AbbVie and Celgene Secure FDA Approval for Second-Generation JAK Inhibitors Rinvoq and Inrebic on the Same Day

On the 17th, Celgene announced that the U.S. FDA had approved Inrebic (fedratinib), a highly selective JAK2 inhibitor, for the treatment of adult patients with myelofibrosis (MF). On the same day, AbbVie announced that the FDA had approved Rinvoq (upadacitinib), a selective JAK1 inhibitor, for the treatment of patients with rheumatoid arthritis. Today’s two approvals mark the official debut of second-generation JAK inhibitors with selectivity for the Janus kinase (JAK) family.

Inrebic——The First New Drug for Myelofibrosis in the Past Decade

FDA Approves Inrebic for the Treatment of Patients with Intermediate-2 and High-Risk Primary or Secondary Myelofibrosis

Myelofibrosis is a rare and serious bone marrow disorder that disrupts the body’s normal production of blood cells. In patients with this condition, the bone marrow is gradually replaced by fibrotic scar tissue, thereby limiting its capacity to produce blood cells. Hematopoiesis shifts from the bone marrow to the spleen and liver, leading to organomegaly. Patients may also experience symptoms such as severe fatigue, shortness of breath, subcostal pain, fever, night sweats, pruritus, and bone pain. When myelofibrosis occurs de novo, it is termed primary myelofibrosis. Secondary myelofibrosis develops when polycythemia vera (characterized by excessive red blood cell production) or essential thrombocythemia (characterized by excessive platelet production) progresses to myelofibrosis. Currently, only one medication is approved for the treatment of myelofibrosis: Jakafi (ruxolitinib), a JAK1/JAK2 inhibitor launched in 2011.

Inrebic (fedratinib) is an oral JAK2 and FLT3 inhibitor that inhibits the activity of both wild-type and mutationally activated JAK2 protein kinases. Inrebic is a JAK2-specific inhibitor with greater inhibitory potency against JAK2 than against JAK1, JAK3, or TYK2. Studies have shown that abnormal activation of JAK2 is associated with myelofibrosis and polycythemia vera. In in vitro and animal studies, Inrebic has been demonstrated to block STAT3/5 phosphorylation and alleviate disease-related symptoms.

▲Mechanism of Action of Inrebic (Image source: Impact Biomedicine official website)

This approval is based on the results of the Phase 2 JAKARTA2 trial and the pivotal Phase 3 JAKARTA trial. A total of 608 patients received treatment with Inrebic, including 459 patients with myelofibrosis and 97 patients who had previously been treated with ruxolitinib. Results from the JAKARTA trial demonstrated that among patients who had not previously received JAK inhibitor therapy, 37% of those treated with Inrebic achieved a spleen volume reduction of >35%, and 40% of patients experienced an improvement of more than 50% in their Myelofibrosis Symptom Assessment Form (MFSAF) total symptom score. Both endpoints were significantly superior to those observed in the placebo group (1% and 9%, respectively).

Furthermore, the results of the JAKARTA2 clinical trial demonstrated that 55% of patients who were resistant to or intolerant of ruxolitinib experienced a reduction in spleen volume, indicating that Inrebic can also be effective in these patients.

▲ Dr. John Hood, Founder and CEO of Impact Biomedicines

The development of this new drug has been a tortuous journey, with its clinical trials once halted by the FDA due to the emergence of severe complications. It was Dr. John Hood, founder of Impact Biomedicines, who breathed new life into the drug, and today’s FDA approval marks its successful crossing of the finish line in development. WuXi AppTec is also pleased to have empowered its partner through R&D support, accelerating the market launch of this novel therapy (for the story of Inrebic’s “resurrection” during development, please read the secondary article in today’s push).

Rinvoq—The First Approved JAK1-Selective Inhibitor

FDA Approves Rinvoq (upadacitinib) for the Treatment of Adults with Moderately to Severely Active Rheumatoid Arthritis (RA) Who Have Had an Inadequate Response or Intolerance to Methotrexate (MTX). The new drug is expected to be available in the United States by late August. The indication for Rinvoq does not include patients who have not previously been treated with MTX.

Rheumatoid arthritis, an autoimmune disease, affects approximately 23.7 million people worldwide. In patients with this condition, the immune system mistakenly attacks their own joints, leading to inflammation, thickening of intra-articular tissues, and damage to bones and associated connective tissues. Symptoms such as pain, fatigue, and joint stiffness significantly impact patients' daily lives. If not properly treated, rheumatoid arthritis can result in permanent, disabling damage to bones and cartilage.

Rinvoq (upadacitinib) is a once-daily oral small-molecule selective JAK1 inhibitor. In addition to the treatment of rheumatoid arthritis, it is undergoing clinical studies for multiple inflammatory indications, including psoriatic arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, and atopic dermatitis.

▲Molecular structure of Rinvoq (Image source: jmorris0x0 [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)])

This approval is based on the results of the SELECT clinical trial program. This Phase 3 clinical research program comprises five clinical trials, with a total enrollment of nearly 4,400 patients. Across all SELECT Phase 3 clinical trials, Rinvoq met all primary endpoints and key secondary endpoints. The primary endpoints included:

SELECT-EARLY Trial: In patients who had not previously received MTX treatment, 52% of those in the Rinvoq-treated group achieved ACR50 (defined by the American College of Rheumatology criteria as >50% improvement in RA symptoms) at 12 weeks, compared with 28% in the MTX group.

SELECT-MONOTHERAPY Trial: In patients receiving MTX, 68% of those switched to Rinvoq achieved ACR20 at 14 weeks, compared with 41% in the group continuing MTX.

SELECT-COMPARE Trial: 71% of patients treated with Rinvoq + MTX achieved ACR20, compared to 36% in the placebo + MTX group.

Moreover, these trial results indicate that over 30% of patients achieved clinical remission following treatment with Rinvoq. In this state, patients exhibit minimal to no disease activity or symptoms, even without the use of methotrexate (MTX). The duration of clinical remission can extend up to 26 weeks.

“Although there are currently multiple therapies for the treatment of rheumatoid arthritis, many patients still fail to achieve the goals of entering clinical remission or maintaining low disease activity,” said Dr. Roy M. Fleischmann, Clinical Professor at UT Southwestern Medical Center and principal investigator of the SELECT-COMPARE clinical trial. “Based on this FDA approval, Rinvoq may help patients with rheumatoid arthritis who have not yet achieved these goals to attain clinical remission.”

On the JAK Signaling Pathway and JAK Inhibitors

The Janus kinase (JAK) family is a group of tyrosine kinases comprising JAK1, JAK2, JAK3, and TYK2. They play crucial roles in the signaling cascades of various type I and type II cytokine receptors. Given the critical involvement of JAK-mediated cytokine signaling pathways in immune-mediated and neoplastic diseases, the JAK kinase family has emerged as an important therapeutic target for these conditions.

▲ Physiological effects mediated by different JAK family members and information on JAK inhibitors (Image source: Reference [4])

First-generation JAK inhibitors include tofacitinib, baricitinib, ruxolitinib, and oclacitinib. They exert inhibitory effects on multiple members of the JAK family. These inhibitors have demonstrated favorable efficacy in the treatment of inflammatory and neoplastic diseases. However, since the JAK family mediates signaling for various cytokines, comprehensive inhibition of the JAK family can also lead to a range of adverse effects, including infections, anemia, neutropenia, lymphopenia, and hyperlipidemia.

Therefore, the development of second-generation JAK inhibitors aims to enhance inhibitor selectivity, suppressing specific disease-related signaling pathways while preserving the function of other cytokines. This approach has the potential to reduce the side effects associated with JAK inhibitors. Currently, in addition to the already approved Inrebic and Rinvoq, filgotinib, a JAK1-selective inhibitor jointly developed by Gilead Sciences and Galapagos, is expected to submit a New Drug Application (NDA) this year for the treatment of rheumatoid arthritis. Furthermore, several JAK1-, JAK3-, and TYK2-specific inhibitors are currently in clinical development.

We anticipate that these JAK-specific inhibitors will not only alleviate patient symptoms but also reduce treatment-related side effects, thereby further improving patients’ quality of life.

References:

[1] U.S. FDA Approves INREBIC® (Fedratinib) as First New Treatment in Nearly a Decade for Patients With Myelofibrosis. Retrieved August 16, 2019, from https://www.businesswire.com/news/home/20190816005292/en/

[2] AbbVie Receives FDA Approval of RINVOQ™ (upadacitinib), an Oral JAK Inhibitor For The Treatment of Moderate to Severe Rheumatoid Arthritis. Retrieved August 16, 2019, from https://www.prnewswire.com/news-releases/abbvie-receives-fda-approval-of-rinvoq-upadacitinib-an-oral-jak-inhibitor-for-the-treatment-of-moderate-to-severe-rheumatoid-arthritis-300903053.html

[3] O’Shea and Gadina, (2019). Selective Janus kinase inhibitors come of age. Nature Reviews Rheumatology, https://doi.org/10.1038/s41584-018-0155-9

[4] Schwartz et al., (2017). JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nature Reviews Drug Discovery. https://doi.org/10.1038/nrd.2017.201

[5] Harrison et al., (2017). Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. The Lancet Haematology. DOI:https://doi.org/10.1016/S2352-3026(17)30088-1

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