Summary Basis of Decision (SBD) for Sogroya

Clinical Pharmacology

Somapacitan, the medicinal ingredient in Sogroya, is a long-acting recombinant human growth hormone derivative with a single substitution in the amino acid backbone to which an albumin-binding moiety has been attached. The non-covalent, reversible binding to endogenous albumin delays the elimination of somapacitan and thereby prolongs the in vivo half-life and duration of action. Somapacitan exerts its effects directly via the growth hormone receptor and indirectly via insulin-like growth factor 1 (IGF-1) produced predominantly by the liver or in tissues throughout the body.

Six Phase I studies in which somapacitan was administered subcutaneously to healthy adults and adults with growth hormone deficiency provided richly sampled pharmacokinetic and pharmacodynamic data. The highest somapacitan dose levels evaluated in these studies were 0.32 mg/kg/week in the single-dose cohorts and 0.24 mg/kg/week in the multiple-dose cohorts (corresponding to approximately 27 mg/week and 20 mg/week, respectively, based on a mean body weight of 85 kg).

Richly sampled pharmacokinetic and pharmacodynamic data from pediatric patients with growth hormone deficiency were collected in one Phase I, single-ascending dose study of somapacitan administered subcutaneously to 32 patients between 6 and 11 years of age. The highest dose level used in the study was 0.16 mg/kg/week.

Data from the Phase I studies were complemented by sparsely sampled data from the Phase II and Phase III studies in adult and pediatric patients with growth hormone deficiency and used to develop population pharmacokinetic, pharmacokinetic-pharmacodynamic, and exposure-response models. All the pharmacometric models were appropriately parameterized and had no apparent biases.

The recommended dosage regimen for somapacitan in adults with growth hormone deficiency involves weekly subcutaneous injections with a starting dose of 1.5 mg/week and a subsequent individualized dose titration based on serum IGF-1 standard deviation score (SDS) values. Serum IGF-1 concentration is commonly used as a screening test for growth hormone deficiency and the calculated IGF-1 SDS value is an indirect measure of growth hormone secretory status. The IGF-1 SDS is defined based on a healthy reference population.

In patients 60 years of age or older and female patients receiving oral estrogen, the recommended starting dose of somapacitan is 1 mg/week and 2 mg/week, respectively, followed by individualized dose titration. These recommendations are supported by pharmacokinetic and pharmacodynamic data demonstrating that patients 60 years of age or older have higher exposures to somapacitan than a typical reference subject at any given dose level, while female patients, especially those receiving concomitant oral estrogen, show markedly reduced somapacitan exposures (by approximately 30% to 50%) compared to a typical reference subject at any given dose level.

In the fixed-dose periods of the Phase III trials, after a dose titration scheme based on maintaining an IGF-1 SDS score between 0 and +2, the mean somapacitan dose was 2.4 mg/week. At this weekly dose of somapacitan, the population pharmacokinetic model estimated a geometric mean average concentration of 2.7 ng/mL. The approximate half-life of somapacitan was 69.2 hours.

A low level of somapacitan accumulation was observed following repeat weekly dosing in adult patients with growth hormone deficiency, with an accumulation ratio of 1.23. In these patients, somapacitan exhibited generally dose-proportional increases in exposure up to a dose of 4 mg/week, after which a larger than dose-proportional increase in exposure was observed.

In pediatric patients with growth hormone deficiency, the recommended dosage regimen of somapacitan is 0.16 mg/kg/week, which also represents the maximum recommended weekly dose. This translates to 13.6 mg/week based on an adult patient with a body weight of 85 kg, indicating that pediatric patients require higher somapacitan doses than adult patients. A greater than dose-proportional increase in exposure was observed across the dosing range of 0.04 mg/kg/week to 0.16 mg/kg/week in pediatric patients. At the somapacitan dose of 0.16 mg/kg/week, the population pharmacokinetic model predicted a geometric mean average concentration of 80.2 ng/mL. The mean half-life was 33.6 hours. There was a low level of accumulation, with an accumulation ratio of 1.06 observed following weekly dosing.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). Antibodies against somapacitan were detected in 16 of 132 (12.1%) pediatric patients with growth hormone deficiency who were receiving somapacitan in the Phase III study REAL 4. Generally, ADAs were transient and of low titer. Somapacitan dose had no apparent effect on the incidence of ADAs, and no consistent effect of ADAs was observed on the pharmacokinetics, efficacy, or safety of somapacitan in pediatric patients with growth hormone deficiency. No ADAs were detected in adult patients with growth hormone deficiency and no neutralizing ADAs were detected in any of the adult or pediatric patients with growth hormone deficiency.

Overall, the clinical pharmacology data support the use of Sogroya for the recommended indication.

For further details, please refer to the Sogroya Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Sogroya was evaluated in pediatric and adult patients with growth hormone deficiency.

Pediatric patients with growth hormone deficiency (study REAL 4)

The efficacy of Sogroya for the treatment of pediatric patients with growth hormone deficiency was primarily supported by data derived from the pivotal active-controlled, open-label, Phase III study (REAL 4, also referred to as study 4263).

Patients enrolled in the study were growth hormone treatment-naïve prepubertal children between 2.5 and under 10 years of age (for girls) or under 11 years of age (for boys), with impaired height, impaired height velocity, and an IGF-1 SDS value lower than ‑1.0. At study entry, 200 patients were randomized in a ratio of 2:1 to receive Sogroya at a dose of 0.16 mg/kg/week (132 patients) or the active comparator Norditropin FlexPro (somatropin) at a dose of 0.034 mg/kg/day, i.e., 0.24 mg/kg/week (68 patients) for 52 weeks. Dose adjustments were permitted if there were safety or tolerability issues requiring decrease or interruption of dosing. Of the randomized patients, 74.5% were male, 57% were White, and 37% were Asian. The mean age of patients was 6.4 years (range: 2.5 to 11 years) and 51.5% of patients were 6 years of age or older.

Overall, 199 children completed the main treatment period of 52 weeks. These patients were eligible to enter an ongoing 3-year safety extension part of the study, in which all patients receive open-label weekly treatment with Sogroya.

The primary efficacy endpoint of study REAL 4 was the annualized height velocity at Week 52. At baseline, patients had mean height velocity of 4.2 cm/year. In both treatment groups, the observed height velocity increased approximately threefold from baseline to Week 13 and thereafter remained at approximately the same level. At Week 52, the estimated mean height velocity was 11.2 cm/year for the Sogroya group and 11.7 cm/year for the Norditropin FlexPro group with an estimated treatment difference of ‑0.5 cm/year (95% confidence interval [CI]: ‑1.1, 0.2). Non-inferiority of Sogroya compared to Norditropin FlexPro was confirmed given that the lower boundary of the 95% CI (‑1.1 cm/year) for the treatment difference was greater than the predefined non-inferiority margin of ‑1.8 cm/year.

While not part of a formal statistical testing plan, data for the secondary endpoints were supportive of the results of the primary endpoint. There were no marked differences between Sogroya and Norditropin FlexPro with respect to changes from baseline to Week 52 in height velocity SDS, height SDS, and in the ratio of bone age to chronological age. At Week 52, the observed mean IGF-1 SDS levels were 0.28 for Sogroya and 0.10 for Norditropin FlexPro. The estimated increases of IGF-1 SDS levels from baseline to Week 52 were similar between the two treatment groups (2.36 and 2.33 for Sogroya and Norditropin FlexPro, respectively).

Adult patients with growth hormone deficiency (study REAL 1)

The efficacy of Sogroya for the treatment of adult patients with growth hormone deficiency was primarily supported by data from a placebo-controlled (double-blind) and active-controlled (open-label) Phase III study (REAL 1, also referred to as study 4054).

In the main phase of study REAL 1, growth hormone treatment-naïve adult patients with growth hormone deficiency were randomized in a ratio of 2:1:2 and received double-blind treatment with once-weekly Sogroya (120 patients) or placebo (61 patients), or open-label treatment with daily Norditropin FlexPro (119 patients) for 34 weeks. An 8-week dose titration was followed by a fixed-dose treatment of 26 weeks. The mean age of patients was 45.1 years (range: 23 to 77 years) and 51.7% of patients were women. Most patients (69.7%) had adult-onset growth hormone deficiency. The majority of patients (66.7%) were White, 28.7% were Asian, and 2.3% were Black or African American.

Of note, while Norditropin FlexPro is authorized in Canada exclusively for use in pediatric patients with growth hormone deficiency, its use in adult patients has been authorized in other countries and there is no reason to expect that its effects would differ substantially from other recombinant growth hormone (somatropin) products that require daily subcutaneous administration and are authorized in Canada for use in adult patients with growth hormone deficiency. Moreover, the primary objective of study REAL 1 was to demonstrate superiority of Sogroya over placebo, whereas the open-label comparison to Norditropin FlexPro was considered supplementary in nature.

Patients who completed the 34-week treatment in the main study phase could continue treatment for 52 weeks in the open-label extension phase. Among patients in the Sogroya, placebo, and Norditropin FlexPro treatment arms, 115 (95.0%), 55 (90.2%), and 107 (89.9%) completed treatment, respectively. There were 272 patients who entered the extension phase of the study. Sogroya-treated patients continued their once-weekly treatment, placebo-treated patients were switched to treatment with Sogroya, and those who had received Norditropin FlexPro were randomized to receive Sogroya or Norditropin FlexPro. Overall, 252 patients completed treatment in the extension phase of REAL 1.

The primary endpoint of study REAL 1 was change from baseline to the end of the main treatment period (Week 34) in truncal fat percentage. At Week 34, the mean change from baseline in truncal fat percentage was ‑1.06% in the Sogroya group and 0.47% in the placebo group. The mean treatment difference of ‑1.53% (95% CI: ‑2.68, ‑0.38) between Sogroya and placebo was statistically significant (p = 0.009), thereby demonstrating superiority of Sogroya over placebo in the change in truncal fat percentage. In addition, Sogroya showed a significant treatment benefit over placebo for body composition measurements of visceral adipose tissue, android fat mass, truncal lean body mass, appendicular skeletal muscle mass, and total lean body mass.

A secondary analysis comparing the results of the primary endpoint between Sogroya and Norditropin FlexPro showed a significantly greater effect of Norditropin FlexPro on the reduction of the truncal fat percentage in comparison to Sogroya. The difference may be attributable to the higher proportion of women receiving oral estrogens in the Sogroya treatment arm, since such patients are known to require higher doses that may not have been achievable during the limited 8-week titration period.

Both the Sogroya and Norditropin FlexPro arms showed significantly higher IGF-1 SDS values compared to placebo; both groups had mean IGF-1 SDS values within the study-defined IGF-1 SDS target range of ‑0.5 to +1.75. In both the Sogroya and Norditropin FlexPro arms, about 45% of patients achieved the real-world IGF-1 SDS target range of 0 to +2 at Week 34 (versus none of the placebo-treated patients) and about 85% of patients had an improvement in their IGF-1 SDS of at least 1 point (versus 5.3% of the placebo-treated patients).

The effects of Sogroya seen at Week 34 in the main phase were maintained in patients who continued with Sogroya treatment for 52 weeks in the extension phase. In patients who were switched from placebo to Sogroya, the treatment with Sogroya resulted in effects that reached or surpassed the results of the Sogroya group at the end of the extension phase.

Indication

The New Drug Submission for Sogroya was filed by the sponsor with the following indication, which Health Canada subsequently approved:

Sogroya (somapacitan) is indicated for:

• the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone (growth hormone deficiency).

• the replacement of endogenous growth hormone in adults with growth hormone deficiency.

For more information, refer to the Sogroya Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Pivotal data to characterize the safety profile of Sogroya in pediatric and adult patients with growth hormone deficiency were provided from studies REAL 4 and REAL 1 (described in the Clinical Efficacy section).

Pediatric patients with growth hormone deficiency (study REAL 4)

In the 52-week treatment period of the pivotal study REAL 4, the most frequently reported adverse events in pediatric subjects treated with Sogroya (occurring in at least 5% of patients and at a higher incidence compared to the Norditropin FlexPro group) were headache (12.1%), nasopharyngitis (11.4%), and pain in extremity (9.1%). The majority of adverse events were of mild or moderate severity.

Seven adverse events (in 4 children, 3%) in the Sogroya group were classified as severe by the investigator. There was no specific pattern of occurrence among these adverse events. In total, 6 (4.5%) children reported 8 serious adverse events in the Sogroya group. There were no patient withdrawals or drug discontinuations due to serious adverse events. All serious adverse events were resolved, and no serious adverse events were considered possibly or probably related to the study drugs by the investigators. No deaths occurred during the study.

Overall, the safety profile of Sogroya in pediatric patients was in keeping with the safety profile of other growth hormone products authorized in Canada. Known class effects of the growth hormone products include, but are not limited to, increased risks of neoplasms, glucose intolerance and diabetes mellitus, intracranial hypertension, fluid retention, hypoadrenalism, hypothyroidism, slipped capital femoral epiphysis in pediatric patients, pancreatitis, lipohypertrophy or lipoatrophy, and hypersensitivity reactions. All the risks identified for this class of products are highlighted in the Warnings and Precautions section of the Sogroya Product Monograph and will be monitored through routine pharmacovigilance activities. Furthermore, relevant contraindications, including contraindications for use in children with closed epiphyses and in children with Prader-Willi syndrome who are severely obese or have severe respiratory impairment have been included in the Sogroya Product Monograph. No significant safety concerns were identified that would preclude the authorization of Sogroya for the treatment of pediatric patients with human growth hormone deficiency.

Adult patients with growth hormone deficiency (study REAL 1)

In the 34-week main treatment period of the pivotal study REAL 1, the most frequently reported adverse events in adult subjects treated with Sogroya (occurring in at least 5% of patients and at a higher incidence compared to the placebo group) were back pain (10%), arthralgia (6.7%), and dyspepsia (5.0%).

Overall, the majority of adverse events reported in the study were of mild (70.2%) or moderate (27.1%) severity, whereas 27 adverse events (2.7%) in 20 (6.7%) patients were reported as severe. In the Sogroya group, seven patients (5.8%) experienced 12 serious adverse events. The rate of serious adverse events was similar across the treatment groups, and the majority of serious adverse events were single events, with the exception of 2 events of gastroenteritis in the Sogroya group. None of the patients in the Sogroya group interrupted or discontinued treatment due to a serious adverse event. Five (1.3%) patients died during study REAL 1 (1 during the main treatment period and 4 during the extension treatment period). All 5 deaths (2 patients in the Sogroya group, 2 patients in the Norditropin FlexPro group, and 1 patient in the placebo group) were assessed by the investigator as unlikely to be related to the study products.

Based on the safety data submitted, the risk profile of Sogroya in adults with growth hormone deficiency is similar to the safety profile of other growth hormone products authorized in Canada. As aforementioned, there are many known class effects of the growth hormone products. These risks are addressed in the Sogroya Product Monograph and will be monitored through routine pharmacovigilance activities. Relevant contraindications are listed in the Sogroya Product Monograph. No significant safety concerns were identified that would preclude the authorization of Sogroya for the treatment of adults with human growth hormone deficiency.

For more information, refer to the Sogroya Product Monograph, approved by Health Canada and available through the Drug Product Database.

The non-clinical data package for somapacitan, the medicinal ingredient in Sogroya, included primary pharmacodynamic, safety pharmacology, repeat-dose toxicity, reproductive and developmental toxicity, and genotoxicity studies. All animal studies were conducted using the subcutaneous route of administration.

In primary pharmacodynamic studies, somapacitan was shown to bind to and activate the human growth hormone receptor in vitro and to induce growth in vivo in a rat model of growth hormone deficiency.

Somapacitan did not elicit adverse effects on cardiovascular function in in vitro electrophysiology studies.

In all in vivo toxicology studies, administration of somapacitan resulted in increased body weights and body weight gains, which were associated with increased food consumption. Adverse effects were observed at all doses tested in the repeat-dose toxicity studies and the rabbit embryo-fetal development study. Therefore, no-observed-adverse-effect levels (NOAELs) could not be determined for these studies. Accordingly, there are no safety margins for repeat-dose toxicity or for developmental toxicity.

In a 13-week repeat-dose toxicity study conducted in rats, administration of somapacitan at a dose of 9 mg/kg/day resulted in symptoms of diabetes, which led to a moribund condition that necessitated premature termination of two animals. The diabetic state also resulted in cataract formation. In surviving animals, adverse findings of chronic progressive nephropathy and cortical tubular casts were observed in the kidneys at doses greater than or equal to 2 mg/kg/day. A number of other adverse histopathological findings were observed in a wide range of tissues. While generally consistent with the pharmacological effects of somapacitan, the findings were considered adverse at all doses tested (0.4, 2, and 9 mg/kg/day). In a subsequent 26-week study conducted in rats, administration of somapacitan resulted in similar findings, albeit with reduced severity and with no observations of diabetes or chronic progressive nephropathy owing to the lower doses tested and the less frequent administration (1, 2, and 4 mg/kg twice weekly).

In a 26-week study conducted in cynomolgus monkeys, administration of somapacitan resulted in adverse macroscopic and histopathological findings in the mammary glands in both males and females at all doses tested (0.2, 2, and 9 mg/kg twice weekly).

No adverse effects on male or female fertility were observed in fertility studies. The NOAEL for effects on fertility was 4 mg/kg twice weekly (resulting in exposure corresponding to approximately 30 times the clinical exposure at the maximum recommended human dose [MRHD] of 8 mg/week). However, somapacitan induced irregular estrus cycles and longer estrus cycles in females at all doses tested (1, 2, or 4 mg/kg twice weekly).

In an embryo-fetal development study, administration of somapacitan to pregnant rats during the period of organogenesis led to fetal skeletal malformations consisting of short, bent, or thickened long bones at a dose of 18 mg/kg/day. Fetal skeletal malformations were not observed at lower doses. The NOAEL for developmental toxicity in rats was 6 mg/kg (24 times the clinical exposure at the MRHD of 8 mg/week). In the rabbit embryo-fetal development study, administration of somapacitan to pregnant rabbits during the period of organogenesis resulted in a reduction in fetal weights at all doses tested (1, 3, and 9 mg/kg every two days).

In a prenatal and postnatal development study in rats, no adverse effects were observed on postnatal development of the offspring following administration of somapacitan to pregnant and lactating females. The NOAEL was 18 mg/kg twice weekly (787 times the clinical exposure at the MRHD of 8 mg/week). However, while no adverse effects on reproduction were observed in the offspring, two female offspring derived from dams receiving 18 mg/kg twice weekly were acyclic (i.e., at least 10 days without estrous).

Somapacitan was detected in the plasma of offspring in the prenatal and postnatal development study in rats. In other studies, somapacitan and/or its metabolites were detected in rat fetal tissues and rat milk. These findings indicate somapacitan transfer across the placental barrier and its excretion in milk.

No genotoxic potential was identified in in vitro or in vivo studies conducted with somapacitan.

Carcinogenicity studies were not performed, which was considered acceptable and in accordance with relevant guidelines.

No juvenile toxicity study was performed, which was considered acceptable given that the toxicity profile of somapacitan is consistent with other growth hormone products and there is no indication that growth hormone has the potential to delay sexual maturation.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Sogroya Product Monograph. In view of the intended use of Sogroya, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

For more information, refer to the Sogroya Product Monograph, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

Somapacitan, the medicinal ingredient in Sogroya, is a long-acting recombinant human growth hormone derivative with a single substitution in the amino acid backbone (leucine at position 101 substituted with cysteine) to which an albumin-binding moiety (a side chain) is attached. Binding of endogenous albumin to the albumin-binding moiety of somapacitan delays elimination of the drug, thereby prolonging the duration of action.

Detailed characterization studies were performed to provide assurance that somapacitan consistently exhibits the desired characteristic structure and biological activity. Relevant data were also provided on the structural characterization of the side-chain reagent used during the production of somapacitan.

The product- and process-related impurities that were reported and characterized were found to be within established limits.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The production of somapacitan involves expression of somapacitan precursor intracellularly in genetically engineered Escherichia coli cells and chemical conjugation of an albumin-binding moiety to the digested precursor.

The manufacturing process of somapacitan drug substance consists of fermentation, recovery, and modification and purification stages. In the fermentation stage, Escherichia coli cells from one vial of working cell bank are propagated in shake flasks and transferred into a production bioreactor. Expression of somapacitan precursor is initiated in the production phase. The recovery stage starts with harvest of cells, followed by their homogenization to release intracellular content, and subsequent solubilization, clarification, and capture of the somapacitan precursor. In the modification and purification stage, the captured somapacitan precursor undergoes purification and modification steps, including digestion and chemical conjugation with the albumin-binding moiety (a side-chain reagent) to form somapacitan. Subsequently, the drug substance is concentrated, diafiltered, and stored frozen.

The drug product manufacturing process begins with thawing and weighing of the drug substance. After excipient buffer preparation, the drug substance is formulated, sterile filtered, and filled aseptically into cartridges, which are visually inspected and stored protected from light at 2 °C to 8 °C. The cartridges are subsequently assembled into PDS290 pen-injector devices and stored at 2 °C to 8 °C.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits. Process performance qualification (PPQ) studies of the drug substance manufacturing process were initially performed using three consecutive fermentation and recovery batches. Separately, PPQ studies were performed on three consecutive purification and modification batches. The separated PPQ activities were deemed acceptable as they evaluated the proposed commercial process. During the PPQ studies of the drug product manufacturing process, nine validation batches were manufactured covering the three strengths (5 mg/1.5 mL, 10 mg/1.5 mL, and 15 mg/1.5 mL) and the proposed batch-size range. All PPQ activities were run within the defined operating ranges. The results of all in-process and release tests were within their proposed acceptance criteria and consistent across all batches. Overall, the validation studies demonstrated that the drug substance and drug product manufacturing processes performed consistently and reproducibly within the acceptance limits to produce somapacitan of the specified quality. All ancillary validation studies were deemed successful and supportive of the in-process hold times, impurity clearance, resin and membrane lifetimes, filters, product contact materials (extractables and leachables), mixing steps, media fills, and shipping.

Of note, the side-chain reagent used in the production of somapacitan is chemically synthesized. Data provided on the chemistry and manufacturing process of the side-chain reagent were considered acceptable.

Control of the Drug Substance and Drug Product

The quality of the drug substance and drug product is ensured by suitable specifications for identity, quantity, biological activity, purity, and impurities. The corresponding analytical methods are deemed suitable for their intended purpose and appropriately validated. A two-tiered reference program has been established. The reference standards have been well characterized and an appropriate program is in place to qualify new primary and working reference material in the future.

Sogroya is a Schedule D (biologic) drug and is, therefore, subject to Health Canada’s Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered satisfactory.

The stability data support the proposed shelf life of 24 months for Sogroya, when the drug product is stored protected from light at 2 °C to 8 °C. Importantly, the total time allowed at room temperature (up to 30 °C) is 72 hours (3 days), regardless of whether the drug product is in use (opened) or not (unopened).

The compatibility of the drug product with the primary container closure system was demonstrated through stability studies and extractables and leachables studies.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured.

Based on risk assessment scores determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.

Both sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The manufacturing process of somapacitan incorporates adequate control measures to prevent contamination and maintain microbial control.

The prokaryotic expression system (Escherichia coli) used is not the natural host for mammalian viruses. Hence, testing for endogenous or adventitious viruses is not performed. Bioburden and endotoxin testing procedures are integrated in the control strategy and meet relevant guidelines and requirements.

No raw material of human or animal origin are used for the manufacture of somapacitan. A raw material produced by recombinant deoxyribonucleic acid (DNA) technology, the recombinant enzyme dipeptidyl aminopeptidase I (rDAPI) is used during the manufacturing process of somapacitan drug substance. This enzyme is expressed in a Chinese hamster ovary (CHO) cell line and produced using a serum-free cell cultivation process. Relevant information was provided to demonstrate the safety of this raw material with respect to the risks of introduction of viral adventitious agents and transmissible spongiform encephalopathy agents.

The excipients used in the drug product formulation are not of animal or human origin.