Lipocine Inc. continues to march forward with its 138-subject ambulatory blood pressure monitoring (ABPM) study in patients given the oral testosterone replacement therapy (TRT) Tlando as new discoveries roll out regarding not only the cardiovascular (CV) risk for men on TRTs but also the value of such treatments in easing depression, an idea that has been the subject of much debate.
Salt Lake City-based Lipocine undertook the ABPM study – one of two – to satisfy concerns raised by the FDA in a complete response letter (CRL) delivered in May. One test is a small phlebotomy experiment designed to rule out ex-vivo conversion of testosterone undecanoate to testosterone, thus validating phase III efficacy and safety data, but the main piece of the Tlando puzzle that remains to be fitted is the 16-week, 24-hour ABPM trial. It's due to yield data in the first quarter of next year and intended to assure regulators that Tlando patients need not worry about clinically meaningful increases in blood pressure brought about the product.
In January, the FDA's Bone, Reproductive and Urologic Drugs Advisory Committee made known its safety concerns. While six committee members supported approval of the undecanoate capsule as a TRT for men with primary hypogonadism and hypogonadotropic hypogonadism, 13 panelists said the overall benefit/risk profile was not acceptable. They were particularly concerned about the risks for patients who are older, obese, diabetic and prone to CV issues. The majority of the panelists advised more clinical study, particularly with regard to blood pressure monitoring. They also suggested Lipocine further study testosterone measures in serum and the effects of clotting on measurement, adding that the most meaningful studies would consider real-world implications about sample testing, including the temperature of the sample and the time span from acquiring the sample to testing it.
More recently, researchers at Azienda Usl Bologna Maggiore-Bellaria Hospital in Bologna, Italy, published in Expert Review of Cardiovascular Therapy their meta-analysis of 31 randomized controlled trials made known from 2010 to 2018 in which 2,675 and 2,308 men received TRT and placebo, respectively. In the 16 studies that examined instances of acute coronary syndrome, acute myocardial infarction, stroke, heart failure, or CV mortality, TRT did not line up with significantly more major adverse CV events than placebo, and in the analysis overall, TRT was let off the hook with regard to arrhythmias and other CV-related problems.
The trials didn't go beyond three years, so it's possible that CV trouble with TRT could surface later, but results seem to favor a clean CV profile for TRTs.
The other meta-analysis appeared in JAMA Psychiatry and took in 27 studies. It involved 1,890 men and was carried out by investigators at the Technische Universität Dresden institute in Germany. TRT was associated with a significant reduction of depressive symptoms, especially at the upper range of dosing, with men's moods improving in the first six weeks, whether the subjects were old or young.
"Meta-regression models suggested significant interactions for testosterone treatment with dosage and symptom variability at baseline," the study said. "In the most conservative bias scenario, testosterone treatment remained significant whenever dosages greater than 0.5 g per week were administered and symptom variability was kept low." Authors, however, did note that "given the heterogeneity of the included randomized, placebo-controlled clinical trials, more preregistered trials are needed that explicitly examine depression as the primary endpoint and consider relevant moderators."
Lipocine's Tlando turned up no meaningful blood pressure signal across its full 52-week safety study, and recorded fewer hypertension-related adverse events head-to-head vs. market leader Androgel (testosterone gel, Abbvie Inc.). U.S. regulators, though, were made queasy by the signal that arose with a potentially competing oral TRT called Jatenzo from Northbrook, Ill.-based Clarus Therapeutics Inc., also tested in an ABPM study. Results proved worrisome enough that gatekeepers were unwilling to accept the Tlando phase III results, collected only with single cuff-measurements at office visits. What's next? H.C. Wainwright analyst Orin Livnat expects Lipocine to come out on top.
"We are optimistic that the Tlando 24-hour ABPM will confirm its safety profile, and think the competitor possibly had a worse CV signal due to dose levels as much as 70 percent above Lipocine's," he wrote in a Nov. 19 report.
Testosterone's link to diabetes has been investigated lately, too. TRT knocked down mortality in men with type 2 disease regardless of improvements in CV disease risk factors, according to a paper in BJU International. Researchers examined data on 857 U.K. men gathered between April 2007 and April 2009 for a double-blind, randomized, placebo-controlled trial studying testosterone undecanoate at a 1,000 mg dose.
In late November, Antares Pharma Inc., of Ewing, N.J., launched Xyosted (testosterone enanthate) for injection as a TRT for adult males for conditions associated with a deficiency or absence of endogenous testosterone. Xyosted, an androgen, was approved by the FDA in September as a once-weekly subcutaneous injection via a single-dose, disposable Quickshot autoinjector.
Also in the oral testosterone game is San Francisco-based Tesorx Pharma LLC, which recently disclosed an expanded deal with Aska Pharmaceutical Co. Ltd., of Tokyo, to develop and commercialize the former's TSX-011 in Japan, so that the arrangement will include Southeast Asia. The parties also have agreed to include exclusive rights for the treatment of constitutional delay in growth and puberty (CDGP) in the two territories.
At the same time, Aska made an equity investment in Tesorx. The formulation for CDGP has demonstrated appropriate testosterone levels in phase II studies in men and will be confirmed in trials for adolescent boys. In June 2016, the FDA granted the formulation orphan drug designation.
Lipocine this week learned that it will be among those to present data at the Keystone Symposia on Integrated Pathways of Disease in NASH and NAFLD in Santa Fe, New Mexico, next month. The company will offer LPCN-1144 clinical results in which liver fat was assessed via magnetic resonance imaging-proton density fat fraction in hypogonadal males. The drug is in development for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and cirrhosis.