C34-PEG 4 -Chol first in man Title: A first-in-human study of the novel HIV-fusion inhibitor C34-PEG 4 - Chol. Authors: Killian Quinn 1 , Cinzia Traboni 2 , Sujan Dily Penchala 3 , Georgios Bouliotis 4 , Nicki Doyle 1 , Vincenzo Libri 5 , Saye Khoo 3 , Deborah Ashby 4 , Jonathan Weber 1 , Alfredo Nicosia 2,6, Riccardo Cortese 2,6 , Antonello Pessi 2,6,7 * and Alan Winston 1 *. Affiliations: 1. Department of Medicine, Imperial College London, London, UK, W2 1NY 2. JV Bio, Via Gaetano Salvatore 486, 80145 Napoli, Italy 3. Department of Pharmacology, University of Liverpool, Liverpool, UK, L69 3BX 4. School of Public Health, Imperial College London, London, UK 5. Institute of Neurology, University College London, London WC1N 3BG 6. CEINGE, Via Gaetano Salvatore 486, 80145 Napoli, Italy 7. PeptiPharma, Viale Città D’Europa 679, 00144 Roma, Italy *Joint last author Correspondence: Professor Alan Winston Clinical Trials, Ground Floor Winston-Churchill Wing St. Mary’s Hospital, Praed Street, London W2 1NY, UK E: [email protected]; P/F: +44 203312 1603/6123 Dr. Antonello Pessi JV Bio, CEINGE and PeptiPharma Page 1 of 30
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C34-PEG4-Chol first in man
Title:
A first-in-human study of the novel HIV-fusion inhibitor C34-PEG4-Chol.
Virus 25. In all cases, cholesterol conjugation improved the FI potency 50-100 fold 26. For some of
these viruses, efficacy was demonstrated in vivo 22,23,25 and notably, the peptide was detectable in the
brain 24 hours after administration 22,23,25, indicating that cholesterol conjugation may enable
penetration of the blood-brain barrier, a difficult feat for drugs in general, and for biologics in
particular 27.
The observed improvement of pharmacokinetics through cholesterol conjugation is due to increased
binding to serum proteins 13,28-30. This is a general, sequence-independent mechanism, and
accordingly the preclinical pharmacokinetic data for C34-PEG4-Chol in mice 14 are comparable to
those of a cholesterol-conjugated Nipah virus FI in golden hamsters 22 and a cholesterol-conjugated
NDV FI in chickens 25. Therefore the optimal pharmacokinetic profile observed in humans for C34-
PEG4-Chol suggests that similar data are likely to be observed for other cholesterol-conjugated FIs.
It has been suggested that the improved efficacy and improved pharmacokinetics provided by
cholesterol conjugation offer the basis for the rapid development of cholesterol-conjugated
therapeutics for known and emerging viral diseases 26. In particular for the threat of emerging viral
diseases, it should be noted that FIs can be developed rapidly because their design only requires
knowledge of the viral genome, which is available before or rapidly acquired at the time of an
epidemic. Moreover, since for each viral family the fusion proteins, from which the FIs are derived,
share the same mechanism of action and display considerable sequence conservation, a cholesterol-
conjugated FI for a “sentinel virus” would represent the template for all the other viruses within the
same family.
Although our study included small numbers of participants, the pharmacokinetic and
pharmacodynamic signals were have observed in humans for C34-PEG4-Chol now offer a critical
validation for this strategy.
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C34-PEG4-Chol first in man
Additional Information:
Competing Financial Interests statement:
CT, AN, RC and AP worked for JV Bio.
All other authors have no competing financial interests.
Acknowledgments:
This manuscript is dedicated to our colleague and friend Riccardo Cortese, who passed away on April
27, 2017.
This study was funded by a grant from the Medical Research Council of the UK to Imperial College
London (grant reference MR/J002178/1).
AW, KQ and JW are grateful to the NIHR Biomedical Facility at Imperial College London for
infrastructure support.
We are grateful to all the individuals for participating in this study and to the following individuals for
sitting on the study independent data monitoring committee (IDMC); Charles Lacey (chair), Caroline
Sabin, Clifford Leen, David Bell and David Burger
Some data from this manuscript were presented at the 22nd Annual Conference of the British HIV
Association (BHIVA, Manchester, UK; 19-22 April 2016, poster 13).
We would like to thank the follow groups and individuals for their contributions (listed
alphabetically):
American Peptide Company, Sunnyvale, CA, USA
Stewart Hamilton
CEINGE, Naples, Italy
Nicola Zambrano
Charles River Laboratories, Ormiston, UK
Alasdair MacDonald, Morna McIntosh, and David Falconer.
Chelsea and Westminster Hospital Foundation NHS Trust, London, UK
Mark Nelson and Rachel Jones
Department of HIV Pharmacology, University of Liverpool, UK
Sujan Dily Penchala, Alieu Amara, Laura Else, Saye Khoo and David Back
Imperial College HIV Clinical Trials Unit, St. Mary’s Campus, London, UK
Ken Legg and Scott Mullaney
Imperial Clinical Research Facility, Hammersmith Campus, Imperial College London, UK
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C34-PEG4-Chol first in man
David Lewis, Victoria Latham, Vijay Zala, Benjamin Lodge, Aliki Rizou, Ravinder Summan, and Okdeep Kaur
Imperial Clinical Trials Unit, Imperial College London, UK
Deborah Ashby, George Bouliotis, Alexina Mason, Juan Gonzales-Maffe, Daphne Babalis and Aleisha Miller
Imperial College International HIV Clinical Trials Office, London, UK
Roger Tatoud, Peter Norsworthy, Nicki Doyle and Cherry Kingsley
IRBM Science Park, Pomezia, Italy:
Raffaele Ingenito and Elisabetta Bianchi
Section of Virology, Department of Medicine, Imperial College London
Steve Kaye, Myra McClure
Symbiosis, Stirling, UK:
Joanne Anderson, Katherine Reid, Murray McKay, Martin Cockcroft, and Niall Henderson
UK Community Advisory Board, London, UK
Roy Trevelion and Matthew Williams
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Author contribution:
AW, AP and KQ drafted the manuscript. GB and DA lead the statistical analyses. SDP and SK lead the
pharmacokinetic work. AW, JW, AP, AN, RC, DA and VL lead the funding application to the Medical
Research Council for the grant. All authors contributed to the final manuscript.