FDA Alerts Clinicians and Public of Cardiac and Cancer Risks from Tofacitinib.

Long Term Clinical Trial Data Suggest Tofacitinib (Xeljanz) Increases Cancer and Cardiac Events in Rheumatoid Arthritis Patients.

On February 4, 2021, the FDA published a press release to advise the public and physicians about new concerns that have arisen regarding an increased risk of cancer and heart problems in rheumatoid arthritis patients using tofacitinib. Data from a long term clinical trial that the Pifzer company was required to do showed an increased risk of heart problems (including heart attacks) and strokes and cancers in rheumatoid arthritis patients who were in the trial. Here, we will take a look together at some of the important points and what it means for hair loss patients who might be using tofacitinib.

A new warning from the FDA points to an increased risk of heart problems and cancer in rheumatoid arthritis patients over 50 who use oral tofacitinib. How exactly this applies to hair loss patients who use JAK inhibitors is not clear but patients are advised to review the information on a case by case basis. Final data and recommendations are still pending from the FDA.

A Closer Look at the ORAL Surveillance Study

When FDA first approved tofacitinib in 2012, they required the drug manufacturer Pfizer to keep studying the study and any side effects the drug might have and not simply stop all types of monitoring and close down the trial. Drug companies are no longer able to close up trials once health regulatory bodies like the FDA approve a drug for the public: long term study afterwards is now mandatory and drug companies face huge fines for failing to do so. Therefore, this type of post approval monitoring is mandatory now in clinical trials and is known as “post marketing surveillance” or simply “phase 4” of a clinical trial.

The ORAL Surveillance Trial (Study A3921133; NCT02092467) is the name of this post marketing safety trial that the Pfizer company was required to do. It was a safety trial and involved patients with rheumatoid arthritis who were taking either tofacitinib or a drug known as a TNF inhibitor. The dose of tofacitinib that patients were taking in the study was either 5 mg twice daily or 10 mg twice daily. The TNF inhibitor that was used was adalimumab (Humira) for clinical trial patients living in the United States, Canada, and Puerto Rico, and etanercept (Enbrel) in other countries involved in the study. In total, 4,362 participants in the ORAL Surveillance trial were randomized to either daily doses of 5 mg (n = 1,455) or 10 mg (n = 1,456) of tofacitinib or the TNFi (n = 1,451),

The patients in the ORAL Surveillance trial were required to be at least 50 years old and have at least one cardiovascular risk factor. Clinical trial participants have been closely followed since 2014 to see if they experience side effects such as cancer, blood clots and major cardiac events. In these trials, the terms “MACE” has been used to define a term major adverse cardiac events and included heart attacks (myocardial infarction), and strokes (cerebrovascular event) or cardiovascular death death (defined as death caused by coronary, cerebrovascular, or cardiac events).

In early 2019, the ORAL Surveillance Trial was forced to stop studying the 10 mg twice daily dose and move everyone who was receiving 10 mg twice daily down to 5 mg twice daily because data showed an increased risk of blood clots (pulmonary embolism) and death in those using 20 mg daily. A new black box warning then started to appear on the label.

What are the new results of the Oral Surveillance Study that the FDA is Concerned about?

New data has now emerged showing that rheumatoid arthritis patients over 50 using tofacinitib had more heart attacks, strokes and cancers compared to rheumatoid arthritis patients over 50 who were using a TNF inhibitor instead.

Specifically, the incidence of adjudicated malignancies was significantly higher in the tofacitinib group, compared with the TNFi group (1.13 vs. 0.77 per 100 person-years; hazard ratio, 1.48; 95% confidence interval, 1.04-2.09). The rate of MACE (major cardiac events like heart attacks and strokes) was also higher in the combined tofacitinib group (0.98 vs. 0.73 per 100 person-years; HR, 1.33; 95% CI, 0.91-1.94).

The types of cancers that have been observed in tofactinib users in the past include lung cancer, breast cancer, melanoma, prostate cancer, lymphomas and pancreatic cancer. These types of cancers also occur commonly in the general population in patients who do not use tofactinib. Interestingly, studies up to the year 2019 had suggested that the risk of cancer in tofacitinib users was similar to those who did not use tofacitinib. New data from 2021 this week suggest that the risk of cancer was increased.

What does this data mean practically?

For every 100 patients with rheumatoid arthritis that are treated with tofacitinb over a 10 year period there will be three more cancers attributable to tofacitinb compared to 100 patients in the same practice treated with a TNF inhibitor over a 10 year period.

Conclusion

This new data suggests that that rheumatoid arthritis patients over 50 have a 48% increased risk of cancer and a 33 % increased risk of major cardiac events with use of tofacitinib compared to TNF inhibitors. The FDA has issued this alert to warn the public and physicians but has stated that it is still waiting for final clinical trial data from Pfizer to be released so that a more formal and complete evaluation can be done.

Some of the key Questions that Now Remain

Many important questions now remain for patients with hair loss who wish to apply the information from the rheumatoid arthritis studies to their own situation. Such a direct comparison has its challenges but I will highlight some of the key issues here. Any patient wth hair loss wishing to stop tofacitinib should review the situation on an individual basis wth his or her physicians. There is no one answer that covers everyone.

1. Does this data apply to patients with alopecia areata and scarring alopecia who use tofacitinib?

The short answer is that this data from the FDA announcement applies to rheumatoid arthritis patients over 50. Other groups of patients were not studied and so the best we can do is interpret the data based on these studies the best we can. There will be limitations as to how broadly we can apply this data.

Tofacitinib is approved for rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. It is commonly used off label for treating advanced alopecia areata and sometimes used by dermatologists for lichen planopilaris and frontal fibrosing alopecia.

We do not have studies specifically addressing the risk of major cardiac events and cancer in patients with hair loss who use Tofacitinib. Such carefully controlled studies with Tofacitinib are not likely to be done either in hair loss patients - and we will rely on safety studies in other patient populations to guide us. If a drug company does plan to have a JAK inhibitor formally approved for alopecia areata, these long term studies will need to be done.

It is important to appreciate that patients with rheumatoid arthritis are a very different patient population than patients with hair loss. They have different baseline risks for developing certain diseases. We do need to be careful how we apply this information.

It’s quite likely that there will be an increased risk of heart problems and strokes and cancer in hair loss patients using tofacitinib compared to hair loss patients who don’t use tofacitinb. But how much of an increased risk? That we do not know.

Should a 24 year old patient with advanced alopecia areata who has now regrown hair with use of tofacitinib now stop? What are the harms and risks to the patient’s psychosocial state if he or she now stops Tofacitinib and loses all the hair that was grown back with tofacitinib? I can certainly tell you that the harms of losing hair once a patient has regrown hair are enormous. Does the hair loss patient using tofacitinib have a 33 % increased risk of heart problems and stroke? Probably not although we certainly can’t rule out a small increased risk. And what about cancer? Does remaining on this drug now increase the risk of cancer for this 24 year old patient? Yes, probably it does - but we do not know by how much exactly. The data in this study presented above do not state that patients who use tofacintib will go on to develop cancer. Not at all. The data states there will be an increased risk. Most people using Tofacitinib will not develop cancer and most won’t have a heart problems or stroke.

For every 1000 patients over 50 who use the drug for 10 years, there will be about 30 more cancers than if the drug was not used. The numbers are going to be lower for a person 24 years of age - but we just don’t know how much lower. For every 1000 patients in the 20s with alopecia universalis who use tofacitinib, how many of these will develop a cancer ? Will it be 2 or will it be 20 or will it be 30? We don’t know and certainly even one extra cancer is of great concern.

The reason this is such a challenging decision in some hair loss conditions like alopecia areata is that we don’t have any better treatment right now. For other hair loss conditions, like frontal fibrosing alopecia and lichen planopilaris, tofacitinib is not at the top of the list of treatments. There are equally good if not even better treatments. For advanced alopecia areata tofacitinib is the best treatment. There is presently nothing more consistently effective for managing alopecia universalis and alopecia totals than oral tofacitinib (or other JAK inhibitors). Hopefully soon there will be. For now, there is not.

These are some pretty hard discussions that doctors must have with patients. These are some pretty hard reflections that patients must have too. The patient, together with his or her doctor, must use what little information is available now to decide what do to. Given that these risks are long term risks, it’s okay for anyone with hair loss to take his or her time coming to the right decision.

2. Will short term use of tofacitinib be okay?

The risk of developing cancer and the risk of developing a heart attack or stroke have been studied by researchers for many decades. Older patients are at increased risks than younger patients. Lifestyle factors, like smoking, and obesity increase risk of these diseases. Some underlying genetic issues contribute to risk of both cancer and cardiovascular disease.

Short term use of tofacitinib in a patient with hair losss will likely carry less risk than long term use, but this of course, has not been studied. A 20 year old patient who uses tofacitinib for 2 years if probably at different risk than a 20 year old who has now used it for 6 years. Overall, both have relatively low risk for heart disease and cancer overall - but still it’s a very small bit elevated compared to a peer who does not use this medications. Neverthess, given that cancer and heart disease are so rare in this age group anyways - most clinicians are never going to see a hair loss patient in his or her 20s using tofacitinib that come into clinic with new diagnosis of cancer or heart disease. Is it still possible? Yes. Is it likely ? No.

A 60 year old patient who uses tofacitinib for 2 years if probably at much different risk than a 20 year old who has now used it for 2 years. We don’t have numbers because these key studies have not been done, but prior research in the cancer research field teaches us this would likely be the case.

The other issue that is highly relevant is whether short term use of tofacitinib is going to alter cancer risk later in life. That we don’t know yet, but it would be a mistake to think that it would have no impact. Does a patient who used Tofacitinib in his or her 30s for a period of 4 years and then stopped have an increased of cancer down the road in his or her 70s, 80s and 90s? We don’t know because thee studies have not been done. It’s certainly possible although the risk are likely small.

3. Does this apply to other JAK inhibitors like Baricitinib and Ruxolitinib?

We don’t know that answer yet but there could be some amount of increased risk. Baricitinib was approved in 2018 also with a black box warning for infections, malignancy and blood clots. In fact, the FDA only approved the lower 2 mg dose of the drug after highlighting safety concerns in the higher 4 mg dose was in question. Baraticinitb is conducting a post marketing surveillance study but that won’t be completed until 2025.

4. What are the key messages from this study that patients with hair loss should hold on to?

A key message is that there is a small risk of heart attacks, strokes and cancer in rheumatoid arthritis patients who use tofacitinib. It is challenging to know how exactly to apply this information to patients with alopecia areata or scarring alopecia who use tofacitinib but nevertheless we should not ignore the Pfizer company data. Any patient who is using this drug or plans to use this drug or any drug in its class needs to be aware of this information.

The FDA will review the data from the Pfizer company in more detail in the weeks and months to come. Patients should stay tuned with the final recommendations from the FDA. We don’t have those final recommendations quite yet. Those are coming. Certainly this will lead to new wording on the current black box warnings that a already exist with this drug. If the FDA is sufficiently concerned after going through all the safety data that Pfizer submits, they do have the authority to restrict or remove the drug from the market. I do hope this information leads to stricter post surveillance studies of ruxolitinib (Jakafi/Jakavi) and Upadacitinib (Rinvoq) and modifications of what data the FDA is going to be watching in post surveillance studies of baricitinib (Olumiant).

Right now, stopping the drug in all patients with alopecia totalis and universalis is not a primary recommendation. However, reflecting on the risk and benefits of the drug with each patient is something that is advisable. Some will want to stop after reviewing all risks and benefits. Many will want to continue. Tofacitinib has dramatically changed lives for the good. Given that there is no substitute yet that is anywhere near as effective for treating alopecia areata, the decision to continue must be balanced again the estimated risks.

Reference

https://www.fda.gov/drugs/drug-safety-and-availability/initial-safety-trial-results-find-increased-risk-serious-heart-related-problems-and-cancer-arthritis