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The Future of JAK Inhibitors


Pharma companies have faced hurdles in gaining approval of Janus kinase (JAK) inhibitors for the treatment of rheumatoid arthritis. Denise Baldock, Elizabeth Baynton, Amanda Baskett, and Nicola Bailey look at what can be learned from the lessons of the past.

Over the last 6 years, pharma companies have experienced certain hurdles in gaining approval of Janus kinase (JAK) inhibitors for the treatment of rheumatoid arthritis (RA). Denise Baldock, Elizabeth Baynton, Amanda Baskett, and Nicola Bailey look at what can be learned from the lessons of the past.

News of Xeljanz, marketed by Pfizer, was shrouded in much excitement; it was set to be the first oral advanced therapy to treat RA. However, things did not go as smoothly as expected. The brand was successful in achieving FDA approval in the US in November 2012, but was hit with a negative opinion from the European Medicines Agency in April 2013[1] – only gaining EMA approval four years later in March 2017[2]. It is now launched in both regions.

In April 2017, Eli Lilly & Company faced a major setback in bringing its own JAK inhibitor, Olumiant, to the US market. The FDA requested additional clinical data on Olumiant’s dosing to further characterize safety concerns in specific treatment arms[3]. Then, in April 2018, the FDA voted against the approval of the 4mg once-daily dose of Olumiant, again citing safety concerns, this time for the risk of venous and arterial thrombosis[4].

It isn’t all doom and gloom for Olumiant, however. For one, the FDA Arthritis Advisory Committee has approved the once-daily 2mg dose of Olumiant for treatment of moderate to severe RA. Meanwhile, across the pond in Europe, Olumiant was the first JAK inhibitor to market in the EU, achieving EMA approval with both the 2mg and 4mg dosing in February 2017.

Olumiant has been making the most of its time on the market thus far – already posting sales of $49.5 million for the year[5], which is no small feat for a newly launched product entering an entrenched marketplace. This is corroborated by data from Ipsos’ Global RA Therapy Monitor – a syndicated patient record study among prescribing rheumatologists* – which show the brand having already attained 3+% of the EU5 biologic/targeted synthetic DMARD market by Q4 2017.

The real unknown is what hurdles Lilly will face with Olumiant in the US market. To give us some indication, we looked at the parallels between Pfizer’s experience with Xeljanz and that of Lilly…

Xeljanz vs. Olumiant

Xeljanz’s success in the US market (where it has achieved $1.1 billion in sales in 2017 alone[6]) suggest that some of Pfizer’s tactics have paid off, regardless of its EU setback. It will be interesting to see how the brand now performs in the EU market where it has reported similar sales levels to Olumiant for the year, coming in at $39 million in sales in 2017[7].

Despite the fact that the markets which first gave Xeljanz and Olumiant the green light are reversed, the parallels between these brands’ situations are worthy of note. Lilly – and other pharmaceutical clients with JAK inhibitors in development – can learn from the challenges Xeljanz has encountered, as well as consider the approaches taken to overcome initial setbacks.

Any time lost on the market due to approval delays obviously has implications for a new brand’s overall potential, but there are other factors that will impact its success too – namely, the ability of existing brands to further establish their market presence and any damage done by initial setbacks to physician and patient perceptions.

When considering the difficulties faced by the JAKs in getting to market, the two forerunning brands have weathered the storm well. The prescribing behavior of the c.100 EU5 rheumatologists in Ipsos’ RA Therapy Monitor suggests that both brands have had a healthy uptake in their first year of launch – with around 35% of our panelists prescribing at least one of the brands.  

Click here for Figure 1: Venn diagram showing distribution of prescribing by brand loyalty

How does the breadth of usage pan out over time?

Given that the US has had a JAK inhibitor on the market for some time, US physician usage may be a useful proxy for EU5 physician usage. Ipsos’ US data show a significant increase in breadth of usage for Xeljanz in its first year of availability – from 31% to 77%. While our European data do not reflect this level of uptake for either brand in its first year, looking at growth across 5 quarters tells a different story. From Q3 2017 to Q1 2018, the data show a circa 30% increase in the proportion of panelists managing Olumiant patients. If we were to assume a similar growth rate up to Q3 2018 (data available in October 2018), this would bring the proportion of rheumatologists in our panel managing Olumiant patients to around 75%. This is in line with what we’ve seen of Xeljanz’s uptake in the US.

Click here for Figure 2: Breadth and depth of Olumiant vs Xeljanz in the EU5 and US

Of course, breadth of usage is only one part of the puzzle. We also need to understand the number of patients to which these early prescribers are issuing the new JAKs.

In the US, adoption among early prescribers in our panel grew quite rapidly. Between 2013 and 2015, our data show Xeljanz prescribers increasing their patient caseload depth – meaning not just more doctors prescribing, but more doctors prescribing to more patients.  

This was also reflected in the EU5, but at nowhere near the same magnitude. RA Therapy Monitor data show that, within a year of launch, Xeljanz is being prescribed by 37% of rheumatologists and Olumiant by 47% of rheumatologists – so, already quite different to the uptake we’ve seen in the US. Additionally, our EU5 panelists’ caseload of JAK patients is considerably smaller than that of our US panelists.

At the brand level, Olumiant is winning on achieving a greater increase in breadth and depth among our panelists, quarter on quarter, versus Xeljanz.  This is evidenced by the 12% of EU5 rheumatologists who prescribe Olumiant to 5+ patients each versus Xeljanz which, as of Q1 2018, had 6% of EU5 rheumatologists prescribing at the same patient volumes.

What are the key drivers for JAK choice and how has perception shifted over time?

Biologics that work by inhibiting the tumor necrosis factor (TNF) have been used for several years and are well-entrenched in the advanced therapy market. So, what drives a rheumatologist to choose a TNF or a JAK for their patient? When selecting reasons from a pre-defined list, 45% of the rheumatologists in our panel noted ‘positive personal experience’ with TNFs – reflecting the established heritage of the TNF class in treating RA. By contrast, just 12% selected this as a reason for choosing JAKs. 

However, for a very long time, only injectable therapies were available to combat disease progression among moderate to severe RA patients – so it is no surprise to find that ‘mode of administration’ is a statistically significant differentiating driver for the orally-administered JAKs versus the injectable TNF inhibitors.  Furthermore, it can be argued that the oral administration offered by the JAKs has also played a role in differentiating JAKs from TNFs on another factor, including ‘patient request.’

Pfizer and Lilly have obviously been trying to make the most of their products’ oral administration, but what other reasons of choice have resonated with rheumatologists?  Based on our panel’s responses to a pre-defined list of reasons for choice, some were significantly higher for JAKs than for TNFs – including ‘efficacious as a monotherapy,’ ‘pain reduction,’ and ‘reduction in morning stiffness.’

So, based on our data, we can see some clear trends coming through: the TNFs are still benefitting from our panelists’ familiarity and long-term real-world market experience, whilst the JAKs are leveraging their oral administration as well as honing in on specific efficacy attributes to strategically position themselves in the crowded RA market. Although they will still have to overcome the natural market barriers that exist for all new entrants (e.g. safety, efficacy and patient persistence), the relative infancy of JAKs in the market, coupled with the increasing number of rheumatologists in our panel prescribing Xeljanz and Olumiant, suggest there is a bright future for the class.

Click here for Figure 3: Selected reasons to prescribe TNF inhibitors vs. JAKS (EU5)

According to our data, despite key differentiating drivers affording a successful post-launch impact, the initial EMA rejection of Xeljanz did affect its performance in the US.  Six months after the initial rejection, Ipsos asked the US rheumatologists in our panel to share how they felt: 35% indicated that the recent EU rejection did affect their prescribing and half cited safety as their main concern, despite Xeljanz having been on the US market for a year. That said, there were also positive inroads being made a year after launch in the US. ‘Waiting to assess outcomes in patients’ significantly decreased as a concern of using Xeljanz. This suggests US physicians’ growing confidence in the drug alongside a significant decline in patient apprehension around Xeljanz, with just 4% of rheumatologists in our panel having residual concern.

The question is, will Olumiant face a similar scenario in the EU – with the initial setback in the US dampening its overall potential?  Based on Xeljanz feedback, it is likely to have some impact, but to what extent and whether this will ever be truly measurable is another matter.  Olumiant has already been carving a piece of the EU advanced therapy market and, as Pfizer has proven, even an initial setback does not preclude success – it may just affect the speed and degree of that success.

With Gilead’s filgotinib and AbbVie’s upadacitinib in development – both having strong efficacy and safety data and no apparent hurdles looming – the advanced therapy market for RA is expected to become increasingly crowded. How will the future landscape change to accommodate this? There is no clear answer to this question, but one thing is certain: pharmaceutical companies will need to ensure clear messaging strategies to secure a spot in the evolving treatment paradigm.

Denise Baldock, Elizabeth Baynton, Amanda Baskett, and Nicola Bailey are members of Ipsos’s Global Autoimmune Therapy Monitors Team.

About the research

Drug treatment patterns discussed in this article were investigated using the Ipsos Rheumatoid Arthritis (RA) Therapy Monitor, a patient record database. A panel of treating physicians reported on drug-treated RA patients seen in consultation during the study period. Data were taken from 3 waves of research: Q4 2017 (256 physicians in EU5 reporting on their patients), Q4 2012 (95 physicians in US reporting on their patients), and Q4 2013 (98 physicians in US reporting on their patients). All data were collected online. Data are copyright Ipsos 2018, all rights reserved.


[1] European Medicines Agency. 2018. Xeljanz. [ONLINE] Available at: https://www.ema.europa.eu/documents/smop-initial/questions-answers-refusal-marketing-authorisation-xeljanz_en.pdf. [Accessed 15 October 2018].

[2] Pfizer.com. 2018. XELJANZ® (tofacitinib citrate) Receives Marketing Authorisation in the European Union for the Treatment of Moderate to Severe Active Rheumatoid Arthritis (RA). [ONLINE] Available at: http://press.pfizer.com/press-release/xeljanz-tofacitinib-citrate-receives-marketing-authorisation-european-union-treatment- [Accessed 15 May 2018]

[3] Reuters. 2017. U.S. FDA declines to approve Eli Lilly and Incytearthritis drug Olumiant. [ONLINE] Available at: http://www.reuters.com/article/us-lilly-incyte-fda/u-s-fda-declines-to-approve-eli-lilly-and-incyte-arthritis-drug-olumiant-idUSKBN17G16Z. [Accessed 15 May 2018].

[4] FirstWordPharma. 2018. FDA panel backs lower dose of Eli Lilly, Incyte'sbaricitinibfor rheumatoid arthritis; votes against higher dose. [ONLINE] Available at: https://www.firstwordpharma.com/node/1559167?tsid=28®ion_id=2. [Accessed 15 May 2018].

[5] PR Newswire. 2018. Lilly Reports Strong Fourth-Quarter and Full-Year 2017 Revenue Growth, Increases 2018 EPS Guidance. [ONLINE] Available at: https://www.prnewswire.com/news-releases/lilly-reports-strong-fourth-quarter-and-full-year-2017-revenue-growth-increases-2018-eps-guidance-300590998.html. [Accessed 15 May 2018].

[6] Pfizer financials. Pfizer reports fourth-quarter and full-year 2017 results. 2017. [ONLINE] Available at: https://s21.q4cdn.com/317678438/files/doc_financials/Quarterly/2017/Q4_2017_PFE_Earnings_Release.pdf [Accessed 16 May 2018]  

[7] Pfizer financials. Pfizer reports fourth-quarter and full-year 2017 results. 2017. [ONLINE] Available at: https://s21.q4cdn.com/317678438/files/doc_financials/Quarterly/2017/Q4_2017_PFE_Earnings_Release.pdf [Accessed 16 May 2018]  


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