Lipocine Testosterone Therapy Faces Safety, Stopping Criteria Concerns At US FDA Advisory Cmte

Tlando's product would offer convenient oral route of administration, but may carry some secondary (endpoint) problems.

A failure of Lipocine Inc.'s Tlando (testosterone undecanoate) to meet any of its three pre-specified maximal serum testosterone concentrations (Cmax) secondary endpoints highlights a series of issues the testosterone replacement therapy will have to overcome in front of a US FDA panel in its quest for approval.

The agency's Bone, Reproductive, and Urologic Drugs Advisory Committee will convene Jan. 10 to discuss a slew of safety issues related to Tlando, as well as Lipocine's proposed stopping criteria for the oral treatment.

Lipocine is specifically seeking an indication identical to that for the class of other FDA-approved testosterone therapies as a replacement therapy in adult men for conditions associated with a deficiency or absence of endogenous testosterone. The product's key advantage over existing therapies would be the convenience of the oral route of administration compared to topical formulations, a buccal system, an intranasal gel, intramuscular injections and subcutaneously implanted pellets.

If Tlando is approved, the agency says in briefing documents released Jan. 8 in advance of the meeting, "it will likely dramatically change the landscape of testosterone therapies, because the oral route of administration will be considerably easier to use than the more cumbersome routes of administration available with the commonly used marketed products."

The same holds true for its potential rival, Clarus Therapeutics Inc.'s Jatenzo (testosterone undecanoate) which the advisory committee is reviewing the day before. (Also see "Oral Testosterone Therapy Jatenzo Faces CV, Sampling Tube Issues At Advisory Cmte" - Pink Sheet, 8 Jan, 2018.)

Tlando is in the middle of its second review cycle after previously landing a complete response letter in June 2016, which cited the generalizability of the titration scheme as a deficiency. Specifically, FDA raised concerns about the proposed dosing algorithm for clinical practice, which differed from the titration scheme used in a 52-week Phase III trial, which included which included an Androgel (testosterone gel) 1.62% comparator arm. (Also see "Oral Testosterone Battle Looms As Lipocine's Tlando Joins Clarus' Jatenzo In US FDA Review Queue" - Pink Sheet, 14 Aug, 2017.)

Lipocine is now seeking approval for Tlando as a fixed dose of 225 mg twice daily with no titration after conducting two additional 24-day, open-label Phase III studies evaluating the safety and efficacy of the drug in adult hypogonadal male subjects. Patients in one trial received 225 mg of Tlando two times a day, while patients in the other trial received 150 mg of Tlando three times a day.

The 150 mg dose, however, did not meet the primary endpoint of the percentage of Tlando-treated subjects achieving a 24-hour average serum testosterone concentration within the normal range. Lipocine is therefore only pursuing approval for the 225 mg dose.

Following a Class 2 resubmission, Tlando has a Prescription Drug User Fee Act (PDUFA) date of Feb. 9, 2018 or earlier.

Elevated Cmax

Trials for testosterone therapies have three standard secondary endpoints to assess for "unacceptably high maximal exposures to testosterone that could potentially raise safety concerns," the briefing documents state.

Yet, the 225 mg dosage failed to meet any of the three targets, which will likely garner significant attention from the advisory committee. Jatenzo, conversely, met two of the Cmax criteria.

"We will seek the advisory committee’s input on the relevance of these findings to the safe use of Tlando" FDA says.

Measure	Target	T Cmax (0-24h)
Cmax(0-24h) ≤ 1500 ng/dL in ≥ 85% of subjects	≥ 85%	74%
Cmax(0-24h) between 1800 and 2500 ng/dL in ≤ 5% of subjects	≤ 5%	14%
Cmax(0-24h) > 2500 ng/dL in no subjects	No subject	One subject

A Flawed Stopping Criteria?

Another area where FDA raised concerns is Lipocine's proposed stopping criteria, which the agency feels might lead to patients discontinuing use of Tlando unnecessarily.

Roughly 80% of patients taking the 225 mg dose achieved a time-averaged testosterone concentration (Cavg) in the target range, according to FDA, which means some patients will not achieve the target ranges of testosterone concentrations and should therefore discontinue treatment.

Lipocine is proposing serum testosterone concentrations be measured 7 to 9 hours after the morning dose after at least 3-4 weeks on the drug, and stopping medication if concentrations are consistently below 300 ng/dL or above 1080 ng/dL.

While the drugmaker says this approach would identify most patients with non-therapeutic testosterone Cavg, FDA noted that 30% of patients met this criterion in the Phase III trial for the 225 mg dose.

"This suggests that while the proposed criteria may lead to appropriate discontinuation of patients not achieving Cavg within the normal range it may also result in a large percentage of patients being discontinued inappropriately," the briefing documents state.

Other Safety Issues

Just as with Jatenzo, cardiovascular safety issues will also come under the spotlight before the advisory committee.

All approved testosterone replacement therapies contain a warning in the label that some studies have reported an increased risk of major adverse cardiovascular events associated with the use of the therapies. However, the initial 52-week trial appears to have some reassuring data, as patients in the Tlando arm had a consistent decrease from baseline in mean systolic blood pressures and mean diastolic blood pressures.

FDA nevertheless feels the blood pressure data are limited by the non-duplicative (single morning) cuff pressure readings, open-label trial design and 38% dropout rate in the Tlando arm.

"FDA cardiologists concluded that we cannot definitively exclude a blood pressure effect with Tlando and recommend that the Applicant perform an ambulatory blood pressure monitoring study to further assess the effects of Tlando on blood pressure and heart rate," according to the briefing documents.

Lipid parameters will also be part of the cardiovascular risk discussion at the meeting.

The agency additionally raises the alarm with Lipocine's use of plain tubes to collect serum and analyze testosterone concentrations in the clinical trials. Although these tubes are commonly used for measuring testosterone concentrations FDA says, they do not contain an esterase inhibitor, and any esterases present in the serum sample could convert testosterone undecanoate to testosterone.

"If there is significant ex vivo conversion to testosterone, those testosterone data would not reliably reflect endogenous testosterone concentrations," the agency says. "The data presented by the Applicant regarding the extent of ex vivo conversion to testosterone are conflicting."

Lipocine's data on testosterone undecanoate concentration appear to be stable, the briefing documents state. FDA, however, suggests that measuring testosterone undecanoate directly "may not be a sensitive method to detect small changes, and because [testosterone undecanoate] is present at very high concentrations in blood compared to testosterone, conversion of a small fraction of [testosterone undecanoate] to testosterone would result in a large change in testosterone concentrations."

Lastly, FDA is calling on its advisory committee to discuss the safety issues related to elevated dihydrotestosterone (DHT) and estradiol concentrations in Tlando patients, as well the drug's possible link to adrenal insufficiency.