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LPCN 1021 is an oral testosterone replacement product candidate containing Testosterone Undecanoate that is designed to help restore normal testosterone levels in hypogonadal men.

Two on-going Phase 3 clinical studies with LPCN 1021 are being conducted, the Dosing Validation ("DV") Study and the Dosing Flexibility ("DF") Study. The DV study will assess the impact of LPCN 1021 in hypogonadal males (testosterone < 300 ng/dL) on a fixed daily dose of 450 mg divided into two equal doses whereas the DF study will assess LPCN 1021 in hypogonadal on a fixed daily dose divided in to three equal doses. Both of the DV and DF studies are an open-label, fixed dose, no titration, single treatment arm study of LPCN 1021 and are expected to enroll up to 100 hypogonadal males in each study. Efficacy will be assessed via responder analysis at the end of the dosing period which is 24 days. The pre-specified primary endpoint is the percentage of subjects with an average 24-hour serum testosterone concentration ("Cavg") within the normal range, with secondary endpoints based on maximum serum testosterone concentrations ("Cmax"). Enrollment in both the DV study and DF study is complete and we currently expect top-line results from the DV study and DF study in June 2017. Additionally, resubmission of the NDA is expected in the third quarter of 2017.

Prior to conducting the DV study and the DF study, the Study of Androgen Replacement ("SOAR") pivotal Phase 3 clinical study evaluating efficacy and safety of LPCN 1021 was completed and efficacy results and 52-week safety results have been received.

A NDA was submitted to the FDA in September 2015 based on data from the SOAR trial. The FDA accepted the NDA in October 2015 and assigned a Prescription Drug User Fee Act ("PDUFA") goal date of June 28, 2016 for completion of the review. On June 28, 2016 we received a Complete Response Letter ("CRL") from the FDA. A CRL is a communication from the FDA that informs companies that an application cannot be approved in its present form. The CRL identified deficiencies related to the dosing algorithm for the label. Specifically, the proposed titration scheme for clinical practice was significantly different from the titration scheme used in the Phase 3 trial leading to discordance in titration decisions between the Phase 3 trial and real-world clinical practice. In response to the CRL, Lipocine met with the FDA in a Post Action meeting, and proposed a dosing regimen to the FDA based on analyses of existing data. The FDA noted that while the proposed dosing regimen might be acceptable, validation in a clinical trial would be needed prior to resubmission. The on-going DV study is in response to the FDA's request. Prior to initiating the DV study, the FDA reviewed the DV study protocol through a Special Protocol Assessment ("SPA"). Lipocine received the FDA's initial feedback on the protocol submitted via SPA prior to initiating the DV study in December 2016.

 

Phase 3 SOAR Trial

SOAR was a 52-week, multicenter, randomized, open-label, parallel-group, active-controlled Phase 3 study of LPCN 1021. Males 18 to 80 years old with a diagnosis of hypogonadism and confirmed low testosterone (< 300 ng/dl) were eligible for the study; a documented diagnosis of onset of hypogonadism prior to age 65 was required for patients older than 65 years. A total of 315 subjects were randomized across 40 study sites in 2:1 ratio, such that 210 were randomized to LPCN 1021 and 105 were randomized to Androgel 1.62% (active control for safety evaluation). LPCN 1021 subjects were started at 225 mg TU (equivalent to ~ 142 mg of T) twice daily (BID) and then titrated up to 300 mg TU BID or down to 150 mg TU BID based on serum testosterone as measured during weeks 3 and 7.

The safety of LPCN 1021 was monitored over 52 weeks of treatment. Additional parameters assessed after 52 weeks of treatment included:

  • Change from baseline in safety laboratory parameters
  • Number of subjects with adverse events

Primary statistical analysis was conducted using the Efficacy Population Set ("EPS") and additional analysis was performed using the Full Analysis Set ("FAS") as defined below:

  • Primary Analysis: Efficacy Population Set (EPS, N = 151)
    • Subjects randomized into the study with at least one PK profile and no significant protocol deviations
    • Imputed missing data by Last Observation Carried Forward (LOCF)
  • Additional Analysis: Full Analysis Set (FAS, N = 193)
    • Subjects randomized into the study and had at least one post baseline efficacy variable response
    • Imputed missing data by Last Observation Carried Forward (LOCF)

Efficacy:

  • Primary endpoint target ≥ 75% subjects should achieve Cavg within normal range (300 ng/dL to 1140 ng/dL) and lower bound of 95% CI ≥ 65%

Measure

FDA Targets

Efficacy Population

Safety
Set

Number of subjects

 

151

193

% subjects with Cavg
within normal range

≥75%

87.4%

87.0%

95 % CI lower bound

≥65%

81.7%

82.0%

Parameter

 

Mean (%CV)

Mean (%CV)

Cavg (ng/dL )

 

446 (38%)

471 (41%)


In the EPS analysis, 87% of the subjects on LPCN 1021 achieved testosterone Cavg within the normal range with lower bound CI of 82%. Results for the sensitivity analysis using the FAS were similar to results for the EPS.

Other highlights from the efficacy results include:

  • Mean Cavg was 446 ng/dL with coefficient of variance of 38%
  • Less than 13% of the subjects were outside the testosterone Cavg normal range at final dose
  • 85% of subjects arrived at final dose with no more than one titration
  • 52% of subjects were on final dose of 225 mg BID

Final dose distribution of subjects:

Dose (mg TU, BID)

% of Subjects

150

32 %

225 *

52 %

300

16 %

* Most subjects with final dose of 225 mg BID

SOAR trial titration outcomes

Parameter

% of subjects

% subjects requiring  no more than one dose change
(either after week 3 or week 7)

89.2 %

% subjects requiring two dose changes
(both after week 3 and 7)

10.8 %

Most subjects (89%) achieved optimal LPCN 1021 dose with one or fewer titrations whereas 61% of subjects required 2 titrations with active control

Secondary Endpoints

  • Proportion of subjects achieving maximum serum total T concentrations (Cmax) in predefined Cmax range

Measure

FDA Threshold

Efficacy Population

Number of subjects 

 

152

Cmax < 1500 ng/dL

≥ 85 %

82.8%

1800 ≤ Cmax ≤ 2500 ng/dL

≤ 5 %

4.6%

Cmax > 2500 ng/dL

None

2.0%


Safety Summary:

  • Adverse Events and Adverse Drug Reactions
    • AE's occurring in more than 5% of subjects with either treatment were upper respiratory tract infection (5.2% with LPCN 1021 and 5.8% with active control) and fatigue (2.4% with LPCN 1021 and 6.7% with active control).
    • No reported hepatic, cardiac, or drug-related serious adverse events occurred with either treatment.
    • None of the cardiac adverse events occurred in more than 1% of subjects in LPCN 1021 arm, and none were classified as severe.
    • ADRs, drug-related AEs, occurring in more than 2% of subjects with either treatment were headache (0.5% with LPCN 1021 and 3.9% with active control), acne (2.9% with LPCN 1021 and 2.9% with active control) and patient reported weight increase (2.4% with LPCN 1021 and 0% with active control).
    • Weight changes greater than 10% from baseline over 52 weeks occurred in 2.3% of subjects with LPCN 1021 and 3.8% of subjects with active control.
    • All observed adverse drug reactions were classified as mild or moderate in severity and no serious ADRs occurred during the 52-week treatment period.
  • Other Safety Parameters
    • No significant changes in mean systolic and diastolic blood pressure from baseline for either treatment.
    • Mean HDL level following LPCN 1021 decreased slightly from baseline but was not significantly different from the active control after 52 weeks.
    • Mean hematocrit, hemoglobin, platelet count, prothrombin time, and prostate specific antigen values were not significantly different from baseline.
    • Mean DHT levels increased from baseline following LPCN 1021 but were comparable to changes seen with active control.
  • Additional study results
    • LPCN 1021 achieved consistent intraday and interday performance

Phase 1 Food Effect Study

The food effect study was a single-center, open-label, randomized, single-dose, 4-period, 4-way crossover study. Subjects received the recommended starting dose of LPCN 1021, 225 mg as a single dose under fasted conditions and under the following fed conditions: approximately 30 minutes following an 800 to 1000 calorie meal with ~15% of calories from fat (i.e., low fat meal), ~30% calories from fat (i.e., standard fat meal), and ~50% calories from fat (i.e., high fat meal).

  • Bioequivalent levels of testosterone (Cmax and AUC) were achieved when LPCN 1021 was administered with various fat content of meal

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