The co-marketers of Imbruvica® (ibrutinib), AbbVie and Janssen (Johnson & Johnson), said that the FDA has approved their drug in combination with the Genentech/Biogen co-marketed Rituxan® (rituximab) as the first non-chemotherapy combination treatment for the rare blood cancer Waldenström's macroglobulinemia (WM).
The approval marks the ninth FDA authorization since November 2013 for Imbruvica, a first-in-class Bruton's tyrosine kinase (BTK) inhibitor developed and commercialized by Janssen Biotech and Pharmacyclics. AbbVie acquired Pharmacyclics for $21 billion in a deal completed in May 2015 and announced in March 2015, two months after Imbruvica was approved as a monotherapy for WM.
“Today's approval represents an important milestone for people living with this rare and incurable blood cancer who have limited FDA-approved treatment options,” Andree Amelsberg, M.D., vp of oncology medical affairs at Janssen Scientific Affairs, said in a company statement. “We remain dedicated to a comprehensive clinical development program to explore the full potential of Imbruvica, including in combination with other therapies.”
Rituxan is the first monoclonal antibody to win FDA approval as a cancer treatment, with the agency granting a Biogen predecessor company, Idec Pharmaceuticals, and Genentech (now a member of the Roche companies) its first authorization for the drug in November 1997, for relapsed or refractory, CD-20 positive, B-cell, low-grade or follicular non-Hodgkin's lymphoma. Rituxan was the first single agent approved specifically for therapy of a lymphoma. Biogen acquired Idec for approximately $6.8 billion in 2003.
The FDA based its approval on positive results from the Phase III iNNOVATE trial (NCT02165397). The randomized, double-blind, placebo-controlled study was designed to assess Imbruvica in combination with Rituxan versus placebo plus Rituxan in 150 patients with either relapsed/refractory (r/r) disease or previously untreated WM.
At 30 months following treatment, a progression-free survival (PFS) rate of 82% was reported in patients randomized to Imbruvica plus Rituxan, compared to just 28% for patients treated with placebo plus Rituxan. Patients treated with Imbruvica plus Rituxan also experienced an 80% reduction in relative risk of disease progression or death compared with participants who were only treated with Rituxan, Janssen said.
“Based on these results, Imbruvica in combination with rituximab may be considered as a first- and second-line option for appropriate people diagnosed and living with WM,” iNNOVATE lead study investigator Meletios A. Dimopoulos, M.D., professor and chairman of the department of clinical therapeutics, National and Kapodistrian University of Athens School of Medicine, said in Janssen’s statement.
According to Janssen, iNNOVATE—also known as PCYC-1127—was the largest Phase III study of a non-chemotherapy combination in WM patients. Data from iNNOVATE were simultaneously published in The New England Journal of Medicine and presented at the American Society of Clinical Oncology (ASCO) 2018 Annual Meeting, held in Chicago.
‘Should Be Considered a Standard’
The Imbruvica/Rituxan combination “should be considered a standard therapeutic option for patients with WM,” according to the presentation abstract.
The most common adverse reactions of all grades in patients treated with Imbruvica plus Rituxan in the iNNOVATE trial were bruising (37%), musculoskeletal pain (35%), hemorrhage (32%), diarrhea (28%), rash (24%), arthralgia (24%), nausea (21%), and hypertension (20%).
Rituxan is designed to work by binding to the CD20 antigen on the surface of mature B cells and B-cell tumors, then recruiting the body's natural defenses to attack and kill both malignant and normal mature B cells. In addition to WM, a rare and incurable type of non-Hodgkin's lymphoma (NHL), Rituxan is approved for indications in chronic lymphocytic leukemia (CLL), rheumatoid arthritis, Granulomatosis with Polyangiitis (GPA or Wegener’s Granulomatosis) and Microscopic Polyangiitis, and Pemphigus Vulgaris.
Imbruvica is designed to work by blocking BTK, a key signaling molecule in the B-cell receptor signaling complex that has been shown to play an important role in the survival and spread of malignant B cells as well as other serious, debilitating conditions.
Another BTK inhibitor, AstraZeneca’s Calquence® (acalabrutinib), won FDA approval in October 2017 as a treatment for adults with mantle cell lymphoma (MCL) who have received at least one prior therapy. The company submitted data from a Phase II trial showing an 80% overall response rate for Calquence, with 40% complete response and 40% partial response.
Calquence’s $20 million in first-half sales pale compared to the blockbuster results of Imbruvica and Rituxan. For January–June 2018, Imbruvica generated $2.819 billion—$1.612 billion for AbbVie and $1.207 billion for Janssen parent Johnson & Johnson. Rituxan (also marketed as MabThera) racked up $4.435 billion—consisting of CHF 3.624 billion ($3.692 billion) for Roche and $743 million for Biogen.
Imbruvica is FDA-approved in WM, CLL, and four other patient populations, including small lymphocytic lymphoma, previously-treated MCL, previously-treated marginal zone lymphoma, and previously-treated chronic graft-versus-host disease.
“This new approval reflects our continuous commitment to exploring the full potential of IMBRUVICA's mechanism of action for treating patients with diseases that have great unmet medical need,” adds Thorsten Graef, M.D., Ph.D., head of clinical development at Pharmacyclics.