Home | Clinical | New Drugs Online
NDO Logo

Home | Additional information is available to accredited, [registered, NHS users]

New Drugs Online Report for tofacitinib
Generic Name:
Trade Name: Xeljanz 
Synonym: CP 690,550, CP-690,550, tasocitinib 
Entry Type: New molecular entity  
Development and Regulatory status
UK: Phase II Clinical Trials 
EU: Phase II Clinical Trials 
US: Launched 
UK launch Plans: Available only to registered users
Actual UK launch date:  
Feb 15: PII for RA in the EU [28]. 
13/03/2015 13:39:17
Jun 14: Pfizer announce that activities were underway to re-file an application with the EMA [29]. 
13/03/2015 13:39:03
Tofacitinib was launched in the US in Nov 12 (first launch worldwide). The US FDA approved twice-daily tofacitinib (5mg) for treatment of adults with moderately to severely active RA who have had an inadequate response or intolerance to methotrexate earlier that month. The approval allows tofacitinib to be administered as a monotherapy or in combination with MTX or other non-biologic DMARDs [27]. 
02/09/2013 14:55:40
Aug 13: Pfizer plans to work with the EMA to determine what additional data will be needed in order to resubmit a MAA; they anticipate a delay of several years [26]. 
02/09/2013 14:53:46
Jul 13: EU second negative opinion [24]. 
26/07/2013 14:32:42
Jul 13: Tofacitinib, 5 and 10mg twice-daily. has been approved in Switzerland for the treatment of moderate to severe RA in patients who had an inadequate response to existing therapies, as both monotherapy and in combination with a DMARD. Tofacitinib 5mg twice daily has also been approved in Argentina, Kuwait and the UAE, and tofacitinib 5mg and 10mg in Russia [23].  
15/07/2013 21:10:01
Apr 13: EU negative opinion, recommending refusal of marketing authorisation for Xeljanz in the treatment of RA. The CHMP concluded that studies were not sufficient to show a consistent reduction in disease activity & structural damage to joints, particularly at the lower 5mg dose & in pts in whom treatment with at least two other DMARDs has been unsuccessful. The CHMP had major concerns about the overall safety profile of Xeljanz, including serious infections, certain cancers, gastro-intestinal perforations, liver damage & hyperlipidaemia [22]. 
26/04/2013 12:40:50
Nov 12: Approved in US [20]. 
07/11/2012 13:27:44
Aug 12: FDA announces new PDUFA date is Nov 21 [17]. 
22/08/2012 09:59:34
Aug 12: The FDA has requested further data analysis that will delay the decision on approval beyond Aug 12 [15]. 
01/08/2012 17:53:22
May 12; The FDA arthritis advisory committee voted 8 to 2 that tofacitinib offered enough benefits to overcome potential safety risks, including higher rates of lymphoma and other cancers and serious infections. The agency is scheduled to decide on approval by August. [14] 
10/05/2012 16:56:43
May 12: FDA staff have raised concerns about increased risks of malignant cancers, particularly lymphomas, & infections with tofacitinib, & critiqued the X-ray methodology Pfizer used to measure efficacy. The advisory committee is to meet on 9th May [13]. 
08/05/2012 10:48:48
Dec 11: Filed in the US with a decision on approval expected by August [11]. 
20/12/2011 22:20:37
Nov 11: Market Authorisation Application for tofacitinib for the treatment of moderate-to-severe active rheumatoid arthritis is complete and the EMA is beginning its review procedure. [10] 
22/11/2011 08:15:25
May 11: EU and US filings expected by end of 2011 [8]. 
10/05/2011 18:06:45
PIII trials in RA started (1). 
02/12/2009 11:56:51
Trial or other data
Aug 13: PIII ORAL Sync study (A3921046; NCT00856544) published in Annals Internal Medicine. Mean treatment differences for ACR20 response rates (month 6) for the 5mg and 10mg tofacitinib gps vs. the combined placebo gps were 21.2% (95% CI, 12.2 to 30.3; p<0.001) & 25.8% (16.8 to 34.8; p<0.001), respectively. The HAQ-DI scores (month 3) & DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib gps vs placebo. The incidence rates of serious adverse events for pts receiving 5mg tofacitinib, 10mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 pt-years of exposure, respectively. In the tofacitinib gps, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, & 4 deaths occurred. Neutrophil counts decreased, hemoglobin & low- and high-density lipoprotein cholesterol levels increased, % serum creatinine levels had small increases in the tofacitinib gps [25]. 
22/08/2013 10:23:20
Jan 13: PIII ORAL Scan trial (N=797) published in Arth Rheum. ACR20 response rates (month 6) for tofacitinib 5 & 10mg BD were higher than placebo (51.5% & 61.8%, respectively, vs. 25.3%; both p<0.0001). Least squares (LS) mean changes in mTSS (month 6) for 5 & 10 mg BD were 0.12 (p=0.0792) & 0.06 (p≤0.05), respectively, vs. placebo, 0.47. LS mean changes in HAQ-DI (month 3) for 5 & 10 mg BD were -0.40 & -0.54 (p<0.0001), respectively, vs. placebo; -0.15. DAS28 < 2.6 rates (month 6) for 5 & 10 mg BD were 7.2% & 16.0%, respectively, vs. placebo, 1.6% [21]. 
28/01/2013 08:50:22
Sep 12: Interim 1 year results reported at the ACR 2012 meeting from the ongoing PIII ORAL Start (A3921069) study in methotrexate (MTX)-na´ve patients with moderate-to-severe active RA randomized to receive tofacitinib 5 or 10mg twice-daily as monotherapy or MTX. The study met its primary endpoints at both the 5 and 10mg doses; tofacitinib monotherapy was superior to MTX, with statistically significant changes shown in inhibiting structural damage as measured by change from baseline in van der Heijde modified Total Sharp Score (mTSS) and in reducing signs and symptoms of RA as measured by ACR70 response rates, both assessed at 6 months. Secondary endpoints, including ACR20 and ACR50 responses, DAS-defined remission (DAS28-4(ESR) <2.6), and mean change in HAQ-DI, were statistically significantly greater with tofacitinib versus MTX at all time points [19].  
19/09/2012 10:27:23
Sep 12: Data from a pooled analysis of two long-term, open-label extension studies (NCT00413699, NCT00661661) involving pts with moderate-to-severe RA who had participated in randomized PII/PIII studies of tofacitinib dosed at 5 or 10 mg BID showed a consistent safety profile and sustained efficacy over 48 months. Safety and efficacy were similar for pts receiving tofacitinib as monotherapy or with background nonbiologic disease-modifying antirheumatic drugs (DMARDs). Primary endpoints were adverse events and confirmed laboratory safety data. Secondary endpoints included ACR responses, DAS28-4(ESR) and HAQ-DI [18].  
19/09/2012 10:08:30
Sep 12: The two-year analysis of the ORAL Scan trial evaluated consistency of the efficacy and safety profile of tofacitinib 5 or 10 mg BID in patients who remained on active treatment through 24 months. The two-year results showed that patients on tofacitinib maintained improvements in efficacy including reductions in signs and symptoms, inhibition of structural damage, and improvements in physical function through month 24. No new safety signals emerged [18].  
19/09/2012 10:00:21
Aug 12: ORAL Solo (n=611) and ORAL Standard (n=717) published in NEJM [16]. 
10/08/2012 10:23:56
May 11: Top-line results of A3921109 reported: PII study (n=111 with RA) to evaluate safety and efficacy of atorvastatin 10mg od vs. placebo in reducing LDL-C, given for 6 weeks after a 6 week run-in with tofacitinib 10mg bd. Median LDL-C increased after 6 weeks of tofacitinib treatment and then decreased after randomisation in the atorvastatain group to value below tofacitinib-pretreatment levels. LDL-C was reduced by 35% in pts taking atorvastatin vs. 5.8% increase in those on placebo. After 6 weeks, 76% of pts showed ACR20 response, and at week 12 and ACR20 was seen in 82.6% (atorvastatin group) and 65.2% (placebo group). [9] 
26/05/2011 08:45:27
Apr 11: Top-line results from the ORAL Standard (A3921064) and ORAL Step (A3921032) PIII studies reported. ORAL Standard is a completed 12-month study in 717 patients with moderate-to-severe active RA with an inadequate response to methotrexate (MTX). Patients received tofacitinib 5 or 10mg twice daily, adalimumab 40mg subcutaneously every other week or placebo, + stable background MTX. At 3 months, patients not responding to placebo were switched to tofacitinib in a blinded manner, and at 6 months, all placebo-assigned patients were switched to tofacitinib. The study met all primary endpoints at both doses of tofacitinib, showing statistically significant changes vs placebo in reducing signs and symptoms of RA, measured by ACR20 response rates at 6 months; in improving physical function, measured by mean change in HAQ DI at 3 months; and in reaching DAS28-4(ESR) <2.6 at 6 months. ORAL Step is a completed 6 month study in3 99 patients with moderate-to-severe active RA with an inadequate response to a TNF inhibitor; they were randomized to receive tofacitinib 5 or 10mg twice daily or placebo, + a stable background MTX. The study met all primary endpoints at both doses, showing statistically significant changes vs placebo in the same measures as above, all assessed at 3 months [7].  
05/05/2011 10:15:08
Apr 11: An abstract concerning the ORAL Sync PIII study posted for the European League Against Rheumatism (EULAR) conference describes 4 deaths in the tofacitinib arms, 3 of which were determined by the investigators not to be study drug related (one case each of brain injury, worsening of RA and of acute heart failure). One case of respiratory failure was reported by the investigator as study drug related [6].  
26/04/2011 09:51:36
Apr 11: Top-line results from the ORAL Scan PIII study (A3921044) reported. In this ongoing 2-year study, 800 patients with moderate-to-severe active RA with inadequate response to methotrexate (MTX) were randomized to tofacitinib 5 or 10mg twice daily or placebo added to background MTX. The data reported are from a planned analysis at 1 year. The study met all primary endpoints at the 10mg dose, showing statistically significant changes vs placebo in ACR20 response rates at 6 months; in reducing the progression of structural damage measured by the modified Total Sharp Score (mTSS) at 6 months; in improving physical function, as measured by mean change in HAQ DI at 3 months; and in reaching DAS28-4 (ESR) <2.6 at 6 months. For the 5mg dose, there were statistically significant improvements vs placebo in ACR20 but not in mTSS at 6 months. Due to the pre-specified step-down statistical procedure, HAQ DI and DAS28-4(ESR) <2.6 outcomes were not measured for this dose. The two year data are expected in 2012 [5]. 
16/04/2011 19:01:50
Mar 11: Company announced that the ORAL Sync PIII study (A3921046) of tofacitinib, 5mg and 10mg twice daily, in patients with moderate-to-severe RA with a previous inadequate response to a DMARD, met its primary endpoints, showing statistically significant changes vs placebo in reducing signs and symptoms of RA, as measured by ACR20 response rates at 6 months; in improving physical function, as measured by mean change in HAQ DI at 3 months; and in reaching DAS28-4 (ESR) <2.6 at 6 months. No new safety signal was detected. A full analysis of data will be submitted to a future scientific meeting [4]. 
06/03/2011 18:54:19
Nov 10: Top line results from ORAL Solo (1045) and ORAL Sequel studies reported at the American College of Rheumatology. ORAL Solo was a six-month, double-blind study in 611 patients with moderately to severely active RA who had an inadequate response to at least one DMARD. Patients were randomised to tasocitinib 5 or 10mg monotherapy or placebo twice a day. After 3 months patients in the placebo group were switched to tasocitinib 5 or 10mg in a blinded manner. Tasocitinib met two primary endpoints, demonstrating a statistically significant reduction in signs and symptoms of RA as measured by ACR 20 (response rates 60% (5mg), 66% (10mg) and 27% (placebo), and improvement in physical function as measured by mean change in HAQ-DI, (-0.5, -0.57 and -0.19), at 3 months. There was no significant difference in the third primary endpoint, the rate of DAS28-4(ESR) <2.6, a measure of disease remission. ORAL Sequel (1024), an open label, follow-up PII/III study in 1,070 patients, had safety findings consistent with the global PII RA clinical program and showed sustained efficacy over 24 months when tasocitinib was used as monotherapy or in combination with methotrexate. The most frequent AEs were infections including bronchitis, URT infections and UTI; there were 2 cases of TB. 6.3% of patients discontinued due to AEs. The increases seen in mean total cholesterol, LDL, Hb, serum creatinine and transaminases and the decrease seen in mean absolute neutrophil counts from baseline during the first 6-12 weeks in prior randomized studies did not progress during the two years in ORAL Sequel [3]. 
08/11/2010 10:03:18
Dec 09: There are 8 ongoing PIII studies. Four are comparing two doses of CP-690,550 (5mg and 10mg twice daily) vs placebo only: one is a monotherapy study (NCT00814307), and the others are in combination with methotrexate (NCT00847613), with a variety of DMARDs (NCT00856544) and with methotrexate in patients who have had an inadequate response to TNF inhibitors (NCT00960440). The trials started between Feb and Oct 09 and are expected to complete between Nov 10 and May 11. Together they plan to enroll 2,400 patients. There are two active comparator studies, NCT01039688 (ORAL1069), which will compare CP-690,550 to methotrexate in 900 methotrexate-na´ve patients, and NCT00853385 vs adalimumab on a background of methotrexate in 700 patients. The former will complete in Jun 13 and the later in Mar 11. The remaining two studies are long-term open label extension safety studies (NCT00413699 and NCT00661661, which is being conducted in Japan) [2]. 
31/12/2009 19:34:47
Evidence Based Evaluations
NICE scope  http://www.nice.org.uk/Guidance/InDevelopment/GID-TAG438/Documents 
EMA doc  http://www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC500146629 
Available only to registered users
BNF Category:
Drugs that suppress the rheumatic disease process (10.01.03)
Pharmacology: Janus kinase (JAK) 3 inhibitor  
Epidemiology: Prevalence ranges from 0.5-1.5% of the population in industrialised countries. The incidence of the condition is low, with around 1.5 men and 3.6 women developing RA per 10,000 people per year. [12]  
Indication: Rheumatoid arthritis (RA) 
Additional Details: mod-severe in pts unresponsive to DMARDs or MTX 
Method(s) of Administration
Company Information
Name: Pfizer 
US Name: Pfizer 
Further Information
Anticipated commissioning route (England) CCG 
High cost drug list? Yes
In NICE timetable: Yes 
When:  /  
Note: www.nice.org.uk/Guidance/InDevelopment/GID-TAG438 
Implications Available only to registered users