of a recent evolution in scleroderma treatment, according to Dinesh Khanna, MD, MSc, Frederick G. L. Huetwell Professor of rheumatology and director of the Scleroderma Program at the University of Michigan.
“In my mind, there is a paradigm shift in how we think about SSc,” he said. “Historically, it has been thought of as a fibrotic disease, but if you look at recent data, it is clear that early disease is immunoinflammatory, and later it becomes fibrotic.”
The clinical implications of this are clear: Inflammation, if caught early on, can be treated; but fibrosis is more problematic, according to Spiera.
“There is a paucity of anti-fibrotic therapies,” he said. “A major challenge is that some disease manifestations are only recognized at a relatively late stage, when the functional limitation relates to incurred damage rather than active inflammatory disease, which in theory would be more easily treatable.”
However, simply understanding that the disease can progress differently in every patient is only part of the battle for rheumatologists. Developing effective therapies to manage that progression is also critical. That starts with research.
Lessons From RESOLVE-1
Challenges to clinical trial design — relating primarily to meaningful outcome measures that can capture impact of an investigational therapy — has been a persistent thorn in the side of scleroderma researchers, almost across the board, for decades. Few disease states demonstrate that more clearly than SSc, and few studies in SSc demonstrate that more clearly than RESOLVE-1.
Conducted by Spiera and colleagues, and published in EMJ Rheumatology, the analysis included 375 patients randomly assigned 1:1:1 to receive lenabasum 20 mg, 5 mg or placebo, all twice daily. Importantly, background immunomodulatory therapies, including mycophenolate mofetil (MMF) and methotrexate, were allowed in all patient groups as per clinician discretion. The primary outcome measure — a novel American College of Rheumatology composite response index in systemic sclerosis (ACR CRISS) — served as another key detail.
Results at week 52 showed no significant difference between the lenabasum 20 mg and placebo groups in terms of ACR CRISS.
There are multiple possible interpretations of this result. One explanation is that there may be a move toward CRISS, as opposed to modified Rodnan skin scores (MRSS), as an endpoint that can lead to FDA approval in cutaneous scleroderma.
“CRISS is currently undergoing assessment for approvability,” Spiera said.
For his own part, the RESOLVE-1 researcher noted another complication related to this endpoint.
“There was a much greater improvement in placebo treated patients than was anticipated, resulting in a ceiling effect of our primary outcome measure,” Spiera said.
For Volkmann, the presence of background therapies in this trial is also noteworthy.
“MMF is effective in the skin, so what this showed us is that patients receiving background MMF could do well,” she said.
According to Volkmann, this point complicates the ability to draw a clear conclusion on the efficacy of lenabasum in the skin.
Spiera explained the inclusion of background therapies in the study protocol, stating it was meant to replicate real-world practice.
“This was a very ethical trial design,” he said. “By that I mean that it approximated real-world practice, as most clinicians would treat patients with active and/or early diffuse cutaneous SSc (dcSSc) with immunomodulatory drugs and feel uncomfortable having such a patient treated with placebo for a year.”
Despite its failure to meet the primary endpoint, there are positives to be taken from RESOLVE-1, according to Monique Hinchcliff, MD, MS, director of the Yale Scleroderma Program.
“This is good news in the sense that the immunosuppression that we have been prescribing to patients for years is likely beneficial,” she told Healio Rheumatology.
Perhaps remembering tocilizumab’s roundabout path to FDA approval in SSc, Hinchcliff has not ruled out the possibility that lenabasum could have a place in scleroderma treatment.
“The trial results indicate that lenabasum was efficacious vs. placebo in patients who were not taking any additional immune suppression — for example, MMF or methotrexate,” she said. “Thus, lenabasum may be a useful therapy for dcSSc in patients who have tried and failed, or who are intolerant to, more standard immunosuppressive therapies.”
However, Spiera qualified this interpretation, noting the small number of participants who went without background immunosuppression.
“In that small group of patients in whom investigators chose not to use background therapy, CRISS improvements were minimal in placebo-treated patients, and there was a numerical advantage to treatment with lenabasum, although the numbers were small, so the differences were not statistically significant, and that observation should be interpreted with caution,” he said.
Learning From Failure
Like the tocilizumab trial before it, RESOLVE-1 is currently undergoing post hoc analysis to explore the possibility that lenabasum could show benefit in forced vital capacity or other pulmonary manifestations.
“We need to improve our ability to do subgroup analyses,” Volkmann said. “We need to look at patients with certain phenotypes to see who could derive the most benefit. Now, we just lump everyone together.”
According to Volkman, another take-home lesson from RESOLVE-1 pertains to individual doctor-patient relationships among participants in clinical trials.
“If the clinician is new, or has limited experience with scleroderma, or has not been trained well, it can be difficult to get an accurate MRSS or conduct a sufficient physical exam to determine the extent of the impact on the skin,” Volkmann said.
This may have impacted not only the results of this study, but other studies of dcSSc, she added.
Meanwhile, according to Merkel, it is encouraging that researchers are learning from setbacks and phase 3 failures.
“We are getting better at designing trials with outcomes that are measurable and meaningful to patients and clinicians, and that will lead to approval by regulatory organizations,” he said, noting the approvals of nintedanib and tocilizumab. “What we need to do now is apply those same principles in other manifestations of this disease.”
With CRISS as a novel endpoint, and a deeper understanding of the pathogenesis of scleroderma, researchers may eventually succeed in developing both an all-purpose drug and more targeted therapies. Meanwhile, as those agents undergo investigation, there are other therapeutic approaches that could potentially gain a place in SSc treatment, including stem cell transplantation.
Stem Cells: A ‘Safer Intervention’?
In a paper published in the New England Journal of Medicine, Sullivan and colleagues compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation (HSCT), plus immunosuppression with 12 monthly infusions of cyclophosphamide, in a cohort of adults aged 18 to 69 years with scleroderma. There were 1,404 paired comparisons assessing mortality, event-free survival (EFS), forced vital capacity, Disability Index of the Health Assessment Questionnaire score and MRSS.
Results showed that 67% of comparisons favored transplantation, vs. just 33% that favored cyclophosphamide, in terms of global rank composite score of the endpoints at 54 months of follow-up (P = .01).
The researchers concluded that myeloablative autologous HSCT demonstrated long-term benefits in patients with scleroderma, including improved event-free and overall survival, albeit with increased expected toxicity. They added that rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation.
“It is important to note that stem cell transplantation has been studied in randomized controlled trials,” Volkmann said, underscoring her earlier point about clinical trial design. “Data sets in both Europe and the United States have demonstrated the benefit of this approach in terms of mortality.”
However, not all experts are convinced that stem cells are the future. Safety is the primary concern, and, in particular, patients with cardiovascular complications of scleroderma can be at risk during this procedure.
“Patients have to be carefully selected,” Volkmann said. “This is usually not first-line therapy.”
Merkel acknowledged that safety should be top of mind when performing HSCT. However, he stressed that major centers that have been performing it for a long period of time have increased safety and minimized risk.
“It is a safer intervention than it was when many of the key clinical trials that led to its approval were done,” Merkel said.
Another reason that stem cell transplantation has become a more viable option is that patient selection has considerably improved, according to Hinchcliff.
“I do refer patients with progressive scleroderma for stem cell transplant when therapy does not seem to be working and at least one internal organ is involved,” she said. “The tough thing is deciding how long one should wait for immunosuppression to work. You want to be patient, but not wait too long or the patient may be too sick to undergo the procedure.”
As with so many other decisions in the rheumatology clinic, Hinchcliff stressed that patient input is critical.
“The best approach is a shared medical decision-making approach, where you work as a team in conjunction with the patient to review the risks and benefits,” she said, and noted one issue that she would discuss with the patient. “Stem cell transplant does not seem to improve hand fibrosis, and I make that clear when I refer a patient for severe skin involvement.”
According to Merkel, rheumatologists considering stem cell transplantation must also consider the fact that merely having scleroderma puts patients in the crosshairs for a number of adverse outcomes.
“We have to remember that scleroderma is a difficult disease that carries its own substantial burdens and complications,” Merkel said. “You have to measure stem cell transplantation against that.”
It is possible that the role of HSCT will become more clearly defined as researchers gain a deeper understanding of disease processes in scleroderma. Efforts to gain that understanding are currently underway in the research arena.
Meanwhile, other experts argue in favor of still other alternatives.
Molecular Profiling
According to Khanna, the rheumatology community should be following oncology and other specialties down the pathway of precision medicine. He suggested that a “deep dive” into the molecular profiling of scleroderma patients — looking at fibroblasts, immune system parameters, extracellular matrix production, interferon signaling and other factors — may reveal targets related to underlying disease pathogenesis.
“If we can reach a point where we are using a precision medicine approach, treating a patient to a target based on molecular profiling, you can see results,” he said.
However, before patients can be treated using this approach, the research community needs to be on board, Khanna said.
“There needs to be an a priori understanding of which patients will be put in clinical trials, whether we are targeting the lungs or the skin or other manifestations,” he added.
Khanna outlined strategies for translating such clinical trials into FDA approvals, stating, “Education of pharma and regulators is critical.”
That said, even achieving approval of one molecular profile for one indication could prove to be tricky business, according to Khanna.
“Will the FDA approve just one specific indication based on a molecular profile?” he said.
Like Khanna, Hinchcliff stressed the importance of pairing the right patient with the appropriate drug, and of conducting molecular profiling to determine subsets of patients who may benefit from a particular therapy.
“This is done in cancer all the time, so we should be able to accomplish this in scleroderma,” Hinchcliff said. “The problem is that cancer is a common disease and scleroderma, thankfully, is rare. Finding enough patients with scleroderma who have similar disease is challenging.”
Once those patients are found, there is an ever-growing “armamentarium of molecular assays” to assess their disease, according to Hinchcliff.
“The cost of these techniques is declining,” she said.
In addition, these are not the only technological advances becoming more prevalent in scleroderma.
“Similarly, new medical imaging and machine learning approaches are now being applied to solve the problem of accurately measuring disease and change in disease in patients,” Hinchcliff said, offering one final challenge for rheumatology researchers. “A blood marker would be most practical for screening patients, but to date, no robust blood biomarkers to inform treatment have been identified.”
It may be some time before these technological challenges are met and patient stratification tools are applied widely in clinical practice. However, in the meantime, scleroderma patients need treatment.
To that end, forward-thinking experts are now exploring the possibility of combination therapies and looking into the pipeline to see what is on the horizon.
Exploring the Combos and Beyond
According to Merkel, it is increasingly unlikely that a scleroderma “silver bullet” will present itself to heal all patients all of the time.
“It is a complex disease,” he said, echoing Volkmann’s comments that it is dermatological, vascular, inflammatory and fibrotic. “It would be difficult to find one thing that causes all that and address it therapeutically.”
Without a disease master switch, attention has turned to the use of concurrent or sequential combination therapies directed at different aspects of scleroderma.
Using all available tools and knowledge — from molecular profiling to experience with agents in other diseases — will help rheumatologists assess and treat scleroderma patients regardless of when they present or which disease manifestations happen to be flaring at that time.
“There are so many therapies out there and so many potential combinations of anti-inflammatories, antifibrotics and other drugs,” Khanna said, adding that JAK inhibitors and LPA1 antagonists are on the radar of the scleroderma world, as well. “Targeting different aspects of the immune system in early disease; that is where the field of scleroderma must go.”
According to Khanna, the goal should be to capture the effectiveness of autologous stem cell transplantation, but with reduced toxicity. MMF plus pirfenidone may be effective in the skin and fibrosis, respectively, and is currently being studied in the Scleroderma Lung Study 3, he added.
“People are looking at other targeted therapies such as anifrolumab in patients with an elevated interferon signature or anti-TLAI antibodies in those with elevated signature,” Khanna said. “We can use molecular profiling to find patients with elevated IL-6 and target those pathways. This strategy was successful in the approval of tocilizumab for scleroderma-associated lung fibrosis.”
For Hinchcliff, all of this points to a new era of research and, with it, hope for the future of scleroderma treatment.
“This is a super exciting time for scleroderma patients, doctors and researchers,” Hinchcliff said. “There are so many new agents that are in development for different scleroderma manifestations, I have to decline participation in some new studies to ensure that I fulfill my responsibilities for existing trials.”
- References:
- Khanna D, et al. Arth & Rheum. 2020;doi:10.1002/art.41055.
- Spiera R, et al. EMJ Rheumatol. 2021;8:60-62.
- Sullivan KM, et al. N Engl J Med. 2018;doi: 10.1056/nejmoa1703327.
- For more information:
- Monique Hinchcliff, MD, MS, can be reached at 300 Cedar Street, The Anlyan Center PO BOX 208031, New Haven, CT 06519; email: monique.hinchcliff@yale.edu; colleen.moriarty@yale.edu.
- Dinesh Khanna, MD, MSc, can be reached at 300 North Ingalls Street, SPC 5422, Ann Arbor, MI 48109; email: khannad@med.umich.edu.
- Peter A. Merkel, MD, MPH, can be reached at the White Building, 5th Floor, 3400 Spruce Street, Philadelphia, PA, 19104; pmerkel@upenn.edu.
- Robert Spiera, MD, can be reached at 535 East 70th Street, New York, NY 10021; email: spierar@hss.edu; sotoe@hss.edu.
- Elizabeth R. Volkmann, MD, MS, can be reached at 200 Medical Plaza Driveway Suite B365, Los Angeles, CA 90024; email: evolkmann@mednet.ucla.edu.
Collapse
Click Here to Manage Email Alerts