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All sales are in millions of dollars.
In millions of dollars, except EPS
Amgen leaders say 2013 was a landmark year for the company, and 2014 and beyond appear just as promising for this Thousand Oaks, Calif.-based biotechnology force. Worldwide growth of 8 percent drove company revenue to $18.7 billion in 2013. Also during the year, total shareholder return of 35 percent outshined the S&P 500. Long-term investments have been made to continue advancing Amgen’s later-stage pipeline, with pivotal and/or registrational-enabling data on 10 innovative molecules anticipated by 2016, including potentially eight of those projects by year-end 2014. Additionally, the company has six biosimilar molecules that could be introduced to the marketplace starting in 2017. Amgen’s presence extends to 75 countries, including Japan, China, and emerging markets.
“All of this gives me great confidence that we are creating a very exciting future for Amgen,” comments Robert A. Bradway, company chairman and CEO. “We are pushing the boundaries of biotechnology to find new ways to deliver for patients suffering from serious illnesses. We are also bringing our medicines to new markets, providing new treatment options around the world.”
Since its birth in 1980, Amgen has transformed into the world’s largest independent biotechnology company. Management is dedicated to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. According to the company, this approach starts by using tools such as advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.
Amgen concentrates on areas of high unmet medical need and leverages the company’s biologics manufacturing expertise to strive for solutions that improve health outcomes and dramatically improve people’s lives. The company markets primarily recombinant protein therapeutics for supportive cancer care, inflammation, nephrology and bone disease.
Amgen’s principal products consist of a variety of current and future blockbuster medicines including Neulasta,Neupogen, Enbrel,Aranesp,Epogen, XGEVA,Prolia, and Sensipar/Mimpara. Amgen markets several other products such as Vectibix,Nplate (romiplostim) and, through its wholly owned subsidiary Onyx Pharmaceuticals,Kyprolis. During 2013 Amgen acquired Onyx, a leading biopharma company with innovative medicines that further strengthens Amgen’s oncology business.
For 2013, worldwide revenue growth of 8 percent was fueled by strong performances across the portfolio. Amgen’s product sales in 2013 rose 10 percent in the United States and 8 percent in the rest of the world (ROW). The company’s product sales outside the United States consist mainly of sales in Europe.
The company during 2013 continued to pay quarterly dividends. In December 2013, Amgen declared a dividend of 61 cents per share of common stock payable in March 2014, representing 30 percent growth compared to the quarterly dividend paid in each of the previous four quarters.
In addition to delivering strong operating results, Amgen significantly invested in the business in 2013 and management notes that performance is reflected in the company’s pipeline advancements. During the year, Amgen reported positive readouts for evolocumab, talimogenelaherparepvec, and trebananib. Amgen has started pivotal trials for three of its six biosimilar programs, including versions for three current blockbuster brands: Avastin, Herceptin and Humira. Amgen’s global expansion to more than 75 countries has been partially helped by the company reacquiring rights to filgrastim and pegfilgrastim in Eastern Europe, Latin America, Asia, the Middle East and Africa, effective Jan. 1, 2014. The anticipated blockbuster brand Kyprolis was added to the company’s marketed products portfolio via the acquisition of Onyx. Amgen also during 2013 in-licensed the U.S. commercial rights to the promising pipeline project ivabradine from Servier. This move positions Amgen in the cardiovascular arena for the first time, ahead of the expected market arrival of its investigational dyslipidemia treatment evolocumab (product code AMG 145).
With those building blocks from 2013 to work with, Amgen anticipated 2014 to be a data-rich year with various opportunities to continue growing its business. Management believes that the currently approved indications for XGEVA and Prolia represent significant commercial opportunities. Longer-term growth may additionally be generated by the successful development of 10 innovative molecules in the later-stage pipeline, including Kyprolis and evolocumab in the United States and internationally. Longer-term growth may also be attained by continued expansion into emerging markets and via strategic business development opportunities. Amgen’s continued focus on increasing cost efficiencies are expected to help provide the necessary resources to fund many of these future opportunities.
A restructuring plan was announced during July 2014 that will reduce staff by 2,400 to 2,900 people by year-end 2015. The company will shut down its facilities in the states of Washington and Colorado. Additionally, Amgen will reduce the number of buildings at its headquarters in Thousand Oaks. Amgen managers say these actions will result in pre-tax accounting charges in the range of $775 million to $950 million, primarily incurred during 2014 and 2015. As a next step, company execs are evaluating additional efficiency initiatives, particularly in the area of shared services and other external expense categories to support Amgen’s growth objectives.
“Robust growth through the first half of 2014 affirms the underlying strength of our business,” Mr. Bradway noted. “We are making excellent progress in advancing our pipeline as we prepare to launch a number of promising new innovative medicines. From a position of strength, we have announced today [July 29, 2014] restructuring initiatives that will allow us to reallocate resources to invest in our upcoming launches and drive growth.”
Amgen’s global sales continue to accrue annually at company-record levels. Total revenue grew from $14.64 billion for 2009 to $18.68 billion in 2013, with product sales during that time frame elevating from $14.35 billion to $18.19 billion. The increase in U.S. product sales for 2013, up 10 percent versus the prior-year performance, reflects growth across the portfolio except for Aranesp, which decreased 4 percent. The growth was driven mainly by increases in average net sales prices and, to a lesser extent, unit growth. The 8 percent improvement in ROW product sales for 2013 reflects growth for all of Amgen’s marketed products except Aranesp, which fell 7 percent, and Neupogen, which dropped off 9 percent. The ROW increase was spurred by unit growth.
Net income for 2013 was reported at $5.08 billion compared to $4.35 billion during the previous year. The growth was due primarily to a lower effective income tax rate as well as higher operating income. Diluted earnings per share rose from $5.52 for 2012 to $6.64 in 2013. Adjusted EPS rose 17 percent to $7.60, which Amgen management says reflects strong execution and continued momentum in the company’s business. The improvement was mainly spurred by an increase in net income and, to a lesser extent, by the favorable impact of Amgen’s stock repurchase program during 2012 and first-quarter 2013, which reduced the amount of shares used to compute diluted EPS. The company did not repurchase any shares during the second, third, or fourth quarters of 2013.
Amgen reported 2013 research and development expenses of $4.08 billion compared to the 2012 total of $3.38 billion. Amgen’s R&D costs for 2013 equaled 22.4 percent of product sales for the full year. The year-over-year growth in the R&D budget was led primarily by an increase of $665 million in Amgen’s later-stage clinical programs, including evolocumab and Kyprolis; and an increase of $96 million in Discovery Research and Translational Sciences activities, offset partially by reduced expenses associated with marketed product support of $58 million.
For the first half of 2014, Amgen recorded global product sales of $9.31 billion and total revenue of $9.7 billion, representing increases of 6 percent and 9 percent respectively compared to the January-June 2013 results. The growth in worldwide product sales for the six-month period ended June 30, 2014, was led by Kyprolis, Prolia, XGEVA, and Neulasta. The year-over-year improvement in other revenue for first-half 2014 was due mainly to Nexavar collaboration revenue and Stivarga royalties stemming from the Onyx acquisition.
Amgen’s net income for January-June 2014 came to $2.62 billion, down 3 percent year-over-year. Diluted earnings per share fell by the same percentage, from $3.52 in the first six months of 2013 to $3.41 during the first two quarters of 2014. The drop-offs in net income and diluted EPS during first-half 2014 were due primarily to favorable tax items that occurred in first-quarter 2013.
R&D expenses climbed up from $1.85 billion during the first six months of 2013 to $2.05 billion for first-half 2014. The research and development amount for January-June 2014 represented 22 percent of Amgen’ product sales during that time frame. The expenditure growth was spurred primarily by increased costs of $244 million associated with Onyx across all categories of R&D spend, and increased costs associated with other later-stage clinical-program support. Overall, costs associated with later-stage clinical program support rose by $264 million, offset partially by reduced expenses associated with marketed product support of $46 million and Discovery Research and Translational Sciences activities totaling $18 million.
Introduced in 1998, Enbrel (etanercept) is one of the world’s top-selling prescription medicines. The product is used primarily in the approved indications for treating adult patients with the following conditions: moderately to severely active rheumatoid arthritis; chronic moderate to severe plaque psoriasis patients who are candidates for systemic therapy or phototherapy; and active psoriatic arthritis. Amgen markets Enbrel primarily in the United States. Pfizer Inc. holds the rights to market and sell the product outside the United States and Canada.
Enbrel was Amgen’s No. 1 selling drug worldwide in 2013 at $4.55 billion, up 7 percent compared to the full-year 2012 figure. A majority of Amgen’s sales for Enbrel come from the United States, with the 2013 amount reaching $4.26 billion, a 7 percent increase year-over-year. Enbrel remained Amgen’s top seller in first-half 2014 with global sales of $2.23 billion, rising 2% versus the January-June 2013 tally. According to the company, Enbrel continues to benefit from strong underlying demand and segment growth.
Amgen has collaborated for years on its best-selling medicine Enbrel with Pfizer. The co-promotion deal for Enbrel in the United States and Canada expired on Oct. 31, 2013. Upon expiration of the joint-promotion pact, Amgen was required to pay Pfizer residual royalties based on a declining percentage of annual net Enbrel sales in the United States and Canada for three years, ranging from 12 percent to 10 percent. The totals of such payments are anticipated to be significantly less than what would be owed based on the terms of the previous Enbrel profit share. As of Nov. 1, 2016, there will be no additional royalty payments. For 2014, Amgen anticipated an $800 million incremental operating income contribution from Enbrel.
Amgen markets Neulasta, a pegylated protein based on the filgrastim molecule, and Neupogen, a recombinant-methionyl human granulocyte colony stimulating factor (G-CSF), primarily in the United States and Europe. Neulasta was introduced during 2002 and is indicated to decrease the incidence of infection associated with chemotherapy-induced febrile neutropenia in cancer patients with non-myeloid malignancies. Neupogen was launched in 1991 and is marketed for five different indications. The drug is used primarily for reducing the incidence of infection as manifested by febrile neutropenia for patients with nonmyeloid malignancies undergoing myelosuppressive chemotherapy associated with a significant incidence of severe neutropenia with fever.
Neulasta was Amgen’s No. 2 medicine in terms of sales during full-year 2013 and first-half 2014. Global Neulasta sales for 2013 rose 7 percent to $4.39 billion compared to the drug’s 2012 performance. Of the 2013 amount, $3.5 billion was generated in the United States and $893 million stemmed from ROW sales. Neulasta global six-month sales during first-half 2014 totaled $2.22 billion, up 3 percent compared to January-June 2013. ROW sales improved 9 percent year-over-year, benefiting from sales in new markets as a result of reacquiring rights to filgrastim and pegfilgrastim.
Containing filgrastim, Neupogen requires more frequent dosing compared to Neulasta, which is administered as a single dose per chemotherapy cycle. Neupogen 2013 sales advanced 11 percent over its 2012 amount, reaching $1.4 billion, including 16 percent growth in U.S. sales that amounted to $1.17 billion. According to company management, the growth in worldwide Neupogen sales for 2013 was driven by a $155-million order from the U.S. government. Global Neupogen sales during January-June 2014 fell 6 percent year-over-year to $585 million. The drop-off in worldwide Neupogen sales for first-half 2014 was driven by a U.S. unit decline and by the positive Medicaid rebate estimate adjustment in 2013, offset partially by the increased sales as a result of reacquiring rights to filgrastim in certain regions. Amgen’s material U.S. patents for filgrastim expired during December 2013.
During October 2013, Amgen entered into a deal to acquire the licenses to filgrastim and pegfilgrastim effective Jan. 1, 2014, that were held by F. Hoffmann-La Roche Ltd. in 100 markets in Eastern Europe, Latin America, Asia, the Middle East and Africa (Product Rights). Additionally, Amgen agreed to settle its pre-existing relationship related to the Product Rights for total consideration of $497 million. According to management, this acquisition provides Amgen with an opportunity to expand its geographic presence and reach more patients in more countries that could benefit from the company’s therapies.
Aranesp was launched during 2001 and is indicated for treating anemia associated with chronic kidney disease (CKD) in patients on dialysis and patients not on dialysis. The drug is also marketed for the treatment of anemia due to concomitant myelosuppressive chemotherapy in patients with non-myeloid malignancies. Aranesp (darbepoetinalfa) is a recombinant human protein agonist of the erythropoietin receptor. A Phase III clinical trial for the treatment of low-risk myelodysplastic syndromes is under way.
Global 2013 sales for Aranesp declined 6 percent from 2012 to $1.91 billion. ROW sales for 2013 accounted for $1.16 billion and the U.S. amount came to $747 million. The decreased U.S. sales for 2013 was due to declines in unit demand, reflecting changes in practice patterns resulting from alterations to the label and to the reimbursement environment that occurred in 2011. The drop-off in ROW Aranesp sales for 2013 reflects unit declines and price pressure in Europe.
Aranesp first-half 2014 sales dropped 2 percent from the first six months of 2013, falling to $977 million. The decreases in worldwide Aranesp sales during January-June 2014 were driven mainly by the positive Medicaid rebate estimate adjustment during 2013. According to Amgen, underlying demand continues to decrease slightly due to practice patterns in the United States and competitive pricing pressures in Europe.
Aranesp’s fellow erythropoiesis-stimulating agent Epogen (epoetinalfa) was made available in 1989. The first-generation drug is indicated to treat a lower-than-normal amount of red blood cells (anemia) caused by CKD in patients on dialysis to lessen the need for red blood cell transfusions. The product’s sales for 2013 reached $1.95 billion, rising 1 percent compared to its 2012 performance because of unit growth. Epogen sales growth continued into first-half 2014, increasing 4 percent from the corresponding 2013 period to $974 million.
Denosumab is the active ingredient in two products marketed by Amgen: XGEVA and Prolia. The brands are available for different indications, patient populations, doses, and frequencies of administration. A human monoclonal antibody, denosumab specifically targets a ligand known as RANKL (that binds to a receptor known as RANK), a key mediator of osteoclast formation, function, and survival. The drug compound is being investigated across a range of conditions such as osteoporosis, treatment-induced bone loss and various tumor types across the spectrum of cancer-related bone diseases, including hypercalcemia of malignancy.
XGEVA was introduced in the United States in 2010 and is indicated for the prevention of skeletal-related events (SREs) (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in patients with bone metastases from solid tumors. XGEVA debuted in Europe during 2011 and is marketed for the prevention of SREs in adults with bone metastases from solid tumors. The medicine was approved by U.S. regulators in 2013 as the first treatment for adults and skeletally mature adolescents with giant cell tumor of bone (GCTB) that is unresectable or where surgical resection is likely to result in severe morbidity. In clinical studies, XGEVA demonstrated a clinically meaningful improvement compared to the previous standard of care in preventing these bone complications.
Sales for XGEVA rose from $748 million during 2012 to $1.02 billion for 2013. The 2013 sum included $764 million in U.S. sales. The growth continued into 2014, with global first-half sales increasing 22 percent versus the first six months of 2013 to $578 million, including U.S. sales of $407 million (up 11 percent YoY). XGEVA represents the seventh Amgen medicine to exceed $1 billon in annual sales.
XGEVA is being explored in clinical development for new potential uses. Phase III studies under way include the delay or prevention of bone metastases in breast cancer and cancer-related bone damage in patients with multiple myeloma.
Prolia made its debut in the United States and Europe in 2010. In the United States, Prolia has four different approved indications and is used primarily for treating postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. In Europe, Prolia is mainly used for the treatment of osteoporosis in postmenopausal women at increased risk of fractures.
Sales for Prolia improved from $472 million during 2012 to $744 million for 2013. U.S. sales paced the performance during 2013, totaling $462 million for the year (up 58 percent versus 2012). For the first two quarters of 2014, the drug’s global sales jumped up 39 percent year-over-year to $460 million, including U.S. sales of $278 million (up 36 percent).
During August 2013, Amgen filed a marketing application to the EMA for Prolia for treating osteoporosis in men at increased risk of fracture. The medicine is undergoing Phase III development for glucocorticoid-induced osteoporosis and male osteoporosis (in the EU only for the latter indication).
The orally administered small molecule cinacalcet is branded as Sensipar in the United States and as Mimpara in Europe. The drug was launched in 2004, and according to Amgen is used primarily in the approved indication for treating secondary hyperparathyroidism in CKD patients on dialysis. Sensipar/Mimpara lowers parathyroid hormone (PTH) levels in blood by increasing sensitivity of the calcium-sensing receptor (CaSR) to extracellular calcium. The drug is being evaluated in Phase III studies for post-renal transplant patients.
Sensipar/Mimpara sales increased 15 percent in 2013, rising to $1.09 billion from $950 million during the previous calendar year. Sensipar’s U.S. sales for 2013 amounted to $757 million, an 18 percent advancement over the drug’s 2012 sum. First-half 2014 sales for Sensipar/Mimpara totaled $568 million, up 9 percent over the January-June 2013 result. Sensipar U.S. sales rose 7 percent year-over-year to $382 million, and ROW sales climbed up 12 percent to $186 million.
Acquisitions & Collaborations
A significant development for Amgen occurred during October 2013 with the acquisition of Onyx Pharmaceuticals. A worldwide biopharmaceutical company, Onyx has been engaged in the development and commercialization of innovative therapies for improving the lives of people with certain cancers. Now a subsidiary of Amgen, Onyx’s growing multiple myeloma franchise includes Kyprolis (carfilzomib) for Injection. During July 2012, U.S. regulators granted accelerated approval of Kyprolis for treating patients with multiple myeloma who have received at least two prior therapies (including bortezomib and an immunomodulatory agent) and have shown disease progression on or within 60 days of completion of the last therapy.
In addition to multiple myeloma, the novel proteasome inhibitor carfilzomib is being studied as a treatment for patients with small-cell lung cancer. Amgen management believes that there is significant market potential for Kyprolis, which is the therapy of choice in the relapsed/refractory multiple myeloma setting in the United States.
The Onyx portfolio also consists of the pipeline project oprozomib. The oral proteasome inhibitor is being studied for treating hematologic malignancies, including multiple myeloma.
Onyx has three partnered oncology assets, including two marketed medicines with Bayer: Nexavar (sorafenib) tablet and Stivarga (regorafenib) tablet. Onyx additionally partners with Pfizer on palbociclib.
Amgen agreed in June 2014 to collaborate with the National Cancer Institute – part of the National Institutes of Health – and other public and private sector partners on the Lung Master Protocol (Lung-MAP). The groundbreaking new clinical-trial program will use biomarker-driven research and genomic profiling to match squamous cell lung cancer patients to investigational treatments based on their individual cancer profiles. Lung-MAP is the first study of its kind to examine a large amount of rare lung cancer subsets under one trial protocol.
Between 500 and 1,000 patients will be screened annually for more than 200 cancer-related genes. The screenings will inform trial-arm selection. Five investigational drugs have been chosen for inclusion in the initial study, including Amgen’s rilotumumab. The investigational fully human monoclonal antibody is designed to inhibit cancer cell growth and migration. In addition to evaluating the potential of rilotumumab in treating squamous cell carcinomas in lung cancer as part of the Lung-MAP clinical trial program, the product candidate is undergoing Phase III evaluation in advanced gastric/gastroesophageal junction cancer.
Amgen and Merck entered into an agreement through a subsidiary during February 2014 to evaluate the safety and efficacy of talimogenelaherparepvec in a Phase Ib/II trial of patients with mid-stage to late-stage melanoma. The multicenter, open-label clinical study will be conducted in two parts and was expected to start in the fall of 2014. Phase Ib is designed to determine the safety and tolerability of talimogenelaherparepvec in combination with Merck’s investigational, highly selective anti-PD-1 immunotherapy MK-3475 in patients with previously untreated, unresected, stage IIIB to IVM1a melanoma. The Phase II portion will evaluate efficacy, as assessed by the confirmed objective response rate (ORR), with talimogenelaherparepvec in combination with MK-3475 versus MK-3475 alone in patients with previously untreated, unresected, stage IIIB to IVM1c melanoma. The study will additionally evaluate the efficacy of treatment with talimogenelaherparepvec in combination with MK-3475 following disease progression on MK-3475 alone.
A collaboration has been in place between Amgen and GlaxoSmithKline subsidiary Glaxo Group Ltd. for the commercialization of denosumab for osteoporosis indications in Europe, Australia, New Zealand and Mexico (the Primary Territories). Through the initial deal, Amgen retained the rights to commercialize denosumab for all indications in the United States and Canada and for oncology indications in the Primary Territories. Also, the biotech entity has the option of expanding its role in the commercialization of denosumab in the Primary Territories and certain of Glaxo’s Expansion Territories (China, Brazil, India, Taiwan and South Korea).
On April 1, 2014, Amgen entered into a Termination and Transition Agreement with Glaxo that partly terminated and amended their deal for denosumab. According to Amgen, the Transition Agreement terminated the Collaboration Agreement for all countries and regions, except for Australia. All commercial activities assigned to Glaxo under the Collaboration Agreement other than those in Australia were to be transitioned back to Amgen by Dec. 31, 2014. In exchange for the early termination (except Australia) of the Collaboration Agreement, Amgen is responsible for payments to Glaxo amounting to $275 million. That figure represents the reacquisition of a previously shared economic interest in geographic territories where Amgen already was marketing denosumab.
Another top 10 company that Amgen has a collaboration with is AstraZeneca. The collaboration is for the joint development and commercialization of certain monoclonal antibodies from Amgen’s clinical inflammation portfolio, including brodalumab, AMG 139, AMG 157, AMG 181 and AMG 557. The deal covers the global development and commercialization of these antibodies (except for certain Asian countries) for brodalumab and Japan for AMG 557, which are licensed to other third parties.
Amgen and UCB have a deal to jointly develop and commercialize the investigational bone-forming agent romosozumab. Amgen holds the rights to commercialize romosozumab for all indications in the United States, Canada, Mexico and Japan. UCB retains rights for all EU members at the time of initial regulatory approval, Australia and New Zealand. Before commercialization, countries that have not been initially designated will be designated to Amgen or UCB in accordance with the agreement terms.
Romosozumab is designed to increase bone formation and decrease bone breakdown by inhibiting the protein sclerostin. Romosozumab is being investigated for its potential to reduce fracture risk in an extensive worldwide Phase III program. The program includes two pivotal clinical trials evaluating romosozumab against placebo and active comparator in more than 10,000 patients with osteoporosis.
In The Pipeline/Recent Product Approvals
Management says Amgen was one of the first companies to develop therapeutic proteins, which can replace or augment beneficial human proteins, and monoclonal antibodies, which can strike disease targets with enhanced precision. Amgen scientists have additionally engineered new types of medicines, such as peptibodies, and the company pipeline features other entirely novel treatment modalities.
The company’s R&D concentrates on novel human therapeutics for treating grievous illness in the fields of oncology, hematology, inflammation, bone health, nephrology, cardiovascular and general medicine, which includes neuroscience. Executives say the company takes a modality-independent approach to research and development with a focus on biologics. As a result, discovery research programs could yield targets that lead to the development of human therapeutics delivered as large molecules, small molecules, or other combinations or new modalities.
R&D costs for Amgen totaled $4.1 billion in 2013, $3.4 billion during 2012, and $3.2 billion in 2011. The expenditure totaled $2.05 billion in first-half 2014 compared to $1.85 billion for January-June 2013.
According to Amgen, the success of its R&D is evident in the company’s product portfolio, which includes novel therapies for hard-to-treat diseases. These therapies have been used to treat more than 25 million patients globally with diseases such as cancer, kidney failure, blood and autoimmune disorders, and bone diseases. Amgen is building on these successes with a drug pipeline that intends to help patients with conditions including heart disease, schizophrenia, and migraine.
As of Feb. 17, 2014, Amgen had 16 Phase III programs. Those Phase III programs include the potential cancer treatment talimogenelaherparepvec. The first-in-class oncolytic immunotherapy is derived from HSV-1. The product candidate is designed to selectively replicate in tumors (but not normal tissue) and to initiate an immune response to target cancer cells that have metastasized. Talimogenelaherparepvec was designed to work in two significant and complementary ways. First, it is injected directly into tumors where the drug replicates inside the tumor’s cells, causing the cell to rupture and die in a process known as lysis. The rupture of the cancer cells can release tumor-derived antigens, along with GM-CSF, that can stimulate a system-wide immune response. Through this response, white blood cells are able to locate and target cancer that has spread throughout the body.
Favorable clinical results were reported for talimogenelaherparepvec as a single agent and as part of a combination regimen in patients with metastatic melanoma during 2014. A positive overall survival trend was observed in a Phase III trial. Also, a Phase I study evaluating talimogenelaherparepvec in combination with ipilimumab demonstrated tolerability at the doses administered. Tumors shrank in size or were no longer detectable in 56 percent of patients. Findings from a pre-specified Phase III retrospective analysis of patients with metastatic melanoma demonstrated that talimogenelaherparepvec reduced the size of injected tumors and also non-injected tumors that had metastasized to other parts of the body.
On Sept. 2, 2014, Amgen announced the submission of a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) through the centralized procedure for talimogenelaherparepvec seeking approval for treating adults with melanoma that is regionally or distantly metastatic. The MAA represents the first for an oncolytic immunotherapy in the European Union. According to Amgen, during July 2014 the company announced its filing of a BLA with U.S. regulators for regionally and distantly metastatic melanoma.
Positive clinical-trial results were announced for Kyprolis during summer 2014. A planned interim analysis revealed in August showed that the Phase III study ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) met its primary endpoint of progression-free survival. Patients treated with Kyprolis for Injection in combination with Revlimid (lenalidomide) and low-dose dexamethasone (KRd) lived significantly longer without their disease worsening (median 26.3 months) versus patients treated with Revlimid and low-dose dexamethasone (Rd) (median 17.6 months) (HR=0.690, 95 percent CI, 0.570, 0.834, p<0.0001). Although the data for overall survival, a secondary endpoint, are not yet mature according to Amgen, the analysis demonstrated a trend in favor of KRd that did not reach statistical significance. Amgen says the safety profile observed in this clinical trial is consistent with the current U.S. Kyprolis label, including the rate of cardiac events. Treatment discontinuation due to adverse events and on-study deaths were comparable between the two arms, per Amgen.
Results from the ASPIRE study will form the basis for regulatory submissions globally starting during first-half 2015. In the United States, the data may support the conversion of accelerated approval to full approval and expand Kyprolis’ already-approved indication.
Through its own R&D efforts and innovative partnerships, Amgen has formed a robust cardiology pipeline consisting of several investigational molecules in an effort to address important unmet patient needs. Those needs include high cholesterol and heart failure.
Also on Sept. 2, Amgen filed an MAA for evolocumab as a treatment for high cholesterol. Five days earlier, the company announced the Biologics License Application (BLA) with the U.S. Food and Drug Administration. The evolocumab approval applications contain data from 6,800 patients, including more than 4,500 patients with high cholesterol in 10 Phase III studies. Overall, the novel LDL cholesterol-lowering medication is being investigated in 22 clinical trials, with a combined planned enrollment of 30,000 patients.
Phase III data from the TESLA trial demonstrated that adding evolocumab 420 mg subcutaneous monthly to a stable dose of statin therapy and other lipid-lowering medications significantly reduced low-density lipoprotein cholesterol (LDL-C) by 31 percent (p<0.001) from baseline at week 12 versus placebo. Also announced during second-quarter 2014 were Phase III results from the LAPLACE-2 study. In this trial consisting of 1,896 patients with high cholesterol, treatment with subcutaneous evolocumab (140 mg every two weeks or 420 mg monthly) in combination with different daily doses of statin therapy significantly reduced mean LDL-C regardless of statin dose. In March 2014, Amgen announced that treatment with evolocumab resulted in a statistically significant reduction in low-density lipoprotein cholesterol (LDL-C) between 37-39 percent, compared to ezetimibe in patients with high cholesterol who cannot tolerate statins in the GAUSS-2 Phase III study, and between 55-76 percent compared to placebo when used in combination with statin therapy in patients with high cholesterol (LAPLACE-2). Also during March 2014, results from the separate Phase III studies MENDEL-2, DESCARTES and RUTHERFORD-2 revealed that evolocumab treatment resulted in a statistically significant reduction of 55-66 percent in LDL-C compared to placebo in patients with high cholesterol.
The fully human monoclonal antibody evolocumab inhibits proproteinconvertasesubtilisin/kexin type 9 (PCSK9), which is a protein that cuts down on the liver’s ability to remove low-density lipoprotein cholesterol (LDL-C), or “bad” cholesterol, from the blood. The drug is designed to bind to and inhibit PCSK9 from binding to LDL receptors on the liver surface. Without PCSK9, there are more LDL receptors on the surface of the liver to remove LDL-C from the blood.
In late August 2014, Amgen announced FDA’s priority review designation for ivabradine for treating chronic heart failure (HF). Additionally, during April 2014 U.S. regulators granted fast-track designation for ivabradine for patients with chronic HF. Ivabradine inhibits the If current (“funny” current) in the sinoatrial node, which is the body’s cardiac pacemaker. The oral drug works to slow the heart rate without negative effects on myocardial contractility or ventricular repolarization. Heart failure affects 26 million people globally, including 5.1 million Americans.
Developed by Les LaboratoiresServier, ivabradine was approved by the EU health authorities as Procoralan during 2005 for the symptomatic treatment of stable angina and in 2012 for chronic heart failure in patients with elevated heart rates. Via a collaboration with Servier, Amgen holds U.S. marketing rights.
The peptide velcalcetide (product code AMG 416) could become a significant new treatment option for dialysis patients with secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease. The novel calcimimetic agent is undergoing Phase III studies for treating SHPT. Administered intravenously in patients with CKD who are receiving hemodialysis, AMG 416 binds to and activates the calcium-sensing receptor on the parathyroid gland, thus causing decreases in PTH.
Amgen announced during mid-August 2014 that a second Phase III registrational study for AMG 416 met primary and all secondary endpoints. One month earlier, Amgen reported that a Phase III trial also met its primary and all secondary endpoints. The primary endpoint in both placebo-controlled studies was the proportion of patients with > 30 percent reduction from baseline in parathyroid hormone levels during an Efficacy Assessment Phase defined as the period between weeks 20 and 27. The July 2014 announcement represented the first results to be reported from the Phase III program.
Amgen obtained AMG 416 as part of the July 2012 acquisition of KAI Pharmaceuticals Inc. Results of a head-to-head study evaluating AMG 416 versus Amgen’s cinacalcet will be announced during 2015.
FDA during the summer of 2014 granted Breakthrough Therapy Designation to Amgen’s investigational bispecific T cell engager (BiTE) antibody blinatumomab. The drug compound is intended for adults with Philadelphia-negative (Ph-) relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL), which is a rapidly progressing cancer of the blood and bone marrow. The Breakthrough Therapy Designation was based on the results of a Phase II study of 189 adult patients with Ph- relapsed/refractory B-precursor ALL treated with blinatumomab. The U.S. regulatory agency’s designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
Blinatumomab is designed to direct the body’s cell-destroying T cells against target cells expressing CD19, which is a protein found on the surface of B-cell derived leukemias and lymphomas. Blinatumomab represents the first BiTE antibody. Amgen has received orphan drug designation from FDA for treating ALL, CLL, hairy cell leukemia, prolymphocytic leukemia, and indolent B cell lymphoma. The European Medicines Agency has granted likewise for the treatment of indolent B cell lymphoma, ALL, CLL and mantle cell leukemia (MCL). Blinatumomab is additionally being investigated for its potential to treat pediatric relapsed/refractory ALL, relapsed/refractory Philadelphia positive (Ph+) B-precursor ALL, minimal residual disease positive (MRD+) B-precursor ALL, relapsed/refractory non-Hodgkin’s lymphoma (NHL), including relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
BiTE antibodies are a form of immunotherapy being investigated for use in fighting cancer by helping to engage the body’s immune system to detect and target malignant cells. The modified antibodies are designed to engage two different targets at the same time, thereby juxtaposing T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. BiTE antibodies help place the T cells within reach of the targeted cell, with the intent of enabling it to inject toxins and trigger the cell to die (apoptosis). BiTE antibodies are being explored for their potential to treat a broad array of cancers.
Amgen and AstraZeneca reported during June 2013 that treatment with brodalumab significantly improved signs and clinical symptoms associated with psoriatic arthritis, including tender and swollen joints, at 12 weeks as measured by a 20 percent improvement in the American College of Rheumatology response criteria (ACR20). The Phase II results additionally demonstrated that many patients continued to improve, and that the improvements were sustained through the first 52 weeks of the study as reported in The New England Journal of Medicine.
Amgen and AstraZeneca have launched two Phase III trials of brodalumab in psoriatic arthritis, known as AMVISION-1 and AMVISION-2. The studies will provide detailed information on the effect of brodalumab on improving clinical signs and symptoms in psoriatic arthritis, as well as the drug’s ability to prevent joint damage.
Brodalumab is regarded as the only investigational treatment in development that binds to the interleukin-17 (IL-17) receptor. The novel human monoclonal antibody inhibits inflammatory signaling by blocking the binding of several IL-17 ligands to the receptor. By preventing IL-17 ligands from activating the receptor, brodalumab stops the body from receiving signals that may result in inflammation. The IL-17 pathway has a central role in inducing and promoting inflammatory disease processes. In addition to psoriatic arthritis, brodalumab is being studied in Phase III trials for treating moderate-to-severe plaque psoriasis and in Phase II trials for asthma.
Amgen and AstraZeneca revealed in late May 2014 that the Phase III AMAGINE-1 study for brodalumab in patients with moderate-to-severe plaque psoriasis met all primary and secondary endpoints for the evaluated doses. Primary endpoints were patients attaining at least a 75 percent improvement from baseline in disease severity at week 12, as measured by the Psoriasis Area Severity Index, and patients achieving clear or almost clear skin at week 12 according to the static Physician Global Assessment.
FDA cleared for marketing on May 23, 2014, Vectibix plus FOLFOX chemotherapy as a first-line treatment for patients with wild-type KRAS metastatic colorectal cancer. Upon approval, Vectibix became the first biologic therapy indicated for use with FOLFOX, which is one of the most commonly used chemotherapy regimens in the first-line treatment of wild-type KRAS metastatic colorectal cancer patients.
Vectibix is also the first fully human anti-EGFR antibody FDA-approved for treating metastatic colorectal cancer. Vectibix was initially approved by U.S. regulators during September 2006 as a monotherapy for treating patients with EGFR-expressing metastatic colorectal cancer after disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy.