Gene Therapy for Rare Disorders Becoming More and More Viable

Gene Therapies Becoming More Common for Rare Orphan Disease

Resurgent across the biomedical engineering and clinical trial landscape, gene-therapy owes its new vitality to a better understanding of rare diseases, the discovery of new gene delivery vectors, and the development of site-specific genome editing technology. Already pushing up new shoots, gene therapy may flourish if it extends its roots deep into an increasingly fertile manufacturing base. Manufacturing trends that nurture gene therapy’s growth include the development of production systems for adeno-associated virus (AAV) vectors for gene delivery.

All these advances are encouraging gene-therapy developers to stake new claims in rare disorder territory, which is where gene therapy was first applied, before most clinical trials turned from monogenic disorders, such as severe combined immunodeficiency, cystic fibrosis, and Duchenne muscular dystrophy (DMD), to polygenic disorders (such as heart disease, diabetes, and cancer).

Monogenetic disorders resisted early gene therapy, which struggled to achieve long-term expression of genes that were introduced with the intention of replacing or disrupting faulty genes. Also, monogenetic disorders, which affect small patient populations, seemed to offer limited commercial reward.

Given that gene therapies against monogenetic disorders now seem more workable from a technological perspective, old commercial assumptions are being reconsidered. It remains true that monogenetic disorders afflict relatively few people, but monogenetic disorders are numerous. In fact, they account for about 80% of the 7,000 rare disorders that have been identified.

The cultivation of gene therapy for rare disorders is not limited to pharmaceutical, biotechnology, and medical device companies. This kind of gene therapy also enjoys government support. For example, the National Institutes of Health (NIH) Common Fund has allotted approximately $200 million for the NIH Undiagnosed Diseases Network to “accelerate diagnosis of rare and undiagnosed conditions … and uncover the underlying disease mechanisms associated with these conditions.”

In addition, the NIH has launched the Therapeutics for Rare and Neglected Diseases (TRND), a program that oversees a suite of pilot projects to address specific obstacles in gene therapy development. In collaboration with biotechnology and academic groups, the TRND hopes to scale up gene-vector manufacturing and disseminate the best practices to achieve regulatory approval for new gene therapies.

Delivery Options

“This is a very exciting time for gene therapy in rare diseases,” said Philip J. Brooks, Ph.D., program director, Division of Clinical Innovation and Office of Rare Diseases Research, National Center for Advancing Translational Sciences, NIH. “Two viral vector platforms are emerging—AAV for in vivo gene therapy, and lentivirus for ex vivo gene therapy involving hematopoietic stem cells.”

At the recent Gene Therapy for Rare Disorders 2018 conference in Boston, Dr. Brooks’ optimistic take was …finish reading article. 

Oligonucleotides: Opportunities, Pipeline and Challenges At Long Last, Nucleic Acid Therapeutics Are Coming of Age

Six Fascinating AI Applications in the Life Sciences

AI - Artificial Intelligence in Life Sciences

More is better when it comes to Big Data and machine learning. This is particularly true in the fields of medicine and pharma. A report by Accenture estimates that by the year 2026, Big Data in conjunction with machine learning in medicine and pharma will be generating value at a prodigious rate: $150 billion/year.

This figure reflects how the tools of artificial intelligence (AI) are expected to help doctors, patients, insurers, and overseers reach better decisions, optimize innovations, and improve research and clinical trial efficiency.

Healthcare data comes from myriad sources: hospitals, doctors, patients, caregivers, and research. The challenge is putting all the data together in a compatible format and using it to develop better healthcare networks and protocols. This is where machine learning comes in.

The main purpose of machine learning applications specific to medicine and pharmacotherapy is to make data accessible and usable for improving prevention, diagnosis, and treatment as a matter of course. Pioneers in medicine and pharma machine learning are already addressing some key areas.

Machine Learning Applications in Medicine and Pharma

This article is informed by a TechEmergence analysis of AI initiatives undertaken by the five largest global drug makers. Whereas the analysis presents a broad survey, covering all the major trends of industry applications in life sciences and biotech, this article is more focused. It emphasizes six of the trends that TechEmergence believes will be most meaningful in the near term including:

  • Diagnosis and Disease Identification
  • Personalized Medicine
  • Drug Discovery and Manufacture
  • Clinical Trials
  • Radiotherapy and Radiology
  • Electronic Health Records

Continue reading article

2018 BPI West Attendees Hungry for Process Validation & Regulatory Strategies for Fast-track and Breakthrough Therapies

Process Validation for Expedited Approval Drugs

BioTechLogic’s Tracy TreDenick delivered a very well-received presentation at this year’s BPI West discussing process validation and regulatory strategies for expedited approval drugs.

BioTechLogic has done numerous projects supporting clients working to bring therapeutics with accelerated approval status to market. Given the complexity and the challenge of these programs, it’s little surprise that the talk was of such great interest.

Highlights of the presentation included discussion of:

  • Overview of FDA’s Expedited Pathway Designations
  • Look at 2012-2017 Breakthrough Therapy (BT) designation by therapy
  • Expedited vs traditional development program timelines
  • Common challenges for Breakthrough Therapy products
  • Regulatory
  • Common process development challenges for BT Products
  • Common analytical challenges for BT products
  • Common manufacturing challenges for BT products
  • Keys to a successful regulatory strategy
  • Understanding scientifically complete CMC sections
  • Process validation
  • Keys for successful validation

Review full presentation deck below:

Article: Why Data Integrity Is More Important Than Ever

 

We are thrilled that our contributed article, “Why Data Integrity Is More Important Than Ever,” was published in the January/February 2018 issue of Pharmaceutical Manufacturing magazine.

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Access full January/February 2018 issue of Pharmaceutical Manufacturing

Cellular Therapeutics – Exploring Challenges within the Regulatory Framework

This presentation explores the progress that has been made and the challenges ahead as cellular therapeutics strive to mature in the marketplace.




Cell Therapies Come of Age: Overcoming Challenges Within the Regulatory Framework

Cell Therapies Come of Age

By Tracy TreDenick, Head of Regulatory and Quality Assurance, BioTechLogic

While the field of stem cell therapy has been in development for decades, most notably with the first successful bone marrow transplant in 1968, regenerative medicine is now experiencing rapid progress fueled by scientific and technology advancements. Although cellular therapeutics benefits greatly from embryonic stem cells, debates over the ethics of this type of research has led to the discovery of a more sustainable alternative, somatic stem cell research.

This said, many of the emerging cell therapies are scientifically and medically complex with many learnings and understandings still to come. As if core scientific and medical complexities were not enough, the industry, medical community and regulators are grappling with the challenge of conforming the regulatory framework to support the commercialization of cellular therapies, for instance cellular therapy classification, quicker approval pathways, and CMC challenges.

Cell Therapies:  A Drug or not a Drug?

Within the cell therapy arena, regulators, the medical community and industry alike are often confronted with an unsettling question. What is this, really? Should a given cell therapy be regulated as human cells, tissues, and cellular and tissue-based products (HCT/Ps), or should the cell therapy be regulated as a drug with the FDA oversight and regulatory approval process that accompanies that designation?

As cell therapies have become more common and indications have expanded, it’s becoming increasingly common to be trapped in “no man’s land” trying to answer this question, creating tension and confusion for the range of stakeholders involved in the decision-making process. Today, the dispute primarily centers around somatic stem cells that are harvested and prepared for transplantation through minor surgical procedures at stem cell clinics and other medical service providers.

Mesenchymal stem cells (MSCs) are collected from a patient’s own bone marrow or fat tissue, or from donor tissue not altered or manipulated and can form fat, bone or cartilage, making them useful for repairing bones and joints, minimizing inflammation caused by conditions such as rheumatoid arthritis, and promote the repair of a range of tissues. Hundreds of stem cell clinics now perform procedures with MSCs that are regulated as HCT/Ps under Public Health Service Act (PHSA) section 361. Procedures falling under section 361 classification are subject to regulations similar to that of other surgical procedures that are primarily aimed at avoiding contamination, infection and the spread of infectious disease.

HCT/Ps that require “manipulation” or alteration are governed by PHSA section 351. These products/procedures are considered to be indistinguishable from drugs and must undergo a rigorous regulatory approval process before being administered to patients. Some of the lines that separate section 351 products from those of section 361 are clearly drawn. For example, cells and tissues used homologously, meaning they perform the same function in the recipient as they do in the donor — such as the transplantation of bone marrow to restore healthy blood-cell production, are regulated under section 361. And therapies that employ a patient’s own stem cells (autologous) are more likely to fall under section 361 than those that use allogeneic cells (from a donor).

So back to the question at hand: A drug or not a drug? Broadly, the FDA considers a product to be a drug if “more than minimal manipulation” is required for its effectiveness. Ambiguities can arise, however, because merely separating stem cells from their neighboring cells always entails some degree of manipulation.

The question of minimal manipulation was… click to continue reading article.

 

Oligonucleotides: Opportunities, Pipeline and Challenges At Long Last, Nucleic Acid Therapeutics Are Coming of Age

BioTechLogic Perspectives on Oligonucleotide Therapies

Oligonucleotides: Opportunities, Pipeline and Challenges At Long Last, Nucleic Acid Therapeutics Are Coming of AgeRecently, I sat down with Tracy TreDenick, BioTechLogic’s Head of Regulatory and Quality Assurance, to learn more about her insights and experiences from the extensive oligonucleotide therapeutics work BioTechLogic has done.

Q: Briefly describe the types of work you have done within the oligonucleotide space?

A: BioTechLogic has done a great deal of working with oligonucleotide products in recent years, including process validation work for drug substance, drug product and an oligo adjuvant.

Just some of BioTechLogic’s oligonucleotide work has included:

  • CMO on-site support
  • Equipment qualification protocols
  • Commercial-ready batch records
  • Support validation protocols and studies
  • Process validation
  • Manufacturing support
  • Technical support
  • Facility validation reports
  • Microbial monitoring strategies
  • Commercialization plans
  • Formulation development reports
  • Process control strategies
  • Chromatography column troubleshooting
  • Multiproduct facility CV site policies and strategies

Q: What are the most common challenges you have confronted while working on oligonucleotide products, and how has BioTechLogic addressed these challenges?

A: One of the most common challenges is the environmental classifications for manufacturing this kind of product because in many situations, the product is not a finished product or an API, but an adjuvant. There are guidelines for drug products, and ICH Q7 for APIs, but not specific guidelines for adjuvants. BioTechLogic has had to evaluate the environmental requirements based on the needs of the product.

Another challenge is balancing the U.S. FDA filing requirements (macro-molecule) to the EU’s “centralized procedure” which is used for biologics. For the most part, this challenge has been addressed by applying the most stringent of the two requirements, allowing the given product to be filed both in the United States and in the European Union (EU).

Q: Share your views on the oligonucleotide product regulatory debate, including the likely issues that will surface on the regulatory landscape as these products mature.

A: The U.S. technical/regulatory experts for oligonucleotides say these are just macro-molecules, a type of large “small molecule,” as opposed to a biologic. A biologic is typically difficult to characterize using analytical procedures, while small molecules are far easier to characterize. There is some debate about impurities and quality assurance when manufacturing oligonucleotide products; however, via improved analytical instrumental technologies and new approaches, the industry has made a lot of ground here. But typically, the difference in regulatory environment amounts to what type of manufacturing support validation that you have to do for a biologic as opposed to a small molecule, and there is generally more complex work for a biologic.

Oligonucleotides: Opportunities, Pipeline and Challenges At Long Last, Nucleic Acid Therapeutics Are Coming of Age

101 Overview: CRISPR-CAS9

This inforgraphic is a wonderful overview for those familiarizing themselves with work going on within the genetic engineering space – hope you find it helpful. The website that created this infographic, www.Futurism.com, while not dedicated to life sciences, publishes quite interesting content within a range of up and coming areas.


CRISPR-CAS9 Infographic

Stem Cell Manufacturing: Stem Cell–Based Products Aren’t Rolling Off Assembly Lines Yet

Stem Cell Manufacturing: It’s All about Scale

According to one forecast, the stem cell market will grow at an annual rate of 9.2% and attain a value of almost $16 billion by 2025. This prediction, from a 2017 study by Grand View Research, may not justify any career- or life-altering decisions—not by itself. It does correlate, however, with figures showing consistent growth in the volume of published research. Because these market research results and bibliometric figures support each other, their common implication—high year-on-year growth in the stem cell market—seems reasonably certain.

Much of the stem cell market’s growth comes from the development and manufacture of stem cell therapeutic products. In this segment, the challenge is—and always will be—manufacturing at scales commensurate with profitability.

“Stem cell processes involve many complex, open-process steps that are still largely unintegrated and manual,” notes Aaron Dulgar-Tulloch, Ph.D., director of cell therapy R&D at GE Healthcare. “This in turn contributes to high variability and operational costs, which increase risk and drive up cost of goods.”

Stem cell therapies, in particular, face the extraordinary challenge of producing from undifferentiated cells a product that is completely matured into the desired therapeutic cell lineage.

GE Healthcare’s involvement in stem cell production dates from the industry’s earliest days. In January 2016, GE Healthcare contributed to a $40 million investment in the Toronto-based Centre for Commercialization of Regenerative Medicine (CCRM). Later that year, in April, GE Ventures teamed with the Mayo Clinic to launch Vitruvian Networks, which provides software for producers of cell-based therapies. A few months later, in August, GE Healthcare acquired the Biosafe Group, whose specialty was cell and cord blood bioprocessing.

In April 2017, GE Healthcare acquired Asymptote, a cryogenic processing company, and announced a partnership with the Cellular Biomedicine Group to develop chimeric antigen receptor T cell (CAR-T) and stem cell production technologies. In October 2017, the company opened its first 3D printing laboratory in Uppsala, Sweden. Thus, GE Healthcare thus covers quite a few bases in the cell therapy marketplace, in addition to maintaining its eminence in traditional bioprocessing.

With the increasing number of cell and gene therapies moving into mid- to late-stage clinical trials, observes Dr. Dulgar-Tulloch, “companies are challenged to improve their manufacturing process to minimize impact on their clinical development timeline and help ensure cost- and time-effectiveness.” Continue reading article

On the Cusp of a Biomedical Revolution – Best of CRISPR 2017 Articles

Best of CRISPR 2017

One can hardly pick up a science journal or biotech magazine without reading about another CRISPR-related advance. In the past six months, we have seen major advances in editing disease-causing genes in human embryos. New tools include RNA-editing CRISPR systems and ultra-precise base editors. In the latter, a modified Cas protein pinpoints and tweaks a specific nucleotide, rather than completely cleaving the double helix. In this timely supplement, GEN has compiled a selection of topical features on novel applications of CRISPR/Cas9 that neatly capture the incredible excitement and potential of this technology. Kicking things off is Malorye Branca’s excellent feature exploring clinical applications of CRISPR therapies entitled: “A Dose of CRISPR: Can Gene-Editing Cut It in the Clinic?” (This originally appeared as a cover story in GEN’s sister magazine, Clinical OMICs.)

Other articles from GEN in this supplement cover a broad range of issues, including enhancing and scaling up fundamental CRISPR genome-editing technology, and a range of new applications from engineering the pig genome for safer organ transplantation to various novel strategies in gene therapy.

Best of CRISPR 2017 Articles Include:

  • A Dose of CRISPR: Can Gene Editing Cut It in the Clinic?
  • Genome Engineering: CRISPR Proving More User-Friendly
  • Using CRISPR to Improve Disease Modeling
  • Gifted Scientists Rapidly Advance CRISPR Operations
  • Genome Editing Explores New Depths
  • Applications of Novel CRISPR Tools

Read Best of CRISPR 2017 articles