HEXA

Research into gene therapies began more than 40 years ago, but the first FDA approval in 2017 ignited a fresh wave of interest from investors and drug companies who see the technology’s transformative, even curative potential. Approximately 80 percent of rare diseases are caused by mutations in a single gene, and these monogenic disorders can be excellent candidates for gene therapies. These mutations can produce devastating symptoms that limit individuals’ ability to achieve independence, pursue an education, start a family, and participate in the economy and the normal activities of everyday living. As biomedical science continues to advance next-generation treatment paradigms, more companies are engaging their R&D teams and healthcare stakeholders to deliver on the promise of one-time and limited-dose gene therapies that could offer lifetime benefits. For many rare disease patients, gene therapy has become synonymous with hope. Zeroing in on neurological disorders The biggest trend in gene therapy development is the potential of several treatments for rare neurological diseases to move from the bench to the bedside. To date, four gene therapies have been approved for rare monogenic neurological diseases: spinal muscular atrophy; metachromatic leukodystrophy; cerebral adrenoleukodystrophy; and Duchenne muscular dystrophy. The current biopharmaceutical pipeline for central nervous system conditions includes several promising gene therapies targeting monogenic disorders of the brain. Most are caused by enzyme deficiencies, which have historically been treated with enzyme replacement therapy. However, benefits are often limited by the short half-life of the recombinant enzyme, the production of anti-drug antibodies, and the inability of the enzyme to cross the blood-brain barrier. Several gene therapies are in development for monogenic lysosomal storage diseases, characterized by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies. Gene therapies in development could provide a much longer therapeutic duration – either by repairing the mutated gene or replacing it with functional copies. For example, Tay-Sachs disease (TSD) is caused by a defective gene on chromosome 15. In an open-label Phase 1/2 trial of an intrathecal adeno-associated virus (AAV), a gene therapy showed an increase in cerebrospinal fluid HexA activity in these patients, indicating early safety and proof-of-concept in people with TSD. Three gene therapy candidates are under investigation to treat Gaucher disease, another lysosomal storage disorder. Gaucher disease is caused by mutations in the GBA gene, leading to low or absent levels of the enzyme beta-glucocerebrosidase. One study is delivering a modified AAV vector directly into the liver to increase beta-glucocerebrosidase production. Another uses a lentivirus-based approach that modifies patient blood stem cells to deliver healthy copies of the defective gene. The third uses a modified AAV vector containing a healthy copy of the GBA gene to prevent neurodegeneration. Fabry disease is a lysosomal storage disorder that occurs when the enzyme alpha-galactosidase-A cannot efficiently break down lipids into smaller components that provide energy to the body. Currently approved treatments for Fabry disease include enzyme therapy and an oral pharmacologic chaperone, however, investigational gene therapies targeting AAV and lentiviral ex vivo transduction could reduce the number of recurring treatments needed by providing a one-time treatment option. With many neurological diseases being monogenic disorders, there is huge potential for gene therapy in this space by targeting a variety of mechanisms, including AAV, lentiviral vector, and more – and with the volume of studies in these disorders, the life sciences industry and researchers clearly recognize the potential in the space. What about gene therapy for common brain disorders? While clinical development is accelerating for rare monogenic neurological diseases, patients affected by more common central nervous conditions do not have obvious causative gene mutations. Conditions such as Alzheimer’s disease, Parkinson’s disease, and epilepsy are more heterogeneous. For these disorders, gene therapies may be designed to address mechanisms of disease, rather than to deliver healthy copies of a mutated gene. For example, gene therapies in development for Parkinson’s disease focus on delivering dopamine or dopamine-synthesizing enzymes. Several in development for focal epilepsies aim to reverse increases in network excitability that drive seizures rather than attempting to correct a single genetic cause. The expansion of gene therapy into more prevalent neurological disorders continues to be hampered by challenges in crossing the blood-brain barrier. Scientists are still working on ways to safely and effectively introduce genes into the brain to target specific cells. New viral vector technologies and delivery routes are being developed to address these obstacles. Due to the sheer diversity of approaches being taken to treat and functionally cure neurological disorders, gene therapy development often requires a unique approach and a team that can execute in uncharted territory. Companies must navigate the challenges of enrolling trials, be able to manufacture and transport the therapy – perhaps using novel devices or surgery to deliver the treatment, develop and validate safety and efficacy assays, and possibly implement specialty biomarker assays for early proof of principle. It takes a village, and we know the patient is waiting!

10 abstracts accepted for presentation at three top genetic conferences, focusing on topics ranging from Whole Genome and Whole Exome Sequencing to Carrier Screening and Non-Invasive Prenatal TestingHOUSTON, Oct. 02, 2023 (GLOBE NEWSWIRE) -- Baylor Genetics, a clinical diagnostic laboratory at the forefront of genetic testing, today announced its scientists and genetic counselors will present 10 research abstracts at three major upcoming conferences, including the National Organization for Rare Disorders (NORD) Breakthrough Summit, National Society of Genetic Counselors (NSGC) Annual Conference, and the American Society of Human Genetics (ASHG) Annual Meeting. “With our ongoing focus on scientific publications and presentations, Baylor Genetics continues to conduct and share meaningful research findings drawn from our collaboration with the Baylor College of Medicine and other partners so that we can advance the field of genetics and provide better answers for the patients and providers who rely on us,” said Christine Eng, M.D, Chief Medical Officer and Chief Quality Officer at Baylor Genetics. “These annual meetings are an important opportunity for researchers, clinicians, and lab professionals to come together with care teams to exchange knowledge and data that represent the latest insights in genetic testing and personalized care.” NORD Breakthrough Summit, October 15-17, Washington, D.C. The NORD Rare Diseases and Orphan Products Breakthrough Summit brings together more than 900 advocates, experts, and stakeholders to tackle pressing issues facing the rare disease community. Robert Rigobello, Manager of Medical Affairs at Baylor Genetics will present two accepted abstracts: “ACMG Secondary Findings: A Review of Patient Choices in Reporting” Summary: Baylor Genetics reviewed internal data, ordering and reporting practices for secondary findings on Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) tests from 15 US-based laboratories. Researchers found that despite guidance from the American College of Medical Genetics and Genomics (ACMG), there are inconsistencies in families’ selection for reporting secondary findings and significant variation in reporting practices among surveyed laboratories. The authors recommended consistent practice would be beneficial to providers and families. “A Case Report: BCOR-related Congenital Hypertrophy of the Retinal Pigment Epithelium” Summary: Whole exome sequencing revealed a variant in the BCOR gene, which led to a diagnosis of X-linked Microphthalmia, syndromic 2, a spectrum disorder which includes oculofaciocardiodental (OFCD) syndrome on a patient with multisystemic findings, including congenital hypertrophy of the retinal pigment epithelium (CHRPE). BCOR-associated CHRPE has only been reported a few times in literature, but cases suggest BCOR testing should be considered for patients with CHRPE who have additional findings consistent with a congenital anomaly syndrome. NSGC Annual Conference, October 17-21, Chicago The National Society of Genetic Counselors Annual Conference showcases advancements across the genetic counseling profession, to share knowledge of clinical and scientific best practices and insights into emerging research. Christina Settler, Vice President, Medical Affairs, and Carli Andrews, Medical Science Liaison at Baylor Genetics will present findings from three accepted abstracts. “ACMG Secondary Findings: A Review of Patient Choices in Reporting” Baylor Genetics reviewed internal data, ordering and reporting practices for secondary findings on WES and WGS tests from 15 US-based laboratories. Researchers found that despite guidance from ACMG, there are inconsistencies in families’ selection for reporting secondary findings and significant variation in reporting practices among the surveyed laboratories. The authors recommended consistent practice would be beneficial to providers and families. “When Symptoms Don’t Make Sense: The Power of Diagnostic Tools for Identifying Dual Diagnoses” Summary: Researchers performed a retroactive study of patients who had concurrent WES and chromosomal microarray analysis (CMA) tests ordered between 2018-2022. Fifteen patients had a dual diagnosis. For most (10), WES and CMA provided distinct diagnoses. “ACMG Secondary Findings: A Reporting Dilemma” Summary: Baylor Genetics reviewed the practices when returning secondary findings on WES and WGS tests from 15 US-based laboratories. These findings indicate there is no consistent reporting process for secondary findings on WES/WGS with 8 out of 15 labs issuing individual parental reports separate from the proband report. The practice of charging for additional reports and reporting of additional findings aside from secondary findings varied among the labs reviewed as well. ASHG Annual Meeting, November 1-5, Washington, D.C. The American Society of Human Genetics’ Annual Meeting brings together more than 8,000 scientists to discuss advances in the field. Baylor Genetics experts had five abstracts accepted for the annual event. These will be presented by Qin Sun, Ph.D., Senior Division Director of Biochemical Genetics at Baylor Genetics; Hongzheng Dai, Ph.D., Associate Clinical Director NGS/Molecular, Baylor Genetics; Matthew Chau, Fellow, Clinical Genomics, Baylor Genetics; Weimin Bi, Ph.D., Division Director, Cytogenetics, Baylor Genetics, and Janice Smith, Ph.D., Senior Clinical Director, Cytogenetics, Baylor Genetics. “Advancing Tay-Sachs Disease Carrier Screening: Insights from Combined Enzyme and Molecular Approaches” Summary: Researchers conducted a retrospective analysis of Tay Sachs disease carrier test results from the Baylor Genetics laboratory database. Findings highlight the potential value of including molecular testing for HEXA in carrier screening in combination with Hex A enzyme analysis. “Advancing Precision Diagnosis through Simultaneous Detection of Diverse Variant Types: Insights from Clinical Whole Genome Sequencing” Summary: Whole Genome Sequencing (WGS) offers healthcare providers the ability to test for many types of variants with one assay. This abstract summarizes the experience performing clinical WGS at Baylor Genetics to highlight its utility as a first-tier diagnostic test capable of detecting a spectrum of variant types. The review found up to 30% of patients with a diagnostic WGS finding related to phenotype would not have been captured by assays only focusing on SNV/indels. “Not Just One: The Utility of Whole Genome Sequencing for Making a Dual Molecular Diagnosis” Summary: Whole genome sequencing (WGS) offers a comprehensive solution for genetic investigation by capturing a wide range of genomic variations in a single test. Researchers performed a retrospective evaluation of WGS results at Baylor Genetics to look for multiple reportable molecular findings. Reportable multilocus findings were detected in 48 cases. “Prenatal CMA Using Exon-Level Coverage for 'Disease Gene' CNV Interrogations in the Era of Non-Invasive Prenatal Testing” Summary: This study investigated the role of prenatal chromosomal microarray analysis (CMA) in the era of non-invasive prenatal testing (NIPT) over the last 11 years at Baylor Genetics. Researchers found prenatal CMA remains essential for the detection of microdeletions/duplications because NIPT is limited in screening for submicroscopic copy number changes, and a diagnostic test such as CMA in follow up to NIPT results that are positive or at increased risk is important. “Products of Conception Analysis by Chromosomal Microarray: A Single Center Experience” Summary: Researchers reviewed data of products of conception (POC) via conventional chromosome analysis or chromosomal microarray (CMA). The data show CMA has an advantage over conventional chromosome analysis. To learn more about Baylor Genetics, come see us at ASHG (booth 1826), NSGC (booth 200) and NORD (booth 322), or visit baylorgenetics.com. About Baylor Genetics A pioneer of precision medicine for over 40 years, Baylor Genetics is a leading diagnostic genomics partner offering a full spectrum of clinically relevant genetic testing, including Whole Genome Sequencing, Whole Exome Sequencing, and focused panels. A joint venture of H.U. Group Holdings, Inc. and Baylor College of Medicine, which has the #1 NIH-funded Department of Molecular and Human Genetics, Baylor Genetics couples the fastest and most comprehensive precision diagnostics options with the support of genetic counselors to help clinicians and their patients avoid a lengthy diagnostic odyssey, guide medical management, and make sure no patient with a genetic disorder gets left behind. Its test menu spans from family planning, pregnancy, neonatal and pediatric testing, oncology, and specialized test options. Baylor Genetics is located in Houston’s Texas Medical Center and serves clients in 50 states and 16 countries.

Clinical trial news definitely picked up this final week of January. Here’s a look. Clinical trial news definitely picked up this final week of January. Here’s a look. COVID-19-Related Todos Medical announced a data lock for the interim data analysis of its Tollovir Phase II trial in hospitalized COVID-19 patients. The results were on January 27, 2022. Tollovir is a 3CL protease inhibitor and anti-cytokine therapeutic candidate. Arcturus Therapeutics updated data from clinical development programs for ARCT-154 and ARCT-165, investigational, next-generation, self-amplifying mRNA vaccine candidates. Full cohort data from the ARCT-154 arm of the ongoing Phase I/II booster trial showed a 30-fold increase in neutralizing antibody geometric mean concentrations against SARS-CoV-2 at Day 15 post-boost and maintained a 28-fold increase at Day 29. ARCT-165 and ARCT-154 also demonstrated robust neutralizing antibody responses post-boost against several variants of concern and variants of interest. Arcturus also said that, when administered in low doses at least five months after initial vaccination with Comirnaty, the Pfizer-BioNTech vaccine, the candidates provided robust increases of 54- and 47-fold, respectively, in neutralizing antibody responses against the Omicron variant. Sinovac Vaccine A Phase IV study out of Brazil and the University of Oxford evaluated the Chinese-made Sinovac COVID-19 vaccine plus booster shots from either Sinovac, AstraZeneca -Oxford, Pfizer - BioNTech or Johnson & Johnson . The study found that patients who received Sinovac first then received a different booster had significantly higher immune responses to variants. Mixed vaccines induced antibodies at “8-22-fold higher” levels than when older adults were given another shot of the Sinovac vaccine. And giving the boosters from other vaccines increased immunity against both Omicron and Delta variants. Moderna launched the Phase II trial of its Omicron-specific booster vaccine candidate, dosing the first patient. The study will focus on adults 18 years and older and have two cohorts, people who previously received the two-dose Moderna series at least six months ago and people who received the two-dose primary series plus a 50-microgram booster dose of the original vaccine at least three months ago. The company expects to enroll about 300 people in each cohort. Galecto published full results of a trial of its inhaled galectin-3 inhibitor, GB0139, in hospitalized patients with COVID-19 who required oxygen but not mechanical ventilation. It was compared to patients who received only standard of care. The drug hit the primary endpoint of safety with no treatment-related adverse events. The mean age of patients was 65 years, with a mean BMI of 32, multiple comorbidities and breathlessness, but they were all able to effectively inhale the drug and hit pharmacologically relevant plasma levels. Galectin-3 plays a central role in COVID-19-related acute lung injury, cytokine storm, T-cell exhaustion and organ micro-thrombosis. The drug also appeared to rapidly decrease markers of inflammation associated with cytokine storm, micro-thrombosis and short or long-term fibrosis. BerGenBio and Oslo University Hospital will initiate a study of BerGenBio’s bemcentinib in hospitalized COVID-19 patients. The EU-SolidAct trial — European DisCoVeRy for Solidarity: An Adaptive Pandemic and Emerging Infection Platform Trial — is part of EU-RESPONSE, a pan-European research project to identify drugs against COVID-19. Bemcentinib, an AXL inhibitor, will be evaluated in up to 500 hospitalized COVID-19 patients. TFF Pharmaceuticals completed enrollment in its Phase I trial of a dry powder formulation of niclosamide for COVID-19. Niclosamide is a potential antiviral treatment. Non-COVID-19-Related TScan Therapeutics received the green light from the FDA to run a Phase I trial of TSC-100 for patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation (HCT). TSC-100 targets the minor histocompatibility antigen HA-1. Applied Pharmaceutical Science got the go-ahead from the FDA to initiate a Phase I trial of APS03118 for multiple cancers. The drug is a next-generation selective RET inhibitor. Tango Therapeutics ’ IND for a Phase I/II trial of TNG908 for cancers with MTAP deletions, including non-small cell lung cancer, mesothelioma, pancreatic cancer and cholangiocarcinoma, was cleared by the FDA. TNG908 is a synthetic lethal small molecule inhibitor of protein arginine methyltransferase 5 (PRMT5). SQZ Biotech expects to initiate its Phase I/II COMMANDER-001 trial of SQZ-eAPC-HPV in HPV16+ solid tumors after the FDA approved its IND. The therapy was developed by delivering five different mRNAs into a patient’s monocytes, B cells, T cells and NK cells. Lyell received the go-ahead from the FDA to launch a Phase I trial of LYL132 in solid tumors expressing New York esophageal squamous cell carcinoma 1 (NY-ESO-1). LYL132 is a T-cell receptor (TCR) therapy that incorporates Epi-R, the company’s epigenetic reprogramming technology. Genentech published one-year results from four pivotal Phase III trials of faricimab in wet or neovascular, age-related macular degeneration (AMD) and diabetic macular edema (DME). All four studies hit their primary endpoints, demonstrating that patients receiving faricimab up to every four months achieved non-inferior vision gains compared to aflibercept, given every two months. Faricimab is a bispecific antibody designed for the eye that targets and inhibits two pathways linked to several vision-threatening retinal conditions by neutralizing Ang-2 and VEGF-A. Lyra Therapeutics initiated the Phase III ENLIGHTEN trial of LYR-210 in adult, surgically naïve chronic rhinosinusitis patients. LYR-210 utilizes the company’s proprietary XTreo platform to enable six months of local, intra-nasal, anti-inflammatory therapy for a single treatment. Connect Biopharma announced data from the Phase IIb trial of CBP-20-1 administered subcutaneously to adults with moderate-to-severe atopic dermatitis. CBP-201 is an antibody designed to target interleuekin-4 receptor alpha. MediWound announced positive topline results from its Phase II trial of EscharEx for debridement of venous leg ulcers. It hit the primary endpoint, showing that patients receiving the treatment had a statistically significant higher incidence of complete debridement compared to the gel vehicle. Erytech Pharma presented results of two trials of eryaspase in combination with mFOLFIRINOX as first-line treatment for advanced pancreatic cancer. Erypase (GRASPA) consists of L-asparaginase encapsulated inside donor-derived RBCs and targets the cancer cells’ altered asparagine and glutamine metabolism. Mustang Bio announced the FDA had placed a clinical hold on its IND for the planned Phase II study of MB-207 for X-linked severe combined immunodeficiency (XSCID), also known as “bubble boy syndrome.” The hold is in place pending CMC clearance. MB-207 is a gene therapy. Mind Medicine reported the FDA had approved its IND for a Phase IIb trial of MM-120 for generalized anxiety disorder (GAD). It was previously on hold. MM-120 is a pharmacologically optimized form of LSD. Imara expects to launch a Phase II trial of tovinontrine for heart failure with preserved ejection fraction (JFpEF). Tovinontrine is a highly selective and potent small molecule inhibitor of phosphodiesterase-9 (PDE9). Nanoscope received IND clearance from the FDA for a Phase II trial of MCO-010 ambient-light activatable optogenetic monotherapy in Stargardt patients. Stargardt is an inherited retinal disease. The therapy, MCO-010, is a gene therapy that reprograms healthy retinal cells to make them photosensitive. SwanBio Therapeutics received the green light from the FDA for a Phase I/II trial of SBT101 for disease-causing ABCD1 mutation in adrenomyeloneuropathy. SBT101 is an AAV-based gene therapy. Cerevance dosed the first patient in its Phase I trial of CVN766. CVN766 is a potent and highly selective small molecule antagonist of the orexin 1 receptor (Ox1R), which is expressed in the areas of the brain important for regulating fear, anxiety, reward and emotion. The company is developing the drug for panic disorder and schizophrenia. Checkpoint Therapeutics announced positive topline results from its Phase III trial of cosibelimab in metastatic cutaneous squamous cell carcinoma (cSCC). The drug is an anti-PD-L1 checkpoint inhibitor. The trial hit the primary endpoint, demonstrating a confirmed objective response rate (ORR) of 47.4%. Sierra Oncology announced positive topline data from the Phase III MOMENTUM trial of momelotinib in myelofibrosis patients who are symptomatic and anemic and previously treated with an approved JAK inhibitor. The trial hit all primary and key secondary endpoints. Momelotinib is a potent, selective and orally bioavailable JAK1, JAK2 and ACVR1/ALK2 inhibitor. Vaccinex reported positive interim response data in its Phase Ib trial of its pepinemab with Merck ’s Keytruda (pembrolizumab). Pepinemab is a humanized IgG4 monoclonal antibody. In the study, two patients with recurrent or metastatic head and neck squamous cell carcinoma showed complete responses. Gilead Sciences reported the FDA placed a partial clinical hold on studies assessing the combination of magrolimab plus azacytidine over unexpected serious adverse events. Magrolimab is a potential, first-in-class monoclonal antibody against CD47 and a macrophage checkpoint inhibitor. Azacitidine is a chemotherapy agent marketed under the brand names Vidaza and Onureg, both manufactured by Bristol Myers Squibb . 4D Pharma announced additional clinical data from Part A of its Phase I/II study of MRx-4DP0004 for asthma. The drug is an orally delivered single strain Live Biotherapeutic. The study hit the primary endpoint and the safety pro comparable to placebo. Biogen and its partner Eisai Company released additional details about the Phase IV post-marketing study of Aduhelm (aducanumab) for Alzheimer’s disease. As part of the Phase IV trial, the companies plan to enroll 18% of U.S. participants from Black/African American and Latinx populations. The primary endpoint of the study will be measured via the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 18 months after the beginning of treatment. This is a validated measure of both cognition and function broadly used in clinical studies of early symptomatic Alzheimer’s and is consistent with the two Phase III EMERGE and ENGAGE trials. They also plan to increase enrollment from 1,300, which they had previously announced, to 1,500 patients with Mild Cognitive Impairment due to Alzheimer’s and mild Alzheimer’s disease, with confirmation of amyloid beta pathology. They expect to initiate patient screening in May 2022. GeNeuro announced the completion of its ProTEct-MS Phase II trial of temelimab in patients whose multiple sclerosis progresses without relapsed as they have previously received chronic anti-CD20-Ab therapy with rituximab. They expect to report final results by the end of March. Cognito Therapeutics and Providence Health Plan announced plans to run a Phase III trial of its optogenetic, disease-modifying treatment for patients with mild-to-moderate Alzheimer’s disease. Moderna launched a Phase I clinical trial at George Washington University organized by IAVI to evaluate an mRNA vaccine to deliver HIV immunogens to patients. Funded by the Bill & Melinda Gates Foundation, it will evaluate 56 healthy, HIV-negative adults. Excision BioTherapeutics initiated a Phase I study of EBT-101 to remove sections of the HIV genome from the human body. EBT-101 is a CRISPR-based technology. Taysha Gene Therapies reported a patient death in otherwise positive interim data from their gene therapy for Sandhoff and Tay-Sachs diseases. TSHA-101 delivers both the HEXA and HEXB genes that make up the beta-hexosaminidase A enzyme. The patient death appears likely related to an initial COVID-19 infection, which the patient recovered from, but then contracted a secondary hospital-acquired methicillin-resistant staphylococcus aureus (MRSA) infection and died. It does not appear to be associated with the therapy.