First-In-Human Clinical Study of the C3 Complement Inhibitor AMY- 101 in Healthy Male Volunteers

NCT03316521 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: AMY-101/01
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a Single Ascending Dose (SAD) and a Multiple Dose (MD) of the complement inhibitor AMY-101. A prospective, single-center, open-label, First-In-Human (FIH) clinical study in healthy male volunteers.

Conditions

Complement Mediated Diseases

Keywords

complement inhibition; C3 complement inhibitor; AMY-101; Compstatin Cp40; Paroxysmal Nocturnal Hemoglobinuria (PNH); C3 glomerulopathy (C3G); Periodontal disease; Age-related macular degeneration (AMD); ABO incompatible kidney transplantation

Outcome Measures

Primary Outcomes (1)

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  Up to 21 days after treatment.

Secondary Outcomes (16)

• Area under the plasma concentration time curve (AUCt) after a single dose

  Up to 14 days after treatment.

• Area under the plasma concentration time curve from zero to infinity (AUC 0->∞) after a single dose

  Up to 14 days after treatment.

• Peak Plasma Concentration (Cmax) after single and multiple doses

  Up to 14 days after treatment.

• Time to Cmax (Tmax) after single and multiple doses

  Up to 14 days after treatment.

• Terminal elimination rate constant (lambdaz) after single and multiple doses

  Up to 14 days after treatment.

Study Arms (2)

Single Ascending Dose (SAD)

EXPERIMENTAL

In the SAD arm subjects will be sequentially included in one of up to six cohorts (dose levels). All cohorts will include at least four subjects each. Additional subjects may be added in any cohort if necessary. AMY-101 will be administered as a SQ or IV injection. Subjects in each cohort will be dosed sequentially, to allow for close safety monitoring. Between each cohort, safety data will be analyzed, evaluated and reviewed by the internal Safety Review Committee. Subsequent dose levels will be administered until either the maximum tolerated dose (MTD) or the study maximum dose (SMD) is reached based on specified dose escalation criteria.

Drug: AMY-101

Multiple Dose (MD)

EXPERIMENTAL

Depending on the results of the SAD, multiple doses of AMY-101 will be administered at the dose which has been identified as the dose which saturates target C3, for a duration that results to an exposure level equivalent to the maximum exposure achieved in the SAD. The dose and dosing interval will be determined based on the PK data obtained in the SAD part of the study. Each MD cohort will include at least four subjects and may be expanded with additional subjects if necessary. Between each cohort, safety data will be analyzed, evaluated and reviewed by the internal Safety Review Committee.

Drug: AMY-101

Interventions

AMY-101 DRUG

AMY-101 is a selective inhibitor of complement activation, which binds to the complement component C3.

Multiple Dose (MD); Single Ascending Dose (SAD)

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Willing and able to give written informed consent for participation in the study.
• Healthy male subject aged 18-60 years, inclusive at the time of signing the informed consent.
• Body Mass Index (BMI) ≥ 18 and ≤ 30 kg/m2 and weight at least 50 kg.
• Clinically normal medical history, physical findings, vital signs, ECG and laboratory values at the time of screening, as judged by the Investigator.
• Willing to use condom and contraceptive methods with a failure rate of \< 1% to prevent pregnancy and drug exposure of a partner and to refrain from donating sperm from the date of dosing until three (3) months after dosing of the IMP.
• Willing and able to complete all procedures according to the Protocol.

You may not qualify if:

• History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
• History of any Neisseria meningitidis infection
• History of unexplained, recurrent infection, or infection requiring treatment with systemic antibiotics within the last 60 days prior to dosing.
• History of latent or active tuberculosis, as assessed by the investigator based on chest X-ray and positive Quantiferon-TB Gold test.
• History of complement deficiency.
• Diagnosis of autoimmune, immunologic or rheumatologic disease (eg, systemic lupus erythematosus, rheumatoid arthritis).
• Any clinically significant illness, medical/surgical procedure or trauma within four (4) weeks of the administration of IMP.
• High CRP at screening (\> 0.5 mg/dL).
• Current evidence or history of bacterial, viral or fungal infection within 14 days prior to (first) dosing or longer according to the judgment of the investigator for e.g. viral infections including herpes simplex or herpes zoster.
• Any current condition or risk, which, in the opinion of the Investigator, may interfere with the subject's participation in the study, poses an added risk for the subject, or confounds the assessment of the subject or outcome of the study
• Any clinically significant abnormality in clinical chemistry, hematology, or urinalysis results at the time of screening, as judged by the Investigator.
• Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and/or Human Immunodeficiency Virus (HIV).
• After 10 minutes supine rest abnormal vital signs defined as any of the following:
• Systolic BP \> 140 mm Hg
• Diastolic BP \> 95 mm Hg

Sponsors & Collaborators

• Amyndas Pharmaceuticals S.A.: lead

Study Sites (1)

HighPoint Clinical Trials Center

High Point, North Carolina, 27265, United States

Location

Related Publications (16)

• Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: therapeutic interventions. J Immunol. 2013 Apr 15;190(8):3839-47. doi: 10.4049/jimmunol.1203200.

  PMID: 23564578 BACKGROUND

• Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: pathophysiological mechanisms. J Immunol. 2013 Apr 15;190(8):3831-8. doi: 10.4049/jimmunol.1203487.

  PMID: 23564577 BACKGROUND

• Mastellos DC, Yancopoulou D, Kokkinos P, Huber-Lang M, Hajishengallis G, Biglarnia AR, Lupu F, Nilsson B, Risitano AM, Ricklin D, Lambris JD. Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention. Eur J Clin Invest. 2015 Apr;45(4):423-40. doi: 10.1111/eci.12419. Epub 2015 Mar 9.

  PMID: 25678219 BACKGROUND

• Ricklin D, Lambris JD. Therapeutic control of complement activation at the level of the central component C3. Immunobiology. 2016 Jun;221(6):740-6. doi: 10.1016/j.imbio.2015.06.012. Epub 2015 Jun 10.

  PMID: 26101137 BACKGROUND

• Reis ES, Mastellos DC, Yancopoulou D, Risitano AM, Ricklin D, Lambris JD. Applying complement therapeutics to rare diseases. Clin Immunol. 2015 Dec;161(2):225-40. doi: 10.1016/j.clim.2015.08.009. Epub 2015 Sep 1.

  PMID: 26341313 BACKGROUND

• Mastellos DC, Ricklin D, Hajishengallis E, Hajishengallis G, Lambris JD. Complement therapeutics in inflammatory diseases: promising drug candidates for C3-targeted intervention. Mol Oral Microbiol. 2016 Feb;31(1):3-17. doi: 10.1111/omi.12129. Epub 2015 Oct 7.

  PMID: 26332138 BACKGROUND

• Reis ES, DeAngelis RA, Chen H, Resuello RR, Ricklin D, Lambris JD. Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters. Immunobiology. 2015 Apr;220(4):476-82. doi: 10.1016/j.imbio.2014.10.026. Epub 2014 Nov 3.

  PMID: 25468722 BACKGROUND

• Mastellos DC, Ricklin D, Yancopoulou D, Risitano A, Lambris JD. Complement in paroxysmal nocturnal hemoglobinuria: exploiting our current knowledge to improve the treatment landscape. Expert Rev Hematol. 2014 Oct;7(5):583-98. doi: 10.1586/17474086.2014.953926. Epub 2014 Sep 2.

  PMID: 25213458 BACKGROUND

• Risitano AM, Ricklin D, Huang Y, Reis ES, Chen H, Ricci P, Lin Z, Pascariello C, Raia M, Sica M, Del Vecchio L, Pane F, Lupu F, Notaro R, Resuello RR, DeAngelis RA, Lambris JD. Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria. Blood. 2014 Mar 27;123(13):2094-101. doi: 10.1182/blood-2013-11-536573. Epub 2014 Feb 4.

  PMID: 24497537 BACKGROUND

• Mastellos DC, Reis ES, Yancopoulou D, Hajishengallis G, Ricklin D, Lambris JD. From orphan drugs to adopted therapies: Advancing C3-targeted intervention to the clinical stage. Immunobiology. 2016 Oct;221(10):1046-57. doi: 10.1016/j.imbio.2016.06.013. Epub 2016 Jun 16.

  PMID: 27353192 BACKGROUND

• Maekawa T, Briones RA, Resuello RR, Tuplano JV, Hajishengallis E, Kajikawa T, Koutsogiannaki S, Garcia CA, Ricklin D, Lambris JD, Hajishengallis G. Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3. J Clin Periodontol. 2016 Mar;43(3):238-49. doi: 10.1111/jcpe.12507. Epub 2016 Mar 3.

  PMID: 26728318 BACKGROUND

• Hajishengallis G, Maekawa T, Abe T, Hajishengallis E, Lambris JD. Complement Involvement in Periodontitis: Molecular Mechanisms and Rational Therapeutic Approaches. Adv Exp Med Biol. 2015;865:57-74. doi: 10.1007/978-3-319-18603-0_4.

  PMID: 26306443 BACKGROUND

• Hajishengallis G, Hajishengallis E, Kajikawa T, Wang B, Yancopoulou D, Ricklin D, Lambris JD. Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application. Semin Immunol. 2016 Jun;28(3):285-91. doi: 10.1016/j.smim.2016.03.006. Epub 2016 Mar 24.

  PMID: 27021500 BACKGROUND

• Zhang Y, Shao D, Ricklin D, Hilkin BM, Nester CM, Lambris JD, Smith RJ. Compstatin analog Cp40 inhibits complement dysregulation in vitro in C3 glomerulopathy. Immunobiology. 2015 Aug;220(8):993-8. doi: 10.1016/j.imbio.2015.04.001. Epub 2015 May 5.

  PMID: 25982307 BACKGROUND

• Mastellos DC, Reis ES, Ricklin D, Smith RJ, Lambris JD. Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery. Trends Immunol. 2017 Jun;38(6):383-394. doi: 10.1016/j.it.2017.03.003. Epub 2017 Apr 14.

  PMID: 28416449 BACKGROUND

• Hajishengallis G, Hasturk H, Lambris JD; Contributing authors. C3-targeted therapy in periodontal disease: moving closer to the clinic. Trends Immunol. 2021 Oct;42(10):856-864. doi: 10.1016/j.it.2021.08.001. Epub 2021 Sep 2.

  PMID: 34483038 DERIVED

MeSH Terms

Conditions

Hemoglobinuria, Paroxysmal; Periodontal Diseases; Macular Degeneration

Interventions

AMY-101

Condition Hierarchy (Ancestors)

Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Myelodysplastic Syndromes; Bone Marrow Diseases; Mouth Diseases; Stomatognathic Diseases; Retinal Degeneration; Retinal Diseases; Eye Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a prospective, single-center, open-label FIH study investigating the safety, tolerability, PK and PD after single and multiple doses of AMY-101 in healthy male volunteers. In the SAD part of the study, a single dose at ascending dose levels of AMY-101 will be administered to different cohorts, following a careful dose-escalation strategy. In the MD part of the study, multiple doses will be administered using different dosing intervals; the cohorts will include a minimum of four (4) subjects each. Additional subjects may be added in the cohorts if necessary.

Study Record Dates

• First Submitted: August 11, 2017
• First Posted: October 20, 2017
• Study Start: April 24, 2017
• Primary Completion: November 30, 2017
• Study Completion: November 30, 2017
• Last Updated: January 16, 2018

Record last verified: 2018-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)