Abstract
“The context is this gigantically expensive disease to treat,” Jeff Ajer, BioMarin's executive vice president and chief commercial officer, told NPR in an interview. “It's likely that our gene therapy would save a lot of money—millions, perhaps many millions.” 1
The company has said that Roctavian could potentially save health care systems >$20 million since it is a one-time treatment, and annual current standard-of-care treatment costs run into hundreds of thousands of dollars per patient.
In June, BioMarin announced additional data from its previously reported 4-year update of an open-label Phase I/II study of Roctavian. All study participants remained off Factor VIII prophylaxis therapy, while also experiencing a >90% reduction in bleeding episodes from a single administration of the gene therapy.
“These data demonstrate the very real potential of a paradigm shift in the treatment of hemophilia A and that ongoing research into gene therapies could represent an entirely new way to approach meeting the high unmet need in patients with severe hemophilia A,” said the trial's chief investigator, Prof. John Pasi, MBChB, PhD, of Barts and the London School of Medicine and Dentistry, who presented results at the World Federation of Hemophilia virtual summit. 2
The FDA has set a target Prescription Drug User Fee Act action date of August 21, 2020, whereas BioMarin has said it expects an opinion from the European Medicines Agency's committee for medicinal products for human use in late 2020 or early 2021.
NOVARTIS, SANGAMO INK UP-TO-$795M
Neurodevelopmental collaboration
Through Sangamo's ZFP-TFs, the companies plan to develop treatments targeting three genes associated with neurodevelopmental disorders, by upregulating the expression of key genes that are inadequately expressed in individuals with those disorders.
Sangamo's ZFP-TF genome regulation technology, delivered through adeno-associated viruses (AAVs), is designed to selectively repress or activate the expression of specific genes to achieve a desired therapeutic effect. Novartis will have exclusive rights to ZFP-TFs targeting the genes, which are undisclosed, during the 3-year collaboration period. Novartis also has the option to license Sangamo's AAVs.
Sangamo has agreed to oversee specified research and associated manufacturing activities, all to be funded by Novartis. Novartis agreed to oversee additional research activities, investigational new drug-enabling studies, clinical development, related regulatory interactions, manufacturing, and global commercialization.
“The goal is to create new gene regulation therapies that act at the genomic level, moving us beyond the symptom focused treatments of today and toward therapies that can address some of the most challenging neurodevelopmental disorders,” said Jay Bradner, president of the Novartis Institutes for BioMedical Research. 3
Novartis agreed to pay Sangamo a $75 million upfront “license fee” within 30 days, plus up to $720 million tied to achieving development and commercial milestones. Sangamo is also eligible to receive from Novartis tiered high single-digit to subteen double-digit royalties on potential net commercial sales of products arising from the collaboration.
ENCODED RAISES $135M
The round included participation from ARCH Venture Partners, Boxer Capital, Farallon Capital Management, Illumina Ventures, HBM Genomics, Matrix Capital Management, Menlo Ventures, Meritech Capital, Nolan Capital, RTW Investments, SoftBank Vision Fund 2, 1 and additional unnamed investors.
“We are grateful to our investors for supporting our vision to transform patients' lives with cell type-selective genetic medicines,” said Encoded cofounder and CEO Kartik Ramamoorthi, PhD. 4
Based in South San Francisco, CA, Encoded plans to use proceeds from the Series D to conduct clinical studies that include first-in-human trials for ETX101, the company's lead candidate. ETX101 is an AAV vector designed to treat SCN1A+ Dravet Syndrome by restoring SCN1A to normal expression levels specifically within the affected cell type, GABAergic inhibitory neurons.
Encoded also plans to use the financing to fund a natural history study designed to better understand the progression of the rare severe genetic disorder.
The U.S. Food and Drug Administration (FDA) has granted ETX101 its orphan drug designation and rare pediatric disease designation for the treatment of SCN1A+ Dravet Syndrome.
TRAGIC LESSONS FROM A CLINICAL TRIAL
Researchers must absorb the tragic lessons arising from the deaths of two boys dosed with Audentes Therapeutics' X-linked myotubular myopathy (MTM) gene therapy candidate AT132, Human Gene Therapy Editor-in-Chief Terence R. Flotte, MD, and his predecessor, James M. Wilson, MD, PhD, wrote in a commentary published in Genetic Engineering & Biotechnology News (GEN).
Dr. Flotte is the provost and executive deputy chancellor of University of Massachusetts (UMass) Medical School and dean of the School of Medicine. Dr. Wilson is director of the gene therapy program at the University of Pennsylvania.
“It is imperative that the scientific community work together with full transparency and cooperation to learn from these tragedies to assure that we can deliver safe and effective treatments to individuals living with rare genetic diseases such as MTM”, Drs. Flotte and Wilson wrote. 5
Audentes—which was acquired by Astellas Pharma last year for $3 billion—disclosed the first death to patient advocates in May, and the second in June. Both were among three older patients treated in the Phase I/II ASPIRO trial (NCT03199469) with the higher 3 × 1014 GC/kg dose of AT132, an adeno-associated virus serotype 8 (AAV8) vector containing a functional copy of the MTM1 gene. All three experienced severe hepatotoxicity.
In 2018, Dr. Wilson and colleagues reported severe life-threatening toxicity in monkeys and piglets given high doses of gene therapy delivered using an AAV serotype 9 (AAV9) vector capable of accessing spinal cord neurons.
News of the deaths from AT132 “is a tragic reminder of how difficult it is to predict outcomes in first-in-human studies,” Drs. Flotte and Wilson added.
U.K. COMMITS £100M TO MANUFACTURING INNOVATION
The U.K. government said it will spend £100 million ($128 million) to fund a Cell and Gene Therapy Catapult Manufacturing Innovation Centre designed to accelerate the mass production of a successful COVID-19 vaccine domestically.
The government initiative will upgrade the existing benchmark facility in Braintree, Essex, to create a fully licensed manufacturing center capable of producing millions of doses each month. The center is expected to increase the U.K.'s ability to respond to COVID-19 and potential future pandemics while creating new, high-skilled jobs. 6
The new center is designed to complement the Vaccines Manufacturing and Innovation Centre (VMIC), now under construction in Oxfordshire with £93 million (∼$120 million) funding from the government. Once complete next year, the government added, the VMIC will have the capacity to produce enough vaccine doses to serve the entire U.K. population.
During VMIC construction, the government has committed an additional £38 million (∼$49 million) to establish a rapid deployment facility, opening later this summer
GLAXOSMITHKLINE'S THE PICK OF THE ORCHARD
The LV-SCLT permanently and stably enables all lentiviral vector components to be introduced into a cell line in one step, according to GSK. Selection and expansion of a resulting clonal producer line in either suspension or adherent culture are designed to deliver consistent levels of high titer lentiviral production comparable with those seen using conventional methods. 7
An overview of the technology, coauthored by Orchard and GSK scientists, was presented at the European Society of Gene & Cell Therapy Annual Congress in October 2019 using work done in the OTL-300 program for TDT. Under the licenses, GSK has granted patents and pending patent applications related to its LV-SCLT.
Orchard plans to submit a biologics license application and marketing authorization application for OTL-103 for the treatment of WAS in the United States and European Union, respectively, in 2021.
XYLOCOR DOSES FIRST PATIENTS
The EXACT trial will enroll 12 patients (3 per cohort) who will receive one of four ascending intramyocardial doses of XC001, followed by an expansion cohort of 17 patients of the highest tolerated dose. The trial's primary endpoint is safety, as assessed by adverse events and serious adverse events.
The trial will enroll patients who are not responding to medication and are unsuitable for coronary artery bypass graft or percutaneous coronary intervention, XyloCor said.
“XC001 has the potential as a one-time gene therapy that will relieve chest pain by restoring blood flow to the heart,” said Rickey Reinhardt, MD, PhD, chief medical officer of XyloCor Therapeutics. 8