While there has been evidence of a relationship between low free testosterone (T) levels and non-alcoholic steatohepatitis (NASH) as well as between fibrosis and non-alcoholic fatty liver disease (NAFLD), until recently it had not yet been supported by a biopsy confirmed study in humans. The authors of a recent poster, Sarkar, et al. did identify this relationship between low free T and NASH and between fibrosis and biopsy confirmed NAFLD enrolling adult men with a full spectrum of biopsy confirmed NAFLD. The relationship had been suspected for some time, motivating the research conducted by Sarkar, et al.1 which demonstrated an association between free testosterone and NASH. Results of the work found NAFL patients with free T concentrations of 7.2 ng/dL (ranging from 5.3 to 9.8 ng/dL in 44 individuals) and to NASH patients with concentrations of 5.3 ng/dL (ranging from 3.7 to 8.9 ng/dL in 115 individuals) indicating a decline in the hormone as the disease progresses. Another critical observation from the study was the lack of fibrosis in the NAFL subjects compared to the presence of fibrosis in 28 or 18% of the NASH subjects.
The low median total T level for NAFL (264 ng/dL) and NASH (304 ng/dL) patients suggests that testosterone replacement therapy (TRT) could benefit all NASH patients rather than just a subset. Based on this and other related research, Lipocine (NASDAQ:LPCN) worked with the FDA to explore administering LPCN 1144 to both hypogonadal patients (those below 300 ng/dL of T) and eugonadal males. If the assumption that this will address fatty liver proves successful, this could expand the addressable market for TRT therapy. In a July 23rd release, Lipocine announced that its efforts had been successful and it received FDA clearance for testing LPCN 1144 in patients with total testosterone above 300 ng/dL. This expansion recognizes meaningful liver fat reductions observed in a proof of concept study in hypogonadal males and the Sarkar et al. results. Sarkar data indicated 75% of biopsy confirmed NASH subjects are below 372 ng/dL of total testosterone and that the degree of fibrosis severity is inversely related to free testosterone levels.
Research on the subject suggests that NAFLD is also associated with several other ailments beyond NASH and NAFLD. Sarcopenia in patients with NAFLD is linked to a greater probability of steatohepatitis or advance liver fibrosis as found in Yu et al.2 Another meta-analysis concluded that there is a link between NAFLD and male sexual and reproductive dysfunction3. Testosterone is additionally seen as associated with bone density, hematopoiesis, memory impairment and other conditions and could potentially provide relief4.
Testosterone therapy presents a profile that is favorable for chronic use, as it is a natural hormone generated by the body. Additionally, research has demonstrated gastrointestinal tolerability for the hormone, no increase in low density lipoprotein (LDL), and no signs of nephrotoxicity, skeletal fragility, or drug induced liver toxicity. Over 700 subjects have participated in 14 Lipocine studies with up to 52 weeks of exposure to the testosterone molecule. No signs of drug induced liver enzyme toxicity, no deaths or major adverse cardiovascular events, or drug related serious adverse events were observed. Safety studies for testosterone have been extensive in contrast to other in-development NASH therapies that have not yet been approved for human use and are associated with elevated LDL, fatigue, diarrhea, headache and other adverse side effects.
View Exhibit I – Safety Risks Associated with Select Classes of Competing NASH Therapies5
As Lipocine advances its newest candidate, it appears that the environment for TRT is also moving in the right direction. In May, TLANDO received a November 9, 2019 Prescription Drug User Fee Act (PDUFA) goal date, as provided by the FDA. This was preceded by two other TRT therapy approvals including Antares Pharma’s injectable testosterone enanthate, branded Xyosted. Xyosted was approved in October 2019 and was launched in November 2018.
Antares’ new and experienced sales team combined with a strong marketing push and less competitive pressure from previous generations of testosterone has created the setting for a strong launch. As generic options have emerged in the gels, restrictive contracts with payors appear to be fading. Xyosted sales of $70,000 in the month of December, grew to almost $2 million in the month of May. Weekly total prescriptions exited 2018 at 26 rising to 980 by the last week of June 20196. The 26% growth in weekly prescriptions from May to June suggests a similar increase in month over month sales. This strong performance out of the gate points to a favorable environment for new and improved testosterone therapies. We think Lipocine’s oral option is the most convenient for patients compared to injection, patches or gels. If approved, a fixed dose oral option would be easy to use for patients as it would not require additional dose adjustments or related doctor visits. It should also be less confusing for prescribers as it is not prone to titration decision errors and predictable from a cost perspective for payors relative to products that need significant up-titration in dose.
Lipocine has an attractive portfolio of candidates with the two testosterone-based products garnering the most attention. TLANDO, which has been issued a PDUFA date and LPCN 1144 which has been cleared for a Phase II trial are both in a strong position to address unmet needs in the TRT and NASH spaces. Tlando offers the additional ease of an oral capsule with no titration while LPCN 1144 has an extensive history and substantial research supporting its favorable association with improving fatty liver. We are looking forward to further updates as Lipocine reports second quarter earnings in the next few weeks.
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1. Sarkar, Monika; et al. Poster: Low Testosterone Is Associated with NASH and Fibrosis Severity in Men With Non-Alcoholic Fatty Liver Disease (NAFLD).
2. Yu, Rui; et al. Relationship of sarcopenia with steatohepatitis and advanced liver fibrosis in non-alcoholic fatty liver disease: a meta-analysis. BMC Gastroenterology (2018) 18:51
3. Hawksworth, Dorota; Burnett, Arthur. Nonalcoholic Fatty Liver Disease, Male Sexual Dysfunction and Infertility: Common Links, Common Problems.
4. Seidman, SN. Testosterone deficiency and mood in aging men: pathogenic and therapeutic interactions. World J Biol Psychiatry. 2003 Jan;4(1):14-20.
5. Source: Lipocine July 2019 Slide Deck
6. RAPID Weekly Audit from June 30, 2017 to July 5, 2019