Have JAK inhibitors failed to meet their promise?

6 minute read

The JAKi debate isn’t over: Helen Keen and Andrew Östör argue the cases.

The JAKi debate isn’t over: Helen Keen and Andrew Östör argue the cases.

Recent years have heralded broader uptake of JAK inhibitors globally, but Australia has been particularly forthright in its gusto for doing so. While on one hand, new data and new indications keep being presented, on the other hand, the questions that loomed five years ago have only loomed larger as time had gone on.

The question remains: have JAK inhibitors failed to meet their promise?

While this debate is never black and white, sometimes you need to hear the full-blooded case either way, not least of all for a bit of fun. I asked Associate Professor Helen Keen and Associate Professor Andrew Östör to put aside their magnanimity, don their best debating jackets, and make their case for and against. Let the games begin…

Yes: Associate Professor Helen Keen

The Great Debate is arguably the highlight of the American College of Rheumatology Annual Scientific Meeting.

Characters from the academic rheumatology world go head-to-head on a topical issue. The scientific evidence is necessarily massaged to build the assigned viewpoint and the audience stands in judgment. The Great Debate is always great fun, but not always great science.

In 2020, Dr Vibeke Strand and Dr Michael Weinblatt debated the question of whether Janus kinase inhibitors (JAKi) should be given before biologics following methotrexate failure in rheumatoid arthritis.

Dr Strand debated the affirmative, focusing on the impressive efficacy data seen across the whole JAKi class in clinical trials in rheumatoid arthritis. Conversely, Dr Weinblatt, in debating the negative, focused on safety. He first visited the established long-term safety of TNF inhibitors, and then turned to the questions that existed in 2020 regarding the safety of JAKi, namely the possible risk of thrombosis, the lack of pregnancy and breastfeeding safety data, and the increased risk of zoster infection.

The audience was asked to vote and 69% agreed that JAKi should not be used before biologics. Americans seemed cautious.

Australians, however, seem enamoured. The first JAKi, tofacitinib, became available in Australia for RA in September 2015, followed by baricitinib in 2019 and upadacitinib in 2020. PBS data demonstrates that in the 2019/20 financial year, the total cost of our old friend adalimumab was $331.6 million and for tofacitinib it was $105.1 million.

The Australian OPAL registry demonstrated that, since 2015, people with RA are prescribed a TNFi 46% of the time, but a JAKi 32% of the time. OPAL clinicians report that the mechanism of action and efficacy was the reason for choosing a JAKi. Clearly, Australians think JAK inhibitors work. But are they safe?

In initially approving tofacitinib for the US market, the FDA required Pfizer to undertake additional safety studies, specifically examining the effect of tofacitinib on CV events, cancer and opportunistic infections.

In February 2021, the FDA released a statement detailing that tofacitinib is associated with an increased risk of serious heart-related events and cancer, when compared with TNF inhibition. On 1 September, the FDA went on to extend the boxed warning to baricitinib and upadacitinib – in the absence of large safety trials – because of “shared mechanisms of action” with tofacitinib.

A post-marketing study comparing treatment with tofacitinib 10mg twice daily versus TNFi, in people with RA over 50, and at least one CV risk factor, found an increased risk of PE events and all-cause mortality.

The 1 September FDA communication states: “The trial’s final results also showed an increased risk of blood clots and death with the lower dose [5mg bid] of Xeljanz.” Another post-marketing study of tofacitinib across RA, PsA and PsO found that thromboembolic events were more common in people with baseline cardiovascular or VTE risk factors.

“At risk of CV disease” was defined as age ≥50 years and one additional risk factor, including: current smoker, low high-density lipoprotein (HDL), hypertension, diabetes, myocardial infarction or coronary heart disease. 

“At risk of thromboembolism” was defined as any of the following: aged ≥60 years, current smoker, previous heart failure, previous VTE (DVT or PE), BMI >/=30, using oral contraceptives or hormone replacement therapy, antidepressants or aspirin.  

I suspect the majority of public tertiary hospital patients might have an “at risk” profile.

The FDA also reports an increased risk of lymphomas associated with JAKi compared with TNFi, and an increased risk of cancer in past or present smokers.

There’s a lot I don’t understand. How do JAKi’s cause clots? Does a pan-JAKi have the same side-effect profile as a selective JAKi? What is the data regarding cancer? Why were filgotinib clinical trials ceased because of concerns about low sperm counts, when the trial apparently showed this occurred more commonly in the placebo arm?

The Great Debate isn’t over. But until it is, perhaps 69% of Americans are right to be cautious.   

No: Associate Professor Andrew Östör

The recent FDA black box warning regarding JAK inhibitors has sent the rheumatology community into a tizz. Decrees regarding AMI, cancer and VTE are, of course, not to be taken lightly. However, there are several issues to consider.

Firstly, the warning was in relation to the FDA-mandated ORAL Surveillance study looking at high-risk individuals (adults >50 with at least one CV risk factor), receiving either tofacitinib or TNFi for RA. Of note, the overall number of actual serious adverse events was low. Although these were seen more commonly in the tofacitinib group (numerically but not statistically), events were also seen in the TNFi group. Overall, the numbers needed to harm were high: 250 for cancer and 500 for AMI. It should be remembered, however, that RA is a serious illness with major complications if left untreated, including cancer and CV disease. Is adalimumab more protective than tofacitinib? It’s unclear at this stage.

Secondly, all JAK inhibitors were implicated whereas the randomised trial data exists only for tofacitinib, – not baricitinib, upadacitinib or filgotinib. The main role of the FDA is safety, so it’s not surprising they issued a blanket warning.  But is this appropriate? To date the published observational data with JAKi have not shown an increased risk, so should the warning not have been focused on the specific results from the ORAL Surveillance study? After all, we are supposed to practice in an evidence-based manner, are we not? Of note, the EMA and TGA have not yet issued similar warnings.

Thirdly, JAK inhibitors have shown to be highly effective and convenient in many patients with RA, so would we now deny these individuals an early shot at ‘normal’ life? So far, when I have broached this subject with patients, they are pretty keen to stay on their treatment.

Finally, with every patient we undertake the risk:benefit calculation prior to introducing a new therapeutic agent. How much time do we spend discussing the pitfalls of NSAIDS or steroids or even conventional DMARDs or, for that matter, not treating at all?

Overall, the benefit of the FDA warning is that it reminds us to keep safety in the forefront of our minds and to be vigilant for treatment complications. Risk stratification is likely to be more focused as a consequence. Will prescribing change in Australia as a result of the warning? I suspect not, but the consultation will take slightly longer.

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