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Madrigal, Galmed, And Galectin In Phase 3 NASH: The Need For Therapeutic Diversity

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Includes: GALT, GLMD, MDGL
by: First Genesis Consulting
Summary

NASH is a complex, asymptomatic, progressive chronic liver disease with incompletely understood pathophysiology and a histopathologically diverse patient population.

As we approach the end of H1/2019, we have documented a Phase 3 clinical success for obeticholic acid by Intercept in NASH fibrosis.

By the end of H2/2019, three diverse Phase 3 drug candidates from biopharmas, Madrigal, Galmed, and Galectin, respectively, would be in clinical trials for NASH fibrosis or NASH cirrhosis.

Mechanistically, Resmetirom, Belapectin, and Aramchol, acting through distinct pharmacological targets, have unintentionally validated the clinical need for diverse NASH therapeutics as shown in Phase 2 clinical studies.

The positive clinical responses by NASH patients to these 3 distinct investigative drug candidates are a confirmation of the clinical importance and need for continuity in developing diverse drug assets.

Introduction

Madrigal Pharmaceuticals (MDGL), Galmed Pharmaceuticals (GLMD), and Galectin Therapeutics (GALT) are small or mid-cap clinical stage biopharmas with a common unifying clinical goal of developing effective therapeutics for NASH disease. Madrigal (Resmetirom), Galmed (Aramchol), and Galectin (Belapectin) are the focus of this article because of their diverse pharmacological targets and clinical effects in NASH. Moreover, these Phase 3 drug assets are the next wave of potential NASH therapeutics seeking NDA approval in the next 3-4 years.

NASH is a two-phase silent/symptomless disease with a progressive, incompletely understood pathophysiology and a patient population that is histopathologically diverse.

Excessive accumulation (>5%) of liver fat as a trigger for NASH has never been in dispute. But understanding the diverse mechanistic effects of liver fat in NASH pathogenesis in regard to "how and why" is an ongoing scientific and clinical debate as reflected in the 3 proposed diverse NASH hypotheses and over 30 investigative drug candidates currently in clinical trials.

Clinical Diversity: Pharmacological Targets

The diversity in NASH hypotheses is a reflection of the lack of total scientific and mechanistic clarity on the early (i.e. NASH fibrosis F2/F3) and late (i.e. NASH fibrosis F4) phases of NASH pathophysiology. It is also a justification on the need for ongoing clinical development of diverse investigative drug candidates with distinct pharmacological and mechanistic targets as seen with MGL-3196/Resmetirom, Aramchol, and Belapectin.

Madrigal

MGL-3196, resmetirom, pharmacological target the THR-β-triiodothyronine (i.e. Thyroid T3 hormone) axis. It is a first-in-class, orally-administered, liver-directed THR β-selective agonist in Phase 3 study for NASH fibrosis. Mechanistically, Madrigal's hypothesis is that MGL-3196 would treat the underlying disease in NASH patients by decreasing liver fat that reduces lipotoxicity to induce NASH resolution. In the Phase 2b NASH study, Madrigal clearly demonstrated via MGL-3196 the critical role of liver fat in driving NASH pathogenesis and ensuing liver fibrosis.

The study showed that patients with ≥30% liver fat reduction in response to MGL-3196 treatment always attained greater medical benefits including histological NASH resolution and regression of liver fibrosis. The notable total regression of liver fibrosis (i.e. normalization of liver) in some patients that achieved NASH resolution is a correlation and confirmation of Madrigal thesis that treating NASH is key to addressing the disease and related pathological events.

Galmed

Aramchol's pharmacological target is Stearoyl-CoA desaturase-1 (SCD1). It is an oral once-daily novel fatty acid-bile acid conjugate in Phase 3 clinical study for NASH fibrosis. Mechanistically, it potently and negatively modulates SCD-1, a key liver-specific lipogenic rate‐limiting enzyme, converting saturated fatty acids into monounsaturated fatty acids.

Aramchol functionally dysregulates the effector function of SCD-1, possibly in hepatocytes, by skewing the fatty acid metabolism pathway away from steatosis toward oxidation. A progressive decrease in relative liver fat reduction was observed with aramchol therapy with significant decreases at the 600 mg dose versus placebo in the Phase 2b study. The preliminary data from the 52-week Phase 2b study also showed that Aramchol induced significant clinical differentiation by directly acting on hepatic stellate cells, to improve liver fibrosis and delay the progression to cirrhosis

Galectin

Belapectin's pharmacological target is galectin 3 and is a Phase 3 anti-fibrotic investigative drug candidate that will enter clinical trial in Q4/2019 for compensated NASH cirrhosis. Mechanistically, belapectin specifically binds to galectin-3 proteins in macrophages/Kupffer cells to potentially disrupt its functional effects in patients with compensated cirrhotic NASH. The 52-week Phase 2b data revealed that belapectin improved portal pressure and also prevented the development of esophageal varices in patients with compensated NASH cirrhosis.

As the sole anti-fibrotic investigative drug candidate in clinical development for compensated NASH cirrhosis, a late phase of NASH disease, belapectin offers significant clinical differentiation. As alluded to previously, 95% of investigative NASH drug candidates are being developed for early NASH disease, making the clinical success of belapectin thus far, in cirrhotic NASH, a monumental scientific and clinical achievement.

Clinical Diversity: Patient Population

It is now well known that individuals with metabolic syndrome (MetS) comprising obesity, type 2 diabetes, hypertension, dyslipidemia are considered high risk for NASH. While the focus of NASH clinical trial is typically in obese individuals, the incidence of NASH in lean individuals could be unknowingly ignored by both the drug and medical community. Specifically, the prevalence of NASH is also on the increase in lean individuals as noted in Asian countries (i.e. China and Japan) that are normally associated with lean or normal weight physique.

The development of these aforementioned NASH therapeutics is unknowingly or knowingly exploring a somewhat personalized patient therapeutic approach due to their distinct pharmacological targets in the diverse NASH patient population. Once again, justifying the clinical importance of diversifying development of drug candidates for NASH.

Epilogue

The clinical development of diverse drug candidates is of utmost importance. The one drug candidate fits all patients therapeutic approach is not feasible and would be clinically ineffective. Ultimately, a personalized combination therapeutic approach involving NASH therapeutics, with diverse mechanistic effects on distinct pharmacological targets, may produce the best clinical relief for NASH patients.

At present, the market has a somewhat evasive approach on the need for the diverse drug candidates for NASH. Science is always ahead of the market, meaning that the market should ultimately catch up with science!

Disclosure: I am/we are long MDGL, GLMD, GALT. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.