Background Analysis: US FDA Advisory Committee to Review Amgen and UCB’s EVENITY (romosozumab) for Osteoporosis - JAN 16, 2019 (BRUDAC)

Announcement

The US FDA has scheduled a Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) meeting for Wednesday, January 16, 2019 to discuss a biologics license application (BLA) for EVENITY (romosozumab) injection, submitted by Amgen, for the treatment of osteoporosis in postmenopausal women 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 of other available osteoporosis therapy.

Amgen and UCB are co-developing EVENITY.

Indication Background

Osteoporosis is a chronic bone disease that is largely asymptomatic until a bone fracture occurs. In the US, one in two women over the age of 50 will experience a fracture. An initial fracture increases the risk of future fractures.

Product Background

EVENITY (romosozumab, a.k.a. AMG 785/CDP7851) is a monoclonal antibody that is designed to inhibit the activity of the protein sclerostin, leading to increased bone formation and decreased bone breakdown. EVENITY has been formulated for monthly administration by subcutaneous injection.

Clinical Trials

The BLA includes results from three clinical trials named FRAME, BRIDGE, and ARCH. In the FRAME trial, postmenopausal women with osteoporosis received either placebo or EVENITY for the first year, followed by year-long treatment with denosumab (US trade name: Prolia). In the BRIDGE trial, men with osteoporosis and a high risk of fractures received either placebo or EVENITY. In the ARCH trial, postmenopausal women with osteoporosis and a high risk of fractures received either EVENITY or alendronate (US trade name: FOSOMAX) for 12 months, followed by open-label treatment with FOSOMAX for 12 months.

A summary of the outcomes from these trials are presented below based on information from company press releases. Comprehensive data and detailed analyses by both Amgen and the FDA will be presented two days prior to the meeting in meeting materials posted by FDA. These materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

The FRAME Trial

The FRAME trial (FRActure trial in postmenopausal woMen with ostEoporosis; ClinicalTrials.Gov ID: NCT01575834) was a randomized, double-blind, placebo-controlled trial that evaluated 7,180 postmenopausal women with osteoporosis. The trial evaluated the effectiveness of EVENITY treatment (210 mg) compared with placebo in reducing the risk of new vertebral (spine) fractures through 12 months. The trial also evaluated the effectiveness of treatment with EVENITY for 12 months followed by Prolia for 12 months, compared with treatment with placebo for 12 months followed by Prolia for 12 months, in reducing the risk of new vertebral fractures through 24 months.

According to Amgen, EVENITY-treated patients experienced a statistically significant 73 percent reduction in the relative risk of a new vertebral fracture through 12 months, the first co-primary endpoint, compared to those receiving placebo (fracture incidence 0.5 percent versus 1.8 percent, respectively [p<0.001]). By six months, new vertebral fractures occurred in 14 EVENITY and 26 placebo patients, and between six to 12 months, fractures occurred in two additional EVENITY patients versus 33 additional placebo patients.

For those patients who received EVENITY in year one, fracture risk reduction persisted through month 24 after both groups transitioned to Prolia treatment in the second year of the trial; there was a statistically significant 75 percent reduction in the risk of vertebral fracture at month 24 (the other co-primary endpoint) in patients who received EVENITY followed by Prolia versus placebo followed by Prolia (fracture incidence 0.6 percent versus 2.5 percent, respectively [p<0.001]). In the second year of the trial, new vertebral fractures occurred in five patients who transitioned from EVENITY to Prolia and 25 patients who transitioned from placebo to Prolia.

When looking at clinical fractures, which encompass all symptomatic fractures (both non-vertebral and painful vertebral fractures), patients receiving EVENITY experienced a statistically significant 36 percent reduction in the relative risk of a clinical fracture, a secondary endpoint, through 12 months compared to those receiving placebo (fracture incidence 1.6 percent versus 2.5 percent, respectively [p=0.008]). A 33 percent reduction in relative risk of clinical fracture was observed through 24 months after patients transitioned from EVENITY to Prolia compared to patients transitioning from placebo to Prolia (nominal p=0.002, adjusted p=0.096).

EVENITY resulted in a 25 percent reduction compared to placebo in the relative risk of non-vertebral fractures through month 12, another secondary endpoint, but the reduced risk was not statistically significant (fracture incidence 1.6 percent versus 2.1 percent, respectively, [p=0.096]). For the non-vertebral fracture endpoint, the overall fracture incidence in the trial was lower than expected (2.1 percent in the placebo group in year one versus an expected rate of 3.5 percent).

In a sub-trial of 126 subjects, EVENITY increased bone marrow density (BMD) with gains of 9.7 percent and 4.7 percent from baseline by six months at the lumbar spine and total hip, respectively, and gains of 13.3 percent and 6.8 percent at 12 months (all comparisons versus placebo p<0.001). BMD continued to increase in the EVENITY group after transitioning to Prolia, reaching 17.6 percent and 8.8 percent increases from baseline at the lumbar spine and total hip, respectively, at 24 months (p<0.001 compared to placebo-to-Prolia group for all comparisons).

According to Amgen, the percentage of patients with adverse events (AEs) and serious adverse events (SAEs) in the 12-month double-blind period and 24-month trial period were balanced overall between the treatment groups. Injection site reactions, mostly mild in severity, were reported in 5.2 percent of patients in the EVENITY treatment group and 2.9 percent in the placebo group during the 12-month period. There were two positively adjudicated events of osteonecrosis of the jaw in the EVENITY treatment group, one after completing EVENITY dosing and the other after completing EVENITY treatment and receiving the initial dose of Prolia. There was one positively adjudicated event of atypical femoral fracture after three months of EVENITY treatment. Adjudicated serious cardiovascular events and cardiovascular deaths were balanced between treatment groups.

The ARCH Trial

The ARCH trial (Active-contRolled fraCture trial in postmenopausal women with osteoporosis at high risk of fracture; ClinicalTrials.Gov ID NCT01631214) was a randomized, double-blind, FOSOMAX-controlled trial of EVENITY in 4,093 postmenopausal women with osteoporosis at high risk for fracture based on previous fracture history. The trial evaluated 12 months of EVENITY treatment (210 mg) followed by at least 12 months of FOSOMAX treatment (70 mg), compared with FOSOMAX treatment alone, to determine effectiveness in reducing the incidence of clinical fracture (non-vertebral fracture and clinical vertebral fracture) and new vertebral fracture.

According to Amgen, at primary analysis, postmenopausal women in the EVENITY treatment group experienced a statistically significant 19.0 percent relative reduction in the risk of non-vertebral fractures (8.7 percent versus 10.6 percent, respectively [p=0.04]). A 38.0 percent relative reduction in the risk of hip fractures was also observed (2.0 percent versus 3.2 percent, respectively [nominal p=0.015]), when compared to those receiving FOSOMAX alone.

Amgen says the trial found that, through 24 months, postmenopausal women with osteoporosis in the EVENITY treatment group experienced a statistically significant 48.0 percent relative reduction in the risk of a new vertebral (spine) fracture compared with those receiving FOSOMAX alone (6.2 percent versus 11.9 percent, respectively [p<0.001]). At primary analysis, women in the EVENITY treatment group also experienced a statistically significant 27.0 percent relative reduction in the risk of clinical fracture, which includes non-vertebral fracture and clinical vertebral fracture (9.7 percent versus 13.0 percent, respectively [p<0.001]).

Postmenopausal women who received EVENITY achieved greater gains in BMD from baseline at all measured sites and at all time points of the trial versus those receiving FOSOMAX alone. At month 12, the percentage change from baseline was greater with EVENITY versus FOSOMAX at the lumbar spine (13.7 percent versus 5.0 percent, respectively [p<0.001]) and total hip (6.2 percent versus 2.8 percent, respectively [p<0.001]). In a subset of patients assessed every six months, significant gains were observed beginning at month six (p<0.001) for all sites.

Overall, AEs and SAEs were generally similar between the treatment groups. An imbalance in adjudicated cardiovascular SAEs was observed during the 12-month period in 50 patients (2.5 percent) treated with EVENITY versus 38 patients (1.9 percent) treated with FOSOMAX, with cardiac ischemic events and cerebrovascular events accounting for the imbalance.

The percentage of patients with AEs and SAEs throughout the trial as well as in the initial 12-month EVENITY treatment period were balanced between the groups, including incidences of osteoarthritis, hypersensitivity, cancer, and hypocalcemia. Injection site reactions, mostly mild in severity, were reported in 4.4 percent of patients in the EVENITY treatment group and 2.6 percent in the FOSOMAX group during the initial 12-month period.

During the open-label FOSOMAX period, there were two positively adjudicated events of osteonecrosis of the jaw, one in a patient treated with EVENITY followed by FOSOMAX and one treated with FOSOMAX alone. There were six patients with positively adjudicated events of atypical femoral fracture during the open-label FOSOMAX period, two patients treated with EVENITY followed by FOSOMAX and four treated with FOSOMAX alone.

The BRIDGE Trial

The BRIDGE trial (placeBo-contRolled trial evaluatIng the efficacy anD safety of romosozumab in treatinG mEn with osteoporosis; ClinicalTrials.Gov ID NCT02186171) was a randomized, double-blind, placebo-controlled trial of men aged 55-90 years with osteoporosis and a history of fragility fracture (excluding hip fracture) or vertebral fracture. The trial evaluated the effectiveness of EVENITY treatment for 12 months, compared with placebo, in increasing BMD at the lumbar spine and the effect on BMD at the femoral neck and total hip. 

The trial involved 245 men with osteoporosis (163 EVENITY, 82 placebo) randomized 2:1 to receive either 210 mg EVENITY or placebo subcutaneously once monthly for 12 months. All patients received daily calcium and vitamin D. According to Amgen, the primary endpoint was met, with EVENITY demonstrating a statistically significant increase (12.1 percent; p<0.01) in BMD at the lumbar spine (as assessed by dual energy x-ray absorptiometry) compared with placebo at 12 months. All secondary endpoints were also met, with EVENITY showing a statistically significant increase in BMD at total hip (2.5 percent) and the femoral neck (2.2 percent) at 12 months (both p<0.01 compared to placebo). A statistically significant increase in BMD at six months was also seen with EVENITY at all sites examined compared to placebo: lumbar spine (9.0 percent), total hip (1.6 percent), femoral neck (1.2 percent; p<0.01 for all sites). The dual effect of EVENITY was reflected by an increase in P1NP (86 percent median increase from baseline peaking at one month), a marker of bone formation, and a decrease in CTX (31 percent median decrease from baseline at one month), a marker of bone resorption.

The overall incidence of AEs and SAEs were balanced between treatment groups. The most frequently reported AEs (greater than five percent in the EVENITY arm) were nasopharyngitis, back pain, hypertension, headache and constipation. Injection site reactions were reported in 5.5 percent of patients in the EVENITY treatment group and 3.7 percent 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 SAEs was 4.9 percent (8/163) in the EVENITY group and 2.5 percent (2/81) in the placebo group. The patient incidence of positively adjudicated cardiovascular death was 0.6 percent (1/163) in the EVENITY group and 1.2 percent (1/81) in the placebo group.

Regulatory Considerations

Cardiovascular safety is expected to be a topic for discussion at this meeting. As noted before, an imbalance in adjudicated cardiovascular SAEs was observed in the ARCH trial. During the 12-month period 50 patients (2.5 percent) treated with EVENITY experienced an adjudicated cardiovascular SAE, compared to 38 patients (1.9 percent) treated with FOSOMAX. Amgen says that in the ARCH trial, cardiac ischemic events and cerebrovascular events accounted for the imbalance. Amgen reports that adjudicated serious cardiovascular events and cardiovascular deaths were balanced between treatment groups. In the BRIDGE trial, the incidence of positively adjudicated cardiovascular SAEs was 4.9 percent (8/163) in the EVENITY group and 2.5 percent (2/81) in the placebo group. Also, in the BRIDGE trial, the incidence of positively adjudicated cardiovascular death was 0.6 percent (1/163) in the EVENITY group and 1.2 percent (1/81) in the placebo group.

The evidence to support effectiveness for the proposed use will likely be discussed at this meeting. Tarius notes that Amgen/UCB proposes a narrow indication for EVENITY. The companies are proposing that EVENITY be approved only for the treatment postmenopausal women who are at high risk for fracture or who have failed or are intolerant of other available osteoporosis therapy, rather than for the treatment of all postmenopausal women. As mentioned before, the FRAME trial, which studied all postmenopausal women, met its co-primary efficacy endpoint (vertebral fracture), but failed on a secondary efficacy endpoint (nonvertebral fracture). The ARCH trial, which studied a subset of postmenopausal women at high risk for fracture, met its co-primary efficacy endpoint (vertebral and nonvertebral fractures), but it is unclear if all secondary BMD endpoints were met.

The overall benefit:risk profile will be reviewed at this meeting. As usual, this will be considered in context with the proposed use and any unmet need for treatments.

Regulatory Background

US Regulatory Background

Unknown – PDUFA date for the BLA resubmission

July 12, 2018 – BLA resubmission date (BLA 761062). The resubmission is based on results from the FRAME, ARCH, and BRIDGE trials.

July 19, 2017 – PDUFA date for the initial BLA submission

July 16, 2017 – Amgen and UCB announced their receipt of a jComplete Response Letter (CRL) from the FDA. The companies said they were informed by the FDA that a resubmission would need to incorporate results from the BRIDGE and ARCH trials.

July 21, 2016 – Amgen and UCB announced the initial BLA submission based on results from the FRAME trial.

Ex-US Regulatory Background

Romosozumab marketing applications in the EU and in Japan are currently underway.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Amgen, UCB Drug Name: romosozumab Drug Class: sclerostin inhibitor Indication: osteoporosis

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.