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1869
Optimization of a Phase 2 Study Design in Chronic
Hepatitis B (CHB) Patients Based on Safety, Pharmacokinetics
(PK) and Pharmacodynamics (PD) from Phase
1 Studies Using Two Prodrugs of a Toll-like Receptor 7
(TLR7) Agonist
Joseph Grippo2, Ilia Folitar1, Jeroen van de Wetering de Rooij3,
Sharon Passe4, David R. Blue4, Ignacio Rodriguez4, Scott H.
Fettner4, Elizabeth Calleja4; 1Roche Innovation Center Basel,
Basel, Switzerland; 2Clinical Pharmacology, Roche Innovation
Center New York, New York, NY; 3PRA Health Sciences, Groningen,
Netherlands; 4Roche Innovation Center New York, New
York, NY
Background: Given orally, RO6870868 (single prodrug) or
RO6864018 (double prodrug) rapidly convert to the TLR7
agonist RO6871765 (1765), which is being evaluated as an
immunomodulator to treat CHB. Clinical and non-clinical data
indicate that in general, safety and tolerability of TLR7 agonists
are associated with their PD effects. The relationship between
1765 exposures, PD biomarkers and safety from these Phase
1 studies were analyzed in order to optimize design of a
Phase 2 study in CHB patients. Methods: Safety, tolerability
and PK/PD after RO6870868 dosing were evaluated from a
single ascending dose study in 60 healthy volunteers (HVs).
Clinical data with RO6864018 dosing was collected from a
study including 41 HVs and 34 Hepatitis C (HCV) patients
who received single and/or multiple doses. Both studies were
double-blind, placebo-controlled and evaluated ascending
doses ranging from 200 to 2000 mg. TLR7 response markers
including neopterin, interferon (IFN)-α, IP-10, ISG-15, OAS1
and TLR7 were measured. Results: The 1765 PK profile was
comparable following oral administration of either prodrug
yielding similar dose-dependent effects. A minimal threshold
of 25 ug*hr/mL 1765 was required to initiate PD responses.
A temporal pattern of PK/PD response was found with 1765
exposures peaking at 1-2 hrs, TLR7 mRNA and IFN-α within
6 hours, OAS1, ISG-15 at ~12 hours and neopterin at 36 to
48 hours post dose. PK/PD correlations were found for neopterin,
IFN-α, IP-10, ISG-15, OAS1, MX1 and TLR7. Little or
no response was observed for TNF-α, IL-6, IL-10 or IL-12p40.
Doses up to 800 mg were well tolerated. Higher doses had
significant variability in tolerability and PD responses and were
associated with some reports of reversible flu-like symptoms.
The number of subjects with measureable systemic IFN, mean
IFN levels and the intensity of flu-like symptoms increased with
higher 1765 exposure. A multinomial logistic regression analysis
was conducted to relate outcomes defined by the presence
of systemic IFN and adverse events associated with flu-like
symptoms to 1765 exposure in subjects receiving RO6864018
every other day. This analysis enabled dose selection to exhibit
TLR7 responses and minimize flu-like symptoms. Conclusion:
Evaluation of clinical safety, PK and PD using two prodrugs of
a TLR7 agonist revealed similar responses and allowed better
design of a Phase 2 study in CHB patients evaluating different
doses and schedules to optimize TLR7 responses while minimizing
potential safety and tolerability liabilities.
Disclosures:
Joseph Grippo - Employment: Roche, Roche, Roche, Roche
Sharon Passe - Employment: Hoffmann-La Roche
David R. Blue - Employment: Hoffmann - La Roche
Ignacio Rodriguez - Employment: Hoffmann - La Roche
Scott H. Fettner - Employment: Hoffmann-LaRoche
Elizabeth Calleja - Employment: Roche
The following people have nothing to disclose: Ilia Folitar, Jeroen van de Wetering
de Rooij
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发表于 2016-10-7 17:10
