An Endocrine News roundup of the week’s pharmaceutical news, breakthroughs, and general information. *
Positive Long-Term Results from Phase 2 HELIOS Clinical Trial of AMX0035 in People with Wolfram Syndrome
On May 12, Amylyx Pharmaceuticals, Inc. announced positive Week 48 data from the Phase 2 open-label HELIOS clinical trial of AMX0035 (sodium phenylbutyrate [PB] and taurursodiol [TURSO, also known as ursodoxicoltaurine]) in adults living with Wolfram syndrome.
These results were presented at the Joint Congress of the European Society for Pediatric Endocrinology (ESPE) and the European Society of Endocrinology (ESE) in Copenhagen, Denmark.
Consistent with the HELIOS trial’s previously presented primary efficacy outcome of improvement in pancreatic function, as measured by C-peptide response to a mixed-meal tolerance test at Week 24, treatment with AMX0035 through Week 48 demonstrated continued and sustained improvement in pancreatic beta cell function.
Treatment with AMX0035 from Week 24 to Week 48 also showed sustained improvements or stabilization in glycemic control, as measured by hemoglobin A1c (HbA1c) and time in target glucose range assessed by continuous glucose monitoring, as well as visual acuity. All participants with available measurements met the responder criteria, defined as either improvement or no change, on both the Patient Global Impression of Change (PGI-C) and Clinician Global Impression of Change (CGI-C) at Weeks 24 and 48, indicating stability or improvement in their Wolfram syndrome-related symptoms. Results from qualitative on-study interviews further supported the potential positive impact of AMX0035 on symptom burden.
Safety data were consistent with safety data from prior studies of AMX0035. All adverse events (AEs) were mild or moderate, and there were no serious AEs related to AMX0035 treatment.
“The results of the Phase 2, open-label HELIOS trial continue to demonstrate that AMX0035 has the potential to favorably alter the trajectory of Wolfram syndrome, a progressive disorder with no approved treatment options. The consistency of the Week 48 results across multiple measures of disease progression that meaningfully impact the daily lives of those living with Wolfram syndrome, including pancreatic function, glycemic control, and vision, reinforce the previously reported Week 24 findings. Additionally, the majority of participants reported meaningful improvement in at least one Wolfram syndrome-related symptom during interviews, underscoring the real-world importance of these results,” says Fumihiko Urano, MD, PhD, Principal Investigator of the Phase 2 HELIOS clinical trial in Wolfram syndrome and the Samuel E. Schechter Professor of Medicine in the Division of Endocrinology, Metabolism & Lipid Research at Washington University School of Medicine in St. Louis.
“These long-term results reinforce both our positive data at Week 24 and our belief in the potential of AMX0035 to stabilize and even improve key manifestations of Wolfram syndrome, a relentlessly progressive disorder,” says Endocrine Society member Camille L. Bedrosian, MD, chief medical officer at Amylyx. “With these findings, we are focused on working closely with the FDA to inform the design of a Phase 3 trial. Our ultimate aim is to address the unmet needs that are still a reality for people living with this devastating disorder. We want to thank the Wolfram syndrome community for their continued collaboration and support.”
HELIOS (NCT05676034) is a single-site, single-arm, open-label, Phase 2 trial designed to evaluate the safety and tolerability of AMX0035, as well as its effects on various measures of endocrinological, neurological, and ophthalmological function in adult participants living with Wolfram syndrome. The U.S. Food and Drug Administration (FDA) and the European Commission granted Orphan Drug Designation to AMX0035 for the treatment of Wolfram syndrome in November 2020 and August 2024, respectively.
Results through Week 48 of the HELIOS trial showed treatment with AMX0035 resulted in improvement or stabilization across measures of glycemic control, visual acuity, and overall symptom burden with AMX0035. Notably, HELIOS showed improvements in the primary endpoint of C-peptide response, as measured by area under the curve from 0-120 minutes during a Mixed Meal Tolerance Test (MMTT). In the Per Protocol group, the mean change from baseline to Week 24 was 20.2 min*ng/mL [standard error (SE) 11.2], and, at Week 48, the mean change from baseline was +34.5 minutes ng/mL(min*ng/mL) [13.0]; descriptive p-value=0.0263). Long-term data at Week 48 included 10 participants in the Per Protocol population with genetically confirmed Wolfram syndrome (one participant was excluded from the Per Protocol population due to not meeting the study inclusion criteria of genetically confirmed Wolfram syndrome) and 11 participants in the Intent-to-Treat (ITT) population. One participant discontinued between Week 24 and Week 48 for reasons unrelated to safety.
About AMX0035
AMX0035 is an oral, fixed-dose combination of sodium phenylbutyrate (PB) and taurursodiol (TURSO; also known as ursodoxicoltaurine outside of the U.S.). AMX0035 was designed to slow or mitigate neurodegeneration by targeting endoplasmic reticulum (ER) stress and mitochondrial dysfunction, two connected central pathways that lead to cell death and neurodegeneration. Amylyx believes that its proprietary combination of PB and TURSO and their complementary mechanisms of action will allow us to synergistically target abnormal cell death to better prevent neurodegeneration than treatment targeted at either mechanism of action alone. AMX0035 is being studied as a potential treatment for Wolfram syndrome and progressive supranuclear palsy, two neurodegenerative diseases.
About Wolfram Syndrome
Wolfram syndrome is a rare, monogenic, progressive neurodegenerative disorder that progressively impacts multiple organs and systems. Wolfram syndrome is characterized by childhood-onset diabetes mellitus, optic nerve atrophy, and neurodegeneration. Common manifestations of Wolfram syndrome include diabetes mellitus and diabetes insipidus, gradual vision loss leading to blindness, hearing loss, neurogenic bladder, difficulties with balance and coordination, and difficulty breathing that can lead to respiratory failure. Wolfram syndrome is caused by pathogenic variants in Wolfram syndrome type 1 gene (WFS1) that leads to premature mortality. Because of the clear link between WFS1 mutations and endoplasmic reticulum (ER) stress, Wolfram syndrome is considered a prototypical ER stress disorder. Wolfram syndrome affects approximately 3,000 people living in the U.S., and there are currently no approved treatment options.
About the HELIOS Trial
HELIOS (NCT05676034) is a 12-participant, single-site, single-arm, open-label, Phase 2 trial designed to evaluate the safety and tolerability of AMX0035, as well as its effects on various measures of endocrinological, neurological, and ophthalmologic function in adult participants living with Wolfram syndrome. Participants in HELIOS receive AMX0035 for up to 144 weeks followed by a four-week safety follow-up. Primary and secondary outcomes are assessed at Week 24 and at longer-term time points. The FDA and the European Commission granted Orphan Drug Designation to AMX0035 for the treatment of Wolfram syndrome in November 2020 and August 2024, respectively.
FDA Approves New Pheochromocytoma Treatment
On May 15, Merck announced the U.S. Food and Drug Administration (FDA) has approved WELIREG® (belzutifan), Merck’s oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, for the treatment of adult and pediatric patients 12 years and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL).
Pheochromocytoma and paraganglioma are rare tumors that come from the same tissue, but pheochromocytoma form in the adrenal gland and paraganglioma form outside the adrenal gland. These tumors can be caused by certain genetic syndromes or mutations. The approval is based on data from the single-arm LITESPARK-015 clinical trial, where the primary endpoint was objective response rate (ORR).
“PPGL, sometimes referred to as pheo para, is a rare condition affecting up to 2,000 people each year in the United States. Patients with these tumors, which arise from the adrenal glands and the extra-adrenal paraganglia, may require specialized care due to their complexity and rare nature, often posing significant challenges for both diagnosis and treatment,” says Camilo Jimenez, professor, department of endocrine neoplasia and hormonal disorders, The University of Texas MD Anderson Cancer Center. “This approval, which is based on objective response rate data from the LITESPARK-015 trial, introduces belzutifan as the only approved and available non-surgical option for locally advanced, unresectable, or metastatic PPGL and could represent a change to the treatment paradigm for eligible patients.”
“For patients with advanced PPGL, there has been a lack of approved systemic treatment options available to help manage their disease, underscoring the importance of this approval in the U.S.,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “This approval marks the third indication for WELIREG in the U.S. and demonstrates our company’s commitment to providing innovative cancer therapies for patients in need, including those with rare diseases.”
The WELIREG label contains a boxed warning that exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception. WELIREG can render some hormonal contraceptives ineffective. WELIREG can cause severe anemia that can require a blood transfusion. Monitor for anemia before initiation of and periodically throughout treatment with WELIREG. WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization.
Study design
LITESPARK-015 is an open-label, multicohort Phase 2 trial (ClinicalTrials.gov, NCT04924075) evaluating the efficacy and safety of WELIREG monotherapy. The study enrolled 72 patients in a single cohort (Cohort A1) who had measurable disease verified by blinded independent central review (BICR) per RECIST v1.1, documented histopathological diagnosis of PPGL, locally advanced or metastatic disease that was not amenable to surgery or curative treatment, and adequately controlled blood pressure (defined as BP <150/90 mm Hg, <135/85 mm Hg for adolescents) with no change in antihypertensive medications for patients with concomitant hypertension for at least two weeks prior to start of study treatment. Patients with carcinomatous meningitis were excluded. Patients received WELIREG at a dose of 120 mg once daily until disease progression or unacceptable toxicity.
The major efficacy outcome measure for the treatment of advanced PPGL was ORR measured by BICR using RECIST v1.1. Additional efficacy outcome measures included duration of response and time to response.
About pheochromocytoma and paraganglioma
Pheochromocytoma and paraganglioma (PPGL), sometimes referred to as pheo para, are rare tumors that can be caused by certain genetic syndromes or mutations. It is estimated that up to 2,000 new cases of PPGL are diagnosed each year in the U.S., and up to 52,800 new cases are diagnosed each year worldwide. Pheochromocytoma form in nerve tissue in the center of the adrenal gland, whereas paraganglioma form in nerve tissue near certain blood vessels and nerves outside the adrenal glands.
New Phase 1 Clinical Trial of ABCL635 for Vasomotor Symptoms Due to Menopause to Start Soon
On May 15, AbCellera announced it received a No Objection Letter (NOL) from Health Canada authorizing its Clinical Trial Application (CTA) for ABCL635, an investigational antibody antagonist targeting neurokinin 3 receptor (NK3R) that is being developed for the non-hormonal treatment of moderate-to-severe vasomotor symptoms (VMS), commonly known as hot flashes, associated with menopause.
“Vasomotor symptoms of menopause affect millions of women, with significant impacts on their well-being, and their personal and professional lives,” says Natalya Nazarenko, MD, executive medical director at AbCellera. “We are excited to advance ABCL635 into a Phase 1 trial and explore it as a potential non-hormonal, long-acting treatment option to address these highly disruptive symptoms.”
The Phase 1 study is anticipated to begin in Q3 of 2025 and will evaluate ABCL635’s safety, pharmacokinetics, and pharmacodynamics in healthy participants and postmenopausal women with moderate-to-severe VMS.
About ABCL635
ABCL635 is a potential first-in-class antibody medicine for the non-hormonal treatment of moderate-to-severe vasomotor symptoms (VMS), commonly known as hot flashes, associated with menopause. ABCL635 specifically targets NK3R, a clinically validated G-coupled protein receptor (GPCR) expressed on kisspetin, neurokinin, and dynorphin (KNDy) neurons in the infundibular nucleus of the hypothalamus. ABCL635 is the first program from AbCellera’s GPCR and ion channel platform to advance into the pipeline. A Phase 1 clinical trial is anticipated to begin in Q3 of 2025.
New 4-Year Data Shows Sustained Response to TransCon® PTH (Palopegteriparatide) Therapy in Adults with Hypoparathyroidism
On May 12, Ascendis Pharma A/S announced new data from Week 214 of its Phase 2 PaTH Forward Trial showing that long-term treatment with TransCon PTH (palopegteriparatide) continued to provide a durable response in adults with hypoparathyroidism. Results were shared in an oral presentation today by Andrea Palermo, MD, from the Campus Bio-Medico University (Rome), during ESPE & ESE 2025, the joint congress of the European Society for Paediatric Endocrinology (ESPE) and the European Society of Endocrinology (ESE).
The PaTH Forward Trial included a 4-week randomized, double-blind, placebo-controlled period followed by an open-label extension period through Week 266. Renal function was assessed by estimated glomerular filtration rate (eGFR). Bone turnover markers C-terminal telopeptide of type 1 collagen (CTx) and procollagen type 1 N-terminal propeptide (P1NP), as well as bone mineral density (BMD) measured by DXA scan, were assessed at baseline and regular intervals through Week 214. Safety assessments included 24-hour urine-calcium and treatment-emergent adverse events (TEAEs). At Week 214, 56 of the original 59 patients enrolled (95%) remained in the open-label extension portion of the trial.
At Week 214, nearly all patients (98%) continued to have normal albumin-adjusted serum calcium levels and 93% remained independent from conventional therapy (defined as taking < 600mg/day of calcium and not taking active vitamin D). Bone turnover markers CTx and P1NP increased from the low end of normal at baseline, peaked by Week 26, then declined and remained stable above baseline levels through Week 214. The data also showed continued improvement in skeletal dynamics, with BMD remaining within age- and sex-matched norms. In addition, at Week 214, most participants (67.8%) had a clinically meaningful (≥ 5 mL/min/1.73 m2) increase in eGFR from baseline, with changes in eGFR evident at Week 4.
In the trial, TransCon PTH treatment was generally well-tolerated, with no new safety signals identified. TEAEs were mostly mild or moderate and no serious TEAEs or discontinuations were related to study drug.
“We set out to address the underlying cause of disease and are pleased to see this long-term data reinforcing the safety profile and durability of response in patients treated with TransCon PTH, including sustained normalization of skeletal dynamics and significant and sustained improvements in kidney function,” says Aimee Shu, M.D. Executive Vice President of Endocrine & Rare Disease Medical Science and Chief Medical Officer at Ascendis Pharma.
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