CHMP gets positive

THOUSAND OAKS, Calif.—Amgen today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted positive opinions recommending marketing authorization for Kyprolis (carfilzomib) in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. In addition, BLINCYTO (blinatumomab) was granted a conditional marketing authorization for the treatment of adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).

"We are pleased to receive positive CHMP opinions for Kyprolis and BLINCYTO as this is an important step in providing new treatment options for patients in Europe with rare forms of cancer," said Sean E. Harper, M.D., executive vice president of research and development at Amgen. "For patients with multiple myeloma, periods of remission become shorter following each new treatment regimen, underscoring the need for additional treatment options. The results of the ASPIRE study demonstrate that Kyprolis extended the time patients live without their disease progressing. Additionally, there is a critical need for new therapies for patients with relapsed or refractory B-cell precursor ALL."

Kyprolis is a proteasome inhibitor for use in the treatment of patients with relapsed multiple myeloma. Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed. Kyprolis blocks proteasomes, which leads to an excessive build-up of proteins within cells. In some cells, Kyprolis can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.

BLINCYTO is the first clinical validation of the bispecific T cell engager (BiTE) platform, an innovative approach that can help the body's own immune system fight cancer.

The CHMP positive opinions will now be reviewed by the European Commission and, if granted, the two products will have marketing authorization in the 28 member countries of the European Union, as well as Iceland, Lichtenstein and Norway.

Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse. Multiple myeloma is an orphan disease and accounts for approximately one percent of all cancers.

Kyprolis was granted orphan drug designation by the EMA in 2008, and in February 2015, its Marketing Authorization Application (MAA) was granted accelerated assessment by the EMA. Kyprolis (carfilzomib) for Injection was approved as a monotherapy in the U.S. in July 2012, and in combination with lenalidomide and dexamethasone in July 2015. Kyprolis is also approved in Argentina, Israel, Kuwait, Mexico and Thailand.

Kyprolis is a product of Onyx Pharmaceuticals, Inc. Onyx Pharmaceuticals is a subsidiary of Amgen and holds development and commercialization rights to Kyprolis globally, excluding Japan.

The MAA was based on data from the Phase 3 ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) trial. The study showed that patients treated with Kyprolis in combination with lenalidomide and dexamethasone (regimen referred to as KRd) had increased median time to progressive disease (PD) or death by 8.7 months compared to patients treated with lenalidomide and dexamethasone (regimen referred to as Rd) (26.3 months for KRd compared to 17.6 months for Rd with HR=0.69; 95 percent CI: 0.57-0.83; 1-sided p<0.0001). Discontinuation of treatment due to adverse events (AEs) occurred in 15 percent of patients in the KRd arm versus 18 percent of patients in the Rd arm.

The international, randomized Phase 3 ASPIRE trial evaluated Kyprolis in combination with lenalidomide and dexamethasone, versus lenalidomide and dexamethasone alone, in patients with relapsed multiple myeloma following treatment with one to three prior regimens. The primary endpoint of the trial was progression-free survival (PFS), defined as the time from randomization to disease progression or death due to any cause, whichever is earlier. The study showed that patients treated with Kyprolis in combination with lenalidomide and low-dose dexamethasone had increased median time to PD or death by 8.7 months compared to patients treated with lenalidomide and dexamethasone (26.3 months for KRd compared to 17.6 months for Rd with HR=0.69; 95 percent CI: 0.57-0.83; 1-sided p<0.0001). Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), disease control rate, health-related quality of life (HR-QoL) and safety. Patients were randomized to receive Kyprolis (20 mg/m² on days 1 and 2 of cycle one only, escalating to 27 mg/m² subsequently), in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on, 7 days off) and dexamethasone (40 mg per week in 4 week cycles), versus lenalidomide and dexamethasone alone. In the Kyprolis arm, patients were given a 10 minute infusion on days 1, 2, 8, 9, 15 and 16. Kyprolis was omitted on days 8 and 9 during cycles 13-18 and not administered beyond 18 cycles. The study randomized 792 patients at sites in North America, Europe and Israel.

While the data for median OS are not yet mature based on the prespecified statistical boundary at the interim (1-sided p-value of smaller than 0.0051), the analysis showed a trend in favor of KRd compared with Rd (HR=0.79; 95 percent CI: 0.63-0.99; one-sided p=0.018, two-sided p=0.04). Patients continue to be monitored for OS. The ORR was 87.1 percent with KRd and 66.7 percent with Rd. Median DOR was 28.6 months for patients receiving KRd (95 percent CI, 24.9 to 31.3 months) and 21.2 months for patients receiving Rd (95 percent CI, 16.7 to 25.8 months). In the KRd and Rd groups, 32 percent versus 9 percent of patients achieved a complete response or higher (stringent complete response [sCR] or complete response [CR]), a measurement indicating depth of response.

The rate of deaths due to AEs within 30 days of the last dose was balanced between the KRd arm and the Rd arm. The most common causes of death not due to PD occurring in patients in the KRd arm compared to the Rd arm included cardiac disorders (3 percent versus 2 percent), infection (2 percent versus 3 percent), renal (0 percent versus less than 1 percent) and other AEs (2 percent versus 3 percent). Serious AEs were reported in 60 percent of the patients in the KRd arm and 54 percent of the patients in the Rd arm. The most common serious AEs reported in the KRd arm compared to the Rd arm were pneumonia (14 percent versus 11 percent), respiratory tract infection (4 percent versus 2 percent), pyrexia (4 percent versus 2 percent) and pulmonary embolism (3 percent versus 2 percent). Discontinuation of treatment due to AEs occurred in 15 percent of patients in the KRd arm versus 18 percent of patients in the Rd arm. AEs leading to discontinuation of Kyprolis occurred in 12 percent of patients and the most common events included pneumonia (1 percent), myocardial infarction (1 percent) and upper respiratory tract infection (1 percent).

The ASPIRE data were presented at the 56^th Annual Meeting of the American Society of Hematology and published in The New England Journal of Medicine in December 2014.

BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE^®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

BiTE^® antibody constructs are a type of immunotherapy being investigated for fighting cancer by helping the body's immune system to detect and target malignant cells. The modified antibodies are designed to engage two different targets simultaneously, thereby juxtaposing T cells. BiTE antibody constructs help place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger the cancer cell to die (apoptosis). BiTE antibody constructs are currently being investigated for their potential to treat a wide variety of cancers.

BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration, and is now approved in the U.S. for the treatment of Ph- relapsed or refractory B-cell precursor ALL. This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.