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FDA Grants Priority Review for Amgen's Supplemental New Drug Application for Expanded Labeling of Kyprolis® (Carfilzomib) in Relapsed Multiple Myeloma

Application Based on Phase 3 Head-to-Head Trial Showing Superiority of Kyprolis and Dexamethasone Over Bortezomib Plus Dexamethasone

THOUSAND OAKS, Calif., Sept. 18, 2015 /PRNewswire/ -- Amgen (NASDAQ: AMGN) today announced the U.S. Food and Drug Administration (FDA) has accepted for priority review the supplemental New Drug Application (sNDA) of Kyprolis® (carfilzomib) for Injection for patients with relapsed multiple myeloma. The sNDA is designed to expand the current indication to include Kyprolis in combination with dexamethasone for patients who have received at least one prior therapy. The Prescription Drug User Fee Act (PDUFA) target action date is Jan. 22, 2016.

The FDA's acceptance of this new sNDA for Kyprolis follows the recent FDA approval for Kyprolis in combination with Revlimid® (lenalidomide) and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy.

Multiple myeloma is a rare and complex blood cancer that has historically been one of the most difficult to treat diseases because of the inherent complexities related to the recurring pattern of remission and relapse. Patients face poor outcomes, which worsen with each relapse.

"Clinicians need a range of options and robust clinical data to make informed choices that can ideally extend the time patients live without their cancer progressing," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "The acceptance of this submission is an important next step toward providing more options for patients with relapsed multiple myeloma and we look forward to working with the FDA over the coming months."

The application is based on data from the Phase 3 head-to-head ENDEAVOR study, which showed that patients with relapsed multiple myeloma treated with Kyprolis and low-dose dexamethasone lived twice as long without their disease worsening, demonstrating statistically and clinically significant superiority over bortezomib and low-dose dexamethasone (median progression-free survival [PFS] 18.7 months versus 9.4 months, HR=0.53, 95 percent CI, 0.44 – 0.65; p<0.0001).

Treatment discontinuation due to adverse events and on-study deaths was comparable between the two arms. The rates of cardiac failure and renal failure for Kyprolis were comparable to those observed in the Phase 3 ASPIRE study. In ENDEAVOR, the rates for cardiac and renal failure were higher in the Kyprolis arm versus the bortezomib arm. There was also an increase in the incidence of hypertension and dyspnea in the Kyprolis arm compared to bortezomib in ENDEAVOR.

Priority review is assigned to applications for drugs that treat serious conditions and would, if approved, provide significant improvements in the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions.
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Source: press release, 9/18/15. http://wwwext.amgen.com//media/media_pr_detail.jsp?year=2015&releaseID=2...

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Amgen Submits Supplemental New Drug Application For Kyprolis® (Carfilzomib) In Relapsed Multiple Myeloma

Filing Based on Data From Phase 3 Head-To-Head ENDEAVOR Study

Relapsed Multiple Myeloma Patients Treated With Kyprolis in Study Lived Twice as Long Without Disease Worsening

THOUSAND OAKS, Calif., July 23, 2015 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced the submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for Kyprolis® (carfilzomib) for Injection to seek an expanded indication for the treatment of patients with a form of blood cancer, relapsed multiple myeloma, who have received at least one prior therapy. Kyprolis currently has accelerated approval in the U.S. for the treatment of patients with relapsed multiple myeloma as a monotherapy.

The sNDA is based on data from the global Phase 3 ENDEAVOR trial. The ENDEAVOR study is the first of two head-to-head Phase 3 trials of Kyprolis versus Velcade® (bortezomib). Relapsed multiple myeloma patients treated with Kyprolis and dexamethasone in the ENDEAVOR study lived twice as long without their disease worsening, demonstrating statistically and clinically significant superiority over Velcade (median progression-free survival [PFS] 18.7 months versus 9.4 months, HR=0.53, 95 percent CI, 0.44 – 0.65; p<0.0001).

"Submission of this new sNDA for Kyprolis is important because if approved, it will mean more treatment options for patients with this serious disease. Multiple myeloma has historically been one of the most difficult to treat diseases because of the inherent complexities related to the recurring pattern of remission and relapse," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "The ENDEAVOR study showed that patients who had failed at least one prior therapy were half as likely to see their disease worsen if they received Kyprolis. This is yet another data set that illustrates Kyprolis' potential to extend the time patients live without their disease progressing and improve the depth and duration of a response."

The Kyprolis combination demonstrated superiority over the Velcade combination for secondary objectives of higher overall response rate and lower neuropathy events. Overall survival data are not yet mature and continue to be monitored.

Treatment discontinuation due to adverse events and on-study deaths was comparable between the two arms. The rates of cardiac failure and renal failure for Kyprolis were comparable to those observed in the Phase 3 ASPIRE study. In ENDEAVOR, the rates for cardiac and renal failure were higher in the Kyprolis arm versus the Velcade arm. There was also an increase in the incidence of hypertension and dyspnea in the Kyprolis arm compared to Velcade in ENDEAVOR and than that observed in the ASPIRE study.

Based on the Phase 3 ASPIRE study Amgen continues to work with the FDA on the related sNDA in the U.S. and with the European Union (EU) regulatory authorities for the Marketing Authorization Application for Kyprolis. Following potential approval based on the ASPIRE study, Amgen plans to submit ENDEAVOR for potential authorization in the EU.

Kyprolis Head-to-Head Studies
The randomized ENDEAVOR (RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) trial of 929 patients evaluated Kyprolis in combination with dexamethasone, versus Velcade with dexamethasone in patients whose multiple myeloma has relapsed after at least one, but not more than three prior therapeutic regimens. The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death.

Patients received Kyprolis as a 30-minute infusion along with dexamethasone (20 mg). Administer Kyprolis at a starting dose of 20 mg/m2 in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to a target dose of 56 mg/m2 on Day 8 of Cycle 1. Patients were kept at 56 mg/m2 on days 9, 15 and 16 on a 28 day cycle. Patients who tolerated 56 mg/m2 in Cycle 1 were kept at this dose for subsequent cycles on days 1, 2, 8, 9, 15 and 16 on a 28 day cycle. Patients who received Velcade (1.3 mg/m2) with dexamethasone (20 mg) were administered Velcade subcutaneously or intravenously at the discretion of the investigator and in accordance with regulatory approval of Velcade. More than 75 percent of the patients in the control arm received Velcade subcutaneously. This study was conducted at 235 sites worldwide. For information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT01568866.

Kyprolis is also being evaluated in the CLARION study, a head-to-head Phase 3 multicenter, open-label, randomized study in transplant-ineligible patients with newly diagnosed multiple myeloma. The study is evaluating the safety and efficacy of carfilzomib, melphalan and prednisone versus bortezomib, melphalan and prednisone. For information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT01818752.
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Source: press release, 7/23/15. http://wwwext.amgen.com//media/media_pr_detail.jsp?year=2015&releaseID=2...

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Compound/DeviceSpecialtyIndicationCompound ClassTarget
Kyprolis (Carfilzomib)Oncology HematologicMultiple Myeloma20S proteasome inhibitor20S proteasome

Mechanism of action: Kyprolis (Carfilzomib) irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome, an enzyme responsible for degrading a large variety of cellular proteins. Inhibition of proteasome-mediated proteolysis results in an accumulation of polyubiquinated proteins, which may lead to cell cycle arrest, induction of apoptosis, and inhibition of tumor growth.

Phase of Development: Filed

Event Type: Regulatory FDA: PDUFA DATE

Dates: 2016-01-22

Results:

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FDA Approves New Kyprolis® (Carfilzomib) Combination Therapy For The Treatment Of Patients With Relapsed Or Refractory Multiple Myeloma
Pivotal Head-To-Head ENDEAVOR Study Shows Kyprolis and Dexamethasone Doubled Progression-Free Survival Versus Velcade® (Bortezomib) and Dexamethasone
Kyprolis Label Expansion Represents Critical Advancement for Patients With Relapsed or Refractory Multiple Myeloma, Offering New Option For Backbone Therapy
Approval Expands Kyprolis Indication and Converts Monotherapy Indication to Full Approval
THOUSAND OAKS, Calif., Jan. 21, 2016 /PRNewswire/ -- Amgen (NASDAQ: AMGN) today announced that the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) of Kyprolis® (carfilzomib) for Injection in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. The FDA also approved Kyprolis as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. This FDA decision converts to full approval the initial accelerated approval Kyprolis received in July 2012 as a single agent.

Experience the interactive Multimedia News Release here: http://www.multivu.com/players/English/74140510-kyprolis-endeavor-expand....

"Kyprolis is the only approved therapy for relapsed multiple myeloma with proven efficacy as a single agent, doublet and triplet combination that is offered in a variety of doses to meet individual patient needs," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "Importantly, this new approval supports the use of Kyprolis as a backbone therapy for the management of relapsed multiple myeloma, a difficult-to-treat blood cancer."

"Multiple myeloma remains an incurable disease where relapse inevitably occurs and over time patients become resistant to treatments," said Dr. Ruben Niesvizky, director of the Multiple Myeloma Center at Weill Cornell Medicine and New York-Presbyterian/Weill Cornell Medical Center. "As a clinician, I'm pleased with the tremendous progress that we have seen in the past 12 months in multiple myeloma treatment. This FDA approval is important because it provides physicians with flexible options for Kyprolis use in helping to manage this challenging disease."

The approval is based on results from the Phase 3 head-to-head ENDEAVOR study. This was a superiority trial in which the primary endpoint was progression-free survival (PFS). The data showed patients with relapsed multiple myeloma treated with Kyprolis and dexamethasone achieved 50 percent greater PFS of 18.7 months compared to 9.4 months in those receiving Velcade® (bortezomib) and dexamethasone (HR=0.53; 95 percent CI: 044, 0.65 p<0.0001), a current standard of care in relapsed multiple myeloma. Patients in the study were treated until disease progression. The most common adverse reactions (greater than or equal to 20 percent) in the Kyprolis arm were anemia, diarrhea, dyspnea, fatigue, insomnia, pyrexia and thrombocytopenia.

This new indication for Kyprolis is the second in six months. In July 2015, the FDA approved another expanded indication for Kyprolis in combination with lenalidomide and dexamethasone (KRd) for the treatment of patients with multiple myeloma who have received one to three prior lines of therapy.

Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.1 It is a rare and very aggressive disease that accounts for approximately one percent of all cancers.2-4 In the U.S., there are nearly 90,000 people living with, or in remission from, multiple myeloma.5 Approximately, 26,850 Americans are diagnosed with multiple myeloma each year and 11,240 patient deaths are reported on an annual basis.5
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Source: press release, 1/21/16. http://wwwext.amgen.com/media/news-releases/2016/01/fda-approves-new-kyp...

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