An Endocrine News roundup of the week’s pharmaceutical news, breakthroughs, and general information. *

Veracyte Announces that New Afirma GRID Data Suggest Prognostic Ability of Molecular Testing for Thyroid Tumors

Veracyte, Inc., announced new research findings suggesting the potential of novel molecular signatures to identify patients with thyroid nodules or cancer who have aggressive disease.

The findings, which could potentially help clinicians further individualize care based on each patient’s tumor biology, are derived from research using Veracyte’s Afirma GRID (Genomic Resource for Intelligent Discovery) tool. The results were presented on June 4 at ENDO 2024 in Boston.

“Clinicians generally want to avoid overtreatment of patients with non-aggressive thyroid tumors while targeting more-intensive treatment to those patients with aggressive disease. The challenge is distinguishing between them, especially given the heterogeneity of thyroid tumors,” said Endocrine Society member Joshua Klopper, MD, Veracyte’s medical director for Endocrinology. “The studies presented at ENDO 2024 today show how our Research-Use-Only Afirma GRID tool, which leverages our whole-transcriptome-derived testing approach, is helping scientists better understand important nuances in the molecular underpinnings of thyroid tumors. These insights may ultimately enable more-personalized care for patients.”

Following are highlights of the three Afirma GRID-focused studies presented at the ENDO 2024 conference:

• Poster presentation (MON-640): Retrospective Analysis of mRNA Expression Based Signatures of Thyroid Tumor Invasion and Metastases. Presented by Sara Ahmadi, MD, Brigham and Women’s Hospital.
  
  Summary: Researchers analyzed novel whole-transcriptome-based signatures, previously presented at the ENDO 2023 meeting, that were designed to help rule out significant thyroid tumor invasion or regional lymph node metastases in patients with indeterminate thyroid nodules. This was a retrospective study of 203 thyroid nodule patients with indeterminate cytology who had Afirma GSC-suspicious results and pathology results from subsequent thyroid surgery. The molecular signatures ruled out the clinically significant features in more than 50% of patients, with a greater than 95% negative predictive value.
  
  “Today, most patients with thyroid nodules that are suspicious for cancer are directed to surgery,” said Sara Ahmadi, MD, of Brigham and Women’s Hospital who presented the findings. “Our results suggest that molecular testing may potentially help to further stratify risk so that clinicians could confidently perform a less-invasive surgical procedure that would reduce complications and potentially mitigate the need for lifelong thyroid hormone replacement therapy. While more study is needed, these findings are an exciting step towards the future of personalized medicine in thyroid nodules and cancer.”
• Oral presentation (OR28-04): Cancer-associated Fibroblasts Correlate with Aggressive Thyroid Cancer Behavior: Insights from Four Large Patient Cohorts. Presented by Endocrine Society member Matthew A. Loberg, BA, Vanderbilt University Medical Center.
  
  Summary: Researchers identified cancer-associated fibroblasts (CAFs) in the thyroid tumor microenvironment that correlate with aggression in thyroid cancers largely by leveraging the Afirma GRID database, which includes whole-transcriptome data derived from the Afirma assay. In this multicenter study involving nearly 50,000 patients, they identified CAFs for the first time in pre-operative fine needle aspiration (FNA) samples. Notably, they found that the SFRP2+ CAF was associated with shorter progression-free survival, tumor invasion and lymph node metastasis. It was also enriched in thyroid nodules that were deemed suspicious by the Afirma Genomic Sequencing Classifier (GSC) or Bethesda V/VI by cytopathology, compared to Afirma GSC-benign nodules. While more study is needed, such insights could potentially help inform more-personalized management strategies for patients with thyroid nodules or cancer.
• Poster Presentation (MON-649) and Rapid-Fire Oral Presentation (RF28-01): Prostate-specific Membrane Antigen (PSMA) Expression in Cytologically Indeterminate and Malignant Thyroid Nodules. Presented by Endocrine Society member Rabail Sadiq, MBBS, Johns Hopkins University School of Medicine.
  
  Prostate-specific membrane antigen (PSMA) is a protein found on the surface of cancer cells and is increasingly used as a biomarker in prostate cancer detection and treatment. Higher PSMA levels have also been associated with more-aggressive thyroid cancers. Researchers leveraged the Afirma GRID database to characterize the expression of PSMA (FOLH1) in a cohort of nearly 50,000 thyroid nodules sent for Afirma GSC molecular testing. They found that PSMA gene expression was higher in indeterminate nodules that were Afirma GSC-suspicious and in nodules whose cytopathology was classified as Bethesda V/VI, compared to Afirma GSC-benign nodules. They also found variability in PSMA expression in the context of certain molecular driver mutations. The authors conclude that PSMA expression may potentially help provide further prognostic information to inform care for thyroid nodule patients.

“The studies presented at ENDO 2024 reinforce our commitment to not only developing high-performing tests, but also to helping the research community advance the science around thyroid cancer and the other indications we serve,” said Phillip Febbo, MD, chief scientific officer and chief medical officer at Veracyte. “They also demonstrate the power of our Veracyte Diagnostics Platform, through which our comprehensive, whole-transcriptome-derived testing approach helps drive continued innovation to ultimately help more patients.”

IBSA USA Renews Partnership With Professional Golfer Aza Muñoz to Promote Hypothyroidism Drug

On June 5, IBSA USA announced that it had renewed its partnership with professional golfer Azahara (Aza) Muñoz to promote Tirosint^®-SOL (levothyroxine sodium) oral solution, a unique liquid hypothyroidism treatment, through the 2025 golf season.

As part of the multi-year renewal, Muñoz will continue to serve as a spokesperson at in-person events, in videos, and on social media to promote the brand while wearing the Tirosint-SOL logo on the sleeve of her golf attire.

Muñoz, who has Hashimoto’s thyroiditis that results in hypothyroidism, has found relief since she began taking Tirosint-SOL and regained control over her hypothyroid symptoms. She attributes her restored energy and improved symptom relief to this innovative treatment option.

“Using Tirosint-SOL has been transformative for me — it has helped me get back in full swing both on and off the golf course. I’ve experienced significant improvements in my energy levels and overall well-being,” said Muñoz. “I now have the energy to keep up with my child’s active lifestyle.”

Tirosint-SOL was the first oral liquid formulation approved by the U.S. Food and Drug Administration (FDA) for the treatment of hypothyroidism, a condition in which a person cannot produce enough thyroid hormone to meet their body’s needs. In November 2023, the FDA approved two new label updates for Tirosint-SOL, offering patients increased flexibility in administration. As a result, Tirosint-SOL is now the only FDA-approved levothyroxine therapy with no labeled interaction with proton pump inhibitors (PPIs) and is the only FDA-approved levothyroxine therapy that can be administered 15 minutes before eating breakfast.

“We are delighted to renew our partnership with Aza Muñoz, whose personal journey with hypothyroidism underscores the efficacy of Tirosint-SOL,” said Michael Scully, Head of Commercial Operations, IBSA USA. “The recent label changes further solidify Tirosint-SOL’s position as a unique treatment option for individuals living with hypothyroidism.”

Tirosint-SOL has 15 dosing strengths, including unique 13, 37.5, 44, and 62.5 microgram dosing options, the widest range of doses of any levothyroxine therapy available in the U.S. It is made with only three ingredients — levothyroxine, glycerol, and water¹ — and is widely available in retail pharmacies.

IBSA offers a Copay Savings Card for Tirosint-SOL, which allows eligible patients with commercial insurance to significantly reduce their out-of-pocket cost for the medication. For patients with high deductibles/copays or without insurance, the company offers a convenient mail-order pharmacy program called Tirosint Direct that offers Tirosint-SOL at a low cash price. Additional information about these money-saving options can be found at TirosintSOL.com.

Septerna Preclinical Data from ENDO 2024 Highlights Therapeutic Potential of its GPCR Drug Discovery Platform

Septerna, a biotechnology company discovering and advancing novel, oral small molecule medicines targeting G protein-coupled receptors (GPCRs), presented preclinical data from the company’s parathyroid hormone 1 receptor (PTH1R) program and its thyroid stimulating hormone receptor (TSHR) program which validate the application of the Native Complex Platform™ for drug discovery in endocrine disorders.

The data were presented in two poster presentations and a rapid-fire oral presentation during ENDO 2024 held June 1-4, 2024, in Boston, Ma.

Data from the PTH1R program showed small molecule agonists of PTH1R engaged endogenous pathways in the kidney and bone similar to native PTH peptide and demonstrated sustained control of serum calcium and phosphate levels over 28 days with daily oral administration. These results suggest that oral small molecule PTH1R agonists may be suitable alternatives to injectable PTH peptides for the treatment of hypoparathyroidism. The company plans to initiate a Phase 1 trial with its lead PTH1R agonist candidate in healthy volunteers in late 2024.

“Our PTH1R agonist is the only small molecule in development to behave similarly to native PTH, and we are excited about its potential to reshape the treatment paradigm for hypoparathyroidism as we advance into the clinic later this year,” said Endocrine Society member Jeffrey Finer, MD, PhD, CEO and co-founder of Septerna. “We are also pleased to showcase data from our TSHR antagonist program demonstrating its ability to target the known drivers of Graves’ disease, an indication for which there are currently no disease-modifying oral small molecules. Together, these data validate the ability of our Native Complex Platform™ to unlock difficult-to-drug GPCRs and to discover novel small molecules to address numerous endocrine disorders.

Summary of PTH1R Data

The rapid-fire oral presentation and poster, entitled “Characterization of a Novel Oral Small Molecule PTH1R Agonist: Proof of Concept for an Alternative to Injectable Peptide-based Therapy for Hypoparathyroidism,” were presented by Endocrine Society member Jun Zhang, PhD, senior director of Disease Biology for Septerna.

• To assess PTH1R engagement in key target tissues, primary tissue from the renal cortex and tibial bone was assessed following in vivo treatment with PTH peptide and Septerna’s small molecule PTH1R agonist. The results suggest that PTH1R-regulated genes were similarly impacted by both PTH peptide and small molecule agonists.
• Oral administration of a single dose of Septerna’s PTH1R agonist in a surgical rat model that mimics hypoparathyroidism in patients resulted in significant upregulation of serum calcium levels for a period of 24 hours in a dose dependent manner. The data also demonstrated sustained control of serum calcium and phosphate levels over 28 days with daily oral administration. The window of calcium upregulation is comparable to injectable PTH peptides currently in development to treat hypoparathyroidism.

Summary of TSHR Data

Additionally, a poster entitled “A Novel, Oral Small Molecule Antagonist Targeting TSHR Improves Hyperthyroidism in an in vivo Model of Graves’ Disease” was presented.

Data from the TSHR program demonstrated that Septerna’s small molecule TSHR antagonist blocks the stimulating effects of autoantibodies known to drive Graves’ disease (GD). Sustained treatment with the TSHR antagonist reduced the overall size of the thyroid gland and improved histological parameters associated with GD, providing proof-of-concept that potent small molecules directly targeting TSHR function have the potential to ameliorate the effects of hyperthyroidism in GD. The company is advancing several lead molecules toward the selection of a development candidate for GD and Graves’ ophthalmopathy (also known as thyroid eye disease or TED).

Sparrow Pharmaceuticals Presents Novel Data on Clofutriben Reducing Glucocorticoid Toxicities with a Low Risk of Adrenal Insufficiency at ENDO 2024

On June 5, Sparrow Pharmaceuticals, announced that it presented interim analyses of ongoing clinical trials at ENDO 2024 held June 1-4, 2024.

To date, the HSD-1 inhibitor clofutriben (SPI-62) has normalized urine free cortisol (UFC) in >60% of patients with endogenous Cushing’s syndrome (EnCS) without suppressing serum cortisol to levels considered to indicate risk for adrenal insufficiency (AI).

Medications for EnCS treatment that inhibit cortisol synthesis, antagonize cortisol production, or block cortisol’s interaction with its receptor must be titrated carefully along a spectrum between controlling the devastating morbidities of cortisol excess and risking the potentially fatal consequences of insufficient cortisol. The new data suggest that clofutriben might step off that spectrum, achieving efficacy without dose titration and with a low risk of AI.

In a symposium presentation, Sparrow’s CEO and Endocrine Society Laureate Award recipient David A. Katz, PhD, described interim results from two separate Phase 2 clinical trials of clofutriben, for ACTH-dependent Cushing’s syndrome and, in combination with the steroid medicine prednisolone, for polymyalgia rheumatica, that support two important hypotheses:

• HSD-1 inhibition, with an inhibitor such as clofutriben, can reduce active intracellular glucocorticoids that can bind to intracellular receptors and thereby reduce glucocorticoid toxicities.
• HSD-1 inhibition can secondarily reduce active systemic glucocorticoids but with low risk of causing AI.

Sparrow’s chief medical officer and Endocrine Society member Frank S. Czerwiec added, “The Sparrow team looks forward to learning if these promising interim results hold for the larger number of patients in the now fully enrolled clinical trial in endogenous Cushing’s syndrome. In anticipation, our team is planning for the initiation of a Phase 3 trial in 2025. We’re grateful to patient participants and the investigators who are such important contributors to progress in Cushing’s research.”

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