Fuzeon Drug Development Timeline
John Riley
- **First Patent Filed Filed June 7, 1993: Pre-clinical
proof of activity.
This invention was made with Government support under
Grant No. AI-30411-02 awarded by the National Institutes
of Health. The Government has certain rights in the
invention. The inventors are Bolognesi; Dani P. (Durham,
NC); Matthews; Thomas J. (Durham, NC); Wild; Carl T.
(Durham, NC) The patent was assigned to Duke University
(Durham, NC) 1
- **Filed: March 23, 1998 Basic methodology for making
large scale batches of T-20. Patented by Trimeris. United
States Patent 6,281,331; Kang , et al. August 28, 2001
were inventors the Assignee is Trimeris, Inc. (Durham, NC)
2
- **Filed: May 1, 1998 More methods for T-20 synthesis
Patented under number 6,015,881 by Kang , et al. The
assignee is Trimeris, Inc.3
- Published November 1998 Paper published showing proof
of concept that T-20 can safely be administered to humans
and lower viral load at high dose levels. Research supported
by Trimeris and NIH Grants (P30 A127767) and (NCRR MO1
RR00032)4
- 2000 Jun 16 Paper published demonstrating possible
source of injection site side effects caused by T-20. Study
done at NIH. 5
Injection site reactions occur in most
patients receiving the drug.
- 2000 Sept. Paper published showing how different
receptors interact with T-20 and with where these receptors
interact with the virus. This research was supported by
Howard Hughes Medical Institute and NIH grants R37A133319
,R37AI24745 and P30-A1-27767. 6
This research is important
in helping define the mechanism of the drug's action.
- 2001 Apr 1. Preclinical experiments show that T-20
combined with another entry inhibitor, both currently in
Phase I/II trials, can have a synergistic effect allowing
the combination to act at much lower doses than
individually. Research supported by NIH grants AI-43084 and
AI-43847 7
- 2001 Sep Preclinical experiments show mechanisms action
of T-20 and T-649 (a version of T-1249). Research was
supported by HHMI and NIH grants R37AI33319 , R01AI24745 ,
P30-A1-27767.8
- May 2002 Test tube studies provide more evidence that T-
20 is useful in combination with standard approved AIDS
drugs and that it is synergistic in its action in with other
not-yet-approved entry inhibitors. Funded by NIH grant
number CA12464, and from Schering-Plough Research Institute.
(C.L.T. was a Research Fellow supported by the Fonds de
Recherche en Sante du Quebeq).9
- 2002 June. Mechanism of creation of T-20 resistant
virus is studied yielding information that may affect the
treatment strategies used when using the drug. The study was
done on virus isolated from individuals who became resistant
from the phase I trial. Research funded by National
Institute of Health grants CA73470, R41 AI46112, and
AI35467; and (P30-AI-27767). Trimeris provided T-20. Howard
Hughes Medical Institute, also provided support for the
studies.10
- 2002 July Phase III trial results reported at
International AIDS Conference for T-20 show that 32.7% of
those treatment resistant patients receiving T-20 had
undetectable levels of virus vs. 15% of those not taking the
drug. The study was funded by Trimeris and Roche.
- 2002 July Study by Community Research Initiative on
long-term treatment satisfaction with subcutaneous T-20,.
Study funded by Roche. 11
- 2002 July Study by the Pediatric AIDS Clinical Trial
Group shows that a 24-week regimen of twice daily s.c.
dosing of T-20 in HIV-1-infected children is safe and
tolerable and that it is associated with suppression of HIV-
1 replication during 24 weeks of administration.
12
- 2002 July Study conducted by investigators at Howard
Hughes Medical Institute shows how resistance to T-20 and
similar drugs arises.13
- 2002 July Another study funded by Howard Hughes Medical
Institute shows how resistance to T-20 arises
14
- 2002 July Another study by Roche tests pharmaco-
kinetics (drug safety and blood levels) in patients using
higher dose of T-20.15
- 2002 September- October Study by Roche shows patients
daily lives are not negatively impacted by use restrictions
in behavior required to use T-20.16
- 2002 Dec 10 Preclinical studies show more about the
mechanism of action of T-20 and how resistance might develop
and which individuals might benefit most from the drug.
Studies Funded by NIH Grant #AI40880, a Burroughs Wellcome
Fund Translational Research Award, and an Elizabeth Glaser
Scientist Award (to R.W.D.). S.P. was supported by a
fellowship from the Deutsche Forschungsgemeinschaft. (drugs
supplied by Trimeris).17
- 2003 Jan French Scientists show that co-receptors are
very important in how effective T-20 is at inhibiting fusion
of the virus with the cell. Research supported in part by
the French National Agency for AIDS Research (Agence
Nationale de Recherche sur le SIDA [ANRS]). B.L. is the
recipient of a Sidaction fellowship.1
18
_______________________________
FOOTNOTES:
1 http://patft.uspto.gov US Patent Office
2 ibid.
3 ibid.
4"Potent Suppression of HIV-1 replication in humans by T-0,
a peptide inhibitor of gp41-mediated virus entry," J.
Michael Kilby et al., Nature Medicine, vol. 4, No. 11
November 1998
5 "The HIV-1 Cell Entry Inhibitor T-20 Potently
Chemoattracts Neutrophils by Specifically Activating the N-
Formylpeptide Receptor," Jennifer K. Hartt, et al. NIAID
Biohemical and Biophysical Research Communications 272,699-
704 2000
6"Sensitivity of Human Immunodeficiency Virus Type 1 to
Fusion Inhibitors Targeted to the gp41 First Heptad Repeat
Involves Distinct Regions of gp41 and is Consistently
Modulated by gp120 Interactions with the Co-receptor,"
Cynthia A. Derdeyn et al., J. of Virology, Sept. 2001 p 8605
7"Human Immunodeficiency Virus Type 1 Entry Inhibitors PRO
542 and T-20 Are Potently Synergistic in Blocking Virus-Cell
and Cell-Cell Fusion," Kirsten A. Nagashima et al. Journal of
Infectious Diseases 2001; 183:1121-1125
8 "Sensitivity of human immunodeficiency virus type 1 to
fusion inhibitors targeted to the gp41 first heptad repeat
involves distinct regions of gp41 and is consistently
modulated by gp120 interactions with the coreceptor" Derdeyn
CA et al. J. Virology 75(18):8605-14.2001 Sep;
9"Anti-human immunodeficiency virus interactions of SCH-C
(SCH 351125), a CCR5 antagonist, with other antiretroviral
agents in vitro," Tremblay CL, Antimicrob Agents Chemother,
6(5):1336-9, 2002 May;4
10"Emergence of resistant human immunodeficiency virus type
1 in patients receiving fusion inhibitor (T-20)
monotherapy," Wei X, et. al.Antimicrob Agents Chemother,
46(6):1896-905, 2002 June
11"Long-term treatment with subcutaneous T-20, a fusion
inhibitor, in HIV-infected patients: patient satisfaction
and impact on activities of daily living." Cohen CJ, AIDS
Patient Care & Stds. 16(7):327-35, 2002 Jul
12 "Safety and antiretroviral activity of chronic
subcutaneous administration of T-20 in human
immunodeficiency virus 1-infected children," Church JA et
al. Pediatr Infect Dis J (7):653-9, 2002 July 21
13 "Emergence of resistant Human immunodeficiency virus type
1 in patients receiving fusion inhibitor (T-20)." Wei X, et
al., Antimicrob Agents Chemother 2002 Jun; 46(6): 1896-906
14Analysis of Patient-derived HIV-1 Isolates Suggests a
Novel Mechanism for Decreased Sensitivity to Inhibition by
Enfuvirtide and T-649 abstract Int AIDS Conf 2002 in
Barcelona, Session 73.Poster
15
16 "Subcutaneous injection survey: psychometric evaluation of
a treatment satisfaction instrument associated with a novel
HIV medication," Green J, et al., HIV Clin Trials, 3(5):387-
95; 2002 Sep-Oct;
17 "Sensitivity of HIV-1 to entry inhibitors correlates with
envelope/coreceptor affinity, receptor density, and fusion
kinetics," Reeves JD, Proc Natl Acad Sci USA, 99(25):16249-
54, 2002 Dec 10
18 "Baseline Susceptibility of Primary Human immunodeficiency
Virus Type 1 to Entry Inhibitors," Beatrice Labrosse, et al.
Journal of Virology, Jan 2003, p 1610-1613 K.S. is a fellow
of the ANR