A Virtual Think Tank Executive Summary

Gene Editing: Clearing Roadblocks to a
New Class of Therapeutics
By: Christi Bird, Principal Consultant,Transformational Health, Frost & Sullivan

Frost & Sullivan recently invited academic and industry leaders in gene editing to participate
in a new and unique thought leadership forum, our Virtual Think Tank series. This forum
brought together leading minds in this emerging field to discuss the current state of gene
editing, the implications of research and development occurring today, key challenges, andexpectations for future applications of gene editing in the clinical space.

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Gene Editing: Clearing Roadblocks to a New Class of Therapeutics

Key opinion leaders
who contributed tothe discussion include:
nChengzu Long, Ph.D.,
Assistant Professor,
New York University Schoolof Medicine

nFyodor Urnov, Ph.D.,
Associate Director,
Altius Institute for
Biomedical Sciencesn

YannJouvenot, Ph.D.,
Senior Manager,
Gene Expression at Bio-Rad
LaboratoriesnKristian Laursen, Ph.D.,
Instructor, Molecular Genetics,
Cornell UniversitynMax Mamonkin, Ph.D.,
Instructor, Pathology &Immunology Center for Celland Gene Therapy,
Baylor College of Medicine

nAdam Hoppe, Ph.D.,
Associate Professor,
Department of Chemistry
and Biochemistry, SouthDakota State University

2Gene editing allows researchers to alter an organism’s phenotype. Aphenotype is simply defined as the set of observable characteristics of anindividual resulting from the interaction of its genotype with theenvironment. Using tools such as zinc finger nucleases (ZFNs), TALENs, andCRISPR-Cas9, nucleotides can be added, deleted, or altered at genetic lociof interest, such as those associated with disease.
Thousands of diseases have an underlying genetic basis. Some result from asingle gene mutation (i.e., cystic fibrosis, sickle cell disease, hemophilia), whileothers are more complex. Many of the existing drugs and therapeutic
regimens for these diseases primarily treat symptoms or target the diseasealong its progression. Gene editing techniques enable new approaches totreat disease, in most cases, at the genetic source. In theory, gene editing cantarget the genetic source of the disease and eliminate it completely from thepatient’s genome. Researchers are also developing ex vivo gene editing
techniques that can modify a patient’s extracted stem or progenitor cells
using CRISPR/Cas9 for subsequent transplantation back into the patient.
Thus, genome editing can contribute significantly to various genetic diseases
and in some cases offer a cure, or at the very least an effective treatment.
Gene editing can also be used to target non-genetic diseases. One suchapproach involves enhancing the body’s ability to fight diseases. Researchers
continue to develop new techniques and spur the development of newtechnologies to utilize the full potential of gene editing.
Regardless of the methodology taken, gene editing techniques are making
global headlines as new discoveries are finally translating into clinical trials.
This makes now the right time to bring together thought leaders to talkabout gene editing, its progress, its challenges, and how we expect the fieldto progress.

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MAJOR PROGRESS IN GENE EDITING
The experts who joined Frost & Sullivan’s Virtual Think Tank on Gene Editing
are studying diseases such as Duchenne muscular dystrophy, spinal muscularatrophy, HIV, sickle cell diseases, and kidney cancer. While the field continues
to make discoveries attributed to gene editing techniques across various
diseases, a few targets have entered clinical trials, and most importantly, someof the first gene editing therapies are being used to treat patients. Dr. Adam
Hoppe, M.D., Associate Professor at South Dakota State University, outlinedthat the largest strides have been made in inmonogenic diseases of the blood
where there is a clear path forward with sickle cell disease. Also promising
are approaches where genetic modification of the liver can take the place ofcurrent enzyme replacement therapies.
During his tenure at Sangamo Therapeutics, our panelist Fyodor Urnov, now
Associate Director at Altius Institute for Biomedical Sciences, coined the term
“gene editing” in 2005 with colleagues Philip Gregory, Michael Holmes, andEdward Rebar. His team at Sangamo was the first to move a gene editing
therapy to a clinical trial in 2009 with a zinc-finger nuclease (ZFN)-based
therapeutic, SB-728-T for HIV. Most recently, Urnov led research on theBCL11A erythroid enhancer as a potential treatment for hemoglobinopathies,
such as β-thalassemia and sickle cell disease. These indications are now in
preclinical testing as collaborations between Sangamo and Bioverativ (recentlyacquired by Sanofi). Vertex Pharmaceuticals and CRISPR Therapeutics havetheir own co-developed gene editing therapy forβ-thalassemia and sickle celldisease, CTX001, expected to enter Phase 1/2 clinical trials in Europe andthe US in 2018. Should any of these treatments be found to be safe andeffective, within the next decade patients with β-thalassemia or sickle celldisease can anticipate a therapy that will substantially improve their qualityof life.
Sangamo Therapeutics also announced in November 2017 that it had treatedthe first patient with an in vivo zinc finger nuclease (ZFN) gene editing therapy,SB-913, in its seminal Phase 1/2 clinical trial for mucopolysaccharidosis type
II (MPS II), or Hunter syndrome. Even with regular weekly enzyme
replacement therapy (ERT), the current treatment method, many patients withMPS II die before the age of 20 from complications of the disease. Sangamo
is using gene editing to introduce a corrective gene into the DNA of liver
cells of patients with MPS II that enables the liver to produce the enzymes
made deficient by the disease.In two additional clinical trials, the company istargeting hemophilia B and MPS I with similar therapies that restore thefunction of enzymes involved in those diseases. Should these therapies becommercialized, not only will they offer cures for these diseases, but they may
reduce healthcare costs over the life of patients given the elimination ofweekly ERT infusions.

During his tenure at
Sangamo Therapeutics,
our panelist Fyodor
Urnov, now Associate
Director at Altius
Institute for BiomedicalSciences, coined theterm “gene editing” in2005 with colleagues
Philip Gregory, MichaelHolmes, and EdwardRebar.

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Besides the outcomebased pricing model, theindustry is actively
discussing thepossibility of pricecomparisons between
gene therapy and 10
years of the current
treatment model.

Another promising gene editing approach Dr. Hoppe and the panel discussed
was what he termed the“weaponization of chimeric antigen receptor T(CAR-T) cells,” cells that already exist in the patient’s body. In fact, in August
2017, the Food and Drug Administration (FDA) approved the first genetherapy in the U.S., a drug called Kymriah from Novartis, for B cell acutelymphoblastic leukemia (ALL). This CAR-T cell therapy removes T cells fromthe patient’s blood and introduces a gene that expresses the chimeric antigen
receptor (CAR) protein that directs T cells to target and destroy leukemia
cells once re-infused. While the therapy carries a hefty $475,000 price tag,
Novartis has instituted an outcome-based pricing model, meaning thecompany will only receive payment if a patient responds to treatment within
the first month of usage. Meanwhile, Cellectis is developing its own geneedited off-the shelf CAR-T cells, which the company claims will dramaticallyreduce costs of this type of immunotherapy. Instead of using the patient’s
own T cells, this therapy will utilize CAR-T cells manufactured on a large
scale to bring down costs.
These examples are just a few of the key gene editing initiatives in advanced
stages that may offer diseased patients a cure, or at the very least, improvetheir quality of life in the near future. Should several gene editing treatments
successfully advance through clinical trials and FDA approval, these outcomes
will bring even greater attention and investment to the field.
ISSUES IN COSTS AND ACCESSIBILITY

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While the industry, physicians, and patients have anxiously anticipated thefirst gene editing treatments, issues of costs and accessibility remain top
concerns.While treatment cost may appear steep at first glance, many expect
the one-time cost for gene editing therapies to pale in comparison to current
lifetime treatment cost estimations. If a gene therapy works, the payer trades
a lifetime of conventional treatments, plus their complications, for a single
one-time cost. Chengzu Long, Assistant Professor at New York University
School of Medicine said, for gene therapy, “the cost is hundreds of thousandsin general, but for these patients, if you want to really take care of them fora lifetime, that is also going to be quite expensive.” This becomes even moreglaring when the gene editing therapy is used as the first line of defense, ortreats a disease that strikes early in life. Kristian Laursen, Ph.D., Instructor,
Molecular Genetics at Cornell University, added, “For terminal cases of cancer,
there’s really no choice.Those patients don’t really have any options. As thesetherapies become more widespread, the pricing will be less elevated. They
might move to the frontline therapies and then a lot of these questions[around cost] will disappear.” This is true of gene editing therapies that target
more prevalent diseases, as larger volumes and the necessity for greater
efficiencies in manufacturing and delivery will bring costs down. In addition,the panel reasons that one cannot put a price on a saved life or better qualityof life.

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In terms of insurance coverage in the U.S., given the nascency of this class oftherapies, debates still surround how these costs will be covered. Besides
the outcome-based pricing model, the industry is actively discussing thepossibility of price comparisons between the gene therapy and 10 years of
the current treatment model. If the one-time cost is less than the 10 yearsof treatment of the chronic disease, then insurance would pay for it. Each
proposed system is not without its concerns.What if a patient fails to returnto the doctor to test for remission? What if the patient switches insurancecompanies? As more gene therapies reach the market and patients demand
them, particularly when the therapy offers a cure, industry stakeholders (i.e.
physicians, researchers, pharmaceutical companies, insurance companies,
lawmakers, bioethicists, and patient advocacy groups) must come to the table
to find solutions to allow for widespread access to the cure.
From a cost perspective, anidealgene therapy will be one that provides a curein a one-time dose and actually reduces the lifetime patient healthcare costs
related to the disease. If a pharmaceutical company can make that case, it
becomes an unequivocal decision for patients to undergo such treatment
and for insurance companies to provide coverage.

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THE CALL FOR MORE DISCOVERY RESEARCH AND NEW
TOOLSUltimately, gene editing
provides hope formillions of people
suffering from diseases
with insufficient or notreatment options.

While major strides have been made in gene editing in a short period oftime, basic discovery research will need to continue, particularly research
focused on the long-term effects of gene editing. Dr. Hoppe expanded, “Ibelieve for anything that manipulates the genome, there is a need to be able
to ascertain that no off-target effects will occur and that is probably one
question for anybody doing gene editing. That is one of the main concerns.
We do have, I believe, a wide variety of tools that help us with this, especiallywith the development and expansion of next-generation sequencing.” While
researchers are certainly studying off-target effects of gene editing in the labwith a growing number of tools available to them, Dr. Hoppe suggests that
continued monitoring of patients over lifetimes will better elucidate any
unanticipated health impacts.
Dr. Hoppe added, “This calls into question the regulatory guidance on gene
editing and what level of risk can be accepted for these therapies.” For
instance, what if a gene therapy cures an immunodeficiency which greatly
increases quality of life for the patient, but long-term could cause a form ofcancer linked to the therapy? Does the risk outweigh the benefit? Current
regulatory guidance by the FDA classifies gene editing for therapeutic
purposes under its existing framework for biological products handled by
the FDA’s Center for Biologics Evaluation and Research (CBER). In its official
blog, the FDA states its awareness of the potential for off-target effects as akey industry concern. Questions like this highlight the need for continued
discovery and clinical research to assess risks associated with gene therapyas
well as the development of new tools to aid such research.
Continuing on the topic of new tools, Dr. Laursen spoke of the need forbetter delivery tools, particularly around CRISPR-based cancer therapies
where all cancer cells need to be targeted to prevent relapse. Furthermore,
the panel discussed the need for better tools and more structured standard
operating procedures (SOPs) to improve clinical trial guidance, manufacturing
practices, and long-term monitoring of efficacy. Thus, while the industry
continues to make great strides using gene editing for therapeutic
applications, and make major headlines along the way, there is a continued
call for more discovery research and improved tools to feed pipelines, help
solve issues of off-gene effects, and develop SOPs to navigate the FDAprocess.

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THE FUTURE FOR GENE EDITING
Gene editing applications are already expanding rapidly as tools get cheaperand easier to use. Looking to the future, our panel touched on both the good
and the bad that could stem from gene editing.
Certainly the more gene therapies move to the clinic, the more basic
research is needed to feed the pipeline. Max Mamonkin, Instructor at thePathology & Immunology Center for Cell and Gene Therapy at Baylor
College of Medicine, commented, “As with any technology that's as
revolutionary as gene editing, as it becomes more and more accessible tolabs around the world, I'm sure there will be a lot of demand, as one canonly imagine the countless applications of these technologies.” Dr. Mamonkin
continued, “This technology really allows us to build a cell that we need. It’s
kind of like Lego blocks. You can customize a cell for a particular application.
You can remove genes. You can add genes and you can remove genes that
potentially cause toxicity, case in point for CAR-Tcell. So you can customize
the cells to switch off some genes that are responsible for cell rejection or
add some safety switch.”7

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The panel discussed theneed for better tools
and more structured
standard operatingprocedures (SOPs)
to improve clinical
trial guidance,
manufacturing
practices, andlong-term monitoringof efficacy.

In this manner, the panel discussed the possible creation of modified cellswith a custom set of genes created through gene editing that could beinserted into a patient to target their particular disease. After testing forsafety and efficacy and going through the required approval process, these“custom” cells could then be utilized as an off-the-shelf therapy, like theCellectis CAR-T cells.This means instead of deriving cells from a patient andperforming gene editing on the cells before restoring them into that patient,
the cells can be prepared in bulk like any other drug and provided to anypatient. Dr. Mamonkin envisioned a cell incapable of malignant transformation
and uncontrollable division that would deliver the required therapeutic effectand could be injected into the patient as needed.These off-the-shelf therapies
manufactured in bulk would significantly bring down the cost of gene therapy
compared to utilizing cells derived from each patient.
While our Virtual Think Tank panel provided many examples of successstories and the future promise expected from gene editing therapies, they
cautioned that multiple negative cases, such as fatal outcomes of clinical trials
or stories of unethical usage of the technology could derail the field. Yann
Jouvenot, Senior Manager, Gene Expression at Bio-Rad Laboratories pointed
to physical enhancements for competitive athletes as a likely alternate useof gene editing technology in the future. Dr. Chengzu mentioned muscle
enhancements, or changing hair, eye, or even skin color as additional unethicaluses of the technology that should be avoided. Dr. Hoppe summarized, “I
think as the technology gets better and you can begin to apply it more readily
to treat more and more diseases that the question becomes, where do you
transition from treating a disease to providing an enhancement orcompetitive benefit, and I think that's where ethics questions come in.”
While our experts felt it was not far-fetched to start thinking and talking
about these possible unintended uses of gene editing, they also cautioned
about over-regulation of a field in its infancy. Dr. Jouve not expanded, “We’ve
started to actually draft a lot of regulations before a lot of the research has
actually been done. So, while I do say let's keep an eye open and be mindfulof what can happen, we also have to make sure that we don't start painting
some super apocalyptic scenario that then starts hindering big actual
progress of research.”8

A VIRTUAL THINK TANKEXECUTIVE SUMMARYCONCLUSION
Ultimately, gene editing provides hope for millions of people suffering fromdiseases with insufficient or no treatment options. The industry, patients,insurers, and policymakers will watch anxiously as more therapies navigate
through clinical trials with the hope of moving this revolutionary technology
from bench to bedside for patients that so desperately need better
treatment options.
Gene editing technology and its applications are evolving at an
unprecedented pace, and our attitude toward it is warming as well. As withmany novel, scientific technologies, gene editing has its own set of challenges
ranging from delivery, safety, and patient access to public opinion and future
unintended applications. With continued collaboration between key
stakeholders and careful, safe advancement of early gene editing therapies,
potential roadblocks can be thwarted.
Frost & Sullivan would like to thank the gene editing thought leaders whojoined our Virtual Think Tank for their time and valuable insights into thispromising field. We hope that this discussion spurs new ideas and fosters
additional exchanges in this burgeoning area.

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