No, I didn´t mean to talk about Yaks, here at Shangri-la.
The oral jak inhibitor tofacitinib (CP-690,550) attracted quite a lot of attention. When will the drug be available? Most probable by 2013, even late 2012 has been reported, it depends on FDA and EMEA approvals. There are enough studies as you will see here.
R.F. van Vollenhoven and colleagues reported a head-to-head phase 3 study on tofacitinb vs. adalimumab. They “compared the effects of tofacitinib 5 and 10 mg twice daily (BID), and active control adalimumab, with placebo (PBO) on patient reported outcomes (PROs) in patients (pts) with active RA and an inadequate response to methotrexate (MTX)”. Pain (VAS) for placebo: -16.34, for tofacitinib 5 mg: -30.68***, for tofacitinib 10 mg: -31.38***, for -27.25** (**p<0.001, ***p<0.0001 vs PBO). All in all the authors concluded that tofacitinib was significantly superior to placebo and numerically similar to adalimumab.
[THU0151] EFFECTS OF TOFACITINIB (CP-690,550), AN ORAL JANUS KINASE INHIBITOR, OR ADALIMUMAB ON PATIENT REPORTED OUTCOMES IN A PHASE 3 STUDY OF ACTIVE RHEUMATOID ARTHRITIS
R.F. van Vollenhoven1, G. Wallenstein2, E.B. Lee3, R. Fleischmann4, S.H. Zwillich2, D. Gruben2, T. Koncz5, J. Bradley2, B. Wilkinson2, V. Strand6. 1Karolinska Institute, Stockholm, Sweden; 2Pfizer Inc, Connecticut, United States; 3Seoul National University, Seoul, Republic of Korea; 4Metroplex Clinical Research Center, Dallas, Texas; 5Pfizer Inc, New York; 6Stanford University, Palo Alto, California, United States
Conclusions: In this phase 3 RCT in pts with RA with incomplete responses to MTX, the efficacy of tofacitinib 5 or 10 mg BID in improving PROs was significantly superior to placebo and numerically similar to adalimumab.
Citation: Ann Rheum Dis 2012;71(Suppl3):206
J. Kremer and colleagues analized subgroups in a pooled phase 2 and 3 rheumatoid arthritis study population efficacy endpoints of tofacitinib (3442 patients in total). “Tofacitinib was consistently efficacious”.
[THU0143] TOFACITINIB (CP-690,550), AN ORAL JANUS KINASE INHIBITOR: ANALYSES OF EFFICACY ENDPOINTS BY SUBGROUPS IN A POOLED PHASE 2 AND 3 RHEUMATOID ARTHRITIS STUDY POPULATION
J. Kremer1, C. Zerbini2, E.B. Lee3, D. Gruben4, S. Krishnaswami4, S.H. Zwillich4, T. Koncz5, J. Bradley4, C.A. Mebus4. 1Albany Medical College, New York, United States; 2Centro Paulista de Investigação Clinica, São Paulo, Brazil; 3Seoul National University, Seoul, Republic of Korea; 4Pfizer Inc, Connecticut; 5Pfizer Inc, New York, United States
Conclusions: Tofacitinib was consistently efficacious, as measured by ACR20 and HAQ-DI, across the range of baseline demographics and disease characteristics such as age, gender, weight, BMI, race, geographic region, disease duration, serological status, disease activity and previous treatment experience.
Citation: Ann Rheum Dis 2012;71(Suppl3):203
The next three studies are on cardiovascular, renal, and gastrointestinal safety.
[THU0136] CARDIOVASCULAR SAFETY FINDINGS IN RHEUMATOID ARTHRITIS PATIENTS TREATED WITH TOFACITINIB (CP-690,550), A NOVEL, ORAL JAK INHIBITOR
C. Charles-Schoeman1, P. Wicker2, U. Sechtem3, M.A. Gonzalez-Gay4, S. Wood5, M. Boy5, J. Geier6, D. Gruben5, K. Soma5, R. Riese5, J. Bradley5. 1University of California, Los Angeles, CA; 2PW Consulting LLC, Mystic, CT, United States; 3Robert-Bosch-Krankenhaus, Stuttgart, Germany; 4Hospital Universitario Marqués de Valdecilla, Santander, Spain; 5Pfizer Inc., Groton, CT; 6Pfizer Inc., New York, NY, United States
Conclusions: Incidence rates of MACE were similar across groups in P3 with lower rates in LTE, suggesting no increased risk over 3 years of follow up. Tofacitinib was not associated with clinically meaningful increases in BP. Although the number of events have been fewand longer observation periods are warranted, CV risk does not appear to be increased with tofacitinib treatment and rates of CV events are consistent with those observed among patients with RA of similar disease severity.
[LTE - long-term open-label extension, CV – cardiovascular, MACE - major adverse CV events (),CHF - events of congestive heart failure]
Citation: Ann Rheum Dis 2012;71(Suppl3):201
[AB0595] CHANGES IN SERUM CREATININE IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS TREATED WITH TOFACITINIB (CP-690,550)
J. Isaacs1, C. Nduaka2, A. Zuckerman2, S. Krishnaswami2, R. Riese2, S. Lan2, M. Hutmacher3, M. Boy2, J. Bradley2. 1Newcastle University, Newcastle, United Kingdom; 2Pfizer Inc., Groton, CT; 3Ann Arbor Pharmacometrics Group (A2PG), Ann Arbor, MI, United States
Conclusions: Tofacitinib treatment was associated with small mean increases in SCr, which were generally reversible. Changes in SCr appeared to be influenced by bCRP and race among patients with RA. The mechanism behind the changes in SCr is undergoing further investigation. MedDRA-defined ARF occurred infrequently with tofacitinib treatment in the P3 and LTE studies, was observed in the setting of concurrent illnesses associated with ARF in the general population and generally reversed on discontinuation of treatment.
[SCr serum creatinine]
Citation: Ann Rheum Dis 2012;71(Suppl3):672
[THU0140] TOFACITINIB (CP-690,550), AN ORAL JANUS KINASE INHIBITOR: ANALYSIS OF GASTROINTESTINAL ADVERSE EVENTS ACROSS THE RHEUMATOID ARTHRITIS CLINICAL PROGRAMME
E.B. Lee1, J.R. Curtis2, R. Riese3, C. Connell3, R. Chew3, M. Boy3, E. Maller4, C. Su4, L. Wang3, J. Bradley3. 1Seoul National University, Seuol, Republic of Korea; 2The University of Alabama at Birmingham, Birmingham, AL; 3Pfizer Inc., Groton, CT; 4Pfizer Inc., Collegeville, PA, United States
Conclusions: GI AEs occurred commonly in all treatment groups including PBO, but were uncommon causes for DCs. Serious GI AEs were uncommon. The rate of GI perforation falls between the rates reported for pts treated with tocilizumab (0.19) and TNF inhibitors (0.13).1
[GI – gastrointestinal, DC – discontinuations]
Citation: Ann Rheum Dis 2012;71(Suppl3):202
X. Mariette and colleagues looked at malignancies. Type and distribution of malignancies of the tofacitinib RA programme are consistent with what is to be expected for patients with moderate to severe RA. The incidence rates for all malignancies are “consistent with published estimates in RA patients treated with biologic and non-biologic DMARDs”.
[THU0131] TOFACITINIB (CP-690,550), AN ORAL JANUS KINASE INHIBITOR: ANALYSIS OF MALIGNANCIES ACROSS THE RHEUMATOID ARTHRITIS CLINICAL PROGRAMME - POSTER TOURS
X. Mariette1, J.R. Curtis2, E.B. Lee3, R. Riese4, I. Kaplan4, R. Chew4, J. Geier5, L. Wang4, J.D. Bradley4. 1Paris-Sud University, Paris, France; 2University of Alabama, Birmingham, AL, United States; 3Seoul National University, Seoul, Republic of Korea; 4Pfizer Inc, Groton, CT; 5Pfizer Inc, New York, NY, United States
Conclusions: The malignancies that occurred in the tofacitinib RA programme are consistent with the type and distribution of malignancies expected for patients with moderate to severe RA. The IRs for all malignancies (excluding NMSC), lung cancer, breast cancer and lymphomas are consistent with published estimates in RA patients treated with biologic and non-biologic DMARDs.3-6 Longer follow-up is necessary to further evaluate the potential risk of malignancies in the CP RA programme.
Citation: Ann Rheum Dis 2012;71(Suppl3):199
M.C. Vieira an colleagues presented a meta-analysis of 33 RCTs on tofacitinib and various biologics. There are still some questions as to confounding factors, but tofacitinib has been similarly efficacious in improving signs and symptoms when compared to biologic DMARDs.
[FRI0185] TOFACITINIB VERSUS BIOLOGIC TREATMENTS WITH AND WITHOUT METHOTREXATE IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS WHO HAVE HAD AN INADEQUATE RESPONSE TO TRADITIONAL DISEASE MODIFYING ANTI-RHEUMATIC DRUGS - A NETWORK META-ANALYSIS
M.C. Vieira1, G.V. Wallenstein2, J.D. Bradley2, D. Gruben2, T. Koncz3, S.H. Zwillich2, J.P. Jansen1. 1MAPI Consultancy, Boston, MA; 2Pfizer Inc, Groton, CT; 3Pfizer Inc, New York, NY, United States
Conclusions: Based on analyses of available RCTs, tofacitinib has similar efficacy in improving signs and symptoms as biologic DMARDs for DMARD-IR patients. Further analyses are needed to explore the impact of factors that may impact the magnitude of the placebo response and confound comparative treatment effects in treatment of RA. Impact of factors that confound comparative treatment effects in treatment of RA needs to be explored (e.g. starting MTX dose, duration and number of prior DMARDs).
Citation: Ann Rheum Dis 2012;71(Suppl3):375
So, as soon as tofacitinib will be launched, we will have patients, who are already waiting for a new mode of action. But we will have to be cautious as the studies still leave a couple of issues open to be looked upon in long-term observational studies.
No comments:
Post a Comment