SI-6603
Ferring Pharmaceuticals and its clinical development partner, Seikagaku Corporation (Seikagaku), today announced the presentation of data looking at the efficacy and safety profile of SI-6603 (generic name: condoliase), an investigational product intended to treat radicular leg pain associated with lumbar disc herniation (LDH). The research, presented at the American Society of Interventional Pain Physicians (ASIPP) Annual Meeting, included a registrational Phase 3 trial and an integrated safety analysis of six clinical studies, as well as a real-world analysis of current treatment options and gaps in the clinical management of patients with newly-diagnosed LDH.
“As the leading cause of sciatica, lumbar disc herniation can cause severe debilitating pain that can affect a person’s mobility and quality of life possibly requiring surgical intervention,” said Raza Ahmed, MD, Senior Director, Medical Affairs, Specialty/Orthopedics, Ferring USA. “These data represent a positive step in our efforts to provide a less invasive option to patients suffering from this serious condition.”
Phase 3 Trial
The registrational Phase 3 trial was a double-blind, sham-controlled, parallel study in which patients (n=352) with LDH were randomized to receive either a single intradiscal injection of SI-6603 1.25 Units or a sham injection. The study met its primary endpoint, with participants in the SI-6603 treatment group showing significantly greater improvement in worst leg pain score vs. the sham group at Week 13 following treatment (least squares mean [LSM] change from baseline of -41.7 vs. -34.2; p=0.0263).
Overall, 71.9% of participants in the SI-6603 group experienced at least one treatment-emergent adverse event (TEAE) vs. 60.3% in the sham group, of which 28.1% and 10.3%, respectively, were considered treatment related. No treatment-related serious adverse events (SAE) occurred.
“For too long, treatment of radicular leg pain associated with LDH has been limited to conservative care with pain medication and physical therapy, or a more invasive surgical approach,” said Kenneth Candido, MD, Chicago Anesthesia Pain Specialists, Chicago, IL, Clinical Professor of Anesthesia & Surgery, University of Illinois. “Based on these findings, SI-6603 could provide another option where a single injection to the lumbar disc could offer patients significant relief from the unrelenting pain often associated with lumbar disc herniation.”
The integrated safety analysis of data from completed Phase 2 and 3 clinical trials for SI-6603 found that up to Week 13, TEAEs were reported in 65.9% patients treated with SI-6603 1.25 U and 54.3% who received sham or placebo, of which 25.8% versus 13.1%, respectively, were considered treatment-related. Most TEAEs were considered mild to moderate in severity. At Week 13, the incidence of SAEs was similar for both groups (2.6% vs. 3.3%, respectively), and only one SAE (back pain) was considered related to SI-6603.
An analysis assessing current treatment patterns and gaps in clinical management of patients with newly diagnosed LDH was also presented. The analysis reviewed medical claims data of more than a million U.S. patients over a four-year period. During a three-year follow-up period, nearly all patients (98.4%) received conservative treatment which entailed pain medication and physical therapy. Overall, about one in five patients (19.8%) required at least one epidural steroid injection (ESI) and more than half of these patients received multiple ESIs (28.4% with two ESIs, and 24.2% with three or more). Nearly half (48.4%) of patients received their second ESI within a year of the first ESI, with 17.0% receiving a second administration within 30 days of the first.
Of the patients who underwent LDH surgery (7.2%), 44.1% had not previously received ESI and 11.1% underwent repeated surgeries. Among patients who received more than one ESI, one in five (22.4%) underwent surgery with 14.2% of those patients receiving repeated surgeries.
About the Registrational Phase 3 Trial
In this double-blind, sham-controlled, parallel Phase 3 study — known as the Discovery 6603 clinical trial (NCT03607838) — participants were randomized 1:1 to receive either SI-6603 (1.25 U) or sham injection followed by 52 weeks of observation. The primary endpoint was defined as the change from baseline to Week 13 in average worst leg pain during the past 24 hours over the previous seven days, as assessed by Visual Analogue Scale, a pain rating score from 0 – 100 with a higher score indicating greater pain intensity. Key secondary endpoints were the change from baseline in average worst leg pain at 52 weeks, (SI-6603: -51.2; sham: -44.7; LSM difference: -6.5; CI: -13.2, 0.2; p=0.0558); herniation volume at 13 weeks (CI= -25.8 (-55.7 to 4.2), p=0.0920), and Oswestry Disability Index (ODI) score at 13 weeks (CI= -4.2 (-8.0 to -0.3), p=0.0336). Since the key secondary endpoint of change in average worst leg pain at Week 52 was not significant, the serial gatekeeping testing algorithm dictated that there were no significant group differences for Week 13 herniation volume or ODI score regardless of their p-values.
The trial included U.S. participants ages 30 to 70 years old who had contained posterolateral LDH with the chief complaint being unilateral radiculopathy/radicular leg pain and inadequate improvement in pain despite more than six weeks of conservative treatment. Among 352 randomized participants, 341 constituted the mITT population (SI-6603 n=169; sham injections n=172).
About the Integrated Safety Analysis
The primary safety pool analysis examined the safety populations from four multicenter, randomized, double-blind, sham or placebo-controlled studies of a single intradiscal injection of SI-6603 (1.25 U) in 578 participants ages 20 to 70 years old with radicular leg pain associated with LDH. Adverse events (AE) and other safety outcomes were measured for 52 weeks in three of the studies and 104 weeks in one study.
The secondary analysis included the primary pool studies plus two open-label studies of a single SI-6603 injection (0.5, 1.25, 2 U) with 26 or 52 weeks of observation. All studies collected full safety monitoring data up to Week 13, after which three studies only collected SAEs and AEs related to the disc/surrounding tissues.
Additional safety results also showed that up to Week 13, TEAEs leading to study discontinuation were less frequent in the SI-6603 group (0.5%) than the sham or placebo group (2.3%). After Week 13, less than 2% of participants had TEAEs leading to study discontinuation. Post-treatment lumbar surgery at the target level occurred in 5.5% of the SI-6603 group and 7.2% of the sham or placebo group. Up to Week 13, the most common TEAEs in the SI-6603 1.25 U group with an incidence greater than sham or placebo were back pain, abnormal spinal MRI (magnetic resonance imaging) and abnormal spinal X-ray. The incidence of spinal abnormality TEAEs was similar between the SI-6603 1.25 U (0.9%) and sham or placebo (1.3%) groups. No deaths were considered treatment related. In the secondary pool (SI-6603 ≥1.25 U; N=1679), across all time intervals, 69.0% of participants reported TEAEs, 4.9% SAEs, and 0.8% TEAEs leading to discontinuation.
About the Real-World Treatment Pattern Analysis
This analysis is based on medical claims data identified from the IQVIA PharMetrics® Plus database of 1,086,552 adult patients ages 30 to 70 years who were first diagnosed (index diagnosis) with LDH (≥1 inpatient diagnosis or ≥2 outpatient diagnoses) between January 1, 2018 and March 31, 2020. As a requirement, patients needed to have at least six months of continuous insurance enrollment prior to and ≥12 months following the index date, excluding those who received ESI or LDH surgical procedures prior to the index date. The average age of the patients was 50.8±10.0 years and more than half (53.8%) were women. The mean Charlson Comorbidity Index (CCI) score was 1.2±1.8, indicating that the severity of existing comorbid conditions was mild to moderate, with the most common being hypertension (28.2%), chronic pulmonary disease (25.9%) and diabetes (22.3%).
During the baseline period, 66.3% of patients had received conservative treatments while during the follow-up period (mean: 27.1±8.5 months), 98.4% of patients received conservative treatments. Overall, patients who received surgery or more than one ESI were older (mean age of 52.1±9.8 and 52.5±9.4 years, respectively) and had higher CCI scores (1.3±1.9 and 1.4±1.9, respectively), indicating more severe comorbid conditions. Following the administration of the first ESI, 17.0%, 35.0%, 42.7% and 48.4% received their second ESI within 30 days, 90 days, six months and one year, respectively, and 18.3% received subsequent surgeries after ESI.
About SI-6603
SI-6603, which contains condoliase as its active pharmaceutical ingredient, is an investigational product intended to treat radicular leg pain associated with lumbar disc herniation via a single, direct intradiscal injection.
SI-6603 was developed by Seikagaku. Marketing approval for SI-6603 in Japan was obtained from the Japanese Ministry of Health, Labour and Welfare in March 2018 and SI-6603 has been marketed as HERNICORE® 1.25 units for intradiscal injection through Seikagaku Corporation’s Japanese sales partner Kaken Pharmaceutical Co., Ltd. (Tokyo, Japan) since August 1, 2018.1
Alliance with Seikagaku
Seikagaku and Ferring entered into a license agreement for SI-6603 in August 2016. Ferring plans to commercialize the product in the United States and has received further rights to develop, register and commercialize SI-6603 worldwide, excluding Japan.