Romosozumab

38186711000001103

New Medicines

EvenityPostmenopausal osteoporosis

Information

Evenity
New molecular entity
UCB Pharma
Amgen

Development and Regulatory status

Launched
Launched
Launched
March 2020
Mar 20Launched in UK. Price for two 105mg pre-filled pens is £427.75 [33].
Dec 19UCB anticipate a launch date of March 2020 for Romosozumab in the UK. There will be one pack size available which contains 2 single-use pre-filled pens. Each pre-filled pen contains 105mg of romosozumab in 1.17ml of solution. UCB will launch romosozumab in the EU [32].
Dec 19Has been available in the US since Apr 19. Amgen plans to launch romosozumab for postmenopausal osteoporosis in the European Economic Area H1 20 [31].
Dec 19Approved in EU [30].
Oct 19Following a re-examination, CHMP have recommended EU approval, but for a more restricted indication than originally sought - the indication will be "Treatment of severe osteoporosis in postmenopausal women at high risk of fracture”. It is proposed that treatment be initiated and supervised by specialist physicians experienced in the treatment of osteoporosis. It is likely to be contra-indicated or heavily restricted in women with a history of heart attack and stroke, and further studies are foreseen to follow its use in practice and to ensure it is used correctly [29].
Jul 19UCB have requested a re-examination of the CHMP recommendation. They have 60 days to submit their grounds for re-examination: CHMP will then re-examine the opinion within 60 days of receiving them. The company is not allowed to submit new scientific data but may request that a Scientific Advisory Group be consulted [28].
Jun 19Not recommended for EU approval - CHMP has adopted a negative opinion recommending the refusal of a marketing authorisation for romosozumab, because of concern that the trial results suggested an increased risk of serious effects on the heart or circulatory system; additionally, there were more deaths in patients over 75 given the medicine. As there was no clear mechanism for the adverse effects, and no clear patient group with a lower risk, measures to reduce the risk could not readily be put in place. Results showed a reduction in fracture risk in patients with severe osteoporosis, however results in less severe disease were less convincing. Under the circumstances, the drug´s benefits were not considered to outweigh its risks. The company has 15 days to request a re-examination of the opinion [27].
Apr 19Amgen announce pricing plan for Evenity in the USA. It will have a list price of $1,825 per dose ($21,900 for a 12-month course of treatment) [25].
Apr 19Approved in US [24].
Jan 19UCB reports that the EU CHMP has issued a positive opinion [26].
Jan 19Advisory panel to US FDA vote 16-1 in favour of approval of romosozumab for treatment of osteoporosis in postmenopausal women at high risk for fracture. This is a narrower indication than the one originally applied for, in view of the CV safety signal. A boxed warning will be added as well as a warning and precaution in the prescribing label. Romosozumab is administered as a monthly injection [22,23].
Jul 18Amgen and UCB resubmit BLA to US FDA. Resubmission includes results from 2 RCTs: ARCH study (n=4093 women) vs. alendronate and BRIDGE study in 245 men with osteoporosis [21].
Apr 18Amgen and UCB announced that the EMA has accepted the Marketing Authorization Application (MAA) for EVENITY™* (romosozumab) for the treatment of osteoporosis in postmenopausal women and in men at increased risk of fracture [20].
Oct 17Amgen will resubmit to the FDA and include data from the ARCH study, and BRIDGE study in men with osteoporosis [19].
Jul 17Not approved in US - FDA has issued a Complete Response Letter asking for new safety and efficacy data from the Phase III active-comparator ARCH study to be integrated into the drug’s submission [17].
May 17Amgen does not expect to get US approval this year, expecting 2018 or beyond. UCB is scheduled to submit a marketing application in Europe in H2 2017 [16].
Jan 17FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of July 19 2017 as a goal for the completion of its review [15].
Jul 16Amgen / UCB announce submission of a Biologics License Application (BLA) to the FDA, for treatment of post-menopausal osteoporosis. The BLA is based on the pivotal FRAME study [13].
Feb 16US filing planned for later in 2016 [11].
Nov 15PIII study is ongoing [2].
Apr 12PIII programme starts. It includes a multicentre, international, double-blind, placebo-controlled, two-year RCT in more than 5,000 women. The primary endpoint is incidence of new vertebral fractures at 12 months. Initial results are expected by the end of 2015 [2].

Category

Humanized monoclonal antibody that inhibits sclerostin, first-in-class.
30% of post-menopausal women in Europe have osteoporosis; 40% of them will suffer osteoporotic fractures in their lifetime. The total direct medical cost of osteoporosis in Europe is estimated at >euro 36 billion annually.
Postmenopausal osteoporosis
Subcutaneous

Further information

Yes
May 2021

Trial or other data

Sep 17Results were published from the PIII ARCH study in postmenopausal women with osteoporosis demonstrating superior fracture reduction with EVENITY followed by alendronate vs. alendronate alone, with additional details on the observed CV safety signal. Amgen is currently evaluating all EVENITY PIII data to ensure a comprehensive understanding of the CV safety results, and will be working in close collaboration with the FDA within the timeline of the complete response letter received in Jul 17 [19].
Jul 17Results of PIII STRUCTURE trial (NCT01796301) published in The Lancet [18].
May 17Romosozumab met all its main clinical endpoints in the ARCH trial, reducing vertebral fractures by 50% vs. alendronate, while also cutting nonvertebral fractures by 19%. Both reductions were statistically significant and taken together translated to a 27% reduction in the risk of fracture. However, there was an imbalance in the rate of serious cardiovascular side effects, seen in 2.5% of patients on romosozumab vs 1.9% with alendronate. That new safety signal was not seen in the earlier phase 3 FRAME trial of the drug, although there was a trend towards cardiovascular adverse events in the earlier trial. There were some other areas of weakness in the data—for example, hip fractures were only slightly reduced—which echoes the results of phase 2 studies where the drug missed the nonvertebral fracture target [16].
Sep 16Results of FRAME study published in NEJM. Patients (n=7,180) received 12 months of romosozumab (RM) or placebo, and then converted to 12 further months of denosumab. At 12 months and 24 months the incidence of vertebral fractures was lower for RM vs placebo (0.5% vs 1.8%, and 0.6% vs 2.5%, p<0.001 for both) [14].
Apr 16Amgen releases data from PIII STRUCTURE trial showing that romosozumab induced a statistically significant increase in hip bone mineral density vs. teriparatide (+2.6% vs. -0.6% at 12 months respectively) in postmenopausal women with osteoporosis transitioning from bisphosphonate treatment [12].
Feb 16Amgen and UCB announce top-line results from the PIII FRAME study. These data showe FRAME met the co-primary endpoints by reducing the incidence of new vertebral fracture through months 12 and 24 in postmenopausal women with osteoporosis treated with romosozumab. The study also met the secondary endpoint of reducing the incidence of clinical fractures (composite of vertebral and non-vertebral fractures) in postmenopausal women with osteoporosis through 12 months. However, the secondary endpoint of reducing the incidence of non-vertebral fractures through months 12 and 24 was not met. Women receiving romosozumab monthly experienced a statistically significant 73% reduction in relative risk of a vertebral fracture through 12 months vs. placebo. The effect size persisted after both groups were transitioned to denosumab through the second year of treatment. Specifically, through month 24, romosozumab followed by denosumab reduced the relative risk of new vertebral fracture by a statistically significant 75% vs. placebo followed by denosumab. Additionally, patients receiving romosozumab experienced a statistically significant 36% reduction in relative risk of a clinical fracture through 12 months vs. placebo. The percentage of patients with adverse events and serious adverse events in the 12-month double-blind period and 24-month study period were balanced overall between the treatment groups. In the initial 12-month treatment period, the most commonly reported adverse events in both arms (greater than 10%) were arthralgia, nasopharyngitis and back pain. Injection site reactions were reported in 5.2% of patients in the romosozumab treatment group and 2.9% in the placebo group during the 12-month period. Most injection site reactions were reported as mild in severity. Substudies evaluating hearing loss and worsening of knee osteoarthritis showed no difference between the treatment groups. There were two positively adjudicated events of osteonecrosis of the jaw in the romosozumab treatment group, one after completing romosozumab dosing and the other after completing romosozumab treatment and receiving the initial dose of denosumab. There was one positively adjudicated event of atypical femoral fracture after three months of romosozumab treatment [11].
Sep 15Amgen and UCB announce the STRUCTURE trial (NCT01796301) met the primary endpoint, demonstrating a statistically significant difference in favour of romosozumab in the percent change of total hip BMD (measured by DXA) through month 12. The overall subject incidence of adverse events was generally balanced between arms. Adverse events in patients treated with romosozumab were similar to those previously reported and no new safety signals were detected. Adverse events reported in the romosozumab arm in more than 5% of patients were nasopharyngitis, arthralgia, back pain, headache and fall [9].
Mar 15Three PIII studies on-going. Two are no longer recruiting patients (NCT02016716 & NCT01796301); NCT01631214 is a alendronate-controlled study in 4000 postmenopausal women with osteoporosis. This study started in May 12 and is due to complete May 17 [8].
Apr 14PIII NCT02016716 study is ongoing but no longer recruiting pts. Primary outcome data collection will be complete in Sep 14 [7].
Mar 14PIII NCT01796301 (STRUCTURE) study is currently recruiting pts. Data collection for the primary outcome should complete early than first planned in Mar 15 [7].
Mar 14PIII NCT01575834 (FRAME) study is ongoing but no longer recruiting pts. Data collection for the primary outcome should complete in Dec 16 [7].
Jan 14Results of a PII study published in N Engl J Med (January 1, 2014 DOI: 10.1056/NEJMoa1305224). The multicentre, international, randomized, study evaluated the efficacy and safety of romosozumab in 419 postmenopausal women who had low BMD. Subcutaneous romosozumab monthly (70mg, 140mg, or 210mg) or every 3 months (140mg or 210mg) was compared with subcutaneous placebo and open-label oral alendronate (70mg weekly) or subcutaneous teriparatide (20μg daily). All doses romosozumab were associated with significant increases in BMD at the lumbar spine at 12 months (primary endpoint). With the 210mg monthly dose, the increase was 11.3% vs 4.1% with alendronate and 7.1% with teriparatide, and a decrease of 0.1% with placebo. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups.
Dec 13NCT02016716 is a multicentre, randomized, multiple-dose PIII study to evaluate 2 different formulations of romosozumab in 272 postmenopausal women with osteoporosis. The primary endpoint is non-inferiority in the % change from baseline in DXA BMD at the lumbar spine at 6 months. The study starts Dec 13 and is due to complete Feb 15 [5].
Feb 13NCT01796301 is an open-label, randomized, teriparatide-controlled study to evaluate the effect of treatment with AMG 785 in 400 postmenopausal women with osteoporosis previously treated with bisphosphonate therapy for at least 3 years. The primary endpoint is the % change from baseline in DXA BMD at the total hip at month 12. The study started in Jan 13 and is due to complete Jun 15 [4].
Apr 12NCT01575834: A PIII multicentre, international, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of AMG 785 treatment in 5600 postmenopausal women with osteoporosis. Treatment groups will receive sc AMG 785 for 12 months, followed by sc open-label denosumab for another 12 months vs sc placebo injections for 12 months, followed by sc open-label denosumab for another 12 months. The primary outcome is incidence of vertebral fracture at 12 months. The study started Mar 12 and is due to complete May 15 [3].
Apr 11Top-line results reported from a 12 month PII multi-center, international, randomized, placebo-controlled study of AMG 785 in around 400 postmenopausal women with low BMD (T-scores between -2.0 and -3.5). Treatment arms included dosing at 70, 140 and 210mg subcutaneously once a month, and 140 and 210mg every three months, against matched placebo. The study met its primary endpoint, demonstrating significant increases in lumbar spine BMD at month 12 for the AMG 785 arms. In addition, AMG 785 compared positively with the two active comparators, teriparatide and alendronate [1].
Apr 11Amgen and UCB are collaborating on the development of AMG 785/CDP7851 for the treatment of bone-related conditions, including postmenopausal osteoporosis and fracture healing [1].
Sep 17: Results were published from the PIII ARCH study in postmenopausal women with osteoporosis demonstrating superior fracture reduction with EVENITY followed by alendronate vs. alendronate alone, with additional details on the observed CV safety signal. Amgen is currently evaluating all EVENITY PIII data to ensure a comprehensive understanding of the CV safety results, and will be working in close collaboration with the FDA within the timeline of the complete response letter received in Jul 17 [19].


July 17: Results of PIII STRUCTURE trial (NCT01796301) published in The Lancet [18].


May 17: Romosozumab met all its main clinical endpoints in the ARCH trial, reducing vertebral fractures by 50% vs. alendronate, while also cutting nonvertebral fractures by 19%. Both reductions were statistically significant and taken together translated to a 27% reduction in the risk of fracture. However, there was an imbalance in the rate of serious cardiovascular side effects, seen in 2.5% of patients on romosozumab vs 1.9% with alendronate. That new safety signal was not seen in the earlier phase 3 FRAME trial of the drug, although there was a trend towards cardiovascular adverse events in the earlier trial. There were some other areas of weakness in the data—for example, hip fractures were only slightly reduced—which echoes the results of phase 2 studies where the drug missed the nonvertebral fracture target [16].


Sep 16: Results of FRAME study published in NEJM. Patients (n=7,180) received 12 months of romosozumab (RM) or placebo, and then converted to 12 further months of denosumab. At 12 months and 24 months the incidence of vertebral fractures was lower for RM vs placebo (0.5% vs 1.8%, and 0.6% vs 2.5%, p<0.001 for both) [14].


Apr 16: Amgen releases data from PIII STRUCTURE trial showing that romosozumab induced a statistically significant increase in hip bone mineral density vs. teriparatide (+2.6% vs. -0.6% at 12 months respectively) in postmenopausal women with osteoporosis transitioning from bisphosphonate treatment [12].


Feb 16: Amgen and UCB announce top-line results from the PIII FRAME study. These data showe FRAME met the co-primary endpoints by reducing the incidence of new vertebral fracture through months 12 and 24 in postmenopausal women with osteoporosis treated with romosozumab. The study also met the secondary endpoint of reducing the incidence of clinical fractures (composite of vertebral and non-vertebral fractures) in postmenopausal women with osteoporosis through 12 months. However, the secondary endpoint of reducing the incidence of non-vertebral fractures through months 12 and 24 was not met. Women receiving romosozumab monthly experienced a statistically significant 73% reduction in relative risk of a vertebral fracture through 12 months vs. placebo. The effect size persisted after both groups were transitioned to denosumab through the second year of treatment. Specifically, through month 24, romosozumab followed by denosumab reduced the relative risk of new vertebral fracture by a statistically significant 75% vs. placebo followed by denosumab. Additionally, patients receiving romosozumab experienced a statistically significant 36% reduction in relative risk of a clinical fracture through 12 months vs. placebo. The percentage of patients with adverse events and serious adverse events in the 12-month double-blind period and 24-month study period were balanced overall between the treatment groups. In the initial 12-month treatment period, the most commonly reported adverse events in both arms (greater than 10%) were arthralgia, nasopharyngitis and back pain. Injection site reactions were reported in 5.2% of patients in the romosozumab treatment group and 2.9% in the placebo group during the 12-month period. Most injection site reactions were reported as mild in severity. Substudies evaluating hearing loss and worsening of knee osteoarthritis showed no difference between the treatment groups. There were two positively adjudicated events of osteonecrosis of the jaw in the romosozumab treatment group, one after completing romosozumab dosing and the other after completing romosozumab treatment and receiving the initial dose of denosumab. There was one positively adjudicated event of atypical femoral fracture after three months of romosozumab treatment [11].


Sep 15: Amgen and UCB announce the STRUCTURE trial (NCT01796301) met the primary endpoint, demonstrating a statistically significant difference in favour of romosozumab in the percent change of total hip BMD (measured by DXA) through month 12. The overall subject incidence of adverse events was generally balanced between arms. Adverse events in patients treated with romosozumab were similar to those previously reported and no new safety signals were detected. Adverse events reported in the romosozumab arm in more than 5% of patients were nasopharyngitis, arthralgia, back pain, headache and fall [9].


Mar 15: Three PIII studies on-going. Two are no longer recruiting patients (NCT02016716 & NCT01796301); NCT01631214 is a alendronate-controlled study in 4000 postmenopausal women with osteoporosis. This study started in May 12 and is due to complete May 17 [8].


Apr 14: PIII NCT02016716 study is ongoing but no longer recruiting pts. Primary outcome data collection will be complete in Sep 14 [7].


Mar 14: PIII NCT01796301 (STRUCTURE) study is currently recruiting pts. Data collection for the primary outcome should complete early than first planned in Mar 15 [7].


Mar 14: PIII NCT01575834 (FRAME) study is ongoing but no longer recruiting pts. Data collection for the primary outcome should complete in Dec 16 [7].


Jan 14: Results of a PII study published in N Engl J Med (January 1, 2014 DOI: 10.1056/NEJMoa1305224). The multicentre, international, randomized, study evaluated the efficacy and safety of romosozumab in 419 postmenopausal women who had low BMD. Subcutaneous romosozumab monthly (70mg, 140mg, or 210mg) or every 3 months (140mg or 210mg) was compared with subcutaneous placebo and open-label oral alendronate (70mg weekly) or subcutaneous teriparatide (20μg daily). All doses romosozumab were associated with significant increases in BMD at the lumbar spine at 12 months (primary endpoint). With the 210mg monthly dose, the increase was 11.3% vs 4.1% with alendronate and 7.1% with teriparatide, and a decrease of 0.1% with placebo. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups.


Dec 13: NCT02016716 is a multicentre, randomized, multiple-dose PIII study to evaluate 2 different formulations of romosozumab in 272 postmenopausal women with osteoporosis. The primary endpoint is non-inferiority in the % change from baseline in DXA BMD at the lumbar spine at 6 months. The study starts Dec 13 and is due to complete Feb 15 [5].


Feb 13: NCT01796301 is an open-label, randomized, teriparatide-controlled study to evaluate the effect of treatment with AMG 785 in 400 postmenopausal women with osteoporosis previously treated with bisphosphonate therapy for at least 3 years. The primary endpoint is the % change from baseline in DXA BMD at the total hip at month 12. The study started in Jan 13 and is due to complete Jun 15 [4].


Apr 12: NCT01575834: A PIII multicentre, international, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of AMG 785 treatment in 5600 postmenopausal women with osteoporosis. Treatment groups will receive sc AMG 785 for 12 months, followed by sc open-label denosumab for another 12 months vs sc placebo injections for 12 months, followed by sc open-label denosumab for another 12 months. The primary outcome is incidence of vertebral fracture at 12 months. The study started Mar 12 and is due to complete May 15 [3].


Apr 11: Top-line results reported from a 12 month PII multi-center, international, randomized, placebo-controlled study of AMG 785 in around 400 postmenopausal women with low BMD (T-scores between -2.0 and -3.5). Treatment arms included dosing at 70, 140 and 210mg subcutaneously once a month, and 140 and 210mg every three months, against matched placebo. The study met its primary endpoint, demonstrating significant increases in lumbar spine BMD at month 12 for the AMG 785 arms. In addition, AMG 785 compared positively with the two active comparators, teriparatide and alendronate [1].


Amgen and UCB are collaborating on the development of AMG 785/CDP7851 for the treatment of bone-related conditions, including postmenopausal osteoporosis and fracture healing [1].

Evidence based evaluations

EvenityOsteoporosis in men

Information

Evenity
New molecular entity
UCB Pharma
Amgen

Development and Regulatory status

Not recommended for approval (Negative opinion)
Not recommended for approval (Negative opinion)
Phase III Clinical Trials
Oct 19The revised indication now recommended for approval specifies post-menopausal women only [11].
Jul 19UCB have requested a re-examination of the CHMP recommendation. They have 60 days to submit their grounds for re-examination: CHMP will then re-examine the opinion within 60 days of receiving them. The company is not allowed to submit new scientific data but may request that a Scientific Advisory Group be consulted [28].
Jun 19Not recommended for EU approval - CHMP has adopted a negative opinion recommending the refusal of a marketing authorisation for romosozumab, because of concern that the trial results suggested an increased risk of serious effects on the heart or circulatory system; additionally, there were more deaths in patients over 75 given the medicine. As there was no clear mechanism for the adverse effects, and no clear patient group with a lower risk, measures to reduce the risk could not readily be put in place. Results showed a reduction in fracture risk in patients with severe osteoporosis, however results in less severe disease were less convincing. Under the circumstances, the drug´s benefits were not considered to outweigh its risks. The company has 15 days to request a re-examination of the opinion [9].
Jan 19UCB reports that the EU CHMP has issued a positive opinion [8].
Jan 18Amgen and UCB announced that the EMA has accepted the Marketing Authorization Application (MAA) for EVENITY™* (romosozumab) for the treatment of osteoporosis in postmenopausal women and in men at increased risk of fracture [7].
Jul 17The Complete Response Letter issued by the FDA in response to the filing for use in postmenopausal women asks for new safety and efficacy data from the PIII active-comparator ARCH study to be integrated into the drug’s submission, to build on that included in the original filing taken from the Phase III placebo-controlled FRAME study. The resubmission will also include efficacy and safety data from the BRIDGE study assessing romosozumab in men with osteoporosis [6].
Nov 15PIII study is ongoing [2].
Jun 14PIII study started Jun 14 [1].

Category

Humanized monoclonal antibody that inhibits sclerostin
The incidence rate of osteoporotic fractures in men aged 50-54 years is 0.67-0.72 per 1,000, rising to 4.35-5.08 per 1,000 in those aged 75-85 years (BMJ 2009;339:b4229)
Osteoporosis in men
Subcutaneous

Further information

Yes
May 2021

Trial or other data

Nov 16Amgen report that PIII BRIDGE study (n=245) (NCT02186171) achieved primary outcome of statistically significant increase (12.1%; p<0.01) in BMD at the lumbar spine vs placebo at 12 months [5].
Mar 16Amgen and UCB announce positive top-line results for romosozumab from the pivotal Phase 3 placeBo-contRolled study evaluatIng the efficacy anD safety of romosozumab in treatinG mEn with osteoporosis (BRIDGE). These data showed the BRIDGE study met the primary endpoint, demonstrating a statistically significant increase in BMD) at the lumbar spine in 245 men with osteoporosis treated with romosozumab 210mg sc monthly vs. placebo at 12 months. All secondary endpoints comparing romosozumab with placebo were also met. Patients receiving romosozumab experienced a statistically significant increase in BMD at the femoral neck and total hip at 12 months and a statistically significant increase in BMD at the lumbar spine, femoral neck, and total hip at six months, compared with those receiving placebo. Overall patient incidence of adverse events and serious adverse events (SAEs) was generally balanced between arms. The most frequently reported adverse events (greater than 5% in the romosozumab arm) were nasopharyngitis, back pain, hypertension, headache and constipation. Injection site reactions were reported in 5.5% of patients in the romosozumab treatment group and 3.7% in the placebo group during the 12-month period. Most injection site reactions were reported as mild in severity. The patient incidence of positively adjudicated cardiovascular (CV) SAEs was 4.9% in the romosozumab group and 2.5% in the placebo group. The patient incidence of positively adjudicated CV death was 0.6% in the romosozumab group and 1.2% in the placebo group [4].
Jun 14NCT02186171 A PIII multicentre, randomized, double-blind study of romosozumab vs placebo in 225 men with osteoporosis. The primary outcome is percent change in bone mineral density (BMD) at the lumbar spine as assessed by dual-energy x-ray abosorptiometry (DXA) at 12 months. The study started in Jun 14 and is due to complete Dec 16 (primary data collection Jun 16) [1].

Evidence based evaluations