Diabetologia
`https://doi.org/10.1007/s00125-023-06053-9
`
`ARTICLE
`
`Dose–response effects on  HbA1c and bodyweight reduction
`of survodutide, a dual glucagon/GLP‑1 receptor agonist, compared
`with placebo and open‑label semaglutide in people with type 2
`diabetes: a randomised clinical trial
`
`Matthias Blüher1
`
` · Julio Rosenstock2
`
` · Josef Hoefler3 · Raymond Manuel4 · Anita M. Hennige5
`
`Received: 18 May 2023 / Accepted: 17 August 2023
`© The Author(s) 2023
`
`Abstract
`Aims/hypothesis The aim of this study was to assess the dose–response effects of the subcutaneous glucagon receptor/
`glucagon-like peptide-1 receptor dual agonist survodutide (BI 456906) on HbA1c levels and bodyweight reduction.
`Methods This Phase II, multicentre, randomised, double-blind, parallel-group, placebo-controlled study, conducted in
`clinical research centres, assessed survodutide in participants aged 18–75 years with type 2 diabetes, an HbA1c level of
`53–86 mmol/mol (7.0–10.0%) and a BMI of 25–50 kg/m2 on a background of metformin therapy. Participants were ran-
`domised via interactive response technology to receive survodutide (up to 0.3, 0.9, 1.8 or 2.7 mg once weekly [qw; dose
`group (DG) 1–4, respectively] or 1.2 or 1.8 mg twice weekly [DG 5 and 6, respectively]), placebo or semaglutide (up to 1.0
`mg qw). Participants and all those involved in the trial conduct/analysis were blinded; the semaglutide arm was open-label.
`The primary endpoint was absolute change from baseline in HbA1c after 16 weeks’ treatment. The key secondary endpoint
`was relative change from baseline in bodyweight after 16 weeks’ treatment.
`Results A total of 413 participants were randomised (DG1, n=50; DG2, n=50; DG3, n=52; DG4, n=50; DG5, n=51; DG6,
`n=50; semaglutide, n=50; placebo, n=60). The full analysis set comprised 411 treated participants (DG6, n=49; placebo, n=59).
`Adjusted mean (95% CI) HbA1c decreased from baseline (mean ± SD 64.7±9.2 mmol/mol [8.07±0.84%] after 16 weeks’ treat-
`ment: DG1 (n=41), −9.92 mmol/mol (−12.27, −7.56; −0.91% [−1.12, −0.69]); DG2 (n=46), −15.95 mmol/mol (−18.27,
`−13.63; −1.46% [−1.67, −1.25]); DG3 (n=36), −18.72 mmol/mol (−21.15, −16.29; −1.71% [−1.94, −1.49]); DG4 (n=33),
`−17.01 mmol/mol (−19.59, −14.43; −1.56% [−1.79, −1.32]); DG5 (n=44), −17.84 mmol/mol (−20.18, −15.51; −1.63% [−1.85,
`−1.42]); DG6 (n=36), −18.38 mmol/mol (−20.90, −15.87; −1.68% [−1.91, −1.45]). The mean reduction in HbA1c was similar
`with low-dose survodutide (DG2: −15.95 mmol/mol [−1.46%]; n=46) and semaglutide (−16.07 mmol/mol [−1.47%]; n=45).
`Mean (95% CI) bodyweight decreased dose-dependently up to −8.7% (−10.1, −7.3; DG6, n=37); survodutide ≥1.8 mg qw
`produced greater bodyweight reductions than semaglutide (−5.3% [−6.6, −4.1]; n=45). Adverse events (AEs) were reported for
`77.8% of survodutide-treated participants (mainly gastrointestinal), 52.5% receiving placebo and 52.0% receiving semaglutide.
`Conclusions/interpretation Survodutide reduced HbA1c levels and bodyweight after 16 weeks’ treatment in participants
`with type 2 diabetes. Dose-related gastrointestinal AEs could be mitigated with slower dose escalations.
`Trial registration ClinicalTrials.gov NCT04153929 and EudraCT 2019-002390-60.
`Funding Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
`
`Extended author information available on the last page of the article
`
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`Keywords Bodyweight loss · Dual incretin agonist · Glucagon · Glucagon-like peptide-1 · Obesity · Pharmacotherapy ·
`Semaglutide · Survodutide · Type 2 diabetes
`
`Abbreviations
`AE
`APRI
`
`biw
`bpm
`DG
`ELF
`EoT
`Fib-4
`GCGR
`GI
`GIPR
`
`GLP-1R
`MCPMod
`
`MMRM
`NAFLD
`NASH
`PGI-S
`qw
`SMBG
`
` Adverse event
` Aspartate aminotransferase to platelet
`ratio
` Twice weekly
` Beats per min
` Dose group
` Enhanced liver fibrosis
` End of treatment
` Fibrosis-4
` Glucagon receptor
` Gastrointestinal
` Glucose-dependent insulinotropic poly-
`peptide receptor
` Glucagon-like peptide-1 receptor
` Multiple comparisons procedure with
`modelling
` Mixed model for repeated measures
` Non-alcoholic fatty liver disease
` Non-alcoholic steatohepatitis
` Patient Global Impression of Severity
` Once weekly
` Self-monitoring of blood glucose
`
`TEAE
`TFEQ-R18 V2
`VAS
`
` Treatment-emergent adverse event
` Three-Factor Eating Questionnaire
` Visual analogue scale
`
`Introduction
`
`Glucagon-like peptide-1 receptor (GLP-1R) agonists, such
`as liraglutide and semaglutide, have been developed for the
`treatment of both type 2 diabetes and obesity. These thera-
`pies have produced placebo-corrected bodyweight decreases
`of up to 5.4% (liraglutide 3 mg) [1] and 12.4% (semaglutide
`2.4 mg), and HbA1c reductions of –12.0 to –17.5 mmol/mol
`(–1.1 to –1.6%) (liraglutide 1.8 mg and semaglutide 1 mg,
`respectively) in adults with type 2 diabetes [2, 3]. Apart from
`the well-characterised gastrointestinal (GI) adverse events
`(AEs), GLP-1R agonists are generally well tolerated [2–4].
`However, dual agonists, such as glucose-dependent insuli-
`notropic polypeptide receptor (GIPR)/GLP-1R and glucagon
`receptor (GCGR)/GLP-1R dual agonists, have the potential
`for enhanced therapeutic efficacy and improved tolerability
`compared with GLP-1R mono-agonists, owing to their mul-
`tiple mechanisms of action [5, 6].
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`In addition to the glucose-lowering effects associated
`with GLP-1R agonism, GCGR agonism, via receptors in the
`liver, may lead to increased energy expenditure [7, 8]. This
`effect can be seen at doses that do not activate the sympa-
`thetic nervous system, thereby avoiding potentially harmful
`effects on the cardiovascular system [7]. GCGR signalling
`also leads to stimulation of hepatic glucose production (via
`glycogenolysis and gluconeogenesis), stimulation of lipoly-
`sis and amino acid breakdown, and suppression of hepatic
`fat accumulation [9].
`The efficacy of GCGR/GLP-1R dual agonism has been
`demonstrated by oxyntomodulin, an endogenous progluca-
`gon derivative [10]. Oxyntomodulin has been shown to
`reduce bodyweight and food intake in rodents and humans
`[11, 12] and to increase energy expenditure in people with
`obesity [13], via activity at both receptors. However, oxyn-
`tomodulin requires frequent dosing owing to its very short
`half-life; therefore, research into longer acting GCGR/
`GLP-1R dual agonists is warranted.
`Survodutide (BI 456906) is a novel subcutaneous GCGR/
`GLP-1R dual agonist in development for the treatment of peo-
`ple with type 2 diabetes, obesity and non-alcoholic steatohepa-
`titis (NASH). Addition of a C18 fatty acid into the acylated
`peptide, as a half-life-extending principle, allows for weekly
`administration of survodutide [14]. Preclinical studies of sur-
`vodutide in murine models showed that survodutide simultane-
`ously engages the GLP-1R and GCGR to produce reductions
`in bodyweight, gastric emptying and energy intake, increas-
`ing energy expenditure and improving glucose tolerance
`[14]. In Phase I studies (ClinicalTrials.gov NCT03175211,
`NCT03591718), survodutide was generally well tolerated
`and showed no unexpected safety or tolerability concerns in
`healthy volunteers and people with overweight/obesity; mul-
`tiple ascending doses of survodutide over 16 weeks produced
`mean bodyweight decreases of up to 14.1% (2.4 mg survodu-
`tide twice weekly [biw] vs −0.3% with placebo) [15].
`Here we report the results of a Phase II study (Clinical-
`Trials.gov NCT04153929) assessing the effects on HbA1c
`levels and bodyweight of multiple rising doses of survodutide
`compared with placebo and open-label weekly semaglutide
`in participants with type 2 diabetes. The safety and tolerabil-
`ity of survodutide were also assessed. As a proof-of-clinical
`concept study, this trial aimed to demonstrate that survodu-
`tide lowers HbA1c levels and bodyweight and to examine the
`dose–response relationship in this participant population to
`inform the design of further studies.
`
`Methods
`
`Study design and participants This study had a mul-
`ticentre, randomised, double-blind within dose groups
`(DGs), parallel-group, placebo-controlled design, with
`
`six dose-escalation schemes for survodutide (BI 456906,
`Boehringer Ingelheim Pharma GmbH & Co. KG, Germany;
`electronic supplementary material [ESM] Fig. 1). The study
`included an open-label semaglutide group, which served as
`a reference control to permit comparison of response curves
`and support assumptions for the design of Phase III studies.
`Participants were assigned to one of six survodutide DGs
`(0.3 mg once weekly [qw; DG1], up to 0.9 mg qw [DG2],
`up to 1.8 mg qw [DG3], up to 2.7 mg qw [DG4], up to
`1.2 mg biw [2.4 mg total; DG5] or up to 1.8 mg biw [3.6
`mg total; DG6]), placebo or semaglutide (up to 1.0 mg qw).
`The trial was conducted in clinical research centres, includ-
`ing hospitals and healthcare centres. Each investigational
`site had a principal investigator who was responsible for the
`conduct of the study. See the ESM for a list of study sites
`and investigators.
`Eligible participants were aged 18–75 years, had been
`diagnosed with type 2 diabetes for ≥6 months, had an
` HbA1c value of 53–86 mmol/mol (7.0–10.0%) and a BMI
`of 25–50 kg/m2 at screening and had been treated with a
`stable dose of metformin of ≥1000 mg/day (immediate or
`extended release) for ≥3 months before screening. Exclu-
`sion criteria are listed in the ESM Methods. The full proto-
`col is available at https:// clini caltr ials. gov/ ct2/ show/ NCT04
`153929.
`
`Randomisation and blinding Randomisation to survodutide
`or placebo was in a 5:1 ratio within DGs (planned randomi-
`sation: survodutide, n=50 per DG; placebo, n=60); it was
`planned to randomise 50 participants to the semaglutide
`group. The trial was double-blind within DG1–6. Further
`details of randomisation and blinding are provided in the
`ESM Methods.
`
`Endpoints The primary endpoint was the absolute change
`in HbA1c from baseline after 16 weeks’ treatment. Second-
`ary endpoints were related to changes in bodyweight from
`baseline after 16 weeks’ treatment: the relative change in
`bodyweight (key secondary endpoint), absolute change in
`bodyweight, absolute change in waist circumference and
`proportion of participants with a ≥5% and ≥10% decrease
`in bodyweight. Further efficacy endpoints are described in
`the ESM Methods.
`Pharmacodynamic endpoints were the changes from
`baseline in exploratory biomarkers related to liver function
`and fatty liver disease (plasma levels of cytokeratin 18 and
`Pro-C3 and enhanced liver fibrosis [ELF] score), glucose
`metabolism (adiponectin and fasting insulin and C-peptide
`levels) and target receptor engagement (amino acid and
`glucagon levels). Exploratory NASH-related scores (Fibro-
`sis-4 [Fib-4] score, aspartate aminotransferase/platelet ratio
`[APRI] and non-alcoholic fatty liver disease [NAFLD]
`fibrosis score) were assessed as safety-related endpoints.
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`The attainment of steady state and dose proportionality
`of survodutide were assessed as pharmacokinetic endpoints.
`
`Procedures After completion of the 16 week treatment
`period, all participants had an end-of-treatment (EoT) visit
`(week 17). Participants then entered a 4-week follow-up
`period and completed the study. Details of treatment admin-
`istration are provided in the ESM Methods.
`HbA1c was assessed at screening, weeks 1, 5, 8, 12 and
`16, EoT and follow-up and analysed centrally. Bodyweight
`was measured at every visit (screening, weeks 1–8, 12 and
`16, EoT and follow-up). Waist circumference was measured
`at screening, weeks 1 and 6 and EoT. Waist circumference
`was measured at the midpoint between the lowest rib and
`the iliac crest. Participants were provided with a glucose
`monitoring device for weekly use at home during the study.
`Participant-reported outcomes (Three-Factor Eating Ques-
`tionnaire [TFEQ-R18 V2], Patient Global Impression of
`Severity [PGI-S] and a hunger visual analogue scale [VAS])
`were assessed at weeks 1, 5 and 8 and EoT in a fasted state.
`Blood sampling for pharmacokinetics was carried out at
`every visit (weeks 1–8, 12 and 16, EoT and follow-up) and
`blood sampling for exploratory biomarkers was carried out
`at weeks 1, 5, 8 and 12, EoT and follow-up. Safety assess-
`ments are described in the ESM Methods.
`
`Statistical analyses The trial planned to screen 615 people
`and randomise 410 participants at 80 study sites in multi-
`ple countries. The sample size calculation was based on an
`assumed maximum effect size for survodutide vs placebo
`of a 0.5–0.6% change (SD 1%) in HbA1c for the primary
`endpoint, similar to that seen in a Phase II trial of semaglu-
`tide [16]. In this study, HbA1c was measured in per cent. In
`order to report HbA1c results in mmol/mol, HbA1c (%) was
`converted to HbA1c (mmol/mol) before analysis using the
`following equation: HbA1c (mmol/mol) = 10.929 × (HbA1c
`[%] – 2.15). Full details of the statistical analyses are pro-
`vided in the ESM Methods.
`
`Study ethics This trial was approved by the relevant insti-
`tutional review boards, independent ethics committees and
`competent authorities, according to national and interna-
`tional regulations. The study was conducted in compli-
`ance with ethical principles laid down in the Declaration of
`Helsinki, in accordance with the International Council for
`Harmonisation Guideline for Good Clinical Practice (ICH
`GCP). All participants provided written informed consent,
`according to the ICH GCP and regulatory and legal require-
`ments of the participating countries.
`
`Trial registration This trial was registered at ClinicalTrials.
`gov (NCT04153929) and EudraCT (2019-002390-60).
`
`Results
`
`Study participants and compliance Participants were recruited
`between 9 June 2020 and 7 June 2021; the last participant com-
`pleted the trial on 5 November 2021. In total, 669 people were
`screened, 413 were randomised and 411 were treated (DGs 1, 2
`and 4, n=50 each; DG3, n=52; DG5, n=51; DG6, n=49; sema-
`glutide up to 1.0 mg qw, n=50; placebo, n=59; ESM Fig. 2). Of
`the 411 participants treated, 80 (19.5%) prematurely discontin-
`ued treatment, 53 (12.9%) owing to an AE. Important protocol
`deviations were reported for 62 of all randomised participants
`(15.0%), with two-thirds (n=41) due to restricted medication
`use. All 411 participants treated were analysed for efficacy (full
`analysis set: all randomised participants who received one or
`more dose of the study drug and had analysable data for one or
`more efficacy endpoint) and safety (treated set: all randomised
`participants who received one or more dose of the study
`drug). Baseline characteristics and demographics were similar
`between DGs (N=411); 83.7% of participants were White and
`mean ± SD age was 57.3±9.8 years, BMI 33.9±6.0 kg/m2 and
` HbA1c 64.7±9.2 mmol/mol (8.1±0.8%) (Table 1). The popula-
`tion included in this study was representative of a large study
`population of people with type 2 diabetes with respect to age
`and HbA1c levels [17]; however, most participants were White
`and had a higher bodyweight, due to the inclusion criteria of
`this trial.
`
`Primary endpoint Absolute HbA1c (mixed model for
`repeated measures [MMRM] estimates; primary endpoint)
`decreased from baseline after 16 weeks’ treatment with sur-
`vodutide, with a markedly weaker treatment effect observed
`in DG1 (0.3 mg qw) than in the other DGs; no obvious dose-
`dependent effects were observed between DG2–6 (Fig. 1).
`The results of the multiple contrast test showed that the
`contrasts of all predefined dose–response models were sig-
`nificant in terms of non-flat dose–response for the absolute
`change from baseline in HbA1c after 16 weeks of treatment
`at a one-sided α=0.025. According to the final multiple
`comparisons procedure with modelling (MCPMod) averag-
`ing model, the predicted dose–response reached a plateau
`at 1.8 mg qw survodutide, with no increase in treatment
`effect seen at doses higher than this (ESM Fig. 3a). After
`16 weeks’ treatment with survodutide, adjusted mean (95%
`CI) HbA1c levels decreased from a baseline (mean ± SD) of
`64.7±9.2 mmol/mol (8.07±0.84%; N=411) as follows: DG1
`(n=41), −9.92 mmol/mol (−12.27, −7.56; −0.91% [−1.12,
`−0.69]); DG2 (n=46), −15.95 mmol/mol (−18.27, −13.63;
`−1.46% [−1.67, −1.25]); DG3 (n=36), −18.72 mmol/mol
`(−21.15, −16.29; −1.71% [−1.94, −1.49]); DG4 (n=33),
`−17.01  mmol/mol (−19.59, −14.43; −1.56% [−1.79,
`−1.32]); DG5 (n=44), −17.84 mmol/mol (−20.18, −15.51;
`−1.63% [−1.85, −1.42]); DG6 (n=36), −18.38 mmol/mol
`
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`Table 1 Participant baseline characteristics and demographics
`Characteristic DG1:
`DG2:
`DG3:
`DG4:
`Survodutide
`Survodutide
`Survodutide
`Survodutide
`0.3 mg qw
`0.9 mg qw
`1.8 mg qw
`2.7 mg qw
`(n=50)
`(n=50)
`(n=52)
`(n=50)
`
`DG5:
`Survodutide
`1.2 mg biw
`(n=51)
`
`DG6:
`Survodutide
`1.8 mg biw
`(n=49)
`
`Semaglutide
`1.0 mg qw
`(n=50)
`
`Placebo
`(n=59)
`
`Total
`(N=411)
`
`28 (56.0)
`
`27 (51.9)
`
`33 (66.0)
`
`27 (52.9)
`
`44 (88.0)
`5 (10.0)
`1 (2.0)
`
`42 (80.8)
`8 (15.4)
`2 (3.8)
`
`43 (86.0)
`4 (8.0)
`2 (4.0)
`
`41 (80.4)
`5 (9.8)
`4 (7.8)
`
`Sex
`26 (52.0)
` Male
`Race and ethnicity
` White
`42 (84.0)
` Asian
`4 (8.0)
` Black or
`3 (6.0)
`African
`American
` American
`Indian or
`Alaska
`Native
` Native
`Hawaiian
`or Other
`Pacific
`Islander
` Missing
`Age, years
`HbA1c,
`mmol/mol
`HbA1c, %
`Time from
`type 2
`diabetes
`diagnosis,
`years
`Weight, kg
`BMI, kg/m2
`Waist circum-
`ference, cm
`Data are presented as n/N (%) or mean ± SD. Sex and race were self-reported
`
`1 (2.0)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`56.1±10.2
`64.9±8.3
`
`8.09±0.76
`6.1±4.7
`
`0
`58.2±9.6
`62.8±8.8
`
`7.89±0.80
`7.7±7.3
`
`0
`55.3±10.3
`65.5±9.4
`
`8.14±0.86
`7.0±5.6
`
`1 (2.0)
`59.6±8.5
`65.9±10.6
`
`8.18±0.97
`7.9±5.7
`
`1 (2.0)
`58.3±8.8
`65.1±10.3
`
`8.11±0.94
`8.8±7.1
`
`97.6±19.7
`33.8±6.1
`110.6±12.8
`
`100.1±19.8
`34.9±5.2
`111.5±15.6
`
`95.9±22.8
`33.6±5.8
`107.2±20.0
`
`96.6±22.8
`34.0±6.8
`110.7±16.4
`
`95.0±22.1
`33.0±5.0
`109.0±18.2
`
`27 (55.1)
`
`34 (68.0)
`
`31 (52.5)
`
`233 (56.7)
`
`42 (85.7)
`3 (6.1)
`3 (6.1)
`
`1 (2.0)
`
`0
`
`43 (86.0)
`5 (10.0)
`2 (4.0)
`
`47 (79.7)
`8 (13.6)
`3 (5.1)
`
`344 (83.7)
`42 (10.2)
`20 (4.9)
`
`0
`
`0
`
`0
`
`2 (0.5)
`
`1 (1.7)
`
`1 (0.2)
`
`0
`57.7±9.4
`63.6±7.8
`
`7.97±0.71
`7.4±5.3
`
`0
`55.8±10.5
`64.3±9.2
`
`8.03±0.82
`7.9±4.7
`
`0
`57.5±10.5
`65.6±9.2
`
`8.15±0.85
`7.9±5.6
`
`2 (0.5)
`57.3±9.8
`64.7±9.2
`
`8.07±0.84
`7.6±5.8
`
`98.3±24.4
`34.9±7.0
`115.1±28.7
`
`96.7±20.0
`33.4±6.1
`108.1±13.5
`
`93.0±21.0
`33.4±5.9
`110.4±16.5
`
`96.6±21.6
`33.9±6.0
`110.3±18.2
`
`(−20.90, −15.87; −1.68% [−1.91, −1.45]). The decrease
`from baseline was significantly greater for all survodutide
`groups compared with placebo (−1.62 mmol/mol [−3.83,
`0.59]; −0.15% [−0.35, 0.05]; n=49) at all tested time points
`(p<0.0001 for all DGs and time points except DG1 week 5
`[p=0.0004]). After 16 weeks’ treatment, low-dose survodu-
`tide treatment (0.9 mg qw [DG2]) reduced HbA1c to approx-
`imately the same extent as semaglutide (n=45) up to 1.0
`mg qw ( −15.95 mmol/mol [−1.46%] vs −16.07 mmol/mol
`[−1.47%], respectively). Descriptive statistics of the primary
`endpoint revealed similar results to the MMRM analysis
`(ESM Fig. 3b); survodutide reduced mean ± SD HbA1c by
`up to 19.5 mmol/mol (1.88%) in both DG3 (n=36) and DG6
`(n=36) after 16 weeks, with a low dose (DG2, n=46) again
`showing similar results to the reductions seen with sema-
`glutide (n=45) up to 1.0 mg qw (−14.9±10.2 mmol/mol
`
`[−1.37±0.93%] vs −16.4±9.2 mmol/mol [−1.50±0.84%],
`respectively).
`
`Secondary endpoints The relative and absolute reduction
`from baseline in bodyweight was greater with increasing
`survodutide dose, with bodyweight loss seen in all survodu-
`tide DGs in a dose-dependent manner (Fig. 2, ESM Fig. 4).
`After 16 weeks of treatment, the relative decrease in body-
`weight from baseline (key secondary endpoint) for DG2–6
`was significantly greater than for placebo (p<0.001), with
`a maximum adjusted mean (95% CI) MMRM estimate for
`relative bodyweight reduction of −8.7% (−10.1, −7.3; DG6,
`n=37; Fig. 2). Survodutide doses of ≥1.8 mg qw produced
`greater adjusted mean (95% CI) bodyweight reductions than
`semaglutide up to 1.0 mg qw (DG3 [n=36] vs semaglutide
`[n=45]: −6.6% [−7.9, −5.3] vs –5.3% [−6.6, −4.1]). Results
`
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`0
`
`−5
`
`−10
`
`−15
`
`−20
`
`Placebo
`
`DG-1: 0.3 mg qw
`
`DG-2: 0.9 mg qw
`
`DG-3: 1.8 mg qw
`
`DG-4: 2.7 mg qw
`
`DG-5: 1.2 mg biw
`
`DG-6: 1.8 mg biw
`
`Semaglutidea 1.0 mg
`
` (mmol/mol)
`
`from baseline in HbA
`
`1c
`
`Adjusted mean (95% CI) absolute change
`
`
`
`Fig. 1 MMRM estimates for the
`absolute change in HbA1c from
`baseline to EoT. aSemaglutide
`arm was open label
`
`Baseline
`
`5
`
`8
`
`12
`
`16 17
`
`(EoT)
`
`Week
`
`of the multiple contrast test showed that all predefined dose–
`response models were significant in terms of non-flat dose–
`response for the relative change from baseline in bodyweight
`at a one-sided α=0.025. A significant dose–response was
`seen in the final MCPMod averaging model and did not
`reach a plateau (ESM Fig. 4a). Descriptive statistics of the
`relative change from baseline in bodyweight were similar
`to the MMRM analysis (ESM Fig. 4b). The adjusted mean
`(95% CI) MMRM estimates for absolute changes from base-
`line in bodyweight after 16 weeks’ treatment were consistent
`with the relative changes, with favourable results seen for
`DG3–6 (up to −8.4 kg [−9.7, −7.1]; DG6, n=37) compared
`
`with semaglutide (n=45) up to 1.0 mg qw (−5.2 kg [−6.4,
`−4.0]) (ESM Fig. 4c).
`Analysis of additional secondary endpoints showed
`that the proportion of participants with ≥5% and ≥10%
`reductions in bodyweight after 16 weeks’ treatment
`increased dose-dependently with survodutide (Table 2). In
`DG6, 57.1% of participants (n=28) had ≥5% and 34.7%
`(n=17) had ≥10% bodyweight reductions; this compares
`with 6.8% (n=4) and 0%, respectively, for placebo and 38.0%
`(n=19) and 16.0% (n=8), respectively, for semaglutide up
`to 1.0 mg qw. The probability of achieving ≥5% or ≥10%
`bodyweight loss was significantly greater in DG2–6 for ≥5%
`
`Placebo
`
`DG1: 0.3 mg qw
`
`DG2: 0.9 mg qw
`
`DG3: 1.8 mg qw
`
`DG4: 2.7 mg qw
`
`DG5: 1.2 mg biw
`
`DG6: 1.8 mg biw
`
`Semaglutidea 1.0 mg
`
`0
`
`−1
`
`−2
`
`−3
`
`−4
`
`−5
`
`−6
`
`−7
`
`−8
`
`−9
`
`−10
`
`from baseline in bodyweight (%)
`
`Adjusted mean (95% CI) relative change
`
`Fig. 2 MMRM estimates for the
`relative change in bodyweight
`from baseline to EoT. aSemaglu-
`tide arm was open label
`
`Baseline
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`12
`
`16 17
`
`(EoT)
`
`Week
`
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`≥5%, n (%)
`Vs placebo
` OR
`
`(95% CI)
`≥10%, n (%)
`Vs placebo
` OR
`
`(95% CI)
`
`Table 2 Proportion of participants achieving ≥5% and ≥10% bodyweight reductions
`DG5:
`DG4:
`DG3:
`DG2:
`Bodyweight
`DG1:
`Survodutide
`Survodutide
`Survodutide
`Survodutide
`reduction
`Survodutide
`1.2 mg biw
`2.7 mg qw
`1.8 mg qw
`0.9 mg qw
`0.3 mg qw
`(n=51)
`(n=50)
`(n=52)
`(n=50)
`(n=50)
`4 (8.0)
`19 (38.0)
`22 (42.3)
`23 (46.0)
`29 (56.9)
`
`DG6:
`Survodutide
`1.8 mg biw
`(n=49)
`28 (57.1)
`
`1.22
`(0.28, 5.20)
`1 (2.0)
`
`7.92
`(2.43, 25.74)
`3 (6.0)
`
`17.68
`(5.21, 60.03)
`7 (13.5)
`
`25.87
`(7.31, 91.55)
`8 (16.0)
`
`21.75
`(6.57, 72.04)
`13 (25.5)
`
`35.00
`(9.84, 124.47)
`17 (34.7)
`
`3.67
`(0.14, 95.68)
`
`7.97
`(0.39, 163.48)
`
`25.17
`(1.35, 470.86)
`
`33.00
`(1.78, 613.20)
`
`42.43
`(2.37, 761.05)
`
`84.51
`(4.71, >999)
`
`Placebo (n=59)
`
`Semaglutide
`1.0 mg qw
`(n=50)
`
`19 (38.0)
`
`8.22
`(2.52, 26.79)
`8 (16.0)
`
`4 (6.8)
`–
`–
`–
`0
`–
`–
`22.44
`(1.22, 413.13) –
`
`loss (OR [95% CI] DG2, 7.92 [2.43, 25.74]; DG3, 17.68
`[5.21, 60.03]; DG4, 25.87 [7.31, 91.55]; DG5, 21.75 [6.57,
`72.04]; DG6, 35.00 [9.84, 124.47]) and DG3–6 for ≥10%
`loss (DG3, 25.17 [1.35, 470.86]; DG4, 33.00 [1.78, 613.20];
`DG5, 42.43 [2.37, 761.05]; DG6, 84.51 [4.71, >999])
`compared with placebo (Table 2).
`Waist circumference decreased from baseline with
`both survodutide and semaglutide treatment, but data
`were highly variable and associated with wide 95% CIs
`(ESM Fig.  5). The maximum adjusted mean ± SEM
`MMRM estimate for decrease in waist circumference
`from baseline was observed after 16 weeks’ treatment
`in DG6 (−10.5±1.7 cm; n=36). Adjusted mean ± SEM
`MMRM estimates for the placebo-corrected absolute
`change from baseline after 16 weeks’ treatment were
`
`significant for DG4 (−4.6±2.25 cm; n=35; p=0.041) and
`DG6 (−8.4±2.24 cm; n=36; p=0.0002).
`
`Further efficacy endpoints Treatment with survodutide
`or semaglutide reduced the mean 7-point self-monitoring
`of blood glucose (SMBG) level to a greater extent than
`placebo at week 16; the maximum mean ± SD decrease
`from baseline was observed in DG3 (−3.03±2.47 mmol/l;
`n=36) (Fig. 3), and decreases were more pronounced at
`post-mealtime time points than at pre-mealtime time
`points.
`Minor treatment effects were observed for all domains of
`the TFEQ-R18 V2, hunger VAS and PGI-S; a full descrip-
`tion of these results is given in the ESM for the 16 week time
`frame (ESM Tables 1 and 2).
`
`Placebo
`
`DG1: 0.3 mg qw
`
`DG2: 0.9 mg qw
`
`DG3: 1.8 mg qw
`
`DG4: 2.7 mg qw
`
`DG5: 1.2 mg biw
`
`DG6: 1.8 mg biw
`
`Semaglutidea 1.0 mg qw
`
`20
`
`15
`
`10
`
`5
`
`overall time points, mmol/l)
`
`7-point SMBG (mean
`
`enilesaB
`
`61keeW
`
`Fig. 3 Change from baseline in 7-point SMBG. Blood glucose meas-
`urements were collected before each meal (assuming three meals a
`day), approximately 2 h after each meal and at bedtime on a single
`day during screening (baseline) and a single day between the last
`dose of study drug and EoT (week 16). Mean overall time points rep-
`resent the mean per participant per visit of the seven blood glucose
`measurements at baseline and week 16. Data are presented per DG.
`
`The centre line denotes the median value, with the symbols within
`the boxes denoting the mean. The box boundaries mark the upper and
`lower quartile of the dataset. The whiskers indicate the variability of
`the data; whiskers are drawn to the nearest value within 1.5× the IQR
`of the upper and lower quartiles. Any observations outside of these
`values are plotted with symbols. aSemaglutide arm was open label
`
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`Table 3 Summary of AEs
`AE
`DG1:
`Survodutide
`0.3 mg qw
`(n=50)
`33 (66.0)
`25 (50.0)
`
`DG2:
`Survodutide
`0.9 mg qw
`(n=50)
`38 (76.0)
`26 (52.0)
`
`DG3:
`Survodutide
`1.8 mg qw
`(n=52)
`42 (80.8)
`33 (63.5)
`
`DG4:
`Survodutide
`2.7 mg qw
`(n=50)
`41 (82.0)
`29 (58.0)
`
`DG5:
`Survodutide
`1.2 mg biw
`(n=51)
`39 (76.5)
`28 (54.9)
`
`DG6:
`Survodutide
`1.8 mg biw
`(n=49)
`42 (85.7)
`36 (73.5)
`
`Any TEAE
`Investigator-
`defined,
`drug-related
` AEsa
` Nausea
` Vomiting
` Diarrhoea
` Dyspepsia
` Decreased
`appetite
` Headache
`Severe AEsb
` Nausea
` Vomiting
` Dizziness
`Serious AEs
`Drug-related
`serious AEs
`AEs leading
`to treatment
`discontinu-
`ation
`Data are presented as n (%)
`a Drug-related AEs reported by preferred term in ≥10% of participants
`b Severe AEs reported by preferred term in two or more participants in all survodutide DGs
`
`10 (20.0)
`6 (12.0)
`11 (22.0)
`4 (8.0)
`6 (12.0)
`
`2 (4.0)
`3 (6.0)
`1 (2.0)
`2 (4.0)
`0
`1 (2.0)
`1 (2.0)
`
`5 (10.0)
`
`13 (26.0)
`7 (14.0)
`5 (10.0)
`3 (6.0)
`7 (14.0)
`
`5 (10.0)
`1 (2.0)
`0
`0
`0
`4 (8.0)
`1 (2.0)
`
`5 (10.0)
`
`24 (46.2)
`12 (23.1)
`8 (15.4)
`3 (5.8)
`5 (9.6)
`
`3 (5.8)
`4 (7.7)
`1 (1.9)
`0
`0
`3 (5.8)
`1 (1.9)
`
`20 (40.0)
`13 (26.0)
`7 (14.0)
`4 (8.0)
`9 (18.0)
`
`0
`3 (6.0)
`0
`0
`0
`2 (4.0)
`1 (2.0)
`
`11 (21.2)
`
`15 (30.0)
`
`14 (27.5)
`6 (11.8)
`8 (15.7)
`3 (5.9)
`8 (15.7)
`
`3 (5.9)
`2 (3.9)
`0
`2 (3.9)
`0
`1 (2.0)
`0
`
`4 (7.8)
`
`22 (44.9)
`10 (20.4)
`9 (18.4)
`6 (12.2)
`15 (30.6)
`
`2 (4.1)
`3 (6.1)
`1 (2.0)
`0
`2 (4.1)
`0
`0
`
`8 (16.3)
`
`Semaglutide
`1.0 mg qw
`(n=50)
`
`Placebo
`(n=59)
`
`Total
`survodutide
`(n=302)
`
`26 (52.0)
`19 (38.0)
`
`31 (52.5)
`13 (22.0)
`
`235 (77.8)
`177 (58.6)
`
`6 (12.0)
`2 (4.0)
`4 (8.0)
`1 (2.0)
`3 (6.0)
`
`0
`0
`0
`0
`0
`0
`0
`
`2 (4.0)
`
`5 (8.5)
`1 (1.7)
`5 (8.5)
`0
`2 (3.4)
`
`1 (1.7)
`4 (6.8)
`0
`0
`0
`3 (5.1)
`0
`
`3 (5.1)
`
`103 (34.1)
`54 (17.9)
`48 (15.9)
`23 (7.6)
`50 (16.6)
`
`15 (5.0)
`16 (5.3)
`3 (1.0)
`4 (1.3)
`2 (0.7)
`11 (3.6)
`4 (1.3)
`
`48 (15.9)
`
`Safety A total of 77.8% of participants (n=235) treated with
`survodutide reported at least one treatment-emergent adverse
`event (TEAE); 52.5% of those receiving placebo (n=31) and
`52.0% receiving semaglutide (n=26) also reported TEAEs
`(Table 3). Of these, severe AEs were reported by 16 par-
`ticipants treated with survodutide (5.3%), four receiving
`placebo (6.8%) and none receiving semaglutide; these were
`mostly GI disorders (n=8/16 [50%] for survodutide; n=1/4
`[25%] for placebo). Serious AEs were reported by 3.6% of
`participants receiving survodutide (n=11: DG1, n=1; DG2,
`n=4; DG3, n=3; DG4, n=2; DG5, n=1) and 5.1% receiving
`placebo (n=3) (Table 3, ESM Table 3). AEs led to treat-
`ment discontinuation in 15.9% of participants receiving sur-
`vodutide (n=48), 5.1% receiving placebo (n=3) and 4.0%
`receiving semaglutide (n=2). Most of these discontinuations
`occurred within the first 6 weeks of the study (n=38/53,
`71.7%), coinciding with the dose-escalation period, and
`were mainly due to GI disorders (survodutide: n=36/48,
`75.0%; placebo n=1/3, 33.3%; semaglutide: 0) such as nau-
`sea and vomiting. More discontinuations due to AEs were
`observed in those with baseline bodyweight <100 kg than
`
`those with bodyweight ≥100 kg. GI disorders were the most
`frequently reported AEs across all DGs, occurring in 55.3%
`of participants receiving survodutide, 22.0% receiving pla-
`cebo and 28.0% receiving semaglutide.
`Of participants treated with survodutide, 58.6% (n=177)
`reported drug-related AEs, compared with 22.0% receiving
`placebo (n=13) and 38.0% of those receiving semaglutide
`(n=19) (Table 3). The majority of AEs were GI disorders
`(nausea, vomiting, diarrhoea and dyspepsia), which were
`reported for 50.0% (n=151) receiving survodutide. Drug-
`related AEs were classed as serious for 1.3% of participants
`receiving survodutide (n=4); DG1 (abdominal pain and
`vomiting), DG2 (mouth ulceration, autoimmune disorder
`and pharyngeal ulceration), DG3 (dehydration) and DG4
`(diarrhoea) (n=1 each; Table 3, ESM Table 3).
`Mean heart rate was slightly increased from baseline in
`all treatment groups; the mean increase after 16 weeks was
`2.3–7.3 beats per min (bpm) across the survodutide DGs, 5.9
`bpm for semaglutide and 1.67 bpm for placebo. The mean
`increases in heart rate from baseline were below 10 bpm at
`all time points except for two in DG4 (10.3 bpm at week 7;
`
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`10.1 bpm at week 16). There were no new onsets reported
`in the QTcF (QT interval corrected for heart rate using the
`method of Fridericia) interval categories >480–500 msec or
`>500 msec; one participant each from DG3 (2.0%) and the
`placebo group (1.7%) reported an increase in QTcF interval
`of >60 msec. The changes from baseline in QTcF interval
`were considered minor and no increased risk of cardiovas-
`cular events was identified.
`
`Pharmacodynamic endpoints Treatment with survodutide did
`not lead to any clear dose-dependent reductions in the NASH-
`related Fib-4 score, APRI and NAFLD fibrosis score relative
`to placebo (Table 4). Mean ± SD Pro-C3 levels were substan-
`tially lowered from baseline over time in all survodutide DGs
`(up to −7.3±9.4 µg/l in DG5; n=43) and the semaglutide group
`(−5.2±7.3 µg/l; n=44) compared with placebo (−0.1±10.2
`µg/l; n=48) (Table 4). Changes from baseline in ELF score
`were detected in all treatment groups, with decreases observed
`in DG2–6, up to a mean ± SD change of −0.2±0.5 in DG6
`(n=36) compared with an increase of 0.2±0.4 in the placebo
`group (n=49) (Table 4). The changes from baseline in other
`exploratory biomarkers are presented in Table 4.
`Plasma exposure to survodutide increased with escalating
`weekly or biweekly doses, with trough concentrations increasing
`
`in an approximately dose-proportional manner (ESM Fig. 6).
`Visually, steady state for survodutide appeared to be achieved
`at week 8 for DG1–5 and at week 12 for DG6 (ESM Fig. 6).
`Glucagon levels decreased dose-dependently from baseline
`over 16 weeks’ treatment with survodutide, suggesting target
`engagement of GCGRs and GLP-1Rs (ESM Fig. 7a). The
`mean ± SEM changes after 16 weeks were most pronounced
`in DG5 and DG6 (−11.0±2.0 pmol/l [n=32] and −15.1±3.4
`pmol/l [n=22], respectively), and no relevant changes from
`baseline were observed in the sema