FDA advisory vote on TLANDO not a knockout for Lipocine

Although Lipocine (NASDAQ:LPCN) is disappointed by a FDA advisory committee vote against the benefit/risk profile of TLANDO, its oral testosterone replacement therapy (TRT), the company believes there is still a path forward for TLANDO.

“Efficacy and safety results from numerous clinical studies with TLANDO are consistent with other FDA approved TRT products,” Morgan Brown, EVP and CFO of Lipocine, says in an interview with BioTuesdays.

“We are currently assessing appropriate clinical and regulatory next steps,” he adds. “We continue to believe that we have the right dose for a TRT therapy, which has comparable blood pressure data to AndroGel 1.62%,” an approved topical TRT, which comes with a Black Box warning, however, about secondary transfer to women and children.

Earlier this month, the Bone, Reproductive and Urologic Drugs Advisory Committee of the FDA voted six in favor and thirteen against the benefit/risk profile of TLANDO, an oral pill indicated for conditions associated with a deficiency of endogenous testosterone, also known as hypogonadism, in adult males.

The FDA decision on whether or not to approve the TLANDO NDA is anticipated by the assigned PDUFA date of May 8, 2018. The NDA includes efficacy and safety data on TLANDO, including results from three Phase 3 clinical trials.

Notwithstanding the TLANDO setback, Mr. Brown contends that Lipocine has a very robust product candidate pipeline outside of its lead asset.

“Our next generation oral TRT product candidate, LPCN 1111, has the potential for once-daily dosing and we currently have a meeting scheduled with the FDA in February to discuss a Phase 3 clinical protocol,” he points out.

In addition, Lipocine has potentially the first oral product candidate, LPCN 1107, for the prevention of preterm birth. LPCN 1107 has received orphan drug designation from the FDA.

Mr. Brown says broad stroke agreement has been reached with the FDA on the Phase 3 protocol for LPCN 1107 and a final agreement will occur once a food/fat effect study is complete.

While Lipocine has demonstrated that TLANDO can reliably increase testosterone levels for 10-to-12 hours on a single dose, the company’s next generation oral TRT, LPCN 1111, can reliably increase testosterone levels for 22-to-24 hours on a single dose.  Both product candidates use Lipocine’s Lip’ral technology to enhance solubility and improve systemic absorption.

Mr. Brown explains that LPCN 1111 has demonstrated feasibility of once-daily dosing in Phase 2a and 2b clinical trials. “Our single-daily oral dose provides testosterone levels in the eugonadal range, with obvious market share benefits,” he adds.

Primary objectives were met in the Phase 2b study, including identifying the dose to be tested in a Phase 3 study. Good dose-response relationship was observed over the tested dose range in the Phase 2b study and the target Phase 3 dose met primary and secondary end points. LPCN 1111 also was well tolerated with no drug-related severe or serious adverse events.

Hypogonadism affects up to 20 million men in the U.S., of which six million have been diagnosed. While 2.2 million currently are being treated, some 3.8 million have been diagnosed but are untreated.

Mr. Brown points out that market research suggests there is high interest for an oral TRT product, with 85% of interviewed physicians having a strong interest in an oral alternative to treat hypogonadism and 94% of interviewed patients likely to ask their physician about an oral TRT alternative.

In its women’s health division, Mr. Brown says LPCN 1107 has the potential to be the first oral product for the prevention of recurrent preterm birth, which is any delivery before 37 weeks of gestation and represents an unmet medical need.

The current standard of care is AMAG’s Makena, which requires 20-to-22 weekly intramuscular injections to prevent recurrent preterm birth. Makena is administered through a 21-guage needle, with each treatment of the viscous oily product taking up to one minute. During clinical testing of Makena, some 35% of women experienced injection site pain and 17% reported injection site swelling, exceeding placebo.

According to the CDC, 12% of all annual U.S. pregnancies result in preterm birth, a leading cause of neonatal mortality and morbidity. Published studies also indicate that 28% of preterm births are to women with a history of early delivery and first year medical costs for preterm birth infants can be 10 times higher than full term infants.

Mr. Brown explains that LPCN 1107 contains the same active ingredient – hydroxyprogesterone caproate – as Makena and “we believe that an oral alternative has the potential to be a major contributor to patient care.”

Lipocine has completed an end-of-Phase 2 meeting with the FDA and submitted its Phase 3 protocol for LPCN 1107 via a special protocol assessment. Manufacturing scale up work has recently been completed in preparation for a pivotal trial.

Mr. Brown says the Phase 3 trial would be a non-inferiority study of LPCN 1107 against intramuscular injections of Makena, with a one-to-one randomization, and primary efficacy analysis using a pre-specified non-inferiority margin of 7%.

The Phase 3 protocol also includes an adaptive design, with an interim analysis, that will allow Lipocine to review the results after roughly one-third of the subjects have completed the study and determine if the results are consistent with pre-determined endpoints.

“If an interim analysis indicates that we are on track to demonstrate non-inferiority based on superiority assumptions, we may be able to enroll fewer subjects in the study before seeking regulatory approval,” he adds.

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