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Biologics such as Enbrel (by Immunex, bought by Amgen (NASDAQ:AMGN)), Humira (by Knoll Pharmaceuticals, bought by Abbott (NYSE:ABT)) and Orencia (by Bristol Myers, (NYSE:BMY)) have revolutionized the treatment of many auto-immune diseases such as rheumatoid arthritis, psoriasis, psoriatic arthritis, and ulcerative colitis. They are huge a commercial success, with sales of biologics in excess of $10 billion a year. However, they are very expensive, costing $15,000 - $20,000 a year per patient, and have to be injected. Consequently, they are second line drugs, used only when the first line drugs such as methotrexate do not work. An oral drug would have the advantage of cost and ease of convenience. It could also challenge methotrexate as a first line agent. One such oral drug is Pfizer's (NYSE:PFE) tofacitinib, a JAK inhibitor. In its NDA filing, Pfizer demonstrated its efficacy and safety in phase III studies: ORAL Standard (A3921064) and ORAL Step (A3921032).

ORAL Standard was a twelve-month study in patients with moderate-to-severe active rheumatoid arthritis who had an inadequate response to methotrexate. Subjects were randomized into four cohorts: tofacitinib 5 or 10 mg BID, adalimumab 40 mg subcutaneously every other week or placebo, each of which was added to stable background methotrexate. At the 5 and 10 mg BID doses tofacitinib showed statistically significant improvement compared to placebo in reducing signs and symptoms of RA, as measured by 20% improvement in the American College of Rheumatology scale (ACR20) at six months; in improving physical function, as measured by mean change in Health Assessment Questionnaire-Disability Index (HAQ DI) at three months; and in inducing remission as measured by Disease Activity Score 28 ESR (DAS28-4(NYSEARCA:ESR) <2.6 at six months.

ORAL Step was a six-month study in patients with moderate-to-severe active rheumatoid arthritis who had an inadequate response to a TNF inhibitor and were randomized to receive tofacitinib 5 or 10 mg BID or placebo, which were added to stable background methotrexate. At the 5 and 10 mg BID doses, tofacitinib showed statistically significant improvement compared to placebo in reducing signs and symptoms of RA, as measured by ACR20 response rates; in improving physical function, as measured by mean change in HAQ DI; and in inducing remission as measured by DAS28-4.

Tofacitinib has been evaluated in about 4,800 patients from five pivotal Phase 3 trials and two ongoing long-term extension studies. In May 2012, the Arthritis Advisory Committee recommended approval of tofacitinib by a vote of 8-2 for adult patients with moderately to severely active rheumatoid arthritis. The FDA has provided an anticipated Prescription Drug User Fee Act (PDUFA) action date in August 2012.

In two successive issues of the New England Journal Of Medicine this and last week, three new studies have been outlined that make tofacitinib even more attractive.

RHEUMATOID ARTHRITIS

In the first study, tofacitinib was compared to placebo as a first line agent in patients with RA on no background methotrexate.

In this phase III six-month study, 611 patients were randomized to tofacitinib 5 mg bid, 10 mg bid, placebo for 3 months followed by tofacitinib 5 mg bid, or placebo for 3 months followed by 10 mg of tofacitinib bid. The primary end points, assessed at month 3, were the percentage of patients with ACR 20 improvement, the change from baseline in HAQ-DI, and the percentage of patients with a DAS28.

Results:

Measure

5 mg bid

10 mg bid

Placebo

Power

ACR20

59.8%

65.7%

26.7%

P<0.001 for both vs placebo

HAQ-DI

−0.50

−0.57

−0.19

P<0.001

DAS28

5.6%

8.7%

4.4%

P=0.62 and P=0.10 respectively

There was a higher rate of adverse events and serious adverse events in the treated groups compared to placebo. Adverse events worth noting include infections, neutropenia, and elevation of elevation of lipids (LDL).

Comments:

Pfizer has finally gone where no other company has gone by conducting a study without background methotrexate. However, Pfizer missed an opportunity - they should have directly gone against methotrexate by conducting a head to head study. They had little to lose - even methotrexate proved superior, tofacitinib would have become the next drug to try instead of a biologic. If tofacitinib proved superior, it could have supplanted methotrexate as the drug of first choice.

In the second study tofacitinib was compared head to head versus Adalimumab and Placebo in Rheumatoid Arthritis.

In this 12-month study, 717 patients who were receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib bid, 10 mg of tofacitinib twice daily, 40 mg of adalimumab SQ once every 2 weeks, or placebo. At the end of 3 months, patients in the placebo group who did not have a 20% reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib bid for another three months. The three primary outcome measures were ACR 20, HAQ-D and DAS28.

Results:

Measure

5 mg bid

10 mg bid

Placebo

Humira

Power

ACR20

51.5%

52.6%,

26.7%

47.2%

P<0.001 for all vs placebo

HAQ-DI

−0.55

−0.61

−0.24

-0.49

P<0.001 for all vs placebo

DAS28

6.2%

12.5%

1.1%

6.7%

P<0.05 for 5mg bid and Humira vs placebo, <0.001 for 10mg bid vs placebo

On the safety side, rates of adverse events were higher in treated groups than placebo, but comparable between treated groups, infections being the most common. Rates of serious adverse events were higher in tofacitinib 5 mg bid, but comparable between Humira and 10 mg bid.

Comments:

Pfizer was brave in going up against Humira, probably the market leader amongst the anti-TNFs. By showing similar efficacy (if not slightly better), it can change the paradigm of treating RA.

ULCERATIVE COLITIS:

Finally, in the third study, Pfizer evaluated the efficacy of tofacitinib in patients with Ulcerative Colitis who had failed conventional treatment. In a phase II study, the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis was compared to placebo. Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo bid for 8 weeks. The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system of 3 or more, relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more, or an absolute rectal bleeding subscore of 0 or 1.

Results:

Measure

0.5 mg bid

3 mg bid

10 mg bid

15 mg bid

Placebo

P value

Mayo score

32%

48%

61%

78%

42%

Only significant for 15 mg bid versus placebo

Clinical Remission

13%

33%

48%

41%

10%

Only 0.5 mg bid not significant versus placebo

Endoscopic Response at 8 weeks

52%

58%

67%

78%

46%

Only significant for 15 mg bid versus placebo

Patients in the 15 mg group also showed significant improvements over placebo-treated patients for endoscopic outcomes, C-reactive protein concentrations, fecal calprotectin concentrations, and Inflammatory Bowel Disease Questionnaire scores. Safety profile was similar to the RA studies, with higher rates of adverse events in treated groups compared to placebo.

Comments:

While a relatively small study, the data is still encouraging for the use of tofacitinib in ulcerative colitis.

CONCLUSIONS: Tofacitinib is a contender for first line treatment in RA and even as a second line, is a serious challenger to anti-TNFs, based on efficacy, ease of administration, and likely cost. It could also be developed for diseases other than RA, including UC, Crohn's Disease, psoriasis and psoriatic arthritis, and Ankylosing spondyltis. This has the potential to be a great drug for patients and for Pfizer.

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.

Source: Pfizer's Success With Its JAK Inhibitor