August could be the month when all patients suffering from rheumatoid arthritis (RA) have a new treatment alternative to injectable TNF-inhibitors, such as Humira (adalimumab, Abbott), Enbrel (etanercept, Amgen Inc.) and Remicade (infliximab, Johnson & Johnson).

Pfizer Inc.'s Janus kinase (JAK) inhibitor tofacitinib for the treatment of adults with moderate-to-severe active RA has a scheduled PDUFA date of August 21. The compound represents the first in a wave of potential new oral therapies for RA now in clinical trials. There is a possibility that the PDUFA data may be extended as Pfizer did say during its second quarter 2012 earnings call that the FDA has requested additional analysis of the existing data in their new drug application (NDA) for tofacitinib.

The company plans to provide the information in early August, which is why it anticipates the FDA may require additional time to review the analysis.

Supporting Data

Supporting the NDA submission are top-line results from the Phase III ORAL Start study, a global clinical development program that included approximately 5,000 patients. Data showed that the drug met the primary endpoints at both the 5-mg and 10-mg twice-daily doses. Tofacitinib was found to be superior to methotrexate, with statistically significant changes shown in inhibiting structural damage, as measured by change from baseline in modified Total Share Score, and in reducing signs and symptoms of RA, as measured by ACR70 responses. Both primary endpoints assessed tofacitinib vs. methotrexate at six months. The data are from a planned analysis at one year. (See BioWorld Today, Aug. 1, 2012.)

The Arthritis Advisory Committee (AAC) voted 8-2 to recommend approval for tofacitinib as a second-line treatment in RA. If the FDA eventually goes along with that recommendation, tofacitinib would become the first JAK inhibitor in the RA space and the first new disease modifying anti-rheumatic drug (DMARD) in 10 years. (See BioWorld Today, May 8, 2012.)

RA, an autoimmune disease that causes inflammation in the joints, affects an estimated 1.3 million people in the U.S., or 1 percent of the population, according to the Arthritis Foundation. The overall market for disease sufferers worldwide has been estimated at more than $13 billion, with tofacitinib expected to grab a piece of that large pie and achieve blockbuster status if it gets the green light from the FDA.

Although multiple treatments are available, many patients do not adequately respond, and there remains a need for additional options. In fact, Pfizer estimates that 30 percent to 40 percent of RA patients fail to respond to the injectable therapies.

The approval of tofacitinib would represent a huge boost to other companies developing oral medicines to treat RA, according to J.P. Morgan analyst Cory Kasimov in a research report. These include: Rigel Pharmaceuticals Inc.'s fostamatinib, a Phase III syk inhibitor partnered with AstraZeneca plc and Incyte Corp.'s baricitinib (INCB28050), which is licensed to Eli Lilly and Co. Both compounds are in Phase II trials.

Incyte and Eli Lilly recently presented 12-week results from a Phase IIb study of baricitinib in patients with active RA at the European League Against Rheumatism's Annual European Congress of Rheumatology. The randomized double-blind, placebo-controlled, dose-ranging study (JADA) involved 301 patients with active RA on stable doses of methotrexate. Patients were randomized to receive either placebo or one of four once-daily doses of baricitinib (1 mg, 2 mg, 4 mg or 8 mg) for 12 weeks. The primary endpoint was achieved, demonstrating a statistically significant difference in the American College of Rheumatology 20 response between the combined 4-mg and 8-mg baricitinib groups (76 percent) compared with placebo (41 percent) after 12 weeks of treatment (p < 0.001). (See BioWorld Today, June 11, 2012.)

AstraZeneca expects to report Phase III results from OSKIRA-1, OSKIRA-2 and OSKIRA-3 in the first half of 2013. It also expects to report data from OSKIRA-4 (a Phase IIb monotherapy study) by late 2012. In addition, AstraZeneca has stated that it expects to file an NDA with the FDA for fostamatinib in the second half of 2013.

While fostamatinib and baricitinib could be the second and third oral RA drugs to reach the market, Kasimov said that these drugs could benefit from Pfizer's "heavy lifting" to trigger a paradigm shift in RA treatment practice.

Partnering Deals in RA

Rigel and AstraZeneca have inked a potential $1.2 billion collaboration covering upfront and milestones, and at the back end Rigel will receive a double-digit sales royalty if the drug makes it to market. Importantly, AstraZeneca is responsible for all development, regulatory, manufacturing and commercialization expenses.

For its part, Incyte could earn up to $665 million in potential development, regulatory and sales milestones under its collaboration with Lilly.

Other JAK inhibitors in development for RA include Vertex Inc.'s VX509, which is in an ongoing Phase IIb study in the U.S. and Europe. The Phase IIa trial resulted in substantial and statistically significant improvements in multiple measurements of RA activity, the company reported. The 12-week study met its two primary endpoints, defined as a statistically significant improvement in the proportion of people who achieved at least a 20 percent improvement in the signs and symptoms of RA, also known as ACR20, and a statistically significant improvement from baseline in Disease Activity Score 28 (DAS28).

Galapagos NV recently landed a deal with Abbott worth $1.35 billion, plus royalties, for its JAK1 inhibitor, GLPG0634, which is in Phase II development for RA. The agreement, the company said, is the largest for a Phase II compound in the history of the industry.

The Phase IIa trial of GLPG0634 delivered positive results on ACR20, the standard measure of disease activity, and also on the standard test for inflammation, serum levels of C-reactive protein. Like Humira, the product could have potential in other autoimmune diseases. (See BioWorld Today, March 1, 2012.)

If JAK inhibitors don't prove their worth then maybe stem cells will become the next therapies for RA.

TiGenix NV, of Leuven, Belgium, completed patient enrollment in a Phase IIa study of Cx611, a suspension of expanded allogeneic adult stem cells, in rheumatoid arthritis. The Phase IIa clinical trial is a 53-subject, multicenter, placebo-controlled study in three cohorts with different dosing regimens, designed to assess safety, feasibility, tolerance and optimal dosing. The company expects the final results to be available in the first half of 2013.

Mesoblast Ltd., of Melbourne, Australia, recently reported positive results in a large animal model of RA following a single intravenous injection of its allogeneic immunomodulatory adult mesenchymal precursor cells (MPCs). The study was conducted on 30 sheep with established collagen-induced arthritis, comparing a single intravenous injection of allogeneic MPCs at one of three doses (0.3, 1 and 2 million MPCs/kg) to saline. Thirty days later, joint synovial tissues from arthritic sheep were examined. The findings demonstrated that MPCs are immunoregulatory and concomitantly suppress the activation and proliferation of T-cells, monocytes and synoviocytes seen in active rheumatoid arthritis. (See BioWorld Today, July 25, 2012.)