ENDO 2021

P33-2 - Results From an Open-Label Extension of the Phase 2 Dose Finding Study of Once Weekly Somatrogon vs Daily Genotropin in Pediatric Patients With Growth Hormone Deficiency (GHD)


Authors

Zvi Zadik, MD1, Nataliya Zelinska, MD, PhD2, Violeta Iotova, MD, PhD, DSc3, Yulia Skorodok, MD, PhD4, Oleg A. Malievskiy, Professor5, Nelly Mauras, MD6, Srinivas R. Valluri, PhD7, Aleksandra Pastrak, MD, PhD8, Ron G. Rosenfeld, MD9.

1Kaplan Medical Center, Rehovot, Israel, 2Ukrainian Scientific and Practical Center of Endocrine Surgery of the Ministry of Health of Ukraine, Kyiv, Ukraine, 3Medical University of Varna, UMHAT "Sv. Marina", Varna, Bulgaria, 4Saint-Petersburg State Pediatric Medical University Institution, Saint-Petersburg, Russian Federation, 5Bashkirian State Medical University, Ufa, Russian Federation, 6Nemours Children's Health System, Jacksonville, FL, USA, 7Pfizer, Inc, New York, NY, USA, 8OPKO Health, Toronto, ON, Canada, 9Oregon Health and Science University, Portland, OR, USA.

Disclosures

Z. Zadik: None. N. Zelinska: Consulting Fee; Self; Novo Nordisk, Berlin-Chemie, Medtronic, Sanofi-Aventis. Research Investigator; Self; MacroGenics, Novo Nordisk, Pfizer, Inc., Merck, OPKO, Ferring Pharmaceuticals, Teva Pharmaceutical Industries Ltd., Paraxel, Genexine. Speaker; Self; Medtronic, Berlin-Chemie, ACINO, Novo Nordisk, Pfizer, Inc., Sanofi-Aventis, Johnson &Johnson, Wörwag Pharma. V. Iotova: Advisory Board Member; Self; Pfizer, Inc., Sandoz, Sanofi, Medtronic. Advisory Board Member; Spouse; Pfizer, Inc., Novartis, AstraZeneca, Boehringer, Bayer, Inc., Servier, Menarini Berlin-Chemie, Amgen Inc. Grant Recipient; Self; Pfizer, Inc.. Research Investigator; Self; OPKO, Pfizer, Inc., Ascendis Pharma, Merck, Novo Nordisk, Sanofi, Resolute, Novartis. Research Investigator; Spouse; Novartis, AstraZeneca, Boehringer, Bayer, Inc., Menarini Berlin-Chemie, Amgen Inc, Teva Pharmaceutical Industries Ltd., Novo Nordisk, Polpharma, Sanofi, MSD, Servier. Speaker; Self; Pfizer, Inc., Sandoz, Novo Nordisk, Sanofi, Berlin-Chemie, Eli Lilly & Company, Medtronic, Shire. Speaker; Spouse; Pfizer, Inc., Novartis, AstraZeneca, Boehringer, Bayer, Inc., Servier, Menarini Berlin-Chemie, Amgen Inc, Teva Pharmaceutical Industries Ltd., Sandoz, Actavis, Gedeon Rihter, Polpharma, Krka, Sanofi, Shire, MSD, Merck. Y. Skorodok: Speaker; Self; Berlin-Chemie, Sanofi. O.A. Malievskiy: None. N. Mauras: Grant Recipient; Self; Novo Nordisk, Abbvie. Research Investigator; Self; OPKO. Speaker; Self; Novo Nordisk. S.R. Valluri: Employee; Self; Pfizer, Inc.. Stock Owner; Self; Pfizer, Inc. A. Pastrak: Employee; Self; OPKO. Stock Owner; Self; OPKO. R.G. Rosenfeld: Advisory Board Member; Self; Lumos, DNARx, BioMarin. Consulting Fee; Self; OPKO.

Abstract

Background Somatrogon, a long-acting recombinant human growth hormone, is being developed as a once weekly treatment for pediatric patients (pts) with GHD. A phase 2, 12 month study (NCT01592500) in pts with GHD showed that weekly somatrogon at 0.66 mg/kg/week had similar efficacy and safety to daily Genotropin. Pts who completed 12 months of treatment could be enrolled into an open-label extension (OLE).

Aims Evaluate the safety and efficacy of long-term exposure to somatrogon in pediatric pts with GHD who continued in the OLE for up to an additional 5 years.

Methods Methods for the main phase 2 study were published previously (Zelinska et al, 2017), in which 53 pts were randomized to 1 of 3 weekly somatrogon dose cohorts (0.25, 0.48, and 0.66 mg/kg/week) or the daily Genotropin cohort (0.24 mg/kg/week) for 12 months. After the main study (Periods I/II), 48 pts who consented to participate continued in the OLE, consisting of 3 periods: Period III=12 additional months at original somatrogon dose (Genotropin recipients randomized to 1 of the 3 somatrogon dose regimens); Period IV=subsequent years 2-4 with all pts receiving somatrogon at 0.66 mg/kg/week; Period V=ongoing, with pts transitioned from the vial to a pre-filled pen device at the same somatrogon dose (0.66 mg/kg/week). Data up to 1 year of Period V are reported.

Results Overall subject retention in different periods of this long-term study ranged from 87.5% to 97.7%. 39 pts (81.3%) reported at least one treatment-emergent adverse event (TEAE). Most TEAEs were mild or moderate in intensity and most were classified as unrelated to study treatment. 3 pts (6.3%) reported at least 1 serious adverse event (SAE); most SAEs were considered unrelated to study treatment, except for 1 instance of scoliosis. At the end of Period III, the mean annual height velocity (HV) was similar for the 0.25 and 0.48 mg/kg/week dose cohorts (7.73±1.89 and 7.54±1.28 cm/year, respectively) but was higher in the 0.66 mg/kg/week dose cohort (8.81±1.12 cm/year), consistent with the results of the main study. The HV at Periods IV and V showed sustained growth response. Height SDS showed consistent improvement and near normalization of height for age and gender after up to 6 years on somatrogon, irrespective of initial cohort assignment; height SDS at baseline of the main study was -3.98±1.22 and was well within the normal range at -0.69±0.87 at the end of Year 1 in Period V. IGF-1 SDS values remained above baseline and were maintained within the therapeutic target range with weekly somatrogon treatment at all time points in all OLE periods. Anti-drug antibodies (ADAs) were reported in 18 pts, of which 10 pts had ADAs in the main study. The presence of ADAs did not impact efficacy or safety.

Conclusions Somatrogon administered once weekly for up to 5 years after the main study was generally well tolerated and participants showed sustained improvement in annual HV, height SDS, and delta height SDS.

P33-7 - Switch Data From the Open-Label Extension of the Pivotal Phase 3 Study of Once Weekly Somatrogon Compared to Daily Somatropin in Pediatric Patients With Growth Hormone Deficiency (pGHD)

Authors

Michael Wajnrajch, MD, MPA1, Bradley Scott Miller, MD, PhD2, Joel Steelman, MD3, Lawrence A. Silverman, MD4, Moshe Phillip, MD5, Elpis Vlachopapadopoulou, MD6, Renata Stawerska, MD, PhD7, Ho-Seong Kim, MD, PhD8, Oleg Malievskiy, MD, PhD9, Cheol Woo Ko, MD, PhD10, Srinivas Rao Valluri, PhD1, Carrie Turich Taylor, PhD, MHS1, Carl L. Roland, PharmD, MS11, John Choe, PhD12, Aleksandra Pastrak, MD PhD12, Cheri L. Deal, PhD, MD13.

1Pfizer Inc, New York, NY, USA, 2University of Minnesota Masonic Children's Hospital, Lino Lakes, MN, USA, 3Cook Children’s Medical Center, Fort Worth, TX, USA, 4Goryeb Children's Hospital, Morristown, NJ, USA, 5Schneider Children's Medical Center, Petah Tiqwa, Israel, 6Children’s Hospital P & A. Kyriakou, Athens, Greece, 7Polish Mother Memorial Hospital-Research Institute, Lodz, Poland, 8Yonsei University College of Medicine Institution City Seoul, Seoul, Korea, Republic of, 9Bashkir State Medical University, Ufa, Russian Federation, 10Kyungpook National University Children’s Hospital, Daegu, Korea, Republic of, 11Pfizer Inc, Sanford, NC, USA, 12OPKO Health, Toronto, ON, Canada, 13Sainte-Justine Hospital, Montreal, QC, Canada.

Disclosures

M. Wajnrajch: Employee; Self; Pfizer, Inc.. Stock Owner; Self; Pfizer, Inc. B.S. Miller: Advisory Board Member; Self; Pfizer, Inc.. Consulting Fee; Self; Pfizer, Inc.. Research Investigator; Self; OPKO Health. J. Steelman: None. L.A. Silverman: Advisory Board Member; Self; Pfizer, Inc.. Consulting Fee; Self; OPKO Health. M. Phillip: Grant Recipient; Self; Pfizer, Inc., OPKO Health. E. Vlachopapadopoulou: Research Investigator; Self; OPKO Health. R. Stawerska: Research Investigator; Self; OPKO Health, Ascendis. H. Kim: None. O. Malievskiy: None. C. Ko: None. S.R. Valluri: Employee; Self; Pfizer, Inc.. Stock Owner; Self; Pfizer, Inc. C. Turich Taylor: Employee; Self; Pfizer, Inc.. Stock Owner; Self; Pfizer, Inc. C.L. Roland: Employee; Self; Pfizer, Inc.. Stock Owner; Self; Pfizer, Inc. J. Choe: Employee; Self; OPKO Health. A. Pastrak: Owner/Co-Owner; Self; OPKO Health. Stock Owner; Self; OPKO Health. C.L. Deal: Advisory Board Member; Self; Pfizer, Inc.. Consulting Fee; Self; Pfizer, Inc., OPKO Health. Research Investigator; Self; Pfizer, Inc., OPKO Health. Speaker; Self; Pfizer, Inc., OPKO Health.

Abstract

OBJECTIVES: Somatrogon (hGH-CTP) is a long acting recombinant human growth hormone, consisting of the amino acid sequence of hGH and three copies of the carboxy-terminal peptide (CTP) of human chorionic gonadotropin (hCG) being developed as a once weekly treatment for children with pGHD. This report summarizes data from the first year of the optional open-label extension (OLE) of the pivotal phase 3 global trial (ClinicalTrials.gov: NCT02968004), comparing the efficacy and safety of children switched from Genotropin (rhGH; somatropin) to somatrogon (Geno/Soma) and children maintained on somatrogon (Soma/Soma).

METHODS: During the main study, 224 children were randomized to receive either once weekly somatrogon (0.66 mg/kg, n=109) or once daily Genotropin (0.24 mg/kg/wk, n=115) for 12 months. Of these, 222 completed the 12-month main study, and 212 chose to enter the OLE study. By Sept 30, 2020, 161 children (including 76 Geno/Soma) had complete auxological data at month 12 of the OLE.

RESULTS: At the end of the main study, mean height velocity and gain in height SDS for the somatrogon cohort were 10.10 cm/year and 0.92; for the Genotropin cohort these were 9.78 cm/year and 0.87. Baseline values for the OLE (Soma/Soma group and Geno/Soma group, respectively): height SDS was -1.95 and -1.84, BMI was 17.03 and 15.48 kg/m2 while bone age was 6.54 and 6.40 years. At month 12 (of the OLE), the mean height velocity and the change in height SDS was 8.04 cm/year and 0.41 (Soma/Soma group) and 8.21 cm/year and 0.47 (Geno/Soma group); BMI was 18.07 and 17.49 kg/m2 and bone age was 8.48 and 8.41 years. IGF-1 SDS values were 1.15, and 1.28, while the IGFBP-3 SDS were 0.29 and 0.42, respectively. Dose reductions were required in 16.3% and 20.4% of patients due to IGF-1 SDS >2. Pubertal status changed from Tanner 1 (at OLE baseline) for 13.6% of Soma/Soma patients and 14.6% of Geno/Soma patients. Mean glucose, HbA1c, thyroid function (free T4 and TSH) and cholesterol (total, LDL and HDL) values remained similar to baseline in both groups across the 12 months OLE. The majority of adverse events in both cohorts were mild to moderate (Soma/Soma 94.2%, Geno/Soma 93.5%) and there were no clinically concerning safety observations. During the first 12 months of the OLE six patients discontinued in the Geno/Soma group due to AEs vs zero in the Soma/Soma group.

CONCLUSIONS: Height velocities and change in height SDS in the OLE were similar between the Geno/Soma and Soma/Soma cohorts. The main phase of the global pivotal phase 3 trial demonstrated that somatrogon (hGH-CTP) given once weekly is non-inferior to Genotropin (hGH) while the OLE demonstrated that catch-up growth continued into the second year of treatment, with ‘switch’ from Genotropin to somatrogon non-inferior to somatrogon given for two years. Metabolic (glycemic, lipid and thyroid) parameters were similar between groups and not meaningfully different from the main study.

Could not really focus on the technical stuff, but dang those are some impressive conclusions!