Corporate Banner
Satellite Banner
ADME Tox
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Tofacitinib: Sacrificing Safety for Novelty?

Published: Wednesday, August 22, 2012
Last Updated: Wednesday, August 22, 2012
Bookmark and Share
FDA has extended the review period of tofacitinib by three months.

Tofacitinib (tasocitinib, CP-690550), Pfizer’s novel Janus Kinase 3 (JAK) inhibitor for the treatment of rheumatoid arthritis (RA), had an anticipated FDA PDUFA (Prescription Drug User Fee Act) date for, August 21, 2012.

The FDA has just announced it has extended the review period of tofacitinib by three months. Interestingly, earlier in August, more data from The ORAL Start Phase III clinical trials were submitted by Pfizer for review, thus pushing the anticipated PDUFA date potentially into Q4.

The safety profile more than the efficacy profile of tofacitinib was brought into question, even during the May 2012 FDA advisory panel meeting.

The oral JAK3 therapy is also in Phase III for other indications, such as psoriasis (oral) and ulcerative colitis (UC), and Phase II for psoriatic arthritis, ankylosing spondylitis, psoriasis (topical), and Crohn’s disease.

Tofacitinib targets the JAK pathway, thus disrupting the intracellular signal pathway which is used by cytokines to regulate immune responses.

Tofacitinib is selective for JAK3, as it is most associated with inflammation, but it overlaps JAK1 and JAK2. This therapy has been shown to prevent inflammation caused by proliferation and cytokine overexpression.

Subsequently, it was shown to prevent further radiographic progression of joint erosion as well. Tofacitinib has been compared to Abbott’s Humira and in a 12-month trial tofacitinib was found to be statistically superior to placebo and similarly effective to Humira.

However, the abundance of safety data accumulated does not mean that tofacitinib comes without baggage. Clinical trial designs, dosage of tofacitinib, and patient populations have differed, not to mention 12 deaths that occurred during trials.

With this said, a definitive conclusion about its treatment effect has come into question, which may have spurred the submission of extra data.

On August 15, 2012, Pfizer released promising tofacitinib results for the treatment of UC. In a randomized trial, 194 patients with moderate to severe UC were given treatment or placebo in a dose-ranging Phase II trial.

Within eight weeks, almost 80% of the treatment arm achieved a clinical response compared with 42% from the placebo group. Clinical remission was achieved in close to 48% and 10% of the treatment arm and placebo group, respectively.

While patients achieved some disease remission, the safety profile was curiously similar, but oddly different to what was recorded from previous RA studies. These statistical changes from the studies were recognized and compared.

In the RA and UC clinical studies, the higher doses of 10mg and 15mg, respectively, had more adverse effects (AEs) than the lower doses and those given placebo.

The AEs reported from the UC clinical trials were similar to those from the RA clinical trials in that cholesterol levels increased, as did infections, while neutrophil counts decreased.

However, hematological laboratory values for liver enzymes, serum creatinine, and hemoglobin were unchanged during the UC trials. This was not the case during the RA studies; these same laboratory values actually decreased, thus becoming flagged warnings, and may have contributed to one or more of the deaths. With values compared, it appears that doses of 10mg and higher of tofacitinib produce undesired AEs. Of particular interest is the type of background medications given to the patients during the RA and UC studies.

Background therapy of methotrexate (MTX) was given to RA patients during one 12-month Phase III study involving 717 RA patients.

During the UC Phase II study, background medication included mesalamine or prednisone, but not azathioprine or MTX, due to their immunosuppressant effect. It is likely the background medications may play a role in increased AEs; however, even with tofacitinib as a monotherapy, laboratory values were seen as undesirable.

The mechanism of action or the formulation of tofacitinib may come into question, thus leaving us to wonder whether novelty is trumping safety of the drug.

As requested by the FDA, Pfizer submitted more supporting Phase III data several weeks before the anticipated FDA PDUFA date for tofacitinib.

GlobalData believes it is possible that Pfizer has felt the scrutiny over the safety of tofacitinib and submitted more data in hopes to cement an approval.

Also, GlobalData feels that the recent release of tofacitinib data from the UC study was timely in that it may inadvertently support tofacitinib as being safe and effective thus promoting the drug to gain approval.

Without the approval of tofacitinib, Pfizer stands to miss out of grossing up to $3 billion in annual sales.


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,500+ scientific posters on ePosters
  • More than 3,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Big R&D Investment Trend as Mid-Cap Biotechs Push to Get Drugs to Market
20% of overall increase in R&D expenditure in just a year.
Thursday, March 07, 2013
Scientific News
Self-Assembling, Biomimetic Membranes May Aid Water Filtration
A synthetic membrane that self assembles and is easily produced may lead to better gas separation, water purification, drug delivery and DNA recognition, according to an international team of researchers.
Study Questions Presence in Blood of Heart-Healthy Molecules from Fish Oil Supplements
A new study from the Perelman School of Medicine at the University of Pennsylvania questions the relevance of fish oil-derived SPMs and their purported anti-inflammatory effects in humans.
New Material Opens Possibilities for Super-Long-Acting Pills
A pH-responsive polymer gel could create swallow able devices, including capsules for ultra-long drug delivery.
Long-sought Discovery Fills in Missing Details of Cell 'Switchboard'
A biomedical breakthrough reveals never-before-seen details of the human body’s cellular switchboard that regulates sensory and hormonal responses.
Tracking Breast Cancer Before it Grows
A team of scientists led by University of Saskatchewan researcher Saroj Kumar is using cutting-edge Canadian Light Source techniques to screen and treat breast cancer at its earliest changes.
Zebrafish Reveal Drugs that may Improve Bone Marrow Transplant
Compounds boost stem cell engraftment; could allow more matches for patients with cancer and blood diseases.
Teeth Reveal Lifetime Exposures to Metals, Toxins
Researchers have identified dental biomarkers to reveal links between early iron exposure and late life brain diseases.
An Innovative Algorithm to Decipher How Drugs Work Inside the Body
Researchers at Columbia University Medical Center (CUMC) have developed a computer algorithm that is helping scientists see how drugs produce pharmacological effects inside the body.
Uncovering the Spread of Bacteria in Pneumonia
Northwestern Medicine scientists have discovered the role a toxin produced by a pneumonia-causing bacterium plays in the spread of infection from the lungs to the bloodstream in hospitalized patients.
Ferring Bets on Bacteriophages to Treat Inflammatory Bowel Disease
Ferring Pharmaceuticals have annoucned that it will collaborate with Intralytix in the latest phase of its early stage development programme for a bacteriophage-based therapy for inflammatory bowel disease (IBD).
SELECTBIO

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!