By John Vandermosten, CFA
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In their August 2018 corporate presentation, Lipocine Inc. (LPCN) announced the pursuit of a new indication in nonalcoholic steatohepatitis (NASH). The compound addressing this indication is designated LPCN 1144 and will be similar to the current Phase 3 candidate TLANDO, which has many characteristics that may contribute to the resolution of NASH. Prior to the announcement, Lipocine examined a library of literature supportive of androgens in the treatment of NASH and also reviewed its own clinical studies for TLANDO which provide evidence of efficacy for the drug on NASH biomarkers. The company is conducting an in vivo proof-of-concept (POC) study in a biopsy-confirmed NASH animal model as well as in a POC clinical study in potential non-alcoholic fatty liver disease (NAFLD) and NASH subjects with confirmed fatty liver. The study will employ magnetic resonance imaging proton density fat fraction (“MRI-PDFF”) measurement techniques. The POC study in mice is expected to be complete in 4Q:18 and the POC liver imaging study is expected to be complete in 1Q:19 followed by a Phase 2 trial.
NASH is a more advanced state of fatty liver disease and can progress to a cirrhotic liver and eventually hepatocellular carcinoma or liver cancer. 20 to 30% of the US population is estimated to suffer from fatty liver (NAFLD) and 15 to 20% of this group progress to NASH, which is a substantially large population that lacks an effective therapy. In men, testosterone deficiency has been associated with an increased accumulation of visceral adipose tissue and insulin resistance, which are factors contributing to NAFLD and NASH1. The relationship with testosterone deficiency has attracted Lipocine’s attention to this indication where the company expects to develop its oral androgen therapy.
LPCN 1144 will use Lipocine’s Lip’ral platform technology. This is an oral formulation able to disperse an associated drug providing low variability and consistent absorption. The lipidic composition is able to provide improved solubilization and bioavailability, high drug loading capacity and reduced sensitivity to food effects. The formulation has been previously used in the development of two products for hypogonadism and one for pre-term birth. Now it is being applied to non-alcoholic fatty liver disease (NAFLD) and more specifically non-alcoholic steatohepatitis (NASH).
In recent years interest in NAFLD and NASH has surged along with the increased incidence and prevalence of the disease. Modern lifestyles are more sedentary and include diets that are high in fat, sugar and carbohydrates, all of which contribute to NAFLD and NASH. As NAFLD and NASH take the lead as contributory factors for cirrhosis, a number of programs have been put into place to identify a cure.
What is NASH?
NAFLD and NASH are a form of chronic liver disease and are common in obese, diabetic and hypertensive individuals. The condition has been increasing in prevalence over the last several decades. Based on the National Health and Nutrition Examination Survey, NAFLD has risen from 18% in about 1990 to 31% in about 2012. It is characterized by hepatic steatosis and an excess of 5% of liver mass in the absence of excessive alcohol use. The disease presents a range of severity, from early stage steatosis, to NASH, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma.
View Exhibit I - Stages of Fatty Liver
NASH is characterized by inflammation and fat accumulation in the liver. Current non-approved treatment for NAFLD and NASH is limited to Vitamin E and pioglitazone; however, their benefit accrues to non-diabetic NASH patients and only limited evidence exists for their utility in NASH patients with diabetes cirrhosis. These treatments are marginally effective for resolving NASH and there is no statistically significant improvement for fibrosis2. There are pharmaceuticals in development that show a greater level of efficacy, but they remain pre-approval and some have limiting side effects.
A healthy liver can break down fats, but can also be overtaxed by an excess of fat. Triglycerides (TG) can build up in the liver and if excessive, will not break down rapidly enough to avoid accumulation. As fat builds up, this accumulation can produce scarring, inflammation, fibrosis and cirrhosis. As fatty liver transitions to NASH, the liver begins to inflame, a prelude to the scarring and fibrosis which lead to the more serious stages of NAFLD.
The pathogenesis of NAFLD arises from an accumulation of TG and free fatty acids in the liver due to an imbalance between the influx and synthesis of lipids and the export and beta-oxidation of lipids. This first causes steatosis followed by inflammation, then hepatocyte damage and fibrosis. Other factors that also may contribute include genetic predisposition, abnormal lipid metabolism, oxidative stress among others. Oxidative stress can prevent hepatocytes from regenerating, compounding the problem.
Prevalence & Market Size
The disease is becoming more common due to its strong correlation with obesity and metabolic syndrome, including diabetes, cardiovascular disease and hypertension. NAFLD is thought to be present in about 20 to 30% of the Western population leading to liver disease. Based on estimates for drugs in development, the market size is from $203 to $404 billion. It is more common in males, where there is a 65% prevalence, suggesting a market size of $13 to $22 billion.
Diagnosis and Biomarkers
There are a number of risk factors for the disease which include diabetes, obesity and metabolic syndrome. Symptoms of early stage disease are mild, but can include fatigue, abdominal discomfort, swollen belly and jaundice. Diagnosis begins with a patient interview to identify risk factors and a physical exam. For those with signs of the disease, a blood test will be given to test for alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and other tests such as the NAFLD Fibrosis Score. Imaging may also be performed with ultrasounds, CT scans and MRI-based exams such as the liver multiscan. Imaging tests can show fat and inflammation in the liver but they are not effective in verifying fibrosis. Recent research supports the use of MRI-PDFF as a noninvasive, quantitative, and accurate measure of liver fat content to assess treatment response in early-phase NASH trials5. The gold standard for fibrosis diagnosis is a liver biopsy; however, this is an invasive test and has greater risks as compared to blood tests and imaging.
Role of Testosterone
In males, testosterone deficiency has been linked to increased visceral adipose tissue and insulin resistance. Testosterone replacement has been shown to provide a benefit to both6. Testosterone also promotes myocyte and inhibits adipocyte development thereby augmenting muscle mass, in contrast to testosterone deficiency which enhances greater fat mass7. Testosterone is also shown to improve the number of β-andrenergic receptors which play a role in promoting lipolysis and reducing fatty acid synthesis8.
A review of the extant literature on the relationship between testosterone and NAFLD provides compelling support for an inverse relationship between testosterone levels and incidence of NAFLD. The hormone has several beneficial effects related to NAFLD including improvement in lipid homeostasis, reduction in inflammation, mediation of fibrosis, regeneration of liver and anabolic effects. The disease originates from several biological mechanisms that interact with multiple body systems as illustrated in the following exhibit.
View Exhibit II - Proposed Mechanism of Androgen Action via Androgen Receptor (Males)9
During the development of Lipocine’s lead testosterone candidate Tlando, researchers at Lipocine noted a strong inverse correlation between testosterone levels and NAFLD / NASH biomarkers. Researchers observed that testosterone therapy in hypogonadal men normalized key elevated biomarkers of NAFLD / NASH. Not only is this relationship supported by a broad selection of scientific literature but also in the study results for Lipocine’s own SOAR and Dosing Validation (DV) trials. Many of the subjects in the trials presented typical comorbid conditions associated with NASH and reductions in biomarkers associated with fatty liver disease. We first cite a preclinical in vivo study in a rat model conducted at UCLA and presented in 2014.
In the animal model, rats were placed in four groups:
‣ normal gonadal function - regular diet,
‣ normal models - high fat diet,
‣ castrated models - high fat diet and
‣ castrated models - high fat diet with testosterone replacement
The results of the study demonstrated that testosterone deficiency led to diet-induced hepatic steatosis and that testosterone replacement in hypogonadal animals reduces hepatic steatosis and inflammation10.
Human studies have also shown prevalence of testosterone deficiency across the NAFLD histological spectrum wherein low testosterone was independently associated with NAFLD with an inverse relationship between testosterone and NAFLD. A study in 1,944 Korean men found that those diagnosed with NAFLD had lower levels of testosterone compared to a control group11. In Italy, 55 males with spinal cord injury were examined and subjects with lower total testosterone levels (<300 ng/dL) were at twelve times greater risk of NAFLD compared to those with higher levels12. In another study13, serum levels of free testosterone were measured in 66 Japanese men with NAFLD and in 82 age-matched healthy men. Liver histology (i.e., biopsy) was also evaluated in 44 patients with NAFLD. Of the 44 patients, 25 were diagnosed with NASH. Patients with NASH showed significantly lower levels of free testosterone than those with NAFLD. The levels of free testosterone decreased significantly with the increased incidence of lobular inflammation (p <0.001), hepatocyte ballooning (p <0.05), NAFLD activity score (p <0.05), and fibrosis (p <0.001). In an Australian observational study14 with 288 cirrhotic men, testosterone levels below 8.3 nmol/L were associated with the combined outcome of death or transplantation independent of the model for end stage liver disease (MELD) score. A cross-sectional study examined the association between sex hormones and liver fat in 2,899 multi-ethnic males. It observed that subjects with fatty liver had lower total testosterone levels and lower sex hormone binding globulin (SHBG)15.
Mechanism of Action
Testosterone’s mechanism of action is beneficial to several aspects of NASH pathogenesis. It favorably impacts the accumulation of fat in the liver, reduces inflammation, allows the liver to regenerate naturally and reverses cirrhosis. Management believes that the androgen therapy approach to treat NAFLD / NASH is unique given potential well known favorable anabolic, erythropoietic, sexual, and mood effects of androgens which may bring collateral benefits to patients with chronic liver disease. Additional clinical trials will be required to support a significant relationship between androgen therapy and the benefits to NASH pathogenesis; however, there is already substantial research in support of a benefit.
View Exhibit III - Targeting Full Spectrum of NASH Pathogenesis
Competing Products in Development
NAFLD has been an attractive target for development programs for many years, seemingly increasing in number parallel with incidence of NAFLD. There have also been a number of readouts for programs targeting this disease. In mid-September, Viking Therapeutics reported 83% of the patients in their VK2809 study experienced an equal to or greater than 30% reduction in liver fat. There have been other positive reports as well from Madrigal (MDGL) which showed a greater than two point improvement in the NAFLD Activity Score (NAS) in 56 to 70% of patients and NASH resolution in 27 to 39% of patients. Below we summarize some of the leading competitors in the NASH space.
View Exhibit IV - Competing Therapies in Development
Lipocine’s review of its own data provided a compelling argument for the use of its testosterone product in NASH / NAFLD. Compelling key NASH biomarker data from multiple placebo controlled, active controlled as well as uncontrolled studies including consistent reductions in elevated ALT and elevated TG levels were observed in at-risk patients in Lipocine studies with LPCN 1144. Elevated ALT and TG levels are good predictors for NASH steatosis, inflammation and fibrosis. Elevated ALT levels and ALT to aminotransaminase (AST) ratio levels may indicate NASH and advanced fibrosis. TG is also significantly associated with NAFLD16.
View Exhibit V - ALT and TG Comparison of Tlando vs. Baseline and Competing Therapies17
LPCN 1144 demonstrated a substantially greater reduction in TG levels compared to baseline vs. competing therapies, which is expected to offer collateral cardiovascular benefits. ALT levels were also reduced to a greater extent vs. than most of the other competitors listed.
We note that the Phase 2 trials for competing therapies and for LPCN 1144 are using biomarkers to estimate the impact on liver fat content. However, the FDA requires a surrogate marker of outcomes such as biopsy to be performed to validate results when conducting registrational studies for approval under subpart H. The FDA requires that Phase 3 trials for NASH enroll patients with liver fibrosis stage 2 or stage 3, due to the unfavorable risk to benefit ratio for patients with earlier stage disease. The FDA has also guided that for full approval, clinically meaningful outcomes, such as all-cause mortality or events free survival rate, is a requirement as a meaningful outcome for NASH treatment, possibly as a post approval study.
LPCN 1144 is pursuing an in vivo mouse model study that will place the model on a 12-week high fat diet, then provide eight weeks of treatment. This will be a POC study in biopsy confirmed NASH and is expected to be complete in the fourth quarter of 2018. LPCN 1144 is also being studied in a POC clinical study in potential NAFLD / NASH subjects with confirmed fatty liver by MRI-PDFF techniques. The goal of the clinical study is to assess liver fat changes in hypogonadal patients with confirmed NAFLD using MRI-PDFF imaging and is expected to provide a readout in 1Q:19. Successful results from the animal model study and the POC liver imaging study should be sufficient to support the launch of a Phase 2a study.
View Exhibit VI - Lipocine Pipeline
Lipocine has taken advantage of the multi-modal benefit of its androgen therapy to not only help patients with hypogonadism, but also extend this benefit to patients with NAFLD. Testosterone has demonstrated an ability to resolve liver ballooning, inflammation, steatosis and fibrosis providing a strong rationale for further study. Additionally, Lipocine’s oral form of the hormone has improved efficacy and safety over other methods of administration. While there are more advanced products in later stage trials for NASH, the initial review of the group suggests that LPCN 1144 may have a more comprehensive impact on the disease either alone or in combination with other modalities and a well understood safety profile. The market size is also sufficiently large to accommodate a differentiated competitor. With an abundance of safety studies for LPCN 1144 already completed, we anticipate a 2019 launch of a Phase 2 study.
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1 Modi, Avni; et al. Relevance of low testosterone to non-alcoholic fatty liver disease. Cardiovasc Endocrinol. 2015 Sep 1; 4(3): 83–89.
2 Oseini, A. et al. Therapies In Non-Alcoholic Steatohepatitis (Nash). Liver Int. Author manuscript; available in PMC 2018 Jan 1.
3 Market Research Engine. January 2017.
4 Deutsche Bank industry report, “NASH – the next big global epidemic in 10 years?” 2014
5 Caussy C. et al. Noninvasive, Quantitative Assessment of Liver Fat by MRI-PDFF as an Endpoint in NASH Trials. Hepatology. 2018 Aug;68(2):763-772. doi: 10.1002/hep.29797.
6 Muraleedharan, V. and Jones, T. Testosterone and the metabolic syndrome. Ther Adv Endocrinol Metab. 2010 Oct; 1(5): 207–223.
7 Singh R., et al. Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology. 2003 Nov; 144(11):5081-8.
8 De Pergola G. The adipose tissue metabolism: role of testosterone and dehydroepiandrosterone. Int J Obes Relat Metab Disord. 2000 Jun; 24 Suppl 2():S59-63.
9 Source: Lipocine Corporate Presentation for LPCN 1144
10 Testosterone replacement ameliorates nonalcoholic fatty liver disease in castrated male rats. Nikolaenko L, Jia Y, Wang C, Diaz-Arjonilla M, Yee JK, French SW, Liu PY, Laurel S, Chong C, Lee K, Lue Y, Lee WN, Swerdloff RS Endocrinology. 2014 Feb; 155(2):417-28.
11 Prediction of prevalent but not incident non-alcoholic fatty liver disease by levels of serum testosterone. Seo NK, Koo HS, Haam JH, Kim HY, Kim MJ, Park KC, Park KS, Kim YS J Gastroenterol Hepatol. 2015 Jul; 30(7):1211-6.
12 Low testosterone and non-alcoholic fatty liver disease: Evidence for their independent association in men with chronic spinal cord injury. Barbonetti A, Caterina Vassallo MR, Cotugno M, Felzani G, Francavilla S, Francavilla F J Spinal Cord Med. 2016 Jul; 39(4):443-9. The Association of Low Free Testosterone with Histological Severity of Nonalcoholic Fatty Liver Disease in Japanese Men.
13 Sumida et al. The Association of Low Free Testosterone with Histological Severity of Nonalcoholic Fatty Liver Disease in Japanese Men. Gastroenterol Hepatol 2015 (2 ) 4: 00052;
14 Sinclair, M. et al., Low serum testosterone is associated with adverse outcome in men with cirrhosis independent of the model for end‐stage liver disease score. Liver Transplantation 22 1482–1490 2016 AASLD.
15 Association Between Endogenous Sex Hormones and Liver Fat in a Multiethnic Study of Atherosclerosis. Lazo M, Zeb I, Nasir K, Tracy RP, Budoff MJ, Ouyang P, Vaidya D Clin Gastroenterol Hepatol. 2015 Sep; 13(9):1686-93.e2.
16 Tomizawa, M., et al. Triglyceride is strongly associated with nonalcoholic fatty liver disease among markers of hyperlipidemia and diabetes. Biomed Rep. 2014 Sep; 2(5): 633–636. Published online 2014 Jul 1. doi: 10.3892/br.2014.309
17 Source: LPCN October 2018 Slide Deck.
By John Vandermosten, CFA