Ligand’s Partner Viking Therapeutics Announces Positive Top-Line Results from Phase 2b VOYAGE Study of VK2809 in Patients with Biopsy-Confirmed Non-Alcoholic Steatohepatitis (NASH)

Study achieves primary endpoint, demonstrating statistically significant reductions in liver fat from baseline to week 12 in patients receiving VK2809 as compared to placebo

Ligand is entitled to receive a $10 million milestone payment upon initiation of a Phase 3 clinical trial as well as royalties of 3.5% to 7.5% on commercial sales of VK2809, if approved

SAN DIEGO--(BUSINESS WIRE)-- Ligand Pharmaceuticals Incorporated (NASDAQ: LGND) announced that its partner Viking Therapeutics, Inc. (“Viking”) (NASDAQ: VKTX) today announced positive top-line results from its Phase 2b clinical trial of VK2809, a novel liver-selective thyroid hormone receptor beta agonist, in patients with biopsy-confirmed non-alcoholic steatohepatitis (NASH). The study successfully achieved its primary endpoint, with patients receiving VK2809 experiencing statistically significant reductions in liver fat content from baseline to Week 12 as compared with placebo. The median relative change from baseline in liver fat as assessed by magnetic resonance imaging and proton density fat fraction (MRI-PDFF) ranged from 38% to 55% for patients receiving VK2809. Additionally, VK2809-treated patients demonstrated statistically significant reductions in low-density lipoprotein cholesterol (LDL-C), triglycerides, and atherogenic lipoproteins compared with placebo. Viking expects to submit the results for presentation at a future medical conference.

Under a license agreement with Viking for VK2809, Ligand is entitled to receive a $10 million milestone upon initiation of a Phase 3 clinical trial, other potential milestone payments and royalties of 3.5% to 7.5% on future worldwide sales of VK2809 by Viking.

“We extend our congratulations to the Viking team for the impressive topline results from the VK2809 VOYAGE trial reported today,” said Todd Davis, CEO of Ligand Pharmaceuticals. “VK2809 is an important partnered asset for Ligand, and the increasing evidence of its clinical efficacy in treating NASH is encouraging.”

Top-line study results reported by Viking include:

Primary Endpoint: Reduction in Liver Fat Content at 12 Weeks

Patients receiving VK2809 experienced statistically significant reductions in liver fat content, as assessed by MRI-PDFF, relative to placebo after 12 weeks of treatment. Importantly, up to 85% of patients receiving VK2809 experienced at least a 30% relative reduction in liver fat content, a level of reduction that is associated with greater likelihood of histologic response in NASH.

	Placebo (n = 62)	VK2809 1 mg QD (n = 17)3,4	VK2809 2.5 mg QD (n = 58)	VK2809 5 mg QOD (n = 36)4	VK2809 10 mg QOD (n = 56)
Mean baseline liver fat content	20.4%	21.7%	20.2%	18.4%	21.5%
Mean relative change in liver fat by MRI-PDFF1,2	-3.7%	-16.6% (p=0.082)	-45.3% (p<0.0001)	-36.8% (p<0.0001)	-51.7% (p<0.0001)
Median relative change in liver fat	-5.4%	-37.5%	-48.1%	-42.5%	-55.1%
Percentage of patients experiencing ≥ 30% reduction in liver fat2	13.6%	52.9% (p=0.0015)	77.6% (p<0.0001)	66.7% (p<0.0001)	84.9% (p<0.0001)
Notes: Data from Full Analysis Dataset, defined as all randomized patients who received a baseline and post-baseline MRI. 1) Least squares mean change from baseline using an Analysis of Covariance (ANCOVA) model. 2) p-value vs. placebo. 3) Reduced size cohort intended to identify a minimally effective dose. 4) Enrollment suspended at approximately 50% of target to accelerate study completion.

Brian Lian, Ph.D., chief executive officer of Viking, commented, “These results demonstrate VK2809’s impressive potency at reducing liver fat, which we believe represent the largest reductions reported for an oral agent at this stage of development. The high response rates observed in this study suggest improved probabilities of histologic benefit, as has been demonstrated in published clinical studies. In addition, VK2809’s consistent effect at reducing plasma lipids provides further support for its role in improving the metabolic profile of patients suffering from NASH. These results align well with those reported from our prior 12-week NAFLD study, but in a more severe population and at lower doses. VK2809’s excellent safety and tolerability further establish its best-in-class profile, with rates of drug-related adverse events, including GI-related events such as nausea and diarrhea, that are similar to placebo. We believe these data suggest important benefits for patients with NASH, and look forward to reporting the 52-week biopsy data from this study in the first half of next year.”

Reduction in Plasma Lipids

Consistent with prior studies, patients receiving VK2809 demonstrated statistically significant placebo-adjusted reductions in LDL-C ranging from 11% to 20%, as well as statistically significant reductions in triglycerides and atherogenic proteins such as apolipoprotein B (ApoB), lipoprotein (a) [Lp(a)], and apolipoprotein C-III (ApoC-III). Reductions in these plasma lipids improve a patient’s overall cardiometabolic profile and may reduce the risk of cardiovascular-related events.

Safety and Tolerability

VK2809 demonstrated encouraging safety and tolerability in this study. The majority (94%) of treatment related adverse events among patients receiving VK2809 were reported as mild or moderate. Discontinuations due to adverse events were low and balanced among placebo and treatment arms. One treatment-related serious adverse event (SAE) was reported in a patient receiving VK2809. A patient with a history of psychiatric disorders reported a worsening of their symptoms. As in prior studies, VK2809 demonstrated excellent gastrointestinal (GI) tolerability in this study. Rates of nausea, diarrhea, stool frequency, and vomiting were similar among VK2809-treated patients compared to placebo.

	Placebo (n = 65)	VK2809 1 mg QD (n = 17)	VK2809 2.5 mg QD (n = 66)	VK2809 5 mg QOD (n = 37)	VK2809 10 mg QOD (n = 61)	VK2809 combined (n=181)
Treatment emergent adverse events, TEAEs (number of subjects, (%))1	47 (72.3%)	14 (82.4%)	52 (78.8%)	29 (78.4%)	54 (88.5%)	149 (82.3%)
Drug-related TEAEs2	22 (33.8%)	7 (41.2%)	13 (19.7%)	9 (24.3%)	23 (37.7%)	52 (28.7%)
TEAEs leading to study discontinuation	5 (7.7%)	2 (11.8%)	1 (1.5%)	1 (2.7%)	5 (8.2%)	9 (5.0%)
Drug-related GI adverse events	12 (18.5%)	4 (23.5%)	3 (4.5%)	1 (2.7%)	7 (11.5%)	15 (8.3%)
Nausea	5 (7.7%)	2 (11.8%)	2 (3.0%)	1 (2.7%)	3 (4.9%)	8 (4.4%)
Diarrhea	2 (3.1%)	3 (17.6%)	2 (3.0%)	1 (2.7%)	3 (4.9%)	9 (5.0%)
Notes: Study safety population, defined as all patients who were randomized and received at least one dose of study drug. 1) Data as of March 13, 2023. 2) Deemed by investigator as possibly, probably, or definitely related to study drug.

At the 12-week timepoint, there were no numerically or clinically meaningful differences observed in levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) among patients receiving VK2809 compared with patients receiving placebo. Similarly, levels of thyroid hormones such as thyroid stimulating hormone (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) were relatively unchanged among VK2809 treated patients compared to patients receiving placebo. Changes in vital signs, including blood pressure, heart rate, and body weight were similar among patients receiving VK2809 as compared to patients receiving placebo.

Study Design
The VOYAGE study is a randomized, double-blind, placebo-controlled, multicenter, international trial designed to assess the efficacy, safety and tolerability of VK2809 in patients with biopsy-confirmed NASH and fibrosis. Enrollment included patients with at least 8% liver fat content as measured by MRI-PDFF, as well as F2 and F3 fibrosis. The study allowed for up to 25% of enrolled patients to have F1 fibrosis provided that they also possess at least one additional risk factor, such as diabetes, obesity or hypertension, among others. The primary endpoint of the study evaluated the change in liver fat content from baseline to Week 12 in patients treated with VK2809 as compared to patients receiving placebo. Secondary objectives include the evaluation of histologic changes assessed by hepatic biopsy after 52 weeks of treatment. For more information, refer to clinicaltrials.gov NCT04173065.

About VK2809
VK2809 is an orally available, tissue and receptor-subtype selective agonist of the thyroid beta receptor (TRβ) that possesses selectivity for liver tissue, as well as the beta receptor subtype, suggesting promising therapeutic potential in a range of lipid disorders. The compound is currently being evaluated in a Phase 2b clinical trial in patients with biopsy-confirmed non-alcoholic steatohepatitis (NASH) and fibrosis. VK2809 successfully achieved primary and secondary endpoints in a Phase 2a study for the treatment of patients with elevated LDL-C and non-alcoholic fatty liver disease (NAFLD). Selective activation of the thyroid beta receptor in liver tissue is believed to favorably affect cholesterol and lipoprotein levels via multiple mechanisms, including increasing the expression of genes associated with lipid metabolism and clearance.

About Ligand Pharmaceuticals
Ligand is a biopharmaceutical company enabling scientific advancement through supporting the clinical development of high-value medicines. Ligand does this by providing financing, licensing our platform technologies or both. Our business model generates value for stockholders by creating a diversified portfolio of biotech and pharmaceutical product revenue streams that are supported by an efficient and low corporate cost structure. Our goal is to offer investors an opportunity to participate in the promise of the biotech industry in a profitable and diversified manner. Our business model is based on funding mid to late-stage drug development in return for economic rights and licensing our technology platforms to help partners discover and develop medicines. We partner with other pharmaceutical companies to leverage what they do best (late-stage development, regulatory management and commercialization) to generate our revenue. We have two primary platform technologies that are available for outlicense – Captisol and Pelican. Our Captisol platform technology is a chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. For our Captisol partners, our team supplies the Captisol material needed for their programs. Our Pelican Expression Technology is a robust, validated, cost-effective and scalable platform for recombinant protein production that is especially well-suited for complex, large-scale protein production where traditional systems are not. We have established multiple alliances, licenses and other business relationships with the world’s leading pharmaceutical companies including Amgen, Merck, Pfizer, Jazz, Takeda, Gilead Sciences and Baxter International. For more information, please visit www.ligand.com.

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Disclaimer
The information in this press release regarding VK2809 comes from Viking. Ligand is not responsible for, and has no role in, the development of such product.

Forward-Looking Statements
This news release contains forward-looking statements by Ligand that involve risks and uncertainties and reflect Ligand's judgment as of the date of this release. Words such as “plans,” “believes,” “expects,” “anticipates,” and “will,” and similar expressions, are intended to identify forward-looking statements. These forward-looking statements include: the efficacy and safety of VK2809, the timing and amount of milestone payments and royalties Ligand may receive in connection with the development and commercialization of VK2809 and the timing for expected study results. Actual events or results may differ from Ligand’s or its partner’s expectations due to risks and uncertainties inherent in Ligand’s and its partner’s business, including, without limitation: risks relating to the regulatory approval process; changes in the size and nature of the market for VK2809, including potential competition, patient and payer perceptions and reimbursement determinations; Ligand is dependent on Viking for the development and commercialization of VK2809 and Ligand may never receive additional payments under the license agreement; Ligand or its partners may not be able to protect their intellectual property, and patents covering certain products and technologies may be challenged or invalidated; and other risks described in Ligand’s prior press releases and filings with the Securities and Exchange Commission available at www.sec.gov. Ligand disclaims any intent or obligation to update these forward-looking statements beyond the date of this release. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

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