Clinical Trial Result Information

Title of Study:
Tolerance and Pharmacokinetics (PK) of Carbonate and TRIS Buffer High-Strength (100mg/mL) Formulations of T 20/Ro29-9800 (HIV 1 Fusion Inhibitor) Compared to the Current Carbonate Formulation (50mg/mL), Each at Doses of 75 and 100mg bid, in Treatment-Experienced HIV-Infected Patients

Fast Facts:

Protocol number:	T20-208
Sponsor:	Trimeris Inc; Hoffmann-La Roche Inc.
Company division:	Pharmaceutical
Product name:	Fuzeon
Generic name:	enfuvirtide
Phase of development:	II
Therapeutic area, approved indication:	Treatment of HIV-1 infection
Date of report:	10/19/2001

Clinical study summary:
This was a multicenter, open-label, sequential, crossover study of two 100mg/mL formulations of T-20/Ro29-9800 (Fuzeon) compared with the 50mg/mL formulation in Human Immunodeficiency Virus (HIV)-infected adults, administered by subcutaneous (sc) self-injection.

Study center(s) :
4 centers in the United States

Objectives:
Primary: To compare the safety, tolerability, and pharmacokinetics (PK) of new high-strength formulations of Fuzeon with the current formulation.

Secondary: (1) To evaluate the efficacy of 2 doses of Fuzeon with the new high-strength formulations by measurement of viral load; (2) To evaluate the safety and tolerability of 2 doses of Fuzeon with the new high-strength formulations.

Methodology:
Patients were accrued sequentially in 1 of 3 cohorts (I-III) and self-administered either 75mg (or 100mg bid sc of Fuzeon 50mg/mL in carbonate buffer (current formulation) (Formulation A), Fuzeon 100mg/mL in carbonate buffer (Formulation B), or Fuzeon 100mg/mL in TRIS buffer (Formulation C). Once entered into a cohort, patients remained on the dose while sequencing through the various formulations as follows:

	Cohort I	Cohort II	Cohort III
	100mg bid (CO 3)	75mg bid (CO 3)	100mg bid (TRIS)
Formulation for Days 1-14	B	B	C
Formulation for Days 15-28	A	A	A
Formulation for Day 29 and thereafter	B	B	C

Safety/tolerability and response to Fuzeon were evaluated in all patients; full PK evaluations at Days 14 and 28 were performed for all patients.

Number of patients (planned/analyzed):
46 enrolled; 46 intent-to-treat (ITT)

Diagnosis and main criteria for inclusion:
HIV 1 infected adults >=18 years of age; prior antiretroviral (ARV) treatment; ability to initiate treatment with 2 other ARV agents; plasma HIV 1 RNA >=5000 copies/mL, or HIV 1 RNA >=1000 copies/mL and CD4 T-cell count <=100 cells/mm³.

Test product, dose and mode of administration or test procedure:
Fuzeon, 75 or 100mg/sc/bid.

Duration of treatment:
48 weeks, with 48-week extension (total 96 weeks)

Reference therapy, dose and mode of administration or reference procedure:
Not applicable

Criteria for evaluation (efficacy, safety):
PK: C_max, C_min, AUC, t_1/2, accumulation and exploration of exposure of enfuvirtide in Formulations B and C as compared to Formulation A (primary) and at doses of 75mg bid and 100mg bid (secondary).

Safety: Adverse events, vital signs, and clinical laboratory parameters, including fasting glucose, fasting triglycerides, and fasting cholesterol.

Tolerability: Local injection-site reactions (ISRs) to Fuzeon in Formulations B and C compared to Formulation A (primary) and local ISRs to Fuzeon at doses of 75 and 100mg bid (secondary).

Statistical methods:
All data were summarized using descriptive statistics, as this study was not designed to demonstrate significant differences with respect to the efficacy endpoints. No comparisons were made statistically across cohorts or formulations; no hypothesis testing was performed and therefore no P values are presented.

Summary (efficacy, safety, other results):
PK: The 12 hour AUC (AUC_12h) value was 46.2 µg·h/mL and 37.0 µg·h/mL for the 50mg/mL carbonate formulation, and 48.7 µg·h/mL and 34.4 µg·h/mL for the 100mg/mL carbonate formulation in Cohort I and II, respectively. There was dose proportionality between the 75mg and 100mg bid doses of 100mg/mL Fuzeon carbonate formulations. Pharmacokinetic data indicated that the high strength 100mg/mL CO₃ formulation was bioequivalent to the 50mg/mL CO₃ formulation whereas the TRIS formulation was not.

Efficacy: Although no statistical analyses were performed, subjects receiving the 100mg/mL Fuzeon carbonate formulation at doses of either 75mg or 100mg bid performed better than subjects receiving the Fuzeon 100mg/mL TRIS formulation (median log₁₀ change from baseline in viral load -2.97 copies/mL for 100mg/mL carbonate formulation, -3.48 copies/mL for 75mg/mL carbonate formulation, -0.87 copies/mL for 100mg/mL TRIS formulation; median change from baseline in CD₄ cell count 111cells/mm³ for 100mg/mL carbonate formulation, 175 cells/mm³ for 75mg/mL carbonate formulation, and 79 cells/mm³ for 100mg/mL TRIS formulation). The tolerability of all doses and all formulations of Fuzeon used in combination with background oral ARV medications was comparable. There were no adequate differences in PK, chemistry, and stability of enfuvirtide in the carbonate and TRIS formulations, patient demographics, or characteristics that could explain the differences.

All subjects experienced at least 1 ISR during the study, with induration and pain/discomfort the most frequently reported signs/symptoms. Across all cohorts, the average duration of an ISR was <=7 days; no patients withdrew from the study due to an ISR.

Laboratory toxicity evaluations showed no apparent trends with respect to doses and formulations.

Conclusions:
Fuzeon in a 100mg/mL carbonate formulation was bioequivalent to Fuzeon in a 50mg/mL carbonate formulation. Fuzeon 75mg bid and 100mg bid in a 100mg/mL carbonate formulation performed better, in terms of efficacy, than Fuzeon 100mg bid in a 100mg/mL TRIS formulation over 48 weeks; Fuzeon was well tolerated in this heavily-treated HIV-1 population and no apparent trends were observed in the occurrence of clinical adverse events, ISRs, or laboratory toxicities with respect to dose or formulation.

Publications (references, if available):
1) Wheeler DA, Lalezari JP, Kilby JM, et al. Safety, tolerability and plasma pharmacokinetics of high-strength fomulations of enfuvirtide (T-20) in treatment-experienced HIV-1-infected patients. Clin Virol 2004; 30: 183–90