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

Complement Mediated Diseases Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03316521
• Other study ID #: AMY-101/01
• Status: Completed
• Phase: Phase 1
• First received: August 11, 2017
• Last updated: January 11, 2018
• Start date: April 24, 2017
• Est. completion date: November 30, 2017

Study information

• Verified date: January 2018
• Source: Amyndas Pharmaceuticals S.A.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

AMYNDAS is developing a novel peptidic complement inhibitor AMY-101, based on the third-generation compstatin analogue Cp40. AMY-101 is a selective inhibitor of complement activation in humans and in NHP. It binds to the complement component C3, the central "functional hub" that controls the upstream activation/amplification and downstream effector functions of complement. By binding to C3, AMY-101 inhibits the cleavage of native C3 to its active fragments C3a and C3b. As a consequence, the deposition of C3b, amplification via the alternative pathway and all downstream complement responses are prevented. AMY-101 is being developed to treat complement-mediated diseases, which are largely driven by aberrant C3 activation.

This first-in-human study of the C3-targeting complement inhibitor AMY-101 investigates the safety and PK/PD profile of AMY-101 in healthy male volunteers after Single Ascending Dose (SAD) and Multiple Doses (MD) using subcutaneous (SQ) or intravenous (IV) administration. The study is a prospective, single-center, open-label evaluation in healthy male volunteers.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: November 30, 2017
• Est. primary completion date: November 30, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

1. Willing and able to give written informed consent for participation in the study.

2. Healthy male subject aged 18-60 years, inclusive at the time of signing the informed consent.

3. Body Mass Index (BMI) = 18 and = 30 kg/m2 and weight at least 50 kg.

4. Clinically normal medical history, physical findings, vital signs, ECG and laboratory values at the time of screening, as judged by the Investigator.

5. 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.

6. Willing and able to complete all procedures according to the Protocol.

Exclusion Criteria:

1. 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.

2. History of any Neisseria meningitidis infection

3. History of unexplained, recurrent infection, or infection requiring treatment with systemic antibiotics within the last 60 days prior to dosing.

4. History of latent or active tuberculosis, as assessed by the investigator based on chest X-ray and positive Quantiferon-TB Gold test.

5. History of complement deficiency.

6. History of any type of malignancy. However, completely resolved minor malignancies, at the discretion of the Investigator, may not be an exclusion criterion (for example: Non-Melanoma Skin Cancer).

7. Diagnosis of autoimmune, immunologic or rheumatologic disease (eg, systemic lupus erythematosus, rheumatoid arthritis).

8. Any clinically significant illness, medical/surgical procedure or trauma within four (4) weeks of the administration of IMP.

9. High CRP at screening (> 0.5 mg/dL).

10. 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.

11. 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

12. Any clinically significant abnormality in clinical chemistry, hematology, or urinalysis results at the time of screening, as judged by the Investigator.

13. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and/or Human Immunodeficiency Virus (HIV).

14. After 10 minutes supine rest abnormal vital signs defined as any of the following:

• Systolic BP > 140 mm Hg

• Diastolic BP > 95 mm Hg

• HR < 40 or > 90 beats per minute

15. Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant abnormality in the resting ECG, as judged by the Investigator.

16. Any history of any allergy/hypersensitivity or anaphylactic reaction or on-going allergy/hypersensitivity. History of hypersensitivity to antibiotics or drugs with a similar chemical structure or class to AMY-101.

17. Use of any prescribed or non-prescribed medication including antacids, analgesics, herbal remedies, vitamins and minerals within two (2) weeks prior to the administration of IMP, except the occasional intake of paracetamol/acetominophen (maximum 2000 mg/day; and not exceeding 3000 mg/week) or nasal decongestant without cortisone or antihistamine, at the discretion of the Investigator.

18. Administration of another new chemical entity (defined as a compound that has not been approved for marketing) or having participated in any other clinical study that included drug treatment within 30 day or 5 half lives of the last administration of the other IMP. Subjects consented and screened but not dosed in previous phase I studies are not excluded.

19. Immunization with a live-attenuated vaccine one (1) month prior to the first administration of IMP.

20. Current smokers or users of nicotine products. Irregular use of nicotine (e.g. smoking, snuffing, chewing tobacco) less than three (3) times per week is allowed before screening visit.

21. History of alcohol abuse or excessive intake of alcohol, as judged by the Investigator.

22. Positive screen for drugs of abuse at screening or on admission to the unit or positive screen for alcohol at screening or on admission to the unit prior to administration of the IMP.

23. Use of anabolic steroids.

24. Plasma donation within one (1) month of screening or any blood donation/blood loss > 450 mL during the three (3) months prior to screening.

25. Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements.

Related Conditions & MeSH terms

• Complement Mediated Diseases

Intervention

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

Locations

Country	Name	City	State
United States	HighPoint Clinical Trials Center	High Point	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Amyndas Pharmaceuticals S.A.

Country where clinical trial is conducted

United States, 

References & Publications (15)

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. Review. — View Citation

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. Review. — View Citation

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. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. Erratum in: Blood. 2017 Apr 13;129(15):2205. — View Citation

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. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0		Up to 21 days after treatment.
Secondary	Area under the plasma concentration time curve (AUCt) after a single dose		Up to 14 days after treatment.
Secondary	Area under the plasma concentration time curve from zero to infinity (AUC 0->8) after a single dose		Up to 14 days after treatment.
Secondary	Peak Plasma Concentration (Cmax) after single and multiple doses		Up to 14 days after treatment.
Secondary	Time to Cmax (Tmax) after single and multiple doses		Up to 14 days after treatment.
Secondary	Terminal elimination rate constant (lambdaz) after single and multiple doses		Up to 14 days after treatment.
Secondary	Terminal half-life (T1/2) after single and multiple doses		Up to 14 days after treatment.
Secondary	Total apparent clearance of drug from plasma/serum (CL/F) after single and multiple doses		Up to 14 days after treatment.
Secondary	Volume of distribution (Vz) / fraction of drug absorbed (F) after single and multiple doses		Up to 14 days after treatment.
Secondary	Area under the curve at steady state (AUCss) after multiple doses		Up to 14 days after treatment.
Secondary	Activation of the classical complement pathway	CH50	Up to 14 days after treatment.
Secondary	Activation of the alternative complement pathway	AP50	Up to 14 days after treatment.
Secondary	Complement protein C3 plasma levels		Up to 14 days after treatment.
Secondary	Complement protein C4 plasma levels		Up to 14 days after treatment.
Secondary	Measurement of immune response (plasma protein electrophoresis - IgG,IgA, IgM) after single and multiple administrations of AMY-101.		Up to 14 days after treatment.
Secondary	Investigation for anti-drug antibodies after single and multiple administrations of AMY-101.		Up to 14 days after treatment.
Secondary	Measurement of lymphocyte subsets after multiple administrations of AMY-101.		Up to 14 days after treatment.