Monthly Archives: September 2021

The next frontier in genetic medicines could be one-time therapies that do their editing work in vivo, inside the patient. But one challenge is that some genetic diseases have hundreds of mutations. To address all of them, youd need to produce a therapy for each mutationan endeavor thats just not scalable, according to Joseph Truitt, CEO of iECURE.

The number of mutations does not matter to iECURE. Whereas some of the in vivo gene editing therapies in development aim to fix specific mutations on a gene, iECURE aims to swap out the entire problem gene, making the approach independent of any one disease-causing mutation.

This is about gene insertion and replacement, replace a deficient gene with a healthy gene, Truitt said.

The Philadelphia-based company, which is based on the research of University of Pennsylvania scientist James Wilson, a gene therapy pioneer, has demonstrated that its approach can work in animals. Now iECURE has $50 million in Series A financing as it works to bring in vivo gene-editing therapies into human testing. The Series A round of funding announced Thursday was led by Versant Ventures and OrbiMed Advisors.

IECURE will use gene editing and in vivo approaches from Wilson, and the startup may choose up to 13 programs from his lab. Truitt said that iECURE has identified three diseases so far: familial hypercholesterolemia, phenylketonuria, and ornithine transcarbamylase deficiency. Theyre all rare liver disorders, which is the focus of the company.

Truitt said Wilson tried various kinds of gene-editing tools, including CRISPR, with little success, until landing on technology from Precision Biosciences. The clinical-stage biotech in Durham, North Carolina, has developed technology called ARCUS, which delivers a cutting enzyme called an endonuclease to a targeted segment of DNA. The endonuclease is delivered by adeno-associated virus (AAV), an engineered virus that is widely used in genetic medicines.

The Precision Bio enzyme, which is derived from algae, is the smallest compared to others used in gene-editing research, said Chief Scientific Officer Derek Jantz, speaking during the companys virtual R&D event Thursday. That smaller size means that more enzymes can fit onto an AAV, giving it the capability to perform complex edits, such as gene insertion, and do that work in multiple types of tissue.

Penn began working with Precision Bio in 2018, a partnership focused on developing in vivo gene-editing products using ARCUS. That year, preclinical research from the partnership was published in Nature Biotechnology showing that ARCUS was able to knock out the cholesterol-regulating gene PCSK9 in monkeys. In February of this year, Wilson published a paper in Molecular Therapy describing three-year data showing PCSK9 protein reductions of up to 85%, as well as a 56% reduction in LDL cholesterol levels. Also notable was that the one-time treatment continued to demonstrate safety with no adverse effects reported.

The Penn/Precision Bio research showed that ARCUS could knock out a gene thats causing disease. This collaboration paved the way for a new one that is proceeding with iECURE. The startup will also use ARCUS, but to knock in a healthy gene, or gene insertion. The startup has licensed from Precision Bio the rights to use ARCUS for four liver indications. In exchange, iECURE will advance Precision Bios PCSK9 therapy into Phase 1 testing for familial hypercholesterolemia.

Precision Bio gets an unspecified equity stake in iECURE and it also stands to earn milestone payments, plus royalties from sales, if any products that iECURE developed with ARCUS reach the market. But the North Carolina company stands to gain something more. Successful iECURE clinical trial results for therapies that use ARCUS would also provide validation for the technology in gene insertion, said Precision Bios top business development executive Cindy Atwell. The company is pursuing gene knockout validation through internal research, as well as through programs partnered with Eli Lilly.

Precision Bio and iECURE expect an application to begin clinical testing of the familial hypercholesterolemia candidate could be filed in early 2022. Concurrent with that program, iECURE will also work on the programs selected from Penn. The first two diseases the startup aims to address using ARCUS are phenylketonuria and ornithine transcarbamylase deficiency, Truitt said. The other two will be selected later. Precision Bio retains the rights to ARCUS for all other indications.

IECURE came together as a result of an informal meeting that Versant Managing Director Tom Woiwode had with Wilson two years ago, according to Truitt. Versant was one of the initial financial backers of Passage Bio, a now publicly traded gene therapy developer that Wilson had founded. Versants genetic medicine investments had also included gene editing companies, such as CRISPR Therapeutics and Graphite Bio. Wilson mentioned he had been quietly doing gene editing research for several years with a particular focus on neonatal disorders where gene therapies wont work.

One of Wilsons findings was that this gene insertion is best as a neonatal treatment. Newborns have rapidly dividing liver cells, which is necessary for the rapid uptake of the gene editing therapy, Truitt said. Adult livers do not have rapidly dividing cells and therefore, do not take up the therapies as well. Wilson had done research in familial hypercholesterolemia and ornithine transcarbamylase deficiency, and the animal data excited Woiwode, leading Versant to reach out to OrbiMed, another Passage Bio investor. They formed iECURE, bringing biotech industry veteran Truitt aboard as CEO in February. Wilsons lab came up with the name iECURE, a reference to iecur, the Latin word for liver. We added the e for cure, Truitt said.

Penn and Wilson hold equity stakes in iECURE; Wilson is not an employee of the company though he is an advisor, Truitt said. According to iECUREs agreement with the university, Wilsons lab will do the preclinical research and manufacturing of the programs selected by iECURE. When the research is ready for an investigational new drug application, iECURE will take over and handle clinical development, and if approved, commercialization.

Truitt said that the $50 million should support the company until early 2023. A big chunk of that cash will be for manufacturing. But Truitt notes that working with programs that have already been studied extensively by Wilsons lab puts iECURE well ahead of most startups raising their first rounds of funding.

Jim has three years of data with ARCUS, Truitt said. If we would have started all over again, we wouldnt have been able to use that. Its a brand new company but the programs are rather mature for a gene-editing company.

Photo: Mark Makela for The Washington Post, via Getty Images

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Genetic meds pioneer James Wilson has a new startup, this time in gene editing - MedCity News

An Amgen sign is seen at the company's office in South San Francisco, California October 21, 2013. REUTERS/Robert Galbraith (UNITED STATES/File Photo

LONDON, Sept 10 (Reuters) - Lung cancer patients in England will become the first in Europe to receive a drug made by U.S. biotech Amgen Inc (AMGN.O) that targets a specific gene mutation, the country's health service said on Friday.

NHS England said it was fast-tracking lung cancer drug sotorasib after it was shown in clinical trials to stop lung cancer progression for seven months.

The drug, taken as a tablet, will be used on patients with the KRAS G12C mutation that occurs in about 13% of non-small cell lung cancers (NSCLC), the most common type of lung cancer.

The early-access deal will see 600 patients a year receive sotorasib in England through the state-run National Health Service (NHS).

"This revolutionary treatment has taken decades of research to reach the clinic, and now that it is here this new targeted drug will be available for eligible people with lung cancer as quickly as possible thanks to this agreement," said Peter Johnson, NHS clinical director for cancer.

Charles Swanton, chief clinician at charity Cancer Research UK, said the drug was "one of the most exciting breakthroughs in lung cancer treatment in 20 years, targeting a cancer gene that was previously untargetable."

The use of sotorasib in Britain follows its accelerated approval in May in the United States for lung cancer patients with the KRAS G12C mutation whose disease has worsened after treatment with chemotherapy or other medicines. read more It is sold in the United States under the brand name Lumakras.

Britain's medicine regulator, the Medicines and Healthcare products Regulatory Agency (MHRA), has authorised the drug under a partnership with U.S. and Australian counterparts designed to speed up approval for promising cancer treatments, called Orbis.

Reporting by Alistair SmoutEditing by Bill Berkrot

Our Standards: The Thomson Reuters Trust Principles.

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Lung cancer patients in England to receive Amgen drug that targets a gene mutation - Reuters

(UroToday.com)TheAmerican Urologic Association annual meeting included a State-of-the-Art Lecture by Dr. Brian Chapin who discussed personalized medicine in the management of prostate cancer across the patient care continuum. Dr. Chapin notes that the way we think about the personalized approach to prostate cancer therapy involves seeing a patient in the clinic and assessing them on a number of factors (clinical features, genetics, genomics, serum markers, receptors, induced responses, and selection pressures) and then developing a personalized approach to their treatment plan:

In setting the stage for personalized care, it is important to understand the available treatment options in the castration-nave setting, as well as the castration resistant setting:

Dr. Chapin notes that personalized care is compartmentalization by stage, histology and biology. Traditionally we have delineated care by stage of disease in combination with histologic considerations (ie. neuroendocrine, ductal, adenocarcinoma). More recently, there has become an increasingly more sophisticated approach, with regards to assessing the androgen receptor axis (TMPRSS2-ERG, SPOP, AR responsive), loss of tumor suppression (p53, PTEN, Rb), DDR mutations (BRCA, CDK12, FANCONI, CHEK1/2), and mismatch repair (MSI, Lynch syndrome).

Compartmentalization allows for better risk stratification, for example balancing arms in a clinical trial by using stratification factors (ie. M1a/b versus M1c) and balancing groups in retrospective studies by utilizing matching or propensity scoring (ie. NCDB, SEER database). However, this can also generate selection bias in retrospective cohort series, for example in patients with occult node positive prostate cancer, some patients will undergo a completion prostatectomy whereas others will have their radical prostatectomy aborted (thus, unable to compare outcomes). Many of us think of personalized care in prostate cancer by way of DNA, RNA, proteins and receptors, such as in the pre-biopsy, post-biopsy, positive biopsy, post-radical prostatectomy, and metastatic settings:

Dr. Chapin emphasizes that it is critically important to delineate between prognostic versus predictive biomarkers. Prognostic biomarkers are a variable associated with favorable or unfavorable outcomes for patients in the absence of treatment. Predictive biomarkers are a variable used to identify patients or groups of patients most likely to benefit from a specific therapy, for example a patient with a DNA damage repair mutation being a candidate for PARP inhibitor treatment, or a patient with a mismatch repair deficiency being a candidate for anti-PD1 antibody treatment. Prognostic variables can be used incorrectly thus mistakenly influencing management. For example, genomic tests on prostate biopsies have all been based on treated prostate cancer patients, thus these findings may not be applicable to an active surveillance cohort. Findings from these genetic tests are used to make changes in management decisions, resulting in Medicare approval. Dr. Chapin states that it is important to remember that no randomized trials have reported outcomes (although there are several ongoing) assessing if genomic tests improve patient outcomes, and in fact reflexive genomic testing may be detrimental to patients.

Dr. Chapin then discussed several potential predictive markers and prospective trials. The PAM50 gene expression classifier was previously described in the breast cancer literature, but has since been applied to prostatectomy specimens. Zhao et al.1 applied the classifier to 3,782 samples (1,567 retrospective, 2,215 prospective) noting that the PAM50 classifier consistently segregated prostate cancer into three subtypes in both retrospective and prospective cohorts:

Luminal A, luminal B, and basal curves separate based on PAM50 gene expression, with basal tumors having worse prostate-cancer specific survival:

When assessing luminal B and basal tumors with regards to response to ADT, this study suggests there may be a benefit to treatment of luminal B patients with ADT but no benefit seen in those with basal tumors:

Another example is the post-operative radiation therapy outcomes score (PORTOS), which is a genetic prediction score for post-op radiation. PORTOS is made up of 24 genes selected from a training set of 196 men and validate in a separate cohort of 330 men, with a clinical endpoint of metastasis over 10 years of follow-up.2 In this study, patients with a high PORTOS score had a benefit in cumulative incidence of distance metastasis with radiotherapy (HR 0.15, 95% CI 0.04-0.60), whereas patients with a low PORTOS score (HR 0.92, 95% CI 0.56-1.51) did not have a benefit with radiotherapy:

Biomarker examples have also been described in the advanced prostate cancer setting, specifically assessing androgen indifferent or aggressive variant prostate cancer. In a phase 1-2 trial assessing cabazitaxel plus carboplatin for men with mCRPC, at a median follow-up of 31.0 months, combination cabazitaxel plus carboplatin improved the median progression-free survival from 4.5 months (95% CI 3.5-5.7) to 7.3 months (95% CI 5.5-8.2; HR 0.69, 95% CI 0.50-0.95) with cabazitaxel alone.3 Dr. Chapin notes that what is particularly interesting is that for patients with a positive aggressive variant prostate cancer molecular signature, there was an improvement in overall survival with the addition of platinum based chemotherapy, whereas there was no benefit in those that were aggressive variant prostate cancer molecular signature negative. Dr. Chapin highlighted that there are several trials ongoing in the localized setting assessing a personalized approach, including the Genomic Umbrella Neoadjuvant Study (GUNS):

Decipher is a 22 gene classifier that provides risk stratification based on radical prostatectomy specimen analysis, which is prognostic for metastasis. However, there is no data on predictive ability, which is undergoing prospective evaluation in the NRG-GU009 PREDICT-RT trial:

Importantly, there are several barriers to overcome in the era of personalized medicine, including (i) assessing if findings are transferrable across stages of the disease; (ii) tumor heterogeneity, whether intertumoral, intratumoral, or comparing a metastases to the primary tumor; (iii) in order to move from prognostic to predictive markers, prospective trials are required; (iv) it is important to determine drivers in the setting of co-occurences (ie. DDR, +/- p53, +/- Rb1, +/- PTEN); and (v) assess selection pressures over time (ie. the predominant clone).

Dr. Chapin concluded his presentation with the following take-home messages from his presentation of personalizing medicine in the management of prostate cancer:

Presented by: Brian Chapin, MD, Associate Professor of Urology, MD Anderson Cancer Center, Houston, TX

Written by: Zachary Klaassen, MD, MSc Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 American Urological Association, (AUA) Annual Meeting, Fri, Sep 10, 2021 Mon, Sep 13, 2021.

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AUA 2021: State-of-the-art Lecture: Personalized Medicine in the Management of Prostate Cancer Across the Patient Care Continuum - UroToday

Data to include patient safety assessments and a preliminary analysis of secondary endpoints to evaluate biological activity

Abstract selected for oral presentation on September 29

Company to host webcast investor event following the presentation on September 29 at 11:00 a.m. ET

CAMBRIDGE,Mass., Sept. 07, 2021 (GLOBE NEWSWIRE) -- Editas Medicine, Inc. (Nasdaq: EDIT), a leading genome editing company, today announced that an abstract featuring initial clinical data from the BRILLIANCE clinical trial of EDIT-101 has been selected for an oral presentation at the XIXth International Symposium on Retinal Degeneration (RD2021) being held in Nashville, Tenn., and virtually September 28 October 2, 2021. EDIT-101 is under development for the treatment of Leber congenital amaurosis 10 (LCA10), a CEP290-related retinal degenerative disorder.

We look forward to sharing our Companys first clinical data at RD2021 and our progress towards developing a transformative gene editing medicine for people living with CEP290-related retinal degeneration. The presentation will include an evaluation of clinical data from the first two adult cohorts as the study continues into the pediatric mid-dose and adult high-dose cohorts, said Lisa Michaels, M.D., Executive Vice President and Chief Medical Officer, Editas Medicine. I would like to thank all of the patients who have and will participate in this landmark gene editing medicine clinical trial.

The presentation will include patient safety assessments and a preliminary analysis of secondary endpoints relating to signals of gene editing and clinical benefit. Cumulative data from patients in the adult low-dose and mid-dose cohorts and will be presented by one of the studys Principal Investigators, Dr. Mark Pennesi, M.D., Ph.D., Professor of Molecular and Medical Genetics, Kenneth C. Swan Endowed Professor of Ophthalmology, Paul H. Casey Ophthalmic Genetics Division Chief, Casey Eye Institute, Oregon Health & Science University.

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Full details of the Editas Medicine presentations can be accessed on the RD2021 website at http://www.rdmeeting.net/RD2021Program.pdf.

Oral Presentation:Title: BRILLIANCE: A Phase 1/2 Single Ascending Dose Study of EDIT-101, an in vivo CRISPR Gene Editing Therapy, in CEP290-Related Retinal DegenerationSession Title: Platform Session V: Clinical TrialsDate and Time: Wednesday, September 29, 2021, 9:05 9:35 a.m. ETPresenter: Dr. Mark Pennesi, M.D., Ph.D., Professor of Molecular and Medical Genetics, Kenneth C. Swan Endowed Professor of Ophthalmology, Paul H. Casey Ophthalmic Genetics Division Chief, Casey Eye Institute, Oregon Health & Science University.

Investor Event and Webcast InformationEditas Medicine will host a live webcast on Wednesday, September 29, 2021, at 11:00 a.m. ET to review the presented data. To join the webcast, please visit this link or visit the Events & Presentations page of the Investor section of the Companys website on September 29. A replay of the webcast will be available on the Editas Medicine website for 30 days following the call.

About EDIT-101 EDIT-101 is a CRISPR-based experimental medicine under investigation for the treatment of Leber congenital amaurosis 10 (LCA10). EDIT-101 is administered via a subretinal injection to reach and deliver the gene editing machinery directly to photoreceptor cells.

About BRILLIANCEThe BRILLIANCE Phase 1/2 clinical trial of EDIT-101 for the treatment of Leber congenital amaurosis 10 (LCA10) is designed to assess the safety, tolerability, and efficacy of EDIT-101 in up to 18 patients with this disorder. Clinical trial sites are enrolling up to five cohorts testing up to three dose levels in this open label, multi-center study. Both adult and pediatric patients (3 17 years old) with a range of baseline visual acuity assessments are eligible for enrollment. Patients receive a single administration of EDIT-101 via subretinal injection in one eye. Additional details are available on http://www.clinicaltrials.gov (NCT#03872479).

About Leber Congenital AmaurosisLeber Congenital Amaurosis, or LCA, is a group of inherited retinal degenerative disorders caused by mutations in at least 18 different genes. It is the most common cause of inherited childhood blindness, with an incidence of two to three per 100,000 live births worldwide. Symptoms of LCA appear within the first years of life, resulting in significant vision loss and potentially blindness. The most common form of the disease, LCA10, is a monogenic disorder caused by mutations in the CEP290 gene and is the cause of disease in approximately 20-30 percent of all LCA patients.

About Editas MedicineAs a leading genome editing company, Editas Medicine is focused on translating the power and potential of the CRISPR/Cas9 and CRISPR/Cas12a (also known as Cpf1) genome editing systems into a robust pipeline of treatments for people living with serious diseases around the world. Editas Medicine aims to discover, develop, manufacture, and commercialize transformative, durable, precision genomic medicines for a broad class of diseases. For the latest information and scientific presentations, please visit http://www.editasmedicine.com.

Forward-Looking Statements This press release contains forward-looking statements and information within the meaning of The Private Securities Litigation Reform Act of 1995. The words anticipate, believe, continue, could, estimate, expect, intend, may, plan, potential, predict, project, target, should, would, and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. The Company may not actually achieve the plans, intentions, or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including: uncertainties inherent in the initiation and completion of pre-clinical studies and clinical trials and clinical development of the Companys product candidates; availability and timing of results from pre-clinical studies and clinical trials; whether interim results from a clinical trial will be predictive of the final results of the trial or the results of future trials; expectations for regulatory approvals to conduct trials or to market products and availability of funding sufficient for the Companys foreseeable and unforeseeable operating expenses and capital expenditure requirements. These and other risks are described in greater detail under the caption Risk Factors included in the Companys most recent Annual Report on Form 10-K, which is on file with the Securities and Exchange Commission, as updated by the Companys subsequent filings with the Securities and Exchange Commission, and in other filings that the Company may make with the Securities and Exchange Commission in the future. Any forward-looking statements contained in this press release represent the Companys views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date. Except as required by law, the Company explicitly disclaims any obligation to update any forward-looking statements.

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Initial Clinical Data from Editas Medicine's BRILLIANCE Clinical Trial of EDIT-101 for LCA10 to be Presented at the International Symposium on Retinal...