7/11/2019 Financial Disclosures Romosozumab: Newly Approved Anabolic Therapy -Consulting & talks: Zuellig pharma, -Advisory Board: Roche Diagnostics -DSMB (not bone): Eli Lilly Dennis M. Black, PhD Professor Epidemiology and Biostatistics, UCSF 1 Sclerostin: Osteocyte-derived cytokine that Romosozumab inhibits bone formation • Sclerosteosis, van Buchem’s disease • I • Humanized monoclonal antibody that targets sclerostin - Due to mutations in gene SOST • Unique uncoupling of formation and resportion • Sclerostin: protein encoded by gene SOST • New anabolic agent approved by FDA April 2019 – Potent inhibitor of Wnt signaling & bone formation Courtesy of C Lowik/W Van Hul • Given as 2 injections at 12 monthly visits – Deletion of SOST in mice: bone mass • Follow with antiresorptive – Sclerostin expression localized to osteocytes – Inhibition of sclerostin could increase bone formation • Phase 3 studies (2016 & 2017) are modern studies with active – Initially support by preclinical increase in bone density and strength controls/combinations – Meet current ethical guidelines – Opportunities and challenges! 1
7/11/2019 Phase 2 Study of Sclerostin Antibody (Romozosumab) in Phase 2 Study Study Design Postmenopausal Women with Low BMD McClung et al, NEJM 2014 McClung et al, NEJM 2014 % Change in Bone Turnover Markers: P1NP and CTX Lumbar Spine BMD Uncoupling of Bone Turnover P1NP (Formation) CTX (Resorption) Romosozumab TPTD ALN PBO McClung et al, NEJM 2014 2
7/11/2019 Phase III Trial of Romosozumab vs. Pbo (Year 1) Total Hip and Femoral Neck BMD Followed by Open Label Denosumab (Year 2) (FRAME) - 24 month study of 7,180 women - Year 1: Romo vs. placebo - Year 2: Denosumab in all - Romo/denosumab vs. placebo/denosumab over 2 years - Co-Primary endpoints: - New vertebral fractures at 12 Cosman NEJM 2016 months and 24 months Change in BMD Over 2 Years Vertebral Fracture Incidence over 12 and 24 Months Cosman F et al. N Engl J Med 2016;375:1532-1543 Cosman NEJM 2016 Cosman NEJM 2016 3
7/11/2019 Clinical and Non-vertebral Fracture Incidence Fracture Efficacy Summary over 12 and 24 Months • Significant reductions for vertebral fractures at 12 and 24 months (primary) Non-vertebral Fracture Any Clinical Fracture HR=0.75 HR=0.64 HR=0.67 • Clinical and non-vertebral fracture reductions nominally significant at 12 and 24 months HR=0.75 (0.57,0.97) (0.46,0.89) (0.52,0.87) (0.53,1.05) Adj p=0.06 p>.05 after adj for mult. comparisons, 3 of 4 > 0.05 P=.008 Adj P=0.10 p=0.10 • All 24 month comparisons against active control (PBO D’Mab) • Subgroup analysis (post-hoc): larger reductions outside of S. America. Non-vertebral fractures, 12 months Not S. America (57%) HR=0.58 (0.37, 0.89) S. America (43%) HR=1.25 (0.68, 2.27) Cosman F et al. N Engl J Med 2016;375:1532-1543 Cosman NEJM 2016 Phase III Trial of Romosozumab vs. Alendronate (1 year) Percentage Change from Baseline in Bone Mineral Density Followed by Open Label Alendronate (year 2) (ARCH) - 36 month study of 4093 women - Year 1: Romo vs. ALN - Active control - Year 2+: All on ALN - Romo/ALN vs. ALN over 3-4 years - Co-Primary endpoints: - New vertebral fractures at 24 mos - Clinical fractures after 330 fx. Saag KG et al. N Engl J Med 2017;377:1417-1427 Saag NEJM 2016 Saag NEJM 2016 4
7/11/2019 Incidence of Clinical and Non-Vertebral Fracture. Incidence of New Vertebral, Clinical, and Control group=Alendronate Nonvertebral Fracture HR=0.73 Romo/ALN Compared to 2 years ALN HR=0.81 (0.61,0.88 ) (0.66,0.99) Saag KG et al. N Engl J Med 2017;377:1417-1427 Saag KG et al. N Engl J Med 2017;377:1417-1427 Hip Fractures: HR=0.62 (0.42,0.92 ), p=0.02 Saag NEJM 2016 Saag NEJM 2016 Adverse Events in the 2 Phase 3 Romo Studies Fracture Efficacy Summary Alendronate Combo (ARCH, n=4054) Denosumab Combo (FRAME, n=7157) • Significant reductions for vertebral fractures at 12 (primary) and 24 months vs 2 years of ALN • Clinical fractures at 48 months (after 330 events, primary). Non-vertebral fractures also significantly reduced 48 months • All comparisons against active control (Alendronate) for entire study Cosman F et al. N Engl J Med 2016;375:1532-1543 Cosman NEJM 2016 Saag NEJM 2017 5
7/11/2019 Adverse Events in the Phase 3 Romo Studies Adverse Events and Safety Alendronate Combo (ARCH, n=4054) Denosumab Combo (FRAME, n=7157) • Overall AE occurrence similar in Romo vs. controls • Binding antibodies seen in 15%, neutralizing abs in 0.6% but no detectable impact on efficacy or safety • Some injection-site reactions • ONJ and AFF: a few cases including in Romo alone group. More in ALN. - Supports that ONJ and AFF are not solely due to over suppression of turnover • Cardiovascular adverse events larger concern Cosman F et al. N Engl J Med 2016;375:1532-1543 Saag KG et al. N Engl J Med 2017;377:1417-1427 Cosman NEJM 2016 Saag NEJM 2017 Cardiovascular Events in the Phase 3 Romo Studies Interpretation of Cardiovascular Safety Denosumab Combo (FRAME, n=7157) Alendronate Combo (ARCH, n=4054) Summary • No excess events in Romo vs. placebo in FRAME 2016 trial • Slight increase in ischemic and cerebrovascular events in Romo vs. ALN in ARCH 2017 trial (decrease in heart failure). None were statistically significant. Potential Explanations 1. Random Difference 2. ALN (comparator to Romo) decreases cardiovascular events, especially cerebrovascular • Evidence varies in individual ALN studies or meta-analyses 3. Romo increases (slightly) cardiovascular event risk Interpretation by Regulators FDA: after initial review, asked for more information on cardiovascular. Approved 2019, but with black box warning* European: initial review (6/25/19). Did not approve due to cardiovascular concerns. Sponsors can Saag NEJM 2017 Cosman NEJM 2016 reapply. A small study in 245 men also showed a small numeric Saag KG et al. N Engl J Med 2017;377:1417-1427 imbalance (NS) of CV events in Romo (4.9%) vs Placebo *may increase the risk of heart attack, stroke and cardiovascular death and should not be used in patients who have had a heart attack or stroke within the previous year or very high risk. (2.5%) Lewiecki JCEM 2018 6
7/11/2019 Romosozumab Making Choices Among Anabolic Therapies: Romosozumab vs. (Abaloparatide or Teriparatide) Unique aspects • Increase in formation and decrease in resorption. Administration Uncoupling of bone turnover. - Monthly in-office injections 12 monthly (Romo) vs. daily self-injections for 18-24 • Large increases in BMD at spine and especially at mos (TPTD, abalo) hip - Cost • Fast initiation of effect - Patient or physician preference Safety - PTH/analogs: possible osteosarcoma (unlikely) - Romo: Possible but small increase in cardiovascular events Efficacy - All reduce vertebral and non-vertebral, but no head-to-head studies Saag KG et al. N Engl J Med 2017;377:1417-1427 Saag KG et al. N Engl J Med 2017;377:1417-1427 - Larger early increase in hip BMD for Romo vs. Teriparatide (also vs. Abalo) and may be considered for patients at very risk of hip or non-vertebral fx. Lewicki JCEM, 2018 7
Recommend
More recommend
