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Total Product Profile Gregory Addes Koyama March 2013

Total Product Profile Gregory Addes Koyama March 2013. Unmet medical need. What is the Problem?. Solid Tumors. Bone Metastases. Skeletal-Related Events. “Skeletal-Related Event” (SRE). Pathologic Fracture Spinal Cord Compression Radiation to Bone Surgery to Bone. 1. 2.

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Total Product Profile Gregory Addes Koyama March 2013

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  1. Total Product Profile Gregory Addes Koyama March 2013

  2. Unmet medical need

  3. What is the Problem? Solid Tumors Bone Metastases Skeletal-Related Events

  4. “Skeletal-Related Event” (SRE) • Pathologic Fracture • Spinal Cord Compression • Radiation to Bone • Surgery to Bone 1

  5. 2 Implications of Skeletal-Related Events Health-Related Costs: • Impaired Mobility • Reduced Quality of Life • Negative Impact on SURVIVAL Financial Costs: • $11,979 USD per patient • Estimated lifetime SRE-related cost

  6. Medical Need 64% % of untreated patients with Bone Metastases that will EXPERIENCE Skeletal-Related Events. 3 70% • % of patients with metastatic BREAST or PROSTATE cancer that will develop Bone Metastases. 3

  7. Market

  8. Xgeva® (denusomab)Treatable Patients Definition of a “Treatable Patient”—for the purposes of Xgeva®: • Patient with bone metastases from solid tumors* *Based on the data collected, Xgeva® has shown significant efficacy for prevention of SRE’s in patients with bone metastases from solid tumors of the Breast & Prostate 3

  9. Development of SRE’s 4 • Diagnosis: Adv. BREAST Cancer • 64% will develop an SRE • Diagnosis: Adv. PROSTATE Cancer • 40% will develop an SRE

  10. BREAST CANCERPrevalence/Incidence in U.S. 5 INCIDENCE of Breast Cancer PREVALENCE of Breast Cancer

  11. PROSTATE CANCERPrevalence/Incidence in U.S. 5 PREVALENCE of Prostate Cancer INCIDENCE of Prostate Cancer

  12. Treatable Patient Population for Xgeva® (Annually) 5

  13. Domestic Revenue Potential of Xgeva® 6 Potential Annual Domestic Revenue of Xgeva® (denosumab) $1.3 BILLION

  14. Drug Profile

  15. Category and Mechanism of Action • Tumor cells cause increased RANK Ligand production by osteoblasts. • In turn, osteoclasts increase in number and survive longer, leading to excess osteoclast activity and bone resorption. • This bone resorption causes tumor growth which may lead to a skeletal related event. • Xgeva is a monoclonal antibody and first in class RANK ligand inhibitor.

  16. Safety and Efficacy • Xgeva has been studied in primary phase 3 trials in patients with breast cancer, prostate cancer, and in patients with other solid tumors or multiple myeloma. • Each trial compared the Xgeva with zoledronic acid, a biphosphonate.

  17. Patients with Breast Cancer • Randomized, double-blind, double dummy study with 1,026 breast cancer patients • 120 mg SQ denosumab and IV placebo vs. 4 mg IV zoledronic acid (adjusted for renal impairment) and SQ placebo every 4 weeks • All patients were strongly recommended to take daily supplements of calcium and vitamin D.

  18. Patients with Breast Cancer (cont’d) • Denosumab showed statistical superiority compared to zoledronic acid in delaying time to first skeletal related event (HR, 0.82; 95% CI, 0.71 to 0.95; p = 0.01) • Noninferiority: p < 0.001 • Denosumab was superior in preventing first and subsequent skeletal related events (rate ratio, 0.77; 95% CI 0.66 to 0.89, p = 0.001). • Reduction in bone turnover makers was higher with denosumab. • By study week 3, tumor markers had decreased 80% in the denosumab group vs. 68% in the zoledronic acid group (p < 0.001). • Overall survival (HR, 0.95; 95% CI, 0.81 to 1.11, p = 0.49) and disease progression (HR, 1.00; 95% CI, 0.89 to 1.11, p = 0.93) were similar between the two treatment groups.

  19. Efficacy to Prevent First Skeletal Related Event in Breast Cancer

  20. Efficacy to Prevent First and Subsequent Skeletal Related Events in Breast Cancer

  21. Patients with Breast Cancer (cont’d) • Rates of overall severe and serious adverse events were similar in both groups. • Adverse events associated with renal toxicity occurred more frequently in the zoledronic acid group (8.5% vs. 4.9%, p = 0.001). • Hypocalcemia occurred more often with denosumab. • Osteonecrosis of the jaw occurred infrequently in both groups (2.0% denosumab; 1.4% zoledronic acid; p = 0.39).

  22. Patients with Prostate Cancer • Randomized, double-blind phase 3 study that included 1,904 men with castration-resistant prostate cancer and no previous exposure to IV biphosphonates • 120 mg SQ denosumab plus IV placebo vs. 4 mg IV zoledronic acid plus SQ placebo every 4 weeks • Supplementation with calcium and vitamin D was strongly recommended.

  23. Patients with Prostate Cancer (cont’d) • Primary endpoint was time to first skeletal related event which included pathological fracture, radiation therapy, surgery to bone, or spinal cord compression. • This same outcome was evaluated as a secondary outcome for superiority. • Median time to first on-study skeletal event was 20.7 months with the denosumab group vs. 17.1 months in the zoledronic acid group (HR, 0.82; 95% CI 0.71 to 0.95, p = 0.0002). • This finding is significant for noninferiority and superiority with denosumab (p =0.0002 for noninferiority; p = 0.008 for superiority).

  24. Efficacy to Prevent First Skeletal Related Event in Prostate Cancer

  25. Efficacy to Prevent First and Subsequent Skeletal Related Events in Prostate Cancer

  26. Patients with Prostate Cancer (cont’d) • Adverse side effects were recorded in 916 patients (97%) on denosumab and in 918 patients (97%) on zoledronic acid. • Serious events occurred in 594 patients (63%) taking denosumab and 568 patients (60%) on zoledronic acid. • The incidence of hypocalcemia was higher with denosumab (568 (60%) vs. 121 (13%), p < 0.001). • Osteonecrosis of the jaw was the most serious side effect, but it occurred infrequently and incidence was not statistically significant between the two treatment groups.

  27. Patients with Solid Tumors/Multiple Myeloma • Double blind, double dummy trial with 1, 779 subjects with confirmed tumors or myeloma • 120 mg SQ denosumab and IV placebo vs. 4 mg IV zoledronic acid (dose adjusted for renal impairment) and SQ placebo every 4 weeks • Daily calcium and vitamin D supplements were strongly recommended.

  28. Patients with Solid Tumors/Multiple Myeloma (cont’d) • Primary end point was the time to first skeletal related event which included pathologic fracture, radiation or surgery to bone, or spinal cord compression. • Denosumab was noninferior to zoledronic acid in delaying the time to first skeletal related event (HR, 0.84; 95% CI, 0.71 to 0.98, p = 0.0007). • Denosumab was not statistically superior to zoledronic acid in delaying time to first skeletal related event (p = 0.03, p = 0.06 adjusted for multiplicity). • Denosumab was not superior in preventing first and subsequent skeletal related events ( rate ratio, 0.90; 95% CI, 0.77 to 1.04, p = 0.14). • Overall survival and disease progression were similar between the two groups.

  29. Efficacy to Prevent First Skeletal Related Event in Patients with Solid Tumors/Multiple Myeloma

  30. Efficacy to Prevent First and Subsequent Skeletal Related Events in Patients with Solid Tumors/Multiple Myeloma

  31. Patients with Solid Tumors/Multiple Myeloma (cont’d) • Similar rates of overall adverse effects seen in both treatment groups • Hypocalcemia occurred more often with denosumab (10.8% vs. 5.8%). • Osteonecrosis of the jaw occurred at low rates in both the denosumab (0.5%) and the zoledronic acid (0.6%) groups at 1 year. • Acute phase reactions were more common with zoledronic acid (14.5% vs. 6.9%). • Elevations in serum creatinine and renal adverse events occurred more commonly with zoledronic acid (10.9% vs. 8.3%).

  32. Efficacy to Prevent First Skeletal Related Event in Integrated Analysis

  33. Efficacy to Prevent First and Subsequent Skeletal Related Events in Integrated Analysis

  34. Additional Safety Points • Osteonecrosis of the jaw is a rare but serious side effect with Xgeva. • Supplementing with calcium and vitamin D as necessary will reduce the incidence of hypocalcemia. • Osteonecrosis and hypocalcemia are the most common reasons for discontinuation. • Xgeva should not be administered to pregnant women as it may cause injury to the fetus. • Contraindicated in patients with a clinically significant sensitivity to any component of Xgeva. • Atypical femoral fractures have occurred with Xgeva; however, most patients in which this adverse event occurred were osteoporotic and were also receiving glucocorticoids. • Most common adverse reactions include fatigue, hypophosphatemia, and nausea. • Most common serious adverse reaction was dyspnea.

  35. Acute Phase Reactions

  36. Drug Interactions • No formal drug interaction studies have been performed. • Studies did not yield any effects on or by anticancer drugs.

  37. Pharmacokinetics • Bioavailability with SQ administration was 62%. • Steady state was achieved by 6 months. • Mean elimination half-life was 28 days. • Desonumab clearance and volume of distribution are proportional to body weight. • PK parameters with Xgeva were not affected by age, gender, and race. • PK analysis in pediatric patients has not been done. • No clinical trials assess drug properties with hepatic impairment. • In a trial of 55 patients, it was shown that the degree of renal impairment had no effect on PK parameters.

  38. Renal Impairment • A trial of 55 patients without cancer and varying degrees of renal function was conducted using 60 mg denosumab. • Patients with a creatinine clearance less than 30 mL/min or receiving dialysis had a greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. • However, Xgeva offers a significant advantage in renal impairment because, in contrast to zoledronic acid, it does not need to be dose adjusted nor does it need to be withheld in declining renal function.

  39. Dosing and Administration • 120 mg dose (1.7 mL injection) • Administered with 27 gauge needle once every 4 weeks in the upper thigh, upper arm, or abdomen. • No requirement for reconstitution or IV infusion. • Supplement with calcium 500 mg or more and vitamin D 400 units or more daily to prevent hypocalcemia. • Must be refrigerated at 36-46°F. • Upon removal from refrigeration, drug cannot be exposed to temperatures above 77°F or direct light and must be used within 14 days.

  40. Competition

  41. 7 ZOMETA® (zoledronic acid) • Manufacturer: Novartis • Drug Class: Bisphosphonate Derivative • Dosing/Administration: 4mg IV Infusion q 3-4wks

  42. ZOMETA® (zoledronic acid)Pros & Cons 8 3 Pros Cons • Effective in prevention of Skeletal Related Events • Well established as treatment of choice for prevention of SRE’s • American Society of Clinical Oncology (ASCO) recommends Zometa • Less Hypocalcemia (compared to Xgeva) • Cheaper • IV Infusion (monthly) • Renal Monitoring • Contraindicated: CrCL<30mL/min • Dose-Adjust: CrCL <60mL/min • Acute-Phase Reactions during infusion • Patent Expiration*

  43. ZOMETA® in the Marketplace Estimated Cost of Zometa®: $844/dose Estimated GLOBAL Sales: $1.26 BILLION 9 Confirming Projection

  44. Annual GLOBAL Revenue Potential for XGEVA®(denosumab) $1.3 Billion per year (in the United States alone) • This only captures 53% of the current market (based-on current market-share of ZOMETA®) Potential Annual GLOBAL Revenue of Xgeva® (denosumab) $2.5 BILLION

  45. *The Actual Competition *Novartis lost patent protection on March 2, 2013 • Novartis negotiated with TEVA to wait until the 2013 patent expiration to begin developing a generic version. We have to be prepared for the Economic/Reimbursement landscape of the SRE drug market to change in the next few years. 9

  46. Climate:Economics & Reimbursement

  47. Reimbursement Climate 10 Cigna • Covers both Xgeva and Zometa with no restrictions for approved uses. Aetna • Requires pre-certification before reimbursing for Xgeva • Does not require pre-certification for Zometa! BlueShield/BlueCross • Regence BlueCross BlueShield, an insurer in the Northwest that covers 2 million people, recently conducted an analysis and decided to pay for Xgeva only if patients are unable to use Zometa or the generic pamidronate, a drug in the same class as Zometa

  48. 10 Current Debate Is the Bang worth the Buck? • Studies have shown Xgeva to be more effective than Zometa. • Problem: Xgeva costs nearly TWICE as much. • Source of RESISTANCE to Xgeva’s acceptance “Evidence of Xgeva’s superiority is “uncertain” and other drugs such as Zoledronic Acid have a more established track record of safety and effectiveness”. - BlueCross/BlueShield “(We) are currently aware of the difference in price and are cognizant of how this affects treatment costs for our patients”. -Vanderbilt-Ingram Cancer Center

  49. PharmacoEconomic StudiesRoom For Debate 11 2 Stopeck et. al Carter et. al • Denosumab is a more cost-effective treatment option for the prevention of SRE’s in patients with advanced solid tumors and bone metastases compared to Zoledronic Acid. • The overall value of denosumab is based on superior efficacy, safety, and more efficient administration. • Denosumab, while being a more efficacious SRE-limiting agent, may be too costly. • As zoledronic acid will lose patent protection in 2013, it will likely be cost effective versus denosumab.

  50. 12 Pricing Strategy *Don’t Price Ourselves Out of the Market!* • XGEVA FIRST STEP Coupon Program • Ensuring patient access to drug by developing a Co-Pay Assistance Program http://www.amgenfirststep.com/ Is It Working? “Intially, NICE (National Institute for Health and Clinical Excellence) said (Xgeva) was too pricey for its benefits. But Amgen offered a discount, and that made a difference”. - NICE Spokesperson

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