Endocrine-Related Therapeutics Garner Attention and Action at the FDA

Recent regulatory actions clear path for development of insulin biosimilars, expands indications for Pure EPA, and fast paces first possible treatment for end-stage liver disease (NASH).

FDA Waives Clinical Testing Requirement for Insulin Biosimilars

A draft guidance on considerations of insulin biosimilars and other interchangeable insulin products was issued by the Food and Drug Administration (FDA), and in a departure from usual practice, the decision has been made to dispense with the need for clinical trials given that insulins are smaller, structurally simple biologics, negating the need to demonstrate immunogenicity and comparative efficacy so long as the proposed product is similar both immunogenically and pharmacokinetically.1

FDA issues industry guidance on production of insulin biosimilars.

This action appears to have resulted following a citizen petition submitted by Sarfaraz K. Niazi, PhD, an adjunct professor of biopharmaceutical sciences at the University of Illinois in Chicago and the University of Houston, as well as chief executive officer and founder of PharmSci, a biosimilar consulting company.2

Dr. Niazi challenged the validity of comparative efficacy testing of biosimilars due to the arbitrary selection of equivalence intervals, reliance on a single study in order to extrapolation several indications, and the difficulty of obtaining sufficient naïve patients to assure reliability of study results.2 The FDA has already recognized the shortcomings of clinical outcomes testing, so this decision was likely not a surprise to many.

"The new insulin guidance is the first clear statement by the FDA to waive comparative efficacy testing that will extend to other biological drugs, saving billions of dollars” by patients," Dr. Niazi stated. Instead, it will be up to biosimilar producers to create and present viable development plans to the FDA, which should drive insulin prices down—meeting the mandate reflected by congressional legislation such as Senate Bill 2199, the Insulin Price Reduction Act.

Omega-3 EPA Gains Wider Use of Elevated Triglycerides for Reduction of CVD Risk

As EndocrineWeb already reported, “while giving fibrates or niacin to a patient who is aleady on a strong statin has failed to demonstrate a reduction in cardiovascular events, the combination of a strong stain and a pure EPA (icosapent ethyl) or a PCSK9 inhibitor (ie, ezetimibe) both appear to result in fewer cardiovascular events,” according to Eliot A. Brinton, MD, president of the Utah Lipid Center in Salt Lake City.

With an estimated 26 million adults having borderline high triglycerides and another 30 million with triglycerides in the high range (200-499 mg/dL), “we’ve been very LDL-centric in our management approach, not even considering the effects of obesity, fostered by a lack of data, so we have had no clinical impulse to treat beyond LDL,"Dr. Briton said during a presentation at the Heart in Diabetes 2019 meeting.   

Appreciating that LDL-cholesterol and elevated triglycerides independently contribute to coronary vessel blockage, there is now compelling evidence from the REDUCE-IT Outcomes Trial to suggest a shift in our treatment paradigm,4 he said.

To date, the Food and Drug Administration (FDA) has permitted only limited use of the pure eicosapentaenoic acid (Vascepa) as adjunctive therapy in patients with elevated cardiovascular disease (CVD) inclusive of extremely high serum triglycerides.

However, upon reviewing safety and efficacy data from the REDUCE-IT Trial,4 the FDA’s endocrinologic and metabolic diseases advisory committee unanimously granted the manufacturer’s request to expand the indication for this pharmaceutical grade, pure EPA omega-3 fatty acid, to permit a broader use in both primary and secondary prevention for cases of severe hypertriglyceridemia in adults already taking statins.

Based on findings reported out of the REDUCE-IT Outcomes Trial, icosapent ethyl offers superior results in lowering risk of ischemic cardiac events by 30% in patients with persistant elevated triglycerides.4  

FXR Agonist for NASH Gains Fast Track Designation

Having gained Fast Track designation by the FDA, an investigational farnesoid x receptor (FXR) agonist, TERN-101, will be steered through clinical development with the aim of delivering a much-needed treatment for non-alcoholic steatohepatitis (NASH),5 according to Erin Quirk, MD, chief medical officer for Terns Pharmaceuticals.

The farnesoid X receptor, a nuclear hormone receptor, acts in the conversion of serum cholesterol into bile acids and is active in metabolic pathways including lipid metabolism and glucose homeostasis. As such, the investigators believe that by introducing synthetic FZR agonists, it may be possible to offer a therapeutic intervention for NASH.

Data on TERN-101 from a phase 1 preclinical randomized, placebo-controlled study was presented at the 2019 International Liver Congress, in Vienna,6 providing favorable results of the clinical pharmacokinetic properties—for reduction in liver steatosis, inflammatory response, reduction in triglycerides and fibrosis—at once-a-day dosing. 

Administration of TERN-101 in mice with diet-induced obesity produced a dose-dependent increase in FXR-mediated gene expression, reported Kevin Klucher, PhD, senior director of biology at Terns Pharmaceuticals; the findings supported on-target activity and induction of metabolic pathways in the liver, in presenting the study findings.

“Liver fibrosis was significantly reduced at all dose levels,” he said, “and there was a marked decrease in non-alcoholic fatty liver disease (NAFLD) activity scores, demonstrating that TERN-101 is a potent and selective, non-steroidal FXR agonist.”

In addition to the development of TERN-101, a second NASH therapy, TERN-201, is presented as a potent, selective irreversible semicarbazide-sensitive amine oxidase inhibitor, is also under development. This drug aims to counter the inflammation and fibrosis arising from the dual function cell adhesion molecule wth amine oxase ecto-enzyme activity.In a second study, the authors concluded that TERN-201 delivered a dose-response effect in reducing NAFLD acitivity in a murine model.6

Financial disclosures: Dr. Niazi founded Karyo Biologics and Adello Biologics as well as the biosimilar advisory company Pharmaceutical Scientist, Inc, for which he is currently CEO. Dr. Klucher and colleagues are employees of Terns Pharmaceuticals.

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