The recent approval of baricitinib (OLUMIANT) likely signals that the revolution that has been biologics and the new non-biologic, targeted synthetic DMARDs in RA therapy still has a fair way to run yet. It was in the winter of 1982 working as junior resident in a ward full of elderly patients in Montreal, Canada that […]
The recent approval of baricitinib (OLUMIANT) likely signals that the revolution that has been biologics and the new non-biologic, targeted synthetic DMARDs in RA therapy still has a fair way to run yet.
It was in the winter of 1982 working as junior resident in a ward full of elderly patients in Montreal, Canada that Dr Simon Helfgott decided to become a rheumatologist.
Most of his patients were suffering the various ills that appear to come at that time of the year in Montreal, usually accompanying brutally cold winds and the odd snow storm.
He wasn’t interested in endocrinology because he felt it lacked complexity and he wasn’t big on surgery or procedures such as endoscopy. He was unsure what he did want to do but his choices were fast narrowing.
And then Dr Helfgott met Michael, a 19-year-old amid the sea of elderly patients. Since the age of five, Michael had suffered from systematic juvenile arthritis. He was only four feet five inches tall. (135cm)
The image and character of Michael sticks with Dr Helfgott to this day.
“His cherubic, slate grey face with undersized mandibles displayed the ravages of too many years of prednisone and gold therapies”, he wrote in a review piece published in The Rheumatologist in 2012.
“He had already undergone several orthopaedic procedures and one of them, his knee replacement, had become infected …He was admitted for a lengthy stay consisting of surgery, followed by a prolonged course of antibiotics, followed by more surgery.
“Yet Michael’s resilience and determination to get better never wavered. He was upbeat and cheerful to a fault.”1
Dr Helfgott had found his calling.
At that time, strategies for treatment had focussed more on treating current RA flares and the subsequent damage they caused, than preventing its progression.
The “gold standard” for treatment back then? Gold, of course (there’s only one time in medical writing you will get away with this joke). And while gold therapy had been shown to slow the progress of RA, side effects had meant its use was largely limited.
When Dr Helfgott made his choice of specialty in that Montreal winter of 1982, he can’t have known that rheumatology was about to witness a series of revolutionary treatment introductions, which would mean in less than a generation there would be no more “Michaels”.
To say the changes in treatment of RA since the early 1980s have been profound, is an understatement. Led initially by the introduction of methotrexate, and then followed by the development of biologics and most recently, targeted synthetic DMARDs, has meant a plethora of options now exist for RA patients, including those who don’t respond to the primary therapies.
The biggest step change, perhaps underlined by their commercial success as the most profitable drug class in history, has been the introduction of biologic disease-modifying antirheumatic drugs (bDMARDS), and specifically, the TNF-alpha inhibitors, at the beginning of the century.2
In some respects, the bDMARDS may have lulled the profession into a sense of complacency. The TNF-alpha inhibitor step change was so big, that subsequent improvements in therapy, even though they have often significantly expanded treatment options for RA patients have seemed small developments by comparison.
However, bDMARDS are only effective in about two thirds of RA patients and are contraindicated in some circumstances.3
So the need has been there for some time to look at more specific therapies which target certain classes of patients.
There are a range of different drug classes within the bDMARD group. TNF-alpha inhibitor represents just one but the most used. Others include IL-6 inhibitors, rituximab and abatacept.
Enter the Janus kinase (JAK) inhibitors such as tofacitinib (Xeljanz).
First appearing a few years ago, tofacitinib seems now to be the first in a new wave of treatment options for patients who fail to respond to bDMARDs and for many, these new agents will be first line options after failure of the conventional DMARDs .4
Practically, tofacitinib was also an oral medication taken twice daily versus the injectable or infused bDMARDs.
In Australia, after just a few years, tofacitinib already accounts for nearly one third of RA patient initiations if conventional DMARDS have proven inadequate or not been tolerated and up to one third of switches off TNF inhibitors when they have proven inadequate.3
In February, baricitinib (Olumiant) was approved for use in Australia by the TGA, and with it perhaps the idea that the revolution that was started with the TNF-alpha inhibitors, and seemed to stall for a decade or so, still has some way to run.
Baricitinib is a once daily oral JAK1 and JAK2 inhibitor versus twice daily tofacitinib, but in addition, early data from a study recently published in the New England Journal of Medicine suggests it might offer significant clinical improvement over the TNF-alpha inhibitor adalimumab (HUMIRA) which has probably been a defining standard of care for bDMARDS for the last 15 years.5
The RA-BEAM study was a 52-week, randomised trial of 1,307 patients with active RA who were receiving therapy with methotrexate and were randomly assigned either placebo, 4mg of baricitinib once daily, or 40mg of adalimumab every other week.
The study was conducted at 281 centres across 26 countries, was designed by the sponsor, Eli Lilly, and an academic advisory board who were not employees of Lilly. Patients in the study had had RA for an average of 10 years and about 75% had three or more erosions.
The researchers found that baricitinib had significant clinical benefits compared with placebo at week 12 and greater efficacy than adalimumab. Based on radiographic evidence, both baricitinib and adalimumab significantly inhibited progression of the disease at week 24 compared with placebo.
To week 24 serious adverse events were observed to be more frequent with baracitinib and placebo than with adalimumab. Other effects of both baricitinib and adalimumab included reduced neutrophil count, increased aminotransferase and creatinine levels, and increased LDL and HDL cholesterol levels.
The authors summarised their paper as follows:
“… in patients with active rheumatoid arthritis despite receiving therapy with methotrexate, the addition of once-daily oral baricitinib was associated with improvements in signs and symptoms, physical function, patient reported outcomes, and progression of structural joint damage as compared with placebo and with improvements in ACR20 response and DAS28-CRP as compared with adalimumab.”
Secondary analysis of the RA-BEAM study via patient reported outcomes (PROs) was completed in late 2017 and found that “baricitinib provided significantly greater improvement in most PROs compared with placebo and adalimumab, including physical function MJS, pain, fatigue and quality of life. Improvement was maintained to the end of the study (week 52)”.6
Nearly 3000 patients with RA who completed a previous baricitinib trial will be part of an ongoing long-term safety data study called RA-BEYOND.7
It is probably important to note here that although biologics have had a groundbreaking effect on RA treatment, the future of RA treatment is clearly not solely dependent on this drug class. With both biologics and the new non-biologic targeted synthetic DMARDs, the establishment of national registers is thought important in eventually understanding more fully the real-world effectiveness of RA therapies beyond that observed in randomised clinical trials.8
One key safety area researchers investigating the JAK inhibitors will be focusing on, is the possible venous thromboembolism (VTE) risk.
Five patients (0.5%) treated with baricitinib 4mg reported a VTE event during the 24-week, randomised, placebo-controlled time period. Notably, no events were reported with the 2mg dose or placebo during this time period.
On further analysis of data from all those RA patients who took baricitinib, 3492 patients (6726 patient-years of observation), 31 patients experienced a VTE with an exposure-adjusted incidence rate of 0.5 per 100 patient years.9
They are all small numbers so the data is not clear, but despite this, there has been some discussion in the US about the risk of VTE associated with JAK inhibitors, possibly as a class effect.
Commenting on this possibility in Medscape Medical News recently chief of rheumatology research at Swedish Hospital Medical Center and clinical professor of Medicine at University of Washington in Seattle, Philip J. Mease, MD, said.
“I certainly don’t dismiss the question or potential concern, especially since the FDA highlighted the imbalance between placebo and treatment arms in the baricitinib database, but to lump agents together as a class effect, especially since there may be real biological differences between the various JAK inhibitors, is too sweeping and potentially inaccurate. It is reminiscent of how celecoxib got stained when the rofecoxib myocardial infarction data came out, only to be exonerated years later by the PRECISION trial.”10
With its approval only formalised in Australia a few weeks ago, local rheumatologists are understandably wary about where baricitinib might sit in the progression of therapies but the promise seems to be clear at least.
Associate Professor Peter Nash, from the Department of Medicine at the University of Queensland told Rheumatology Republic that the RA-BEAM study is significant given its potential impact on the current, long-term gold standard treatment of RA namely the combination of a TNF inhibitor with methotrexate.
A JAK inhibitor/methotrexate combination showing superior efficacy, particularly on pain measures, compared with TNF inhibitors with methotrexate is an important step in RA treatment, said Professor Nash who is also Director of the Rheumatology Research Unit on the Sunshine Coast in Queensland.
He says the step change here is important enough to suggest that this JAK inhibitor class will likely keep expanding, representing a new era of RA therapy. He noted that there are two new JAK inhibitors currently in phase three trials, upadacitinib (late phase 3) and filgotinib, both of which are showing promise.
Dr Mona Marabani, past president of the Autralian Rheumatlogy Association and current vice president of Arthitis Australia, is enthusiastic about the developments.
“It is fantastic to have another option for treating our RA patients. Oral therapies have great appeal and, coupled with its excellent efficacy data, would provide a good therapeutic choice for patients,” she told Rheumatology Republic.
“[But], patients on these drugs will need their lipids monitored, and there may be a signal for venous thromboembolism, so as with all treatments, optimal patient selection is important.”
Dr Irwin Lim, rheumatologist at Sydney’s BJC Health says of baricitinib’s arrival, “the data looks good but I daresay, we need more time and clinical experience to work out where to use it”.
“Aussie rheumatologists are very comfortable using the incumbent biologic agents, especially the TNF-inhibitors due to the 15 plus years-experience locally and the safety profile over that period of time, in Australia and worldwide.”
However, given the success of tofacitinib (Xeljanz), Dr Lim clearly thinks there will be a market for a once daily oral tablet which is sufficiently potent.
“To my mind, the people I would consider for [tofacitinib], would be the people I would consider for [baricitinib],” he said.
When tofacitinib was introduced, some local rheumatologists noted that patients were coming in and requesting the medication after seeing public media coverage of the drug. As a once daily medication, and with early data indicating greater efficacy, it is likely that baricitinib’s treatment in the mainstream media may create a similar issue for local rheumatologists.
Depending on the long-term safety data (and between tofacitinib and now baricitinib) the JAK Inhibitor class seems to have created a feasible option for RA patients who aren’t responding well to methotrexate and TNF-alpha inhibitors such as adalimumab. And there are more currently under investigation such as filgotinib and upatacitinib which may offer further enhancements to targeted therapy past the baseline therapies on offer.11
Another therapeutic option currently under investigation with possibly a less toxic profile is the proteasome inhibitor. Proteasome inhibitors are molecules whose mode of action is to induce an unfolded protein response.
In their review of emerging RA therapies, Joachim Kalden et al suggest that given their lower toxicity profile, bortezomib or other newly developed proteasome inhibitors might become a “true alternative” for the treatment of RA patients.12
CONCLUSION
While the development of the major biologics at the beginning of the century was profound, the following decade saw a relative stagnation in the progression of RA therapy.
However, the introduction of the first JAK inhibitor just a few years ago, the promise of baricitinib and the development of other JAK inhibitors and small molecules such as the proteasome inhibitors mean that, once again there is progress in the world of RA therapies, particularly for those patients who do not respond to the baseline medications.2
“The last 20 years has seen an incredible change in the management of RA with the focus shifting from symptom management to aggressive targeting of remission and the prevention of disability,” says Dr Marabani.
“The biologics and now the tsDMARDs have powered this revolution.”
Even though the advancements in RA therapy since the days of Dr Simon Helfgott’s patient, Michael, have indeed been life-changing, it appears the run of RA therapy development still has some way to go yet.
References:
1. Helfgott, Simon M, A Short History of Rheumatoid Arthritis Therapeutics, The Rheumatologist, Jan 13, 2012
2. Aggarwal, S & Abraham, Rheumatoic Arthritis Treatments: A Historical Perspective, JSM Arthritis, 28 July, 2016 (1) 2
3. PBS Data, 2016/17. Collated & Analysed
4. Dillhon S, Tofacitinib: A Review in Rheumatoid Arthritis, Drugs, Dec 2017 (18)
5. Taylor PC, et al, Baracitinib Versus Placebo or Adalimumab in Rheumatoid Arthritis, New England Journal of Medicine, 2017, 3376 (7)
6. Keystone ED, et al, Patient Reported Outcomes from Phase 3 Study of Baracitinib or Adalimumab in Rheumatoid Arthritis, Annals of Rheumatic Diseases, Sept 5, 2017, (76)
7. www.ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01885078
8. Elena Nickphorou, et al, Biologics Registers in RA:methodological aspecs, current role and future applications, Nature Reviews: Rheumatology, 2017, MacMillan (13)
9. Australian PI, Olumiant, www.tga.gov.au
10. Kelly, Janis C, RA: Do JAK Inhibitors Increase Blood Clot Risk? , Medscape.com: Medscape medical news, December 22, 2017
11. Nakayamada S, et al, Recept Progress in JAK Inhibitors for the Treatment of Rheumatoid Arthritis, BioDrugs, Oct 2016, 30 (5)
12. Kalden, Joachim, Emerging Therapies for Rheumatoid Arthritis, Rheumatology and Therapy, June 2016, 10 (1007/s40744)
