ABCD1

Seven young boys treated with bluebird bio’s gene therapy for a rare neurological disease have been diagnosed with blood cancer months or years after treatment, according to data published on Wednesday in the New England Journal of Medicine . Researchers have long known that therapies developed with lentiviral vectors could, in some cases, cause cancer, but they have been seeking to understand why Skysona comes with a seemingly greater risk. The cases may relate to the design of the lentiviral vector used in the treatment, scientists hypothesize. Bluebird’s eli-cel was approved in 2022 under the brand name Skysona to treat cerebral adrenoleukodystrophy, also known as CALD. The condition mostly affects young boys and progresses rapidly without treatment, leading to neurological decline or death. Skysona was approved in 2022 with a black box warning for hematologic malignancy, and the FDA updated its label in April to disclose that there had been six cases of the cancer out of 67 patients dosed in clinical studies. An additional case has been diagnosed since then, according to new data published in NEJM. The patients received Skysona when they were between 5 and 13 years old, with the cancer diagnoses occurring 14 to 92 months later, according to the data. In an editorial published alongside the data, Cynthia Dunbar, a hematologist at the NIH’s National Heart, Lung and Blood Institute, wrote that more cases may appear over time. “Unfortunately, I think she’s right,” Christine Duncan, lead author of the NEJM study and Boston Children’s Hospital senior physician, told Endpoints News. “ Patients are being followed very closely. The families are being very educated. They all know about all of these cases.” Duncan and her team hypothesized that the cases may have been driven by the design of the lentiviral vector used in Skysona. CALD is caused by a mutation in a gene called ABCD1. Skysona works by using a lentivirus to insert a functioning form of the ABCD1 gene. Skysona’s lentiviral vector was designed with the use of a viral promoter, intended to help drive strong expression of the gene. But a risk of that type of promoter is oncogenesis, or driving the development of cancer, Duncan explained. “We’re relatively confident that that promoter in the design of the vector is driving this,” she said. “The question then is, in my mind, is it driving it alone, or are there other factors that contribute?” Duncan noted that patients in one study, ALD-102, which has reported only one case of hematologic cancer, received a stronger chemotherapy regimen as part of preparation for treatment than another study, ALD-104, which reported the other six cases. But at this time, it remains unclear whether that made a difference, or whether other factors were involved. “Is it a combination of conditioning regimen and the vector?” she asked. “We can’t know for certain.” Duncan added that the risk-benefit analysis for Skysona may vary from patient to patient. Some patients may be eligible for allogeneic stem cell transplant, but that process comes with its own risks — and just 20% of CALD patients have an available matched donor, according to the NEJM editorial. “We recognize that families of children diagnosed with CALD face urgent treatment decisions, and bluebird is committed to ensuring that treating physicians have access to the most up-to-date safety information to support informed decision making,” bluebird said in a statement. Leaving CALD untreated is the greatest risk, Duncan said. “Both allogeneic stem cell transplant, so the traditional therapy, and gene therapy, they both have things that are good about them, they both have things that are bad about them. And for any individual patient, it’s not the same scale,” Duncan said. “At the end of the day, I think it is very valuable, very important that families have choices that they can personalize with their caregivers and their providers.” Researchers noted there have been no cases of lentivirus-caused cancer reported with bluebird’s sickle cell and beta thalassemia therapy, which used a different lentiviral vector called BB305, and none with Orchard Therapeutics’ metachromatic leukodystrophy therapy Lenmeldy. Lei Lei Wu contributed reporting.

iStock, Love Employee The pediatric patients, with a rare neurodegenerative disease, were treated with bluebird bio’s Skysona to slow the progression of neurologic dysfunction. Six patients developed myelodysplastic syndrome and one patient developed acute myeloid leukemia. Seven children treated with bluebird bio ’s gene therapy Skysona for cerebral adrenoleukodystrophy, a rare and progressive neurodegenerative disease, developed blood cancers, according to a study published Wednesday in The New England Journal of Medicine . Six of the seven cases of hematological malignancies were diagnosed as myelodysplastic syndrome (MDS), arising between 14 and 92 months after Skysona treatment. The other patient was diagnosed with acute myeloid leukemia (AML) at 57 months. Six patients were subsequently treated with stem cell transplantation, which led to one death due to graft-versus-host disease. The single AML patient remains alive and has shown good response to the transplant. According to the researchers, the emergent blood cancers are linked with clonal vector insertions in cancer-related genes, and with the accumulation of somatic mutations in certain sites of interest, including in the KRAS, WT1 and CDKN2A genes. Skysona is a gene therapy that works by delivering functional copies of the ABCD1 gene into patients’ hematopoietic stem cells, which promotes the production of mature monocytes that can express functional ALDP proteins. ALDP plays an important role in the breakdown of very long chain fatty acids. In September 2022, the FDA granted Skysona accelerated approval to the slow the progression neurologic dysfunction in boys four to 17 years of age with cerebral adrenoleukodystrophy (CALD), a rare and neurodegenerative disorder caused by a dysfunctional ABCD1 gene and which leads to severe functional decline. In the Phase II/III Starbeam trial, which formed the basis of its regulatory win, Skysona demonstrated strong major functional disability-free survival over 24 months. In terms of safety, Starbeam detected cases of nausea, vomiting and febrile neutropenia, among other mild toxicities. Adverse events of grade 3 or 4 included lymphopenia, thrombocytopenia and hypokalemia. Skysona’s label carries a boxed warning for hematologic malignancies, including “life-threatening cases” of MDS. These complications appear to be the result of the Skysona lentiviral vector that becomes integrated in proto-oncogenes—similar to what had been documented in the NEJM study. The concerns about secondary blood cancers are not new. In August 2021, about a year before Skysona’s approval, the FDA hit its development program with a clinical hold after one patient developed MDS following treatment. In an advisory committee meeting in June 2022, however, a panel of external experts unanimously backed bluebird, agreeing that Skysona’s benefits outweigh its risks. Wednesday’s study results come less than a month after news broke that patients had finally started receiving infusions of another bluebird gene therapy, Lyfgenia, for sickle cell disease. It is not yet clear whether the new safety signals will have far-reaching implications for bluebird’s portfolio.

Reductions in Very Long-Chain Fatty Acids and Plasma Lipid Levels Observed After 28 Days of Once Daily Dosing VK0214 Shown to be Safe and Well-Tolerated in 28-Day Study SAN DIEGO, Oct. 9, 2024 /PRNewswire/ -- Viking Therapeutics, Inc. (Viking) (NASDAQ: VKTX), a clinical-stage biopharmaceutical company focused on the development of novel therapies for metabolic and endocrine disorders, today announced positive data from the company's Phase 1b clinical trial of VK0214, a novel small molecule agonist of the thyroid hormone receptor beta (TRβ), in patients with X-linked adrenoleukodystrophy (X-ALD). Results from this study showed VK0214 to be safe and well-tolerated following once-daily dosing over the 28-day study period. In addition, significant reductions were observed in plasma levels of very long-chain fatty acids (VLCFAs) and other lipids, as compared to placebo. Highlights from the study results include: Reductions in VLCFAs In addition to safety and tolerability, the study included an exploratory assessment of changes in plasma levels of VLCFAs after 28 days of dosing. VLCFAs are considered biomarkers of disease in patients with X-ALD. Treatment with VK0214 resulted in significant reductions in mean VLCFA levels at both doses evaluated, 20 mg/day and 40 mg/day, compared to placebo. Importantly, cohorts receiving VK0214 demonstrated reductions in mean plasma levels of the 26 carbon lysophosphatidyl choline (C26:0-LPC) derivative, a key diagnostic marker. Percent Change from Baseline in VLCFAs Following 28 Days of Treatment of VK0214 Reductions in Plasma Lipids In addition to VLCFA changes, subjects who received VK0214 demonstrated reductions in other plasma lipids. Mean reductions relative to baseline and placebo were observed for low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and lipoprotein (a) [Lp(a)] following 28 days of treatment. Percent Change in Lipid Markers Following 28 Days of Treatment of VK0214 Safety and Tolerability VK0214 demonstrated encouraging safety and tolerability following 28 days of once-daily dosing. Treatment emergent adverse events were reported as mild to moderate; one subject in the placebo cohort experienced a wrist fracture that was characterized as a severe adverse event. Gastrointestinal adverse events were slightly higher among placebo subjects (33%) compared with VK0214-treated subjects (11%). "We are excited to report these initial results evaluating VK0214 in patients with adrenomyeloneuropathy," said Brian Lian, Ph.D., chief executive officer of Viking. "Patients receiving VK0214 demonstrated progressive improvement in plasma levels of very long chain fatty acids in the relatively brief treatment period evaluated in this study. In addition, VK0214 continued to show benefits on broader plasma lipids, such as LDL-C, important for overall cardiometabolic health. Consistent with prior clinical results in healthy volunteers, VK0214 was shown to be safe and well-tolerated in this 28-day study. We look forward to exploring next steps with this important compound." The Phase 1b trial was a multi-center, randomized, double-blind, placebo-controlled study in adult male patients with the adrenomyeloneuropathy (AMN) form of X-ALD. The study enrolled patients across three cohorts: placebo, VK0214 20 mg daily, and VK0214 40 mg daily. The primary objectives were to evaluate the safety and tolerability of VK0214 in subjects with AMN, when administered once-daily over a 28-day dosing period. Secondary objectives included an evaluation of the pharmacokinetics of VK0214 following 28 days of dosing in this population. An exploratory objective was to evaluate the effects of VK0214 on plasma levels of VLCFAs in subjects with AMN. About X-ALD X-ALD is a rare and often fatal metabolic disorder characterized by a breakdown in the protective barriers surrounding brain and nerve cells; a process known as demyelination. In X-ALD, mutations in a gene known as ABCD1 lead to dysfunction of the adrenoleukodystrophy protein (ALDP), an important peroxisomal transporter. In patients, this dysfunction leads to an accumulation of VLCFAs, which can trigger a rapid, inflammatory demyelination, resulting in cognitive impairment, motor skill deterioration, and even death. Research in disease models has shown that increasing the expression of a related gene known as ABCD2, which encodes a compensatory transporter called the adrenoleukodystrophy related protein (ADLRP), can result in normalization of VLCFA levels. Activation of the thyroid hormone beta receptor, as observed in patients treated with VK0214, has been shown to increase the expression of ABCD2 resulting in reductions in VLCFA levels. X-ALD is estimated to occur in approximately 1 in 17,000 births. Currently there are no pharmacologic treatments approved for the disease. About Viking Therapeutics, Inc. Viking Therapeutics, Inc. is a clinical-stage biopharmaceutical company focused on the development of novel first-in-class or best-in-class therapies for the treatment of metabolic and endocrine disorders, with three compounds currently in clinical trials. Viking's research and development activities leverage its expertise in metabolism to develop innovative therapeutics designed to improve patients' lives. Viking's clinical programs include VK2809, a novel, orally available, small molecule selective thyroid hormone receptor beta agonist for the treatment of lipid and metabolic disorders. The compound successfully achieved both the primary and secondary endpoints in a recently completed Phase 2b study for the treatment of biopsy-confirmed non-alcoholic steatohepatitis (NASH) and fibrosis. In a Phase 2a trial for the treatment of non-alcoholic fatty liver disease (NAFLD) and elevated LDL-C, patients who received VK2809 demonstrated statistically significant reductions in LDL-C and liver fat content compared with patients who received placebo. Viking is also developing VK2735, a novel dual agonist of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors for the potential treatment of various metabolic disorders. Data from a Phase 1 and a Phase 2 trial evaluating VK2735 (dosed subcutaneously) for metabolic disorders demonstrated an encouraging safety and tolerability profile as well as positive signs of clinical benefit. The company is also evaluating an oral formulation of VK2735 in a Phase 1 trial. In the rare disease space, Viking is developing VK0214, a novel, orally available, small molecule selective thyroid hormone receptor beta agonist for the potential treatment of X-linked adrenoleukodystrophy (X-ALD). VK0214 is currently being evaluated in a Phase 1b clinical trial in patients with the adrenomyeloneuropathy (AMN) form of X-ALD. For more information about Viking Therapeutics, please visit . Forward-Looking Statements This press release contains forward-looking statements regarding Viking Therapeutics, Inc., under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, including statements about Viking's expectations regarding its clinical and preclinical development programs, anticipated timing for reporting clinical data and cash resources. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially and adversely and reported results should not be considered as an indication of future performance. These risks and uncertainties include, but are not limited to: risks associated with the success, cost and timing of Viking's product candidate development activities and clinical trials, including those for VK2735, VK0214, VK2809, the company's incretin receptor agonists, and its amylin and calcitonin receptor agonists; risks that prior clinical and preclinical results may not be replicated; risks regarding regulatory requirements; and other risks that are described in Viking's most recent periodic reports filed with the Securities and Exchange Commission, including Viking's Annual Report on Form 10-K for the year ended December 31, 2023, and subsequent Quarterly Reports on Form 10-Q, including the risk factors set forth in those filings. These forward-looking statements speak only as of the date hereof. Viking disclaims any obligation to update these forward-looking statements except as required by law. SOURCE Viking Therapeutics, Inc. 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