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TLANDO is a novel oral product candidate of Testosterone (T) containing Testosterone Undecanoate (TU) that is designed to help restore normal T levels in males for conditions associated with a deficiency or absence of endogenous testosterone.
TLANDO is designed to overcome many of the issues related to TRT products on the U.S. market. TLANDO received a Complete Response Letter from the FDA on June 28, 2016 with two new clinical studies being conducted to address the deficiency cited. TLANDO is being studied for both Primary and Secondary hypogonadism and is targeted to the established chronic US TRT market.
LPCN 111 Once a day Oral TRT
LPCN 1111 is a next-generation, novel ester prodrug of testosterone which uses the Lip'ral technology to enhance solubility and improve systemic absorption. We completed a Phase 2b dose finding study in hypogonadal men in the third quarter of 2016. The primary objectives of the Phase 2b clinical study were to determine the starting Phase 3 dose of LPCN 1111 along with the safety and tolerability of LPCN 1111 and its metabolites following oral administration of single and multiple does in hypogonadal men. The Phase 2b clinical trial was a randomized, open label, two-period, multi-dose PK study that enrolled hypogonadal males into five treatment groups. Each of the 12 subjects in a group received treatment for 14 days. Results of the Phase 2b study suggest that the primary objectives were met, including identifying the dose expected to be tested in a Phase 3 study. Good dose-response relationship was observed over the tested dose range in the Phase 2b study. Additionally, the target Phase 3 dose met primary and secondary end points. Overall, LPCN 1111 was well tolerated with no drug-related severe or serious adverse events reported in the Phase 2b study.
Additionally in October 2014, we completed a Phase 2a proof-of-concept study in hypogonadal men. The Phase 2a open-label, dose-escalating single and multiple dose study enrolled 12 males. Results from the Phase 2a clinical study demonstrated the feasibility of a once daily dosing with LPCN 1111 in hypogonadal men and a good dose response. Additionally, the study confirmed that steady state is achieved by day 14 with consistent inter-day performance observed on day 14, 21 and 28. No subjects exceeded Cmax of 1500 ng/dL at any time during the 28-day dosing period on multi-dose exposure. Overall, LPCN 1111 was well tolerated with no serious AE's reported.
We have initiated a preclinical toxicology study with LPCN 1111 and once complete we plan to meet with the FDA for an End of Phase 2 meeting. We anticipate the End of Phase 2 meeting will occur in the fourth quarter of 2017.
LPCN 1107 to address Pre-term Birth
LPCN 1107, Lipocine's oral hydroxyprogesterone caproate (HPC) product candidate has the potential to become the first oral HPC product indicated for the reduction of risk of preterm birth (PTB) in women with singleton pregnancy who have a history of at least one singleton spontaneous PTB. Prevention of PTB is a significant unmet need as ~ 11.7% of all U.S. pregnancies result in a PTB (delivery less than 37 weeks), a leading cause of neonatal mortality and morbidity. 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 with potential to improve clinical outcomes relative to the current IM therapy.
A multi-dose PK dose selection study in pregnant women has been completed. The objective of the multi-dose PK selection study was to assess HPC blood levels in order to identify the appropriate LPCN 1007 Phase 3 dose. The multi-dose PK dose selection study was an open-label, four-period, four-treatment, randomized, single and multiple dose, PK study in pregnant women of three dose levels of LPCN 1107 and the injectable intramuscular ("IM") HPC (Makena®). The study enrolled 12 healthy pregnant women (average age of 27 years) with a gestational age of approximately 16 to 19 weeks. Subjects received three dose levels of LPCN 1107 (400 mg BID, 600 mg BID, or 800 mg BID) in a randomized, crossover manner during the first three treatment periods and then received five weekly injections of HPC during the fourth treatment period. During each of the LPCN 1107 treatment periods, subjects received a single dose of LPCN 1107 on Day 1 followed by twice daily administration from Day 2 to Day 8. Following completion of the three LPCN 1107 treatment periods and a washout period, all subjects received five weekly injections of HPC. Results from this study demonstrated that average steady state HPC levels (Cavg0-24) were comparable or higher for all three LPCN 1107 doses than for injectable HPC. Additionally, HPC levels as a function of daily dose were linear for the three LPCN 1107 doses. Also unlike the injectable HPC, steady state exposure was achieved for all three LPCN 1107 doses within seven days. We have also completed a proof-of-concept Phase 1b clinical study of LPCN 1107 in healthy pregnant women in January 2015 and a proof-of-concept Phase 1a clinical study of LPCN 1107 in healthy non-pregnant women in May 2014. These studies were designed to determine the PK and bioavailability of LPCN 1107 relative to an IM HPC, as well as safety and tolerability.
A traditional pharmacokinetics/pharmacodynamics ("PK/PD") based Phase 2 clinical study in the patient population is not expected to be required prior to entering into Phase 3. Therefore, based on the results of our multi-dose PK study an End-of-Phase 2 meeting with the FDA occurred as well as other guidance meetings with the FDA to define a Phase 3 development plan for LPCN 1107. During the End-of-Phase 2 meeting and subsequent guidance meetings, the FDA agreed to a randomized, open-label, two-arm clinical study to include a LPCN 1107 arm and a comparator IM arm with treatment up to 23 weeks. The FDA also provided feedback on other critical Phase 3 study design considerations including: positive feedback on the proposed 800 mg BID Phase 3 dose and dosing regimen; confirmation of the use of a surrogate primary endpoint focusing on rate of delivery less than 37 weeks gestation rather on clinical infant outcomes; acknowledged that the use of a gestational age endpoint would likely lead to any FDA approval, if granted, being a Subpart H approval as opposed to a full approval; and, recommended a non-inferiority study margin of 7% with interim analyses. A standard statistical design for a NI study based on the FDA feedback, a NI margin of 7% for the primary endpoint may require ~1,100 subjects per treatment arm with a 90% power. However, based on the FDA's suggestion of including an interim analysis in the NI design, an adaptive study design is under consideration that may allow for fewer subjects. Lipocine plans to submit the LPCN 1107 Phase 3 protocol to the FDA via a SPA in the second quarter of 2017. Additionally, manufacturing scale-up work for LPCN 1107 is on-going and must occur before the start of the Phase 3 clinical study for LPCN 1107. A planned food-effect study will also need to be conducted either before or in parallel with the Phase 3 clinical study.
The FDA has granted orphan drug designation to LPCN 1107 based on a major contribution to patient care. Orphan designation qualifies Lipocine for various development incentives, including tax credits for qualified clinical testing, and a waiver for the prescription drug user fee when we file our NDA.