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LPCN 1107, Lipocine's oral hydroxyprogesterone caproate (HPC) product candidate has the potential to become the first oral HPC product for the prevention of preterm birth in women with a prior history of at least one preterm birth. Potential benefits of our oral product candidate relative to current once-a-week intramuscular (IM) injectable product include the elimination of pain and site reactions associated with weekly injections, elimination of weekly doctor visits or visits from the nurse, and elimination of interference/disruption of personal, family or professional activities associated with weekly visits. Lipocine has successfully completed a Phase 1 study under a US IND designed to determine the pharmacokinetics and bioavailability of LPCN 1107 relative to an IM HPC, as well as safety and tolerability, in healthy non-pregnant female volunteers.

In this Phase 1, pilot, open-label study, ten healthy non-pregnant female subjects of child bearing age received in a randomized cross-over fashion either one single dose of 400 mg of LPCN 1107 or two doses of 400 mg LPCN 1107 administered 12 hours apart, followed by a single dose of 250 mg IM HPC, with a one week washout period between each treatment. Blood samples were collected over 24 hours following the 400 mg QD dose, over 36 hours following the 400 mg twice daily (BID) dose and over 30 days following the IM dose. Plasma samples were assayed for HPC concentration by a validated LC-MS/MS method. The maximum concentration (Cmax) and area under the curve (AUC) for the oral treatments are shown in Table 1.

Table 1: Pharmacokinetic Parameters (geometric mean and associated ranges)


Dosing Regimen

Cmax (ng/ml)
[range]

AUC 0-t (ng.h/ml)
[range]

400mg , BID
(daily dose of 800mg)

23.1
[8.5 - 72.1]

173
[82 - 443]

400mg, QD

13.5
[4.9 - 54.4]

69
[33-207]

Significant absorption of HPC following oral administration was noted. Both mean Cmax and mean AUC increased significantly from the 400 mg QD to the 400 mg BID dose.

The steady state (week 5) pharmacokinetic parameters for the 400 mg BID and the approved label dose of 250 mg IM weekly injection for the prevention of recurrent preterm birth were simulated based on the single dose study data and the simulated Cmax and AUC over a 24-hour period at steady state are shown in Table 2.

Table 2: LPCN 1107 Steady State Pharmacokinetic Parameters


Products / Dosing Regimen

C ss,max (ng/ml)
[range]

AUC SS- 1 (ng.h/ml)
[range]

LPCN 1107 400mg BID

23.9
[9.6 - 70.0]

1348
[673 - 3381]

Intramuscular injection, 250mg

17.8
[14.0 - 27.0]

2468
[1840 - 3180]

LPCN 1107 was well tolerated. The only significant treatment related adverse events observed was abnormal menstrual effects in both the LPCN 1107 and IM arms in some subjects, which is not an unexpected progestogenic effect in non-pregnant females of child-bearing age.

Based on this steady state simulation, LPCN 1107 is expected to match the HPC exposure from the weekly IM injection at an appropriate oral dose. Additionally, based on these results we have initiated a study to assess the pharmacokinetics and bioavailability of LPCN 1107 relative to IM in pregnant females. The study commenced in the third quarter of 2014 and we expect top line results in the first quarter of 2015.