LGD-4665, a new generation small molecule oral thrombopoietin (TPO) mimetic, increases platelet counts in a dose proportional manner, and is associated with a high safety margin in healthy subjects after single and multiple daily, or weekly doses. Phase I characterization of LGD-4665 has demonstrated comparable platelet profiles following daily or weekly dosing, minimal effects of food on absorption, and no drug interaction with CYP 3A4 substrates. These attributes have led to the design of Phase II studies with flexible dose regimens for immune thrombocytopenic purpura (ITP), Hepatitis C and myelodysplastic syndrome (MDS). Weekly dosing regimen for a supportive therapy such as LGD-4665 in thrombocytopenic patients is desirable for patient convenience, compliance and overlap with concomitant therapies including peg-interferon in hepatitis C and certain chemotherapeutic agents in cancer patients. LGD-4665’s long elimination half-life of 90 hrs and sustained increases in platelet counts in the Phase I single or multiple daily dose trials suggested a weekly dosing regimen should be evaluated. A Phase-I study was designed to assess once weekly, oral dosing for safety, pharmacodynamics (PD; platelet response) and pharmacokinetics (PK). This was conducted in 23 healthy volunteers randomized to receive 30 mg, 45 mg or 60 mg capsules of LGD-4665 for up to 6 weeks. All three LGD-4665 doses demonstrated a sustained increase in platelet counts that was dose proportional following weekly administration. The mean maximum percentage increase in platelet counts were 36%, 71% and 81% at 30 mg, 45 mg and 60 mg, respectively. The platelet increase of 71% after a weekly dose of 45 mg was comparable to a 79% increase following daily dosing of 7.5 mg with a loading dose. Platelets responded more quickly following the higher weekly doses (45 mg and 60 mg), with counts approaching 50% above baseline values within two weeks, and reaching a plateau at 4 to 5 weeks. Platelet counts gradually returned to baseline within three weeks post-treatment. Food effects were tested in 16 normal subjects and showed only a minimal decrease (23%) in absorption in a cross-over study, and should have no significant clinical impact. In another Phase I study in 25 healthy subjects, there was no pharmacokinetic drug-drug interaction between LGD-4665 and simvastatin, a sensitive substrate for CYP 3A4. In Phase I studies, LGD-4665 was safe and well tolerated. Only a few adverse events (AEs), with majority being mild in severity, were reported with single doses up to 120 mg, multiple daily doses (14 days) of up to 10 mg/day without a loading dose, up to 7.5 mg/ day with a 6-fold loading dose and following weekly administration of up to 60 mg for 6 weeks. The most common AEs in LGD-4665-treated subjects were: upper respiratory tract infection (7%), nausea (6%), headache (5%), rash (4%), pharyngolaryngeal pain (4%), and constipation (3%). Overall, the frequencies of these events did not appear to be dose-related. Furthermore, there were no clinically significant changes in vital sign measurements, no notable laboratory abnormalities and no early withdrawals related to LGD-4665. In summary, results from several Phase I trials have permitted flexible dose regimens of LGD-4665 due to its long elimination half-life, a faster 3–5 day onset of platelet increases following a loading dose, favorable sustained platelet increases, and a high safety margin across a wide dose range. Interim platelet and safety data from an ongoing Phase-II study of 24 patients with ITP who are treated with 7.5 mg LGD-4665 daily, will be available for comparison with Phase I results. Additional Phase II studies involving weekly dosing are planned in subjects with hepatitis C and MDS.
7227 Background: Bexarotene is a selective modulator of retinoid X nuclear receptors (RXRs), which form heterodimers with many other nuclear receptors playing a critical role in cell growth, differentiation, and apoptosis. Loss of RXRs is seen in many advanced tumors, including NSCLC and higher RXR levels in NSCLC lung biopsies (stages I-III) have been correlated with longer overall survival. Two large first line NSCLC Phase III trials reported at ASCO 2005 (SPIRIT I and II) showed that while no benefit in overall survival was seen adding bexarotene to two chemo regimens, a large (36%) subpopulation of patients in both trials that had high grade hypertriglyceridemia in response to bexarotene had significantly longer survival. A retrospective analysis was conducted to evaluate the baseline characteristics of these patients and to examine the level of expression of RXR and one of its partners (PPARγ) in lung tumor tissue biopsies obtained from a subgroup of patients in both studies. Methods: RXRs (α,β,γ) and PPARγ expression levels in lung tumor tissue from patients in SPIRIT I and II trials (stage IIIB/IV) taken prior to study entry were assessed by Q-PCR analysis of RNA isolated from microdissected lung tumor tissue biopsies. Cox regression and Kaplan-Meier survival estimation were used for statistical evaluations. Results: In an initial subset of 41 patients, RXRβ expression in lung tumor showed positive correlation with survival. High RXRβ = longer survival (median survival 438 days), low RXR shorter (MS = 317). Treatment with bexarotene increased the differences (RXRβ Hi, MS = 627 days; RXRβ low = 211 days). PPARγ showed a negative correlation with survival and those patients with RXRβ Hi/PPARγ low ratios had the longest MS (627 days vs. 226 days for the RXRβ low/PPARγ high group), a difference that was magnified by bexarotene treatment. Conclusions: RXRβ expression level correlates with a positive survival in late stage NSCLC while PPARγ shows negative correlation. Bexarotene treatment enhances the survival differences, supporting an involvement of triglyceride and lipid metabolism as regulated by these two key nuclear receptors in the longer survival seen in the 215 patients in the high triglyceride subgroup. [Table: see text]
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