Pam Harrison

June 02, 2015

Two novel formulations of oral testosterone normalize serum concentrations with no minimal transient excursions into supraphysiologic testosterone levels, a pair new studies suggests.

"Oral testosterone has been sought after because it is convenient, there is no transference like there is with gels and, unlike injections and gels, there is no pain or rash," said Michael Oefelein, MD, from Riverwalk Surgery in Bakersfield and TesoRx Pharma in Pomona, California.

"But the oral administration of testosterone has been challenged by gastric degradation. It is poorly soluble in an aqueous environment so it doesn't get absorbed, and it is metabolized at a very high rate in the small bowel wall or in the liver — a high first-pass metabolic effect," Dr Oefelein told Medscape Medical News.

"These three issues have blunted the ability to formulate and deliver testosterone orally," he explained.

Both studies were presented at the American Urological Association 2015 Annual Meeting in New Orleans.

The SOAR Trial

Different formulations have been developed to resolve these challenges, including an oral formulation of testosterone undecanoate known as LPCN 1021, which is under development by Lipocine.

Results from the SOAR trial of LPCN 1021 were presented by Jed Kaminetsky, MD, from Manhattan Medical Research and the New York University School of Medicine in New York City.

The 12-month randomized open-label multicenter dose-titration trial involved 315 hypogonadal men — with testosterone levels below 300 ng/dL — who were 18 to 80 years of age.

Of the 315 study participants, 210 men were randomized to twice-daily oral LPCN 1021 at a starting dose of 225 mg and 105 men were randomized to testosterone gel 1.62%.

For men in the LPCN 1021 group whose 24-hour average testosterone concentration remained below 300 ng/dL, the dose could be titrated up. If maximum concentration was above 1500 ng/dL, the dose could be titrated down.

At week 13, 24-hour average testosterone concentration was assessed.

Mean 24-hour average testosterone concentration was 447 ng/dL, "which is consistent with nonoral testosterone replacement therapies," he added.

Furthermore, only about 17% of men exceeded the maximum concentration of 1500 ng/dL, and less than 5% of the men had maximum concentrations ranging from 1800 to 2500 ng/dL.

With this formulation of LPCN 1021, the US Food and Drug Administration (FDA) set average testosterone concentrations from 300 to 1140 ng/dL, and "88% of men were within that threshold," Dr Kaminetsky told Medscape Medical News.

Although a few men exceeded the 2500 ng/dL maximum concentration, "we have 24-hour blood levels and we know that these excursions were sporadic, brief, and transient," he said.

The majority of men required one or no dose adjustments, suggesting that the titration algorithm used in this study is safe and effective.

The full 12-month safety dataset will be available shortly, Dr Kaminetsky said.

So far, no significant cardiac-related or drug-related adverse events have been seen with LPCN 1021. Minor gastrointestinal complaints have been the most common adverse effects reported.

Proliposomal Formulation

Dr Oefelein presented results from an open-label phase 2 study of TSX-002, a novel proliposomal oral formulation of unmodified testosterone. The liposomal formulation is absorbed by the intestinal lacteals, bypassing the portal vein and hepatic metabolism.

The 17 symptomatic hypogonadal men — testosterone levels below 300 ng/dL — received TSX-002 120 mg twice daily for 15 days.

Average testosterone concentration decreased over the study period, from 384.77 ng/dL on day 1 to 306.47 ng/dL on day 15.

The ratio of dihydrotestosterone to testosterone — an important factor in the expression of androgenic activity — ranged from 0.10 to 0.25 over 24 hours, which is within the normal range of 0.05 to 0.33.

No testosterone levels exceeded 1500 g/dL in the group, and there were no serious adverse events.

In 86% of the men, serum testosterone levels normalized to a 24-hour average concentration of 300 to 1050 ng/dL.

Fatty Food Requirements

Because testosterone undecanoate is an ester of testosterone, LPCN 1021 must be taken with fatty food. "If you don't take fatty food with the pill, absorption will be minimal or significantly reduced," Dr Oefelein explained.

"Conversely, the more fat in your diet, the higher the absorption with the undecanoates, so it becomes quite challenging to titrate the testosterone," he added.

The vagaries in absorption can be minimized in a clinical trial setting where meal plans are controlled. "But when people go out into their lives and make decisions about what to eat, they'll have much different exposures to the medication," he explained.

In contrast, TSX-002 is dosed on an empty stomach, so men do not have to worry about what they eat when they take the pill.

Not having fat interfere with absorption makes TSX-002 safer, Dr Oefelein said, because it is easier to avoid supraphysiologic and subtherapeutic levels of testosterone.

At this point, "we just have early evidence of clinical benefit, along with our pharmacokinetic profile data showing that we do normalize testosterone after dosing," Dr Oefelein said.

"But as we develop the drug, we are definitely planning larger phase 3 trials," he reported. In addition, the team is planning "phase 3a trials in which you might get a label extension for different patient-reported outcomes."

Another oral formulation of testosterone undecanoate — Rextoro (Clarus Therapeutics) — was recently rejected by the FDA on the grounds that there was insufficient evidence to conclude that the testosterone prodrug is effective.

An effective oral therapy for testosterone replacement would be welcomed by both patients and the healthcare providers who treat them, said session comoderator Kevin Billups, MD, from the Johns Hopkins School of Medicine in Baltimore.

These two agents "show clinical promise as oral therapies but will need further testing in ongoing investigations," he told Medscape Medical News.

The SOAR study was funded by Lipocine, the developer of LPCN 1021. As principle investigator of SOAR, Dr Kaminetsky received compensation from Lipocine. The TSX-002 study was funded by TesoRx, where Dr Oefelein is chief medical officer. Dr Billups has disclosed no relevant financial relationships.s

American Urological Association (AUA) 2015 Annual Meeting: Abstracts PD37-08 and PD37-02. Presented May 18, 2015.


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