Amgen Receives Positive CHMP Opinion To Expand Use Of Prolia® (denosumab) To Patients With Glucocorticoid-Induced Osteoporosis

 Amgen (NASDAQ:AMGN) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion for the marketing authorization of Prolia^®(denosumab) for the treatment of bone loss associated with long-term systemic glucocorticoid therapy in adult patients at increased risk of fracture.

"Today's positive opinion by the CHMP is an important step for Prolia in helping patients suffering from bone loss associated with systemic glucocorticoid therapy," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "Chronic use of oral glucocorticoids has been associated with an increase in spine and hip fractures,¹ and, if approved, an expanded use of Prolia will provide patients and physicians across much of Europe with a new treatment option for this serious condition."

Glucocorticoid medications, which are used to treat many inflammatory conditions such as chronic obstructive pulmonary disorder (COPD), asthma, multiple sclerosis and rheumatoid arthritis, can cause significant side effects, including bone loss.^2,3

The CHMP recommendation is supported by a Phase 3 randomized, double-blind, double-dummy, active-controlled study evaluating the safety and efficacy of Prolia compared with risedronate in patients receiving glucocorticoid treatment.⁴ The study included two patient groups: those on sustained glucocorticoid therapy and those newly initiating glucocorticoid therapy. The study met the primary endpoint (percent change from baseline in lumbar spine bone mass density [BMD] at 12 months, assessing non-inferiority) and all secondary endpoints (the percent changes from baseline in lumbar spine and total hip BMD at 12 and 24 months, assessing superiority). Study results showed that, in patients on sustained glucocorticoid therapy, Prolia treatment led to greater gains in BMD, compared with risedronate, both at the lumbar spine (4.4 percent versus 2.3 percent, respectively) and total hip (2.1 percent versus 0.6 percent, respectively). Similarly, in patients newly initiating glucocorticoid therapy, Prolia treatment led to greater increases in BMD, compared with risedronate, both at the lumbar spine (3.8 percent versus 0.8 percent, respectively) and total hip (1.7 percent versus 0.2 percent, respectively).

Adverse events and serious adverse events were similar between treatment groups and consistent with the known safety profile of Prolia. No serious adverse events were reported with a subject incidence of two percent or greater in either treatment group.

The CHMP positive opinion will now be reviewed by the European Commission (EC), which has the authority to approve medicines for the European Union (EU). Norway, Iceland and Liechtenstein, as members of the European Economic Area (EEA), will take corresponding decisions based on the decision of the EC.

The U.S. Food and Drug Administration (FDA) is currently reviewing a supplemental Biologics License Application for this expanded indication and has set a Prescription Drug User Fee Act (PDUFA) action date of May 28, 2018.

About Glucocorticoid-Induced Osteoporosis (GIOP)
GIOP is the most common form of secondary osteoporosis.³ However, the proportion of patients that qualify for GIOP diagnosis and intervention is very small and depends on the level of exposure to glucocorticoid medications.^5,6 In addition, a significant proportion of the patients treated long-term with glucocorticoid medications are already diagnosed with postmenopausal osteoporosis or treated with osteoporosis medications. Importantly, at similar levels of BMD, postmenopausal women taking glucocorticoids have considerably higher risk of fracture compared with nonusers of glucocorticoids.⁷ The most frequent chronic inflammatory diseases associated with long-term glucocorticoid use are chronic obstructive pulmonary disorder (COPD), asthma, and rheumatoid arthritis.¹ More than 10 percent of patients who receive long-term glucocorticoid treatment are diagnosed with a clinical fracture, and 30 to 40 percent have radiographic evidence of vertebral fractures.^8,1

About Prolia^® (denosumab)
Prolia is the first approved therapy that specifically targets RANK Ligand, an essential regulator of bone-removing cells (osteoclasts). Prolia is approved and marketed in over 80 countries worldwide.

Prolia is approved in the U.S. for the treatment of 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 the U.S., Prolia is also approved for treatment to increase bone mass in men 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. Prolia is also indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer and in men at high risk for fracture receiving androgen deprivation therapy for non-metastatic prostate cancer in the U.S.

Prolia is approved in the EU for the treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. In postmenopausal women Prolia significantly reduces the risk of vertebral, non-vertebral and hip fractures.

Prolia is also approved for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. In men with prostate cancer receiving hormone ablation, Prolia significantly reduces the risk of vertebral fractures.

Prolia is administered as a single subcutaneous injection of 60 mg once every six months. Please see the Important Safety Information below.

EU Important EU Product Information

Calcium and Vitamin D supplementation

Adequate intake of calcium and vitamin D is important in all patients.

Precautions for use

Hypocalcaemia
It is important to identify patients at risk for hypocalcaemia. Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiating therapy. Clinical monitoring of calcium levels is recommended before each dose and, in patients predisposed to hypocalcaemia within two weeks after the initial dose. If any patient presents with suspected symptoms of hypocalcaemia during treatment (see section 4.8 for symptoms) calcium levels should be measured. Patients should be encouraged to report symptoms indicative of hypocalcaemia.

In the post-marketing setting, severe symptomatic hypocalcaemia has been reported (see section 4.8), with most cases occurring in the first weeks of initiating therapy, but it can occur later.

Skin infections
Patients receiving Prolia may develop skin infections (predominantly cellulitis) leading to hospitalisation (see section 4.8). Patients should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis.

Osteonecrosis of the Jaw (ONJ)
ONJ has been reported rarely in patients receiving Prolia for osteoporosis (see section 4.8).

The start of treatment/new treatment course should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with denosumab in patients with concomitant risk factors.

The following risk factors should be considered when evaluating a patient's risk of developing ONJ:

• potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy.
• cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.
• concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.
• poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractions.

All patients should be encouraged to maintain good oral hygiene, receive routine dental check?ups, and immediately report any oral symptoms such as dental mobility, pain or swelling or non-healing of sores or discharge during treatment with denosumab. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Prolia administration.

The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported with denosumab. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving denosumab who present with ear symptoms including chronic ear infections.

Atypical fractures of the femur
Atypical femoral fractures have been reported in patients receiving denosumab (see section 4.8). Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Specific radiographic findings characterise these events. Atypical femoral fractures have also been reported in patients with certain co-morbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with use of certain pharmaceutical agents (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred without antiresorptive therapy. Similar fractures reported in association with bisphosphonates are often bilateral; therefore the contralateral femur should be examined in denosumab-treated patients who have sustained a femoral shaft fracture. Discontinuation of Prolia therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient based on an individual benefit?risk assessment. During denosumab treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.

Long-term antiresorptive treatment 
Long-term antiresorptive treatment (including both denosumab and bisphosphonates) may contribute to an increased risk for adverse outcomes such as osteonecrosis of the jaw and atypical femur fractures due to significant suppression of bone remodelling (see section 4.2).

Concomitant treatment with other denosumab-containing medicinal products
Patients being treated with Prolia should not be treated concomitantly with other denosumab-containing medicinal products (for prevention of skeletal related events in adults with bone metastases from solid tumours).

Renal impairment
Patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis are at greater risk of developing hypocalcaemia. The risks of developing hypocalcaemia and accompanying parathyroid hormone elevations increase with increasing degree of renal impairment. Adequate intake of calcium, vitamin D and regular monitoring of calcium is especially important in these patients, see above.

Dry natural rubber
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.

Warnings for excipients
This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per 60 mg i.e. essentially 'sodium-free'.

U.S. Important Safety Information

Contraindications
Prolia is contraindicated in patients with hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating Prolia. Prolia is contraindicated in women who are pregnant and may cause fetal harm. Prolia is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. Reactions have included anaphylaxis, facial swelling and urticaria.

Same Active Ingredient
Prolia contains the same active ingredient (denosumab) found in XGEVA^®. Patients receiving Prolia should not receive XGEVA^®.

Hypersensitivity
Clinically significant hypersensitivity including anaphylaxis has been reported with Prolia. Symptoms have included hypotension, dyspnea, throat tightness, facial and upper airway edema, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of Prolia.

Hypocalcemia 
Hypocalcemia may worsen with the use of Prolia, especially in patients with severe renal impairment. In patients predisposed to hypocalcemia and disturbances of mineral metabolism, clinical monitoring of calcium and mineral levels is highly recommended within 14 days of Prolia injection. Adequately supplement all patients with calcium and vitamin D.

Osteonecrosis of the Jaw (ONJ)
ONJ, which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients receiving Prolia. An oral exam should be performed by the prescriber prior to initiation of Prolia. A dental examination with appropriate preventive dentistry is recommended prior to treatment in patients with risk factors for ONJ such as invasive dental procedures, diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders. Good oral hygiene practices should be maintained during treatment with Prolia. The risk of ONJ may increase with duration of exposure to Prolia.

For patients requiring invasive dental procedures, clinical judgment should guide the management plan of each patient. Patients who are suspected of having or who develop ONJ should receive care by a dentist or an oral surgeon. Extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Prolia should be considered based on individual benefit-risk assessment.

Atypical Femoral Fractures 
Atypical low-energy, or low trauma fractures of the shaft have been reported in patients receiving Prolia. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents.

During Prolia treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be evaluated to rule out an incomplete femur fracture. Interruption of Prolia therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Multiple Vertebral Fractures (MVF) Following Discontinuation of Prolia Treatment 
Following discontinuation of Prolia treatment, fracture risk increases, including the risk of multiple vertebral fractures. New vertebral fractures occurred as early as 7 months (on average 19 months) after the last dose of Prolia. Prior vertebral fracture was a predictor of multiple vertebral fractures after Prolia discontinuation. Evaluate an individual's benefit/risk before initiating treatment with Prolia. If Prolia treatment is discontinued, consider transitioning to an alternative anti-resorptive therapy.

Serious Infections 
In a clinical trial (N= 7808) in women with postmenopausal osteoporosis, serious infections leading to hospitalization were reported more frequently in the Prolia group than in the placebo group. Serious skin infections, as well as infections of the abdomen, urinary tract and ear were more frequent in patients treated with Prolia.

Endocarditis was also reported more frequently in Prolia-treated patients. The incidence of opportunistic infections and the overall incidence of infections were similar between the treatment groups. Advise patients to seek prompt medical attention if they develop signs or symptoms of severe infection, including cellulitis.

Patients on concomitant immunosuppressant agents or with impaired immune systems may be at increased risk for serious infections. In patients who develop serious infections while on Prolia, prescribers should assess the need for continued Prolia therapy.

Dermatologic Adverse Reactions 
In the same clinical trial in women with postmenopausal osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema and rashes occurred at a significantly higher rate with Prolia compared to placebo. Most of these events were not specific to the injection site. Consider discontinuing Prolia if severe symptoms develop.

Musculoskeletal Pain 
Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking Prolia. Consider discontinuing use if severe symptoms develop.

Suppression of Bone Turnover 
In clinical trials in women with postmenopausal osteoporosis, Prolia resulted in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry. The significance of these findings and the effect of long-term treatment are unknown. Monitor patients for these consequences, including ONJ, atypical fractures, and delayed fracture healing.

Adverse Reactions 
The most common adverse reactions (>5% and more common than placebo) in women with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis. The most common adverse reactions (> 5% and more common than placebo) in men with osteoporosis are back pain, arthralgia, and nasopharyngitis. Pancreatitis has been reported with Prolia.

In women with postmenopausal osteoporosis, the overall incidence of new malignancies was 4.3% in the placebo group and 4.8% in the Prolia group. In men with osteoporosis, new malignancies were reported in no patients in the placebo group and 4 (3.3%) patients in the Prolia group. A causal relationship to drug exposure has not been established.

The most common (per patient incidence ≥ 10%) adverse reactions reported with Prolia in patients with bone loss receiving ADT for prostate cancer or adjuvant AI therapy for breast cancer are arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials. Additionally, in Prolia-treated men with nonmetastatic prostate cancer receiving ADT, a greater incidence of cataracts was observed.

Denosumab is a human monoclonal antibody. As with all therapeutic proteins, there is potential for immunogenicity.

About Amgen
Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to be one of the world's leading independent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.

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