Gene Therapy eBook by Informa Pharma Intelligence

Gene Therapy eBook

Contents Introduction

In Vivo’s Quick Guide To Gene Therapy

The Future Of Medicine: Cell And Gene Therapies Take The Lead

Gene Therapies Will Be A Bigger Cost Issue In 2021, PwC Predicts

Medicare’s CAR-T Payment Change Helps the Entire Regenerative Medicine Field ... A Little Bit

Top US FDA Official Says New ‘Playbook’ Needed For CMC Reviews Of Gene Therapy Products

China Inc. Eyes Gene Therapy In Post-Coronavirus Growth Trajectory

Sickle Cell And Beta-Thalassemia Bend To Gene Manipulation By CRISPR/Vertex And Bluebird

Japan To Reimburse Zolgensma – But At Lower Price Than US

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Introduction Over the past five years, six gene therapy products have been approved by the US FDA and/or the European Commission, and the development pipeline has increased from around 300 to nearly 3,000 candidates. The extraordinary blossoming of this scientific field in recent years comes after several decades of dogged research and development in academic laboratories and to a fluctuating degree by industry. Those years were beset by setbacks, with patient deaths and commercial challenges rightfully giving rise to circumspection and skepticism, but continuing research and growing understanding has led us to the point where we can celebrate the launch of life-changing treatments for conditions including a rare form of blindness and spinal muscular atrophy. As gene therapy comes of age, companies in the space are proliferating and big pharma is squarely back in the game, evidenced by the high number of M&A and partnership deals centered on such technology and the commercialization of approved therapies by the likes of Novartis and Roche. Gene therapy encompasses multiple technical approaches to altering the genetic code in target cells, and this diversity of technology offers hope that previously intractable problems in many different diseases may ultimately be addressed therapeutically. With the recent approval of new gene therapies, new debates have opened up over their pricing and acceptable payment models, especially as their scope promised to expand from a limited number of rare diseases to a broader array of orphan indications and potentially more common conditions. This eBook brings you a selection of key articles from our publications, ranging from a broad overview of the field from In Vivo to commercial strategy and R&D analysis from Scrip and policy and regulatory considerations from Pink Sheet, covering key markets from the US and EU to Japan and China. Eleanor Malone Editor In Chief, Europe | Scrip, Pink Sheet, In Vivo, Generics Bulletin Informa Pharma Intelligence

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In Vivo’s Quick Guide To Gene Therapy

BY ALEX SHIMMINGS Executive Summary Once the stuff of (largely implausible) science fiction, gene therapy is now a clinical reality and one that is taking an increasing share of the pharma R&D limelight. In Vivo takes a look at how these therapies work, how the field has emerged and where it is likely to go next.

When it comes to taking medical science to the next level, gene therapy is one of the most exciting technologies out there. In attempting the leap from treatment to cure it holds the captivating promise of turning the once-miraculous – making the blind see, the lame walk, the deaf hear – into a clinical reality. After a fitful start, these “miracle” cures are now reaching the market sufficient numbers to drive huge investment and a wave of deal-making in the field. Still, gene therapy has much more to prove as a drug class before it can be secure of its place in the array of treatments available to doctors. As well as needing to confirm the durability of these products’ effects, there are issues over manufacturing, pricing and their commercial viability to contend with. With critical mass achieved in both the development pipeline and public awareness, gene therapy is here to stay, but the field is complex

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and wide ranging. Here, In Vivo surveys the landscape. Where Did It All Begin? Gene therapy was first mooted as genuine treatment prospect for human genetic diseases back in 1972 in a paper published in Science by Theodore Friedmann and Richard Roblin. Having made a survey of early research on the genetic modification in mammalian cells, they made their prescient conclusion: “In our view, gene therapy may ameliorate some human genetic diseases in the future. For this reason, we believe that research directed at the development of techniques for gene therapy should continue.” While this did not prompt an immediate rush to the bench, the concept did gain traction and by 1995 there were around 100 gene therapy candidates in development. Their numbers then increased steadily until 2003, when they hit 275. At this point the gene therapy category was the third largest in the overall R&D pipeline. This was to prove an early peak. The death in 1999 of 18-year-old Jesse Gelsinger in a gene therapy trial at the University of Pennsylvania Medical Center was the first major check to the field, and a few years later the development of leukemia in four children in a French study dealt

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another heavy blow. Developers took fright, and the number of gene therapy candidates in the pipeline dropped, not to return to 2003’s levels for more than a decade. But this mini Dark Age fell mainly on the west: companies in Asia plowed on to quick success. In 2004, China approved the world’s first gene therapy product – Gendicine, from the domestic firm Schenzen SiBiono GeneTech, for head and neck cancer – and a year later Shanghai Sunway Biotech launched Oncorine for head and neck and nasopharyngeal cancer, again in China. These were followed in 2006, by Epeius Biotechnologies’ Rexin-G for solid tumors in the Philippines, and in 2011 the Russian Federation approved its first gene therapy. These winds of success slowly cleared the cloud over the west and development there returned. The first regulatory triumph, uniQure NV’s Glybera (alipogene tiparvovec) in the EU, may have failed on the market, but it was followed in 2015 by approvals for Amgen Inc.’s Imlygic for melanoma in the US and EU. Two more products reached the market in 2016 and four in 2017 – all in western markets – as gene therapy finally went mainstream. Now a total of 14 gene therapy products have received approval somewhere worldwide (see Exhibit 1).

Exhibit 1. Approved Gene Therapies Worldwide

Product name

Therapy category

Collategene (beperminogene perplasmid) Gendicine (recombinant p53 gene)

Disease(s)

Country/ countries where approved/ launched

Originator

Licensee(s) (in approved countries)

In vivo

Limb ischemia

Japan

AnGes

n/a

In vivo

Head and neck cancer

China

Shenzhen SiBiono GeneTech

n/a

Amgen

n/a

Vector

In vivo or ex vivo

Gene therapy

Non-viral (plasmid)

Gene therapy

Viral (adenovirus)

Imlygic (talimogene laherparepvec)

Gene therapy

Viral (herpes simplex virus)

In vivo

Melanoma

Australia, Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK, US

*Invossa (tonogenchoncel-L)

Cell and gene therapy

Viral (retrovirus)

Ex vivo, allogeneic

Osteoarthritis

South Korea

TissueGene

Kolon Life Science; Mundipharma

Acute lymphocytic leukemia; diffuse large B-cell lymphoma

Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Japan, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, UK, US

Novartis

n/a

Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, UK, US

Spark Therapeutics (being acquired by Roche)

Novartis

Russian Federation

Human Stem Cells Institute

n/a

Kymriah (tisagenlecleucel-t)

Luxturna (voretigene neparvovec)

Neovasculgen (vascular endothelial growth factor gene)

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Cell and gene therapy

Viral (lentivirus)

Ex vivo, autologous

Gene therapy

Viral (adenoassociated virus)

In vivo

Leberâ&#x20AC;&#x2122;s congenital amaurosis; retinitis pigmentosa

Gene therapy

Non-viral (plasmid)

In vivo

Peripheral vascular disease; limb ischemia

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Oncorine (E1B/ E3 deficient adenovirus)

Gene therapy

Viral (adenovirus)

Rexin-G (mutant cyclin-G1 gene)

Gene therapy

Viral (retrovirus)

Strimvelis (autologous CD34+ enriched cells)

Yescarta (axicabtagene ciloleucel)

Zalmoxis (allogeneic T cells genetically modified to express human low affinity nerve growth factor receptor and the herpes simplex I virus thymidine kinase)

Zolgensma (onasemnogene abeparvovec)

Zynteglo

Cell and gene therapy

Gene therapy

Cell and gene therapy

Viral (retrovirus)

Viral (adenoassociated virus)

Viral (lentivirus)

In vivo

Head and neck cancer; nasopharyngeal cancer

China

Shanghai Sunway Biotech

n/a

In vivo

Solid tumors

Philippines

Epeius Biotechnologies

n/a

Adenosine deaminase deficiency

Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, UK

Orchard Therapeutics

n/a

Diffuse large B-cell lymphoma; non-Hodgkin’s lymphoma; follicular lymphoma

Austria, Belgium Canada, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK, US

Kite Pharma (owned by Gilead)

n/a

Ex vivo, allogeneic

Graft-versushost disease

Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK

MolMed

TTY Biopharm

In vivo

Spinal muscular atrophy with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene

AveXis (owned by Novartis)

n/a

Ex vivo, autologous

Transfusiondependent ß-thalassaemia (TDT) who do not have a ß0/ ß0 genotype

bluebird bio

n/a

Ex vivo, autologous

*In April 2019, Invossa was withdrawn from the South Korean market due to a discrepancy discovered in the cell components Source: Pharmaprojects

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This renaissance was also catalyzed by the development of a solid regulatory framework in both the EU and the US around which companies could build their product research. Although the two regulatory agencies have slightly differing definitions of what they consider to be a gene therapy, there is much overlap. The European Medicines Agency (EMA) was off the mark much quicker, creating the advanced therapy medicinal products (ATMP) regulatory

pathway back in 2007. This included gene therapies along with somatic cell therapies, tissueengineered medicines, and “combined ATMPs” that have one or more devices integrated within the medicine. In the US, gene therapies come under the Food and Drug Administration’s regenerative medicine advanced therapy (or RMAT) designation, which came into existence in 2016 with the 21st Century Cures Act.

EMA Definition of Gene Therapy

FDA Definition of Gene Therapy

• Contains or consists of recombinant nucleic acid, inserted into the body, to regulate, repair, replace, add, or delete a genetic sequence

• Genetic material administered to modify or manipulate gene expression, or to alter the biological properties of living cells for therapeutic use

• Has a therapeutic, prophylactic, or diagnostic effect that is related to the administered recombinant nucleic acid sequence, or to the resulting gene expression

• Modification may include:

• A somatic cell therapy or tissue engineered product that is also defined as a gene therapy

- Inactivating a disease-causing gene that is not functioning properly

• Regulatory pathway eligibility: ATMP

-R eplacing a disease-causing gene with a healthy copy of the gene

- Introducing a new or modified gene into the body to help treat a disease

LEGEND: ATMP = advanced therapy medicinal products; AA = accelerated approval; BTD = breakthrough therapy designation; FT = fast track; PR = priority review; RMAT = regenerative medicine advanced therapy

• Human gene editing technologies that disrupt harmful genes or repair mutated genes

How Do They Work? Put simply, gene therapy seeks to treat or cure a disease by making changes to a patient’s genome. This can be by introducing new nucleic acid code to the patient, by removing a faulty part of their code or by editing their genes to correct a faulty sequence. These changes alter how a single protein or group of proteins is produced by the cell – they may reduce the levels of a diseasecausing protein, increase production of a useful protein, or allow for the production of a missing protein or a modified protein.

mutation, such as cancer. Oncology indications account for just over half of the gene therapies already on the market, and they predominate those launched in western markets.

Gene therapies, therefore, lend themselves best to certain types of disease: congenital genetic conditions and those that arise from a later gene

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• Patient-derived, ex vivo cellular gene therapies • Regulatory pathway eligibility: AA, BTD, FT, PR, RMAT

Of the pipeline, one third consists of candidates in development for rare diseases, about another third represents oncology therapies, with the rest tilted at other therapy areas. Nearly half of the gene therapies in development for rare diseases target rare oncologic diseases. Popular non-cancer choices for development include monogenic diseases such as hemophilia, sickle cell disease, Duchenne muscular dystrophy and spinal muscular atrophy (SMA).

One point to note is that all gene therapies approved for human use so far are directed at somatic cells (specific types of already differentiated cells, such as lung, muscle or blood cells) rather than in germline cells (the cells that when fully developed form into sperm or ova and are passed down the generations). Germline gene therapy is controversial, and the gene therapies developed for inherited genetic diseases act on patients’ somatic not germline cells. In Or Out? Gene therapies can be broadly divided by where the genetic modification is performed. An in vivo approach sees the modifications made in particular cells while inside the body, whereas ex vivo methods make their genetic modifications to cells, such as bone marrow or blood cells, that have been removed from the patient for that purpose; they are then reintroduced to the patient following gene transfer and cell expansion in the lab (see Exhibit 2). Such ex vivo products are also known as “cell-andgene” therapies and some of the front runners – most notably in the CAR-T (chimeric antigen receptor T-cell) therapies Kymriah and Yescarta – fall into this class. These build on the older cell therapies that have been around in a primitive way since the advent of blood transfusions and bone marrow transplants. Making a genetic change to cells within the body, with an in vivo approach, is a much trickier prospect, removing as it does the safety net of being able to check the correct alterations have indeed been made before the cells are returned to the patient. While it was not the first to reach the market, Spark Therapeutics’ Luxturna, which was launched last year as a one-time treatment for an inherited retinal disease caused by mutations in

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both copies of the RPE65 gene, was probably the most notable in vivo gene therapy on the market before Novartis AG’s Zolgensma arrived. The choice between ex vivo and in vivo approaches depends largely on the site of the disease and the accessibility of the target cells. The current pipeline is a near even split between the two approaches, with gene therapies having a slight edge over cell-and-gene therapies. In vivo delivery is weighted towards ocular disorders including retinitis pigmentosa and wet age-related macular degeneration, and in cancer towards solid tumor types, particularly liver and breast. The ex vivo therapies tend to concentrate on blood disorders, particularly sickle cell anemia and thalassemia, and in oncology, on hematological cancers such as myeloma and acute lymphocytic leukemia. The cell-and-gene therapies can be further divided into autologous (made from the patient’s own cells) and allogeneic (made from a another person’s cells), with autologous dominating those products for which the type is known. Kymriah and Yescarta are both autologous, and some companies are looking to the next step, to produce an allogeneic CAR-T cell therapy product (also dubbed “allocart”). Allogeneic therapies promise an off-the-shelf product that would remove the practical and temporal pressures of creating a bespoke treatment; the downside is that they are more likely to provoke unwanted immune reactions. CAR therapies account for the lion’s share of ex vivo gene therapy development in oncology: about 70% of the ex vivo segment is focused on this approach, which also includes other cells types engineered with CAR, such as natural killer cells.

Exhibit 2. Gene Therapy Delivery Approaches, In Vivo Versus Ex Vivo

Gene Therapy Delivery Methods Ex Vivo

In Vivo

ALLOGENEIC: AUTOLOGOUS: Universal/donor cells used Cells extracted from the patient’s body, gene modifications performed, as source that are genetically modified and introduced and genetically modified cells to the body reintroduced to the body Cells extracted from the patient (autologous)

Gene modiﬁcations to cells inside the body

Universal/donor cells (allogeneic) OR Viral or non-viral vector with inserted target gene

Target tissue

Cells grown in lab Transplantation back into the patient

Cells become genetically modiﬁed

The Importance Of Vectors DNA is a delicate molecule so gene therapies need a delivery vehicle to get the new genetic information into its target cells for both in vivo and ex vivo approaches. For most of the products in development, a virus is the delivery vector of choice, but there are some non-viral vectors being investigated. In this space, plasmids (small rings of double-stranded DNA that are distinct from a cell’s chromosomal DNA and can replicate independently) are the most popular pick but other methods include messenger RNA, liposomes and bacteria. Viruses, however, dominate. They are ideally suited as they are evolutionarily designed for, and therefore very efficient at, getting their genetic material into host cells where they then co-opt the cells’ machinery to reproduce. Different viruses do this in different ways. Some, such as adenoviruses, merely introduce 10 / August 2020

their genes into the into the host cell cytoplasm where they produce gene expression that is transient (known as “non-integrating”). Others, namely retroviruses like lentiviruses, deliver their genetic code right into the cell nucleus where it is physically inserted into the host cell’s genome (known as “integrating”), resulting in a permanent change that lasts as long as the cell. The choice of vector rests very much on what it is the developers are trying to do. Does the disease require long-term gene expression? Or will transient expression do the job? What vector will work best for the particular target cell type? Many different viruses – including herpes simplex, influenza, vaccinia and measles – have been used to create gene therapy vectors, but four virus types loom large in the pipeline: lentiviruses, other retroviruses, adenoviruses and adeno-associated viruses. Researchers transform these viruses into gene © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.)

therapy vectors by replacing their disease-causing genetic code with the desired code to produce a therapeutic effect for the condition being treated, without affecting the virus’s ability to infect the cell. As a concept, this sounds straightforward, but in practice it is a lot more complicated – indeed, it was the vectors that caused the safety issues seen with the early gene therapy candidates. What Can Go Wrong? A host of pitfalls await the developer. For a start, the gene therapy might not work if the delivery to the desired cell type is inefficient. Some viruses are limited in the types of cells they can infect (something known as tissue tropism), and some may escape and infect distant sites with resulting difficulties. With integrating viruses there is the risk of the vector injecting the new genetic material into a part of the DNA that causes harmful mutations that cause like cancer, so-called “insertional mutagenesis.” This is what happened in the French study in 2003 in four patients with X-linked severe combined immunodeficiency (SCID) who received CD34+ hematopoietic stem cells transduced ex vivo with a retroviral vector: the therapeutic gene integrated into the LMO2 protooncogene region and triggered the leukemia. Other concerns surround the theoretical danger that the foreign DNA could enter the patient’s gametes (ova and sperm) and produce changes that would be passed on to their children. Then there is the possibility that transferred genes could be over-expressed, producing so much of the protein that it becomes harmful, or the viral vector may get transmitted from the patient to other individuals or into the environment. The vector may also cause an immune response – even a replication-deficient virus can retain enough of its original viral essence to stimulate

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the host’s defense mechanisms. This can lead to neutralizing antibodies and cellular responses that limit or even scupper outright any attempt to produce the therapeutic gene product. Adding another layer of complication, some patients may already have antibodies against those vector viruses that commonly infect humans – these “inhibitors” leave recipients unable to benefit from gene therapy. Moreover, repeated administration of a vector in patients receiving a transient gene therapy may cause an inflammatory response, or patients may mount an immune response to the proteins expressed by the transgene itself. And those are just the hazards posed at the patient level. There are also major challenges that attend the large-scale production of viral vectors for clinical and commercial use. Viral vector manufacturing is probably the main rate-limiting step in cell-andgene therapy. Viral vector particle manufacture is cumbersome, time-consuming, and expensive, and to date has been more of a custom process. Regulators are taking a keen interest in the area, with about 80% of the standard review time for gene therapies in the US being spent on manufacturing and quality concerns, and sponsors are encouraged to have meetings early on to discuss the issues. Into the gap are stepping contract manufacturing organizations or contract development and manufacturing organizations specializing in cell and gene therapies, and more are expected to emerge, but even then demand is likely to exceed supply. A few companies, like bluebird bio, have developed their own capabilities but in future it looks likely that companies will hedge their bets and opt for both solutions.

Who’s Who In Gene Therapy Despite the difficulties, the therapeutic promise of gene therapy has proved a lure for many firms. There are around 425 unique companies – acting as originators or licensees – with developmentstage candidates. These include very small players working on only one or two therapies to more active companies with larger pipelines upwards of 20 programs. Big names such as Novartis, Roche, Amgen Inc. and Celgene figure, thanks in part to the deal making that has begun to characterize the field. Sanofi, Biogen Inc., GlaxoSmithKline PLC, Pfizer Inc., Merck & Co. Inc. and Takeda Pharmaceuticals International also each have at least five gene therapy candidates in their pipelines. Novartis was a CAR-T pioneer, scoring the first marketing approval with Kymriah, but it has since expanded its capabilities towards in vivo approaches through its ex-US deal for Spark’s Luxturna, and its acquisition of AveXis and, with it, the SMA therapy Zolgensma. Kite was second to the CAR-T market with Yescarta, and is now a subsidiary of Gilead Sciences Inc. following one of the largest biotech acquisitions of 2017. It is testing a number of methods in its pipeline, including gene editing (with Sangamo Therapeutics), an allogeneic (“offthe-shelf”) CAR-T therapy, and T-cell receptor therapies in cancer.

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Another major deal saw Celgene buy US-based Juno Therapeutics last year for $9bn. Juno was at one pointed tipped to be first to market with a CAR-T therapy, but is now contenting itself with what it claims will be a safer and more effective offering, lisocabtagene maraleucel, in relapsed/ refractory diffuse large B-cell lymphoma. Smaller firms are clearly making their presence felt. The most recent firm to enjoy regulatory success, bluebird bio with Zynteglo, has a pipeline of ex vivo cell and gene therapies that span cancer and rare diseases with its expertise in lentiviral vectors. It is aiming to commercialize CAR-T therapies against the novel BCMA target in collaboration with Celgene. Other outfits include Sarepta Therapeutics Inc., which is advancing a 14-candidate gene therapy pipeline, led by Phase II microdystrophin for DMD. It wants to be a leader in gene therapies for various types of muscular dystrophies. Currently, however, the company with the biggest gene therapy pipeline is specialist REGENXBIO Inc., with 22 gene therapies in development. It is taking a dual approach by developing an internal pipeline using its NAV AAV platform while licensing the technology to other players including Novartis (see Exhibit 3).

Exhibit 3. Most Active Gene Therapy Companies By Pipeline Size REGENXBIO

22 20

Hrain Biotechnology Hebei Senlang Biotechnology

Amicus Therapeutics

Genethon

14 14 14 14 14

Juno Therapeutics Precigen Sangamo Therapeutics Sarepta Therapeutics 13

CRISPR Therapeutics Benitec Biopharma

Editas

bluebird bio

11 11 11

Helixmith Orchard Therapeutics Abeona Therapeutics

Axovant Sciences

10 10 10 10

Cellectis Novartis Pﬁzer 0

15 NUMBER OF DRUGS

Source: Pharmaprojects Future challenges The real challenge for these products is to prove themselves on the market: can they move from curiosities to cash cows?

Amgen’s Imlygic, the first approved gene therapy in the US, has also struggled and Datamonitor Healthcare analysts envision peak sales of only around $175m in 2026.

Their development costs and manufacturing issues mean gene therapies do not come cheap and the field has not gotten off to an auspicious start commercially. The first western product, uniQure’s Glybera, approved in the EU for lipoprotein lipase deficiency, flopped. Weak clinical efficacy plus a $1m per treatment price tag meant it failed to get reimbursed nationally by any European country and in the end only one patient was ever treated before uniQure decided against renewing its marketing authorization (it expired in 2017).

Sales of the EU’s first cell and gene therapy, Strimvelis, approved in 2016 for SCID, also withered in the face of an extremely small patient population and cross-country reimbursement issues as it could only be administered in a single Italian clinic. GlaxoSmithKline always insisted it did not expect to make a profit from Strimvelis, rather it was looking to use the platform to build out further indications and to “familiarize stakeholders” with these types of therapies. It has now divested the product to Orchard Therapeutics.

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The more recently approved CAR-Ts, Kymriah and Yescarta, have fared much better, becoming part of the standard of care for acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL) but still the sales are less than stellar. Kymriah’s second-quarter 2019 revenues came in at just $58m, only slightly up on $45m in the first quarter. Yescarta, meanwhile, brought in $120m for Gilead in the same time period. Both companies insist they are confident in their longer-term trajectories. But it is the newest arrivals, the one-time therapies for inherited disorders, Luxturna, Zolgensma and Zyteglo, with their pioneering pricing plans, that will really stress test the new field’s commercial prospects. Spark Therapeutics was first to suggest a five-year pricing model for its treatment for vision loss due to a genetic mutation in both copies of the RPE65 gene, Luxturna (now licensed outside the US to Novartis), which it pitched at $850,000 for both eyes.

Zynteglo is yet to launch following its first approval in the EU in June, but bluebird has put a price tag on it of €1.575m ($1.78m), again spread over five years. Novartis took pricing up another gear with Zolgensma, suggesting, upon its first approval in the US at the end of May, an annuity-like model under which Zolgensma would cost $425,000 annually for five years. This makes it the world’s most expensive drug with a total price tag of over $2.1m, and with that kind of notoriety its performance will be key to sentiment. Novartis CEO Vas Narasimham says the launch is going well but stayed mum during its second-quarter financial results presentation as to exactly how well. Its performance, and that of its peers, could determine whether gene therapy will turn the corner as a commercial prospect, or whether failure here will mean a second Dark Age will descend.

Access more coverage on Gene Therapy from In Vivo here

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The Future Of Medicine: Cell And Gene Therapies Take The Lead

BY MANDY JACKSON Executive Summary BIO panel with Roche’s James Sabry, Spark’s Federico Mingozzi and Adaptive’s Harlan Robins imagines a world where cell and gene therapies are preferred over small molecules and antibodies.

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Gene therapies that program the body to make therapeutic antibodies, genetic surgery that replaces anatomical surgery and cell therapies designed to attack individual cancer patients’ tumors almost sound like science fiction, but in the eyes of Roche global partnering head James Sabry those types of innovations are the not-so-distant future of medicine. Sabry, Spark Therapeutics Inc. chief scientific officer Federico Mingozzi and Harlan Robins, Adaptive Biotechnologies Corp. chief scientific officer and co-founder, discussed the future of regenerative medicines during an 8 June discussion of “Next-Generation Medicine: Cell and Gene Therapies and Beyond” as part of the Biotechnology Innovation Organization’s annual international meeting taking place 8-12 June online. Novel cell and gene therapies require risk-taking and partnership to move the field forward, the executives agreed.

Roche completed its $4.8bn acquisition of Spark late last year and kept the gene therapy developer intact as an independent subsidiary. (Also see “Roche/Spark Deal Clears FTC In A Sigh Of Relief For Pharma Dealmakers” - Scrip, 16 Dec, 2019.) Spark, whose most advanced research and development programs include gene therapies for hemophilia A and B, won the first-ever US Food and Drug Administration approval of a gene therapy with Luxturna (voretigene neparvovec) for a rare form of inherited blindness at the end of 2017. Roche also is working with Adaptive, via its subsidiary Genentech Inc., through an early 2019 deal that gave the Seattle-based firm $300m up front with the promise of more than $2bn in potential milestone fees to develop T-cell receptor (TCR) therapies that target neoantigens specific to individual patients’ tumors. Adaptive uses its platform comprised of proprietary computational biology, software and machine learning technologies to develop diagnostics and therapeutics based on the adaptive immune system, including specific T-cell and B-cell responses to disease. Sabry said Roche’s deals with Spark, Adaptive and other cell and gene therapy firms are emblematic of the big pharma’s view of health care in the future. “We’re interested not in just the incremental improvements of antibody therapy or small molecule therapy currently used for human disease, but thinking beyond that to what could be the therapeutic modalities that will dominate therapeutic landscapes 10, 20 and 30 years from now,” he said. “It’s our view that if you look down that kind of a timeframe, that cell and gene therapy will not only be important parts of therapy but will actually dominate therapy, and that therapies like antibodies and small

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molecules, although they will still be around, will be less important health care than cell and gene therapies will be.” Gene Therapy Advances: Better Vectors, More Diseases Spark’s Mingozzi noted that Luxturna and the gene therapies approved since then all use adeno-associated virus (AAV) vectors to deliver the treatments, but Spark and others are looking at ways to improve AAV technology or develop new types of vectors to broaden the application of gene therapies to more and larger diseases. New ways of optimizing the nucleic acids delivered by AAV or other vectors so that they are more specific and controllable also are being explored. AAV “has been proven very safe and very stable over time in terms of delivering therapeutic efficacy,” Mingozzi said, but noted that development of AAV-based gene therapies has been limited to monogenic diseases. “My expectation for the future is to see more larger indications, more complex diseases,” he said. “When you establish the platform then you have enough confidence to move to diseases that are not simply the monogenic disorders, so the potential is really great.” Among gene therapy companies also tackling some of these issues, Dyno Therapeutics Inc. recently emerged with a platform that uses artificial intelligence and machine learning to identify novel AAV capsids that may deliver gene therapy to tissues and organs that can’t be reached with current AAV technologies. It has partnered with Novartis AG and Sarepta Therapeutics Inc. to test its technology in specific disease areas. (Also see “Dyno Therapeutics Emerges With Novartis, Sarepta Deals For Novel AAV Capsids” - Scrip, 12 May, 2020.)

Italy’s Genespire launched earlier this year to develop gene therapies for primary immunodeficiencies and inherited metabolic diseases. It was spun out of the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and is working with SR-Tiget on novel gene editing and lentiviral vector technologies. (Also see “Genespire Glides Into Gene Therapy Space” - Scrip, 30 Apr, 2020.) “What we have today [with AAV vectors] is great, because we can develop products,” Mingozzi said. “We have demonstrated that we can get all the way to have drugs based on the current platform, but we can do better and by improving the platform we can also open up to new indications.” Conducting Genetic Surgery, Generating Antibodies In Vivo Sabry said that in the future gene therapy firms may have a whole library of different delivery mechanisms at their disposal to deliver their genetic payloads into their targeted cells. “And the genetic payload can be more than just a gene that sits outside the genomic DNA episomally,” he added. “It could be one that is truly targeted to integrate into the genome at the specific place where the disordered gene is, in essence opening up a whole field of genetic surgery that is very analogous to anatomic surgery where you go in and remove a diseased organ. Imagine, you go in and remove the diseased gene and you replace it with a normal gene.” Sabry noted Spark’s ongoing research into gene therapies that could deliver instructions to the body for making its own therapeutic antibodies, which could replace monoclonal antibodies, like Roche/Genentech’s pioneering cancer medicines Avastin (bevacizumab) and Herceptin (trastuzumab).

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“There’s no reason that the liver couldn’t be the best way to make Avastin or Herceptin, for instance, if you could find ways to turn off the gene if you ran into trouble,” he said. Turning tissues into biofactories is one area that Spark is exploring, Mingozzi acknowledged, including the ability of gene therapies to deliver an antibody systemically to the liver or to deliver the antibody across a barrier that limits efficacy of biologics today, like the blood-brain barrier. Expression of the antibody could be modulated or controlled via the gene therapy. “I think that’s the leap in the technology that we need to do and is one of the points that we need to address to unleash the potential of the gene therapy technology,” Mingozzi said. “Souping Up” And Personalizing Cell Therapies Adaptive’s Robins noted that there are multiple angles the cell therapy field is progressing to improve the efficacy of engineered cells in cancer and other diseases. “I think one way you can imagine this is souping up the cells themselves so you can make the cells more powerful,” he said. “Are there limits to that? I don’t think we’re anywhere near those limits, but every time you do that you’re opening up safety issues as well.” However, Adaptive is going in another direction with Roche/Genentech to focus less on making cells more potent and more on tailoring them to each patient, which could redefine personalized medicine. “Personalized medicine right now is effectively saying, ‘OK, we have a set of drugs that are sitting there on the shelf and we’re going to use diagnostics to determine which drug you should

use,’” Robins said. “What if instead we said, ‘Let’s look at this person, look at the patient, and actually make the right drug for this person in real time?’ What if you could give a personalized therapy for each person?” Because of the way cells work together – including T-cells reengineered and given back to patients – Sabry said it may be possible in the future to develop integrated systems of cells that work together against diseases. “Once we start to establish that normal immune regulation, then some of the concerns we have right now about either having these cell be too powerful or not powerful enough tends to go away, because all you’re doing is using the normal, very advanced regulatory systems that exist within the immune system to regulate the power and amplitude of the immune response,” he explained. These kinds of treatments could replace small molecules and monoclonal antibodies over the next few decades, but only if big pharma and small biotechnology firms continue to take risks. “There’s risk all over the future and we don’t know what it’s going to look like,” Sabry said. “That should never be a reason not to go down that path, especially for the large pharmaceutical firms that have the capital to do so. And in many ways, this should be part and parcel, I believe, of every large, revenue-positive pharmaceutical company to take chances and go into these risk spaces.” He noted, however, that most cell and gene therapy technologies will originate from small companies, which can buy themselves time by partnering with big pharma. “We’re all working very hard but it just takes time for complex breakthroughs in medicine to

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be discovered and developed,” Sabry said. “And that time requires a certain amount of capital breathing room and that’s what I think a lot of these collaborations give.” Partnering To Progress Cell And Gene Therapy Innovations Robins also noted the importance of partnering for Adaptive to advance its platform beyond diagnostics, where the company has two approved products, to patient-specific T-cell therapies. He said “the horsepower you need to move further along down the food chain in terms of development for a therapeutic is much more intense in terms of just manufacturing, regulatory, commercialization, the clinical trials, etc., so there we were thrilled to be able to partner with Genentech/Roche and have their unbelievable horsepower to leverage for what we just don’t have the capabilities to do as of right now.” Sabry noted that no company – not even Roche with a $12bn annual R&D budget – can do everything on its own. While big pharma companies actually are less likely to take big R&D risks than small biotech companies, he said Roche uses its partnerships to invest in innovation while sharing the risk. The pharma also gives its partners and acquired companies freedom to operate within their area of expertise. Mingozzi said there is a lot of value for big firms that maintain expertise within a subsidiary company, like Spark, rather than integrating it into a much bigger organization. “We remain like we were before – a young company, relatively small, well connected, very energetic,” he said, noting that as part of Roche, “we have more stability; we’re less exposed to the markets and our ability to raise funds.”

“Because we are able to maintain our culture then we can also now think of our outlook of the future as a little longer than a small public company where your goals are very well defined but tend to be shorter-term where you just need to bring to the finish line the candidates that are in your pipeline,” Mingozzi said.

Robins noted that while Adaptive has big partners, it maintains its small company nimbleness that allows it to go after novel development programs, including COVID-19. To advance its initial work related to the novel coronavirus, Adaptive partnered with Amgen Inc. (Also see “Amgen, Adaptive Partner In COVID-19 Neutralizing Antibody R&D Effort” - Scrip, 2 Apr, 2020.)

Access more coverage on Gene Therapy from Scrip here

19 / August 2020

Gene Therapies Will Be A Bigger Cost Issue In 2021, PwC Predicts

BY JESSICA MERRILL Executive Summary The expected launch of BioMarin’s Roctavian for hemophilia A is expected to heighten the profile of expensive gene therapies on payers’ radar. Specialty drug costs are expected to continue to grow in 2021.

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The anticipated launch of BioMarin Pharmaceutical Inc.’s gene therapy Roctavian (valoctocogene roxaparvovec) for hemophilia A later this year is expected to put the high cost of one-time therapies squarely on payers’ radar, according to a new report from PwC’s Health Research Institute (HRI) that explores medical cost trends in the US for 2021, with a focus on the impact for commercial plans and employers. BioMarin hasn’t finalized the price for Roctavian, but it’s clear a drug with a $1m-plus price tag in an indication like hemophilia A – with more patients eligible for treatment than for other gene therapies – is going to heighten concerns about paying for them. The company has floated a price tag of $2m-$3m as one that would fairly reflect the treatment’s value. PwC estimated in its report released on 24 June that Roctavian could cost as much as $76 per American in 2021, depending on its price and how widely it is used.

In contrast, Novartis AG’s gene therapy Zolgensma (onasemnogene abeparvovec), which is priced at $2.1m for spinal muscular atrophy (SMA), costs about $3 per American, PwC said. Zolgensma was approved in 2019 with a relatively narrow indication for children under the age of two. (Also see “It’s Official: Novartis SMA Gene Therapy Zolgensma Is World’s Most Expensive Drug” Scrip, 24 May, 2019.)

Specialty Drug Spend Drives Costs Upwards Gene therapies with multimillion-dollar price tags are attention-grabbing but spending on specialty drugs in the US more generally continues as a concern for insurers and employers. Specialty drug spend is expected to rise in 2021, driven by new high-priced specialty drug launches and indication expansions for existing specialty drugs, PwC said.

“While the per-treatment cost of Zolgensma and Roctavian may be similar, the annual cost of Roctavian to the US health system may be much higher in the next few years because of the number of hemophilia A patients who could be treated,” PwC said.

An analysis of UnitedHealth’s pharmacy benefit manager OptumRx’s brand pipeline forecast from the first quarter of 2020 showed 62% of projected drug launches in 2020 and 73% in 2021 are expected to be specialty drugs, according to the report.

While Novartis has said that about 100 patients are being treated with Zolgensma each quarter in the US, the bolus of patients awaiting a hemophilia A gene therapy could be much bigger. Around 20,000 people in the US with hemophilia A could be eligible for treatment with Roctavian, and there are an estimated 400 babies born with the condition each year, according to PwC.

“Seventy percent of employers surveyed by PwC ranked managing specialty drug cost trend as a top five pharmacy concern,” the report says.

BioMarin has estimated that about 5,000 patients per year in the US may be likely to receive the therapy, since it is expected to be restricted to certain patients, including those over 18 with severe hemophilia A and without Factor VIII inhibitors or a history of them. The gene therapy is pending at the US Food and Drug Administration with a 21 August action date. While the cost of the one-time treatment is expected to break boundaries, it will offset the cost of long-term treatment with prophylactic Factor VIII, which BioMarin estimates averages $700,000-$750,000 per year. (Also see “BioMarin All Set For Hemophilia Gene Therapy Approval, But Is It Overestimating Demand? “ - Scrip, 27 Feb, 2020.)

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The growth rate for retail drug spending for private insurance is expected to increase slightly in 2021 to 2.6% from 1.5% in 2020, the firm said. The PwC report aims to estimate the potential medical cost trend as payers and employers try to determine what they will need to charge for insurance premiums next year. Medical cost trend refers to the projected percentage increase in the cost to treat patients from one year to the next, assuming benefits remain the same. In the PwC report, the term refers to projected increase in per capita costs of medical services and prescription medicines that affects commercial insurers’ large group plans and large self-insured businesses. An unprecedented drop in health care utilization in 2020 caused by the COVID-19 pandemic has made costs even harder to predict. Because of the reduction in health care utilization and employer health care spending in the first half of 2020, HRI is projecting 2021 medical cost trend relative to

2020 estimated health care costs, normalizing for COVID-19, rather than actual 2020 costs, the firm said. HRI developed three scenarios to guide employers and health plans when determining 2021 medical cost trend, ranging from 4%-10%. Last year, HRI projected a 6% trend for 2020, but that figure does not reflect the impact of COVID-19 on 2020 employer health care spending; actual spending is expected to be lower than in 2019 because of deferred care.

Individuals with complex chronic conditions on employer-sponsored insurance were more likely to have delayed care than those in other groups, HRI found in a survey. “Getting those people in for necessary care is important for their health and for employer spending,” PwC said. “On average, people with complex chronic illnesses cost employers eight times more than healthy individuals with an average annual cost per person of over $11,000 – a number that could balloon even higher if their illness is left unmanaged for too long.”

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22 / August 2020

Medicare’s CAR-T Payment Change Helps the Entire Regenerative Medicine Field ... A Little Bit

BY SARAH KARLIN-SMITH Executive Summary Alliance for Regenerative Medicine says CMS’ plan to create new reimbursement category for CAR-T helps validate entire field, but it may not make it any easier for other products to navigate the payment landscape. ARM is prioritizing value-based payment legislation in its Congressional lobbying.

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The Centers for Medicare and Medicaid Services decision to establish a new reimbursement category for chimeric antigen receptor T-Cell (CAR-T) therapies is an important milestone for the cell and gene therapy field, but won’t necessarily make it any easier for other regenerative medicines to get similar payment arrangements, Robert Falb, the director of US policy and advocacy for the Alliance for Regenerative Medicine told the Pink Sheet. Medicare is proposing to establish a new Medicare diagnosis severity related group (MS-DRG) category specifically for CAR-T treatment in 2021, which would result in a higher average payment rate than is currently used for CAR-T (Also see “Medicare CAR-T Payment Policy Walks Line Between Innovation and Cost Concerns” - Pink Sheet, 13 May, 2020.).

That payment arrangement would start about four years after the first CAR-T was first approved in the US. The proposal “sends a message about the validity and promise of these sorts of therapies,” Falb said in an interview. “I think that’s the underlying message out there because now you have a big program like Medicare recognizing these therapies with a standalone DRG and recognizing the importance they play in patients’ lives and the need to try and establish appropriate reimbursement so patients can have greater access to them.” Falb said ARM is still evaluating the details of the proposed rule and soliciting feedback from its members. Despite the positive milestone, he added that this does not mean other cell and gene therapies will now have an easier or faster path to a unique DRG. “If you’ve seen one cell or gene therapy, you’ve seen one cell or gene therapy,” Falb said. “It all comes down to the data,” and CMS had made it clear that understanding the reimbursement data for a particular therapy is key to their decisions making. “It helps in the bigger picture, but that doesn’t mean its now a slam dunk for future cell and gene therapies,” Falb said. Value-Based Payments Are ARM’s Focus With Congress Falb spoke with the Pink Sheet ahead of a “virtual fly-in” Wednesday on 20 May, where its members will speak with lawmakers in Congress about the Alliance’s legislative priorities. The group’s current focus is advancing legislation that will spur the adoption of value-based

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payment agreements for cell and gene therapies. ARM is supportive of the GENE Therapy Payment Act, H.R. 5882, a bipartisan House bill that would allow for value-based contracting for regenerative medicines targeting rare diseases in the Medicaid program, and a companion measure that is included in the leading Senate drug pricing legislation, S. 2543, the Prescription Drug Pricing Reduction Act. However, ARM wants Congress to craft legislation that would lead to adoption of these payment arrangements for all cell and gene therapies in all federal government health programs including Medicare. The bills currently under debate deal with one of two primary obstacles to value-based deals that have been discussed for some time and are a concern of ARM’s – the impact of a value-based deal on Medicaid’s “best price” requirement. Drug manufacturers are required to offer Medicaid the lowest price offered on the US market and there has been concern that if a rebate given when a drug doesn’t work under a value-based deal were to become the new “best price” it could make these types of payment arrangements unsustainable, Flab said. The legislation does not deal with ARM’s other concern, that value-based payments might violate the Anti-Kickback Statue if these payment arrangements are perceived as creating incentives for the adoption of one product over another or for increased use of a product. However, ARM said this concern could likely be better addressed by regulation, not legislation. While Falb acknowledged that Medicaid has already permitted states to implement valuebased payment deals, he said national legislation will create “more predictability,” and more clearly outline “the rules of the road.” Plus, CMS under President Donald Trump has expressed some

interest, but also a good deal of skepticism on value-based contracts and has taken no action to start up value-based arrangements in Medicare. (Also see “New Payment Models For Curative Treatments Have CMS’ Attention, Verma Says” Pink Sheet, 23 May, 2019.)

The organization hasn’t yet thought about whether it might be possible to tie their valuebased payment reform to one of Congress’s COVID-19 legislative packages given the possibility that there may be cell or gene-based treatments to address the virus, Falb said.

Similarly, Falb acknowledged that private sector health plans already make use of value-based agreements, but he hopes broader adoption by federal programs thanks to legislation will increase their use in the commercial sector.

Meanwhile, ARM is undeterred by some of the non-legislative barriers that have been cited for implementing value-based payment arrangements – in particular that payers and drug companies often find it difficult to reach agreement on how to determine whether a drug did or did not help a patient.

“In the US, CMS typically sets the standard for reimbursement through its decisions regarding coverage and payment, private payers often follow their lead,” he said. COVID-19 Creates More Hurdles To Congressional Progress A major near-term challenge to value-based payment reform is that COVID-19 has lowered the chances any drug pricing legislation gets done in 2020, Falb said. Even communicating with Congress members and their staff is harder now, he said. Things “we used to take for granted” are much more difficult because of the amount of time legislators must dedicate to COVID, Falb said. “It is a whole different world.”

Falb said this isn’t an area ARM is focusing on because it involves very specific decisions that will vary by each company, therapy and disease state. “Because this is new, there is going to be lots of challenges,” Falb said, but he didn’t see those challenges as barriers to the overall promise of the reimbursement approach. Another problem he said that needs to be solved is how to deal with contracts that require a patient to be monitored over a period of years, if the patient switches to a new payer or plan during that time.

Access more coverage on Gene Therapy from Pink Sheet here

25 / August 2020

Top US FDA Official Says New ‘Playbook’ Needed For CMC Reviews Of Gene Therapy Products

BY JOANNE S. EGLOVITCH Executive Summary CBER director says lack of a clear regulatory structure is holding back the development and acceleration of gene therapy products, while industry says regulations should be flexible to keep up with changing technology for these products.

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A “new playbook” is needed to ensure consistent chemistry, manufacturing, and controls (CMC) reviews for gene therapy products, the lack of which is hindering the development of these products, asserted a top official at the US Food and Drug Administration . “Now is the time to get things right” asserted Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, who spoke at a 15 June virtual Drug Information Association annual meeting session on how innovation can help overcome hurdles for these products. The session’s moderator, Nancy Myers, president of Catalyst Healthcare Consultants, asked the panelists to describe some of their main CMC “constriction” points in developing gene therapy products, and to identify potential solutions. The other panelists were Karen Walker, the senior advisor for cell and gene therapy at Genentech Inc., who formerly was at Novartis AG and worked on the development of

Kymriah, and Michael Paglia, director of CMC for ElevateBio. Myers said that there are two common types of roadblocks to getting gene therapy products through the development pipeline, and these are logistical and technical challenges. The logistical challenges are having a well-trained workforce, managing global distribution networks and ensuring products are transported in cold temperatures, while the technical challenges are ensuring the quality of the starting materials and scaling up production from the research site to commercial manufacturing. Another roadblock is the lack of standards and lack of a regulatory framework for these products. Myers said that “this is a new and growing field and companies are trying to lay the track as they are trying to drive the train down the track at the same time.” Consistent CMC Playbook Needed Myers first asked the panelists to discuss what they see as constriction points in manufacturing gene therapy products. In response, Marks said that a lack of consistent reviews is hindering their development. “It has become apparent over the last couple of months that, while we have excellent reviewers, it does happen that people can have differences of opinion. I think we will have to come around and have a clear playbook so that everyone gets the same advice especially as we have grown. I know that someone out there will say, ‘we had two different CMC reviewers and two differences pieces of advice.’ I am not going to argue with that. That is an issue here. As we come to the postCOVID period we should to try to have more unity in what comes from our CMC reviews. I cannot say the problem is solved but the problem has been identified and is amenable to solutions.”

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He further noted that the lack of clear regulatory pathway for these products is a major roadblock in accelerating their development. “We do not have the preclinical pathways set up and the clinical set up and the regulatory paradigm is yet to be fleshed out. Now is the ripe time to get things right.” Marks also noted some of the manufacturing challenges in the cell and gene therapy space: “We are in a place where our current vectors are limiting what we can address in terms of our ability to product them on a very large scale, and what will probably take some years to get there. On the other hand, the piece that really interests me is how do we deal with hundreds and thousands of rare diseases that we can’t address right now through the production of gene therapy products where we simply do not have the manufacturing capacity to be able to produce these products in a rapid manner because we just don’t have the systems.” More On Why Device-Like Reviews Could Help Marks expanded on an idea he had suggested in February, that reviews for gene therapies should be more aligned with the device model. (Also see “Individualized Gene Therapy: US FDA Considering Device-Like Manufacturing Approval Process” Pink Sheet, 28 Feb, 2020.) “It is becoming increasingly clear that for cell and gene therapies, the manufacturing is more like a device paradigm with continued innovations,” he said. “With a traditional drug you come up with a chemical process to make a small molecule and you are probably using the process similarly across the lifecycle, but you are not constantly finding ways to do things that fundamentally change the yield or quality of a product. Here we have issues that manufacturing changes can potentially change the product for the better.”

He added that “we have to find some balance here between the traditional drug manufacturing model of ‘once and done’ to something that is asking you go through multiple cycles of a device every two to three years where you are changing the technology. With device cycles, you may have multiple generations of the device over years. With a device you can measure things nicely, with biologicals you cannot measure easily.”

isolate, activate and expand T-cells. After the cells are modified, they are infused back into the patient. The FDA approved the drug in August 2017 (Also see “FDA’s NDA And BLA Approvals: Kymriah, Vabomere, Cyltezo” - Pink Sheet, 1 Sep, 2017.) and the EU approved it in June 2018. (Also see “First CAR T-Cell Therapies OK’d In EU: Novartis’s Kymriah And Kite’s Yescarta” - Pink Sheet, 29 Jun, 2018.)

Walker concurred that “these are not wellcharacterized products and so we need to invest heavily in analytics so that we can gain product and process understanding so that we can facilitate rapid changes that we know will not negatively impact the health of the patients.”

Walker said there also needs to be flexibility from regulators to allow new technologies. “The technology is advancing very rapidly, and that is another challenge for regulators. To understand where they can have flexibility.”

Kymriah Technology Already Outdated Walker said a constriction point for her is not keeping up to date with current technologies. She said that a technology platform developed today may be outdated tomorrow. The rate of change of innovation is now every two or three years, she said. That mirrors the rate of the device cycles that Marks mentioned, lending further credence to the idea that cell and gene therapies should be reviewed similarly. Walker said that “the technology that Kymriah has been based on has been eclipsed. It took three years for start up to approval and now no one is using the same technology as the basis for their platform. The technology and the state of the art is advancing very rapidly. This is a challenge for regulators. They need to understand we can be early adopters of these technologies without changing the product.” Kymriah was the first gene therapy product approved to treat B-cell acute lymphoblastic leukemia (ALL) and diffuse B-cell lymphoma (DLBCL). The product used spherical beads to

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Available Talent Pool A Major Challenge Michael Paglia, senior VP of CMC operations for ElevateBio, said that his main constriction point has to do with “staff and talent and supply chain and the cost of goods and quality and access to capacity.” To address the capacity challenges, the company came up with a model of funding multiple start-ups and to utilize the same R&D and manufacturing facility, rather than individual companies whose cell and gene therapy R&D is slowed by the need to build their own lab and production spaces. (Also see “ElevateBio Brings Centralized Model To Cell And Gene Therapy” Scrip, 13 May, 2019.) “We took the approach to build our own and to build an integrated research to support out cell and gene therapies.” The company in July 2019 announced a partnership with Massachusetts General Hospital. Under the agreement, which runs for 10 years, MGH has access to ElevateBio’s research, process development and manufacturing facility in Waltham, MA, for development and production of cell and gene therapies.

Paglia said that there are now more skilled employees compared to “seven or 10 year ago,” but that it is still challenging to find talent. “We are fortunate to have experienced staff. It is necessary to put procedures in place to have rigorous

training. Training is very important, and we are involved with local universities as well to give them an idea of if you come out of this how do you get into cell and gene therapy.”

Access more coverage on Gene Therapy from Pink Sheet here

29 / August 2020

China Inc. Eyes Gene Therapy In Post-Coronavirus Growth Trajectory

BY BRIAN YANG Executive Summary Eyeing a largely untapped treatment area and huge patient pool, biotechs in China are leaping into the gene therapy foray despite the lack of a distinct regulatory pathway or reimbursement of the highly costly treatments.

Wuhan, China-based Neurophth Therapeutics, founded by a local physician, recently scored CNY130m ($19m) in its latest round of financing, signalling investor interest in the nascent gene therapy sector in the country. The first dedicated gene therapy developer in China was set up by ophthalmic specialist Bin Li, who noticed a growing number of people suffering from genetic eye conditions which eventually led to blindness. He was eager to try something new to give patients hope in a country which potentially has the largest number of sufferers globally from rare and genetic disorders. With some help from Beijing-based Five Plus, a research institute devoted to developing an adeno-associated virus vector, Li founded the company in 2016 and started the first clinical research for its lead

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asset, an AAV2-based gene therapy for Leber hereditary optic nephropathy (LHON).

opportunity to get into a leading position in the world,” he added.

Four years later and this April the company secured its new Series A financing, led by new investors Sequoia Capital China and Fosun Ventures; previous investor Northlight Capital also participated. As a leading gene therapy developer in China, Neurophth came into the spotlight for quickly emerging as the front-runner to test its programs in patients with genetic conditions.

Neurophth will use the new funding towards its R&D platform for advancing ophthalmology treatments and a GMP-standard manufacturing facility. The company is also growing beyond its base in Wuhan to establish new subsidiaries in Shanghai and Suzhou, while a potential US site is also in the works.

Outside China, two gene therapies have already gained approvals in multiple markets - Zolgensma (onasemnogene abeparvovec) for spinal muscular atrophy from Novartis AG/AveXis Inc. and Luxturna (voretigene neparvovec) for inherited retinal disease from Spark Therapeutics Inc.. These nor other gene therapies have so far been approved in China. Quick Expansion Hailed as a potential one-time cure for devastating genetic conditions, gene therapy provides much medical hope, but very few companies in China have taken the leap into the area due to murky regulations and a lack of policy incentives and reimbursement. Leveraging a large patient population in the country, where an estimated 126,000 people suffer from LHON, Li’s Neurophth has so far enrolled more patients than overseas counterparts, which has investors excited about prospects for the field in China. “China’s biotech sector is rapidly evolving and domestic gene therapy is only beginning to take off,” noted Guan Feng, a partner at Fosun Ventures. “We believe as the reimbursement kicks in for rare conditions, along with a multiparty funding mechanism led by the government, aided by insurers and philanthropy organizations, gene therapy developers in China have a real

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To date, the venture has conducted studies in 152 LHON patients, the largest trial to date in a program that includes patients from Taiwan and as far away as Argentina. Another potentially benefit for domestic developers in China is a new regulation placing limits on international developers eyeing the market. National regulators last June issued a framework which could pose challenges to the conduct of work with biologics and gene therapies in potentially the most promising market for these emerging technologies. Companies Moving Forward The rapid growth potential in China also has other orphan drug developers such as CANbridge Life Sciences Ltd. taking note. The Beijing-based firm, founded by a former Genzyme China executive, recently set up a research program to collaborate with Horae Gene Therapy Center at University of Massachusetts Medical School in the US. The program is centered on neuromuscular conditions and led by center director Guangping Guo, a key figure in the discovery of adenoassociated virus vectors. CANbridge has added Gao and Mark Bamforth, founder and former CEO of Brammer Bio, to its strategic advisory board. Another ophthalmology-focused gene therapy developer, Hong Kong-based Reflection Biotechnologies, is developing RBIO-101, an

AAV-based gene therapy for Bietti’s crystalline dystrophy, a rare and progressive retinal degeneration. Founder Richard Yang, formerly an investment banker, started the company after his diagnosis. Under its motto of “for patients, by patients” Reflection Bio in 2018 obtained US FDA orphan drug designation for RBIO-101.

Despite the increasing traction for gene therapy in China, analysts still see a need for further financial incentives if more bioventures are to leap into the fray. The general reimbursement challenges facing the sector include an extremely high upfront therapy cost, uncertain efficacy with limited follow-up and inadequate payer financial systems, notes a report from Datamonitor Healthcare.

Access more coverage on Gene Therapy from Scrip here

32 / August 2020

Sickle Cell And Beta-Thalassemia Bend To Gene Manipulation By CRISPR/Vertex And Bluebird

BY ALEX SHIMMINGS Executive Summary Data for new genetic methods to tackle severe hemoglobinopathies presented at the EHA meeting bring more confidence for bluebird’s gene therapy LentiGlobin and early suggestions of a functional cure with CRISPR gene editing with CRISPR Therapeutics/Vertex’s CTX001.

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CRISPR Therapeutics AG and Vertex Pharmaceuticals Inc.’s investigational CRISPR-based gene editing therapy CTX001 looks like it could offer a new treatment strategy for beta-thalassemia and sickle cell disease, new data presented at the virtual European Hematology Association meeting suggest. The data came amid more mature results also presented at the virtual meeting for bluebird bio Inc.’s gene therapies LentiGlobin and betibeglogene autotemcelin the same indications, and together they reinforce the potential for genetic manipulation to provide lifechanging treatment for these conditions. In recent years, the two hemoglobinopathies have seen novel treatments come to the market that ameliorate their symptoms but these new genetic-based approaches seek to tackle their underlying genetic causes and offer the hope of functional cures.

Bluebird’s product is closer to market having already been approved as Zynteglo in the EU for transfusion-dependent beta-thalassemia (TDT) and additional filings for sickle cell disease (SCD) and TDT in the US are expected next year.

There was a 99.5% mean reduction in annualized rate of VOC and ACS among the 14 patients who had at least six months of follow-up and a history of VOCs or ACS. These 14 patients had a median of eight events in the two years prior to treatment.

Bluebird announced new data from its ongoing Phase I/II HGB-206 study of LentiGlobin for adult and adolescent patients with SCD that showed a near-complete reduction of serious vaso-occlusive crises (VOCs) and acute chest syndrome (ACS). The company is hoping to make an accelerated approval application for the product in the second half of 2021, it said, having already reached an agreement with the US Food and Drug Administration.

The VOC/ACS data were particularly impressive, analysts said, increasing from the 99% reduction that was presented at the American Society of Hematology in December. SC141319

SCD is caused by a mutation in the β-globin gene that leads to the production of abnormal sickle hemoglobin (HbS). LentiGlobin for SCD works by adding functional copies of a modified form of the β-globin gene (βA-T87Q-globin gene) into a patient’s own hematopoietic stem cells (HSCs) so that their red blood cells can produce antisickling hemoglobin, HbAT87Q. This decreases the proportion of HbS, reducing the amount of sickled red blood cells, and thereby hemolysis and other complications such as VOCs and ACS. The new data from HGB-206, in which a total of 34 patients have been treated, are specifically from the 25-patient group C cohort that uses the new manufacturing process for LentiGlobin and takes HSCs collected from peripheral blood after mobilization with plerixafor, rather than via bone marrow harvest. In 16 patients of these patients who have six or more months’ follow-up, median levels of gene therapy-derived anti-sickling hemoglobin, HbAT87Q, were maintained with HbAT87Q contributing at least 40% of total hemoglobin.

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Patients demonstrated consistent expression of HbAT87Q hemoglobin over time, with 44% expression six months after treatment and 52% expression at 24 months. Next it will be key, commented analysts at SVBLeerink in a 12 June note, to show consistency of drug product and durability of treatment effect out to 18 months post-treatment. These data will form the basis of the planned accelerated filing , which is now similar in timing to the planned US filing of the product in TDT in the second or third quarter of 2021, lining up the company for potential back-to-back approvals in 2022, the analysts noted. Meanwhile, the updated data for betibeglogene autotemcelin in TDT from the Phase III Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies were also positive, showing sustained transfusion independence (TI) and TDT across ages and genotypes; again these will support the upcoming US filing. Achieving TI (defined as no red blood cell transfusion requirements for 12 or more months while maintaining normal hemoglobin levels (9 g/dL or higher) is the main aim of treatment. The data from younger patients is important as treatment with gene therapy earlier in life

is thought to be associated with better overall outcomes.

“demonstrate, in essence, a functional cure for patients with beta-thalassemia and SCD.”

Twenty three patients have been treated to date, with a median follow-up of 19.4 months andage range of 4-34. 89% of evaluable patients (17/19) achieved the primary endpoint of TI, with median weighted average total Hb levels of 11.9 g/dL, well within the normal hemoglobin range of 9g/dL or higher. These 17 patients previously required a median of 17.5 transfusions per year.

The results consist of longer-duration follow-up data for the first TDT patient treated with CTX001 and new data for the second TDT patient treated that show they are transfusion independent at five and 15 months after CTX001 infusion. CRISPR Therapeutics and Vertex announced initial data for the first TDT patient in November.

In the Northstar-3 study, 75% (six of eight) of evaluable patients achieved TI, with median weighted average total Hb levels of 11.5 g/dL during TI, and continued to maintain TI for a median of 13.6 months as of the data cut off. 85% of patients (11/13) with at least seven months of follow-up had not received a transfusion in more than seven months at time of data cut off; they previously required a median of 18.5transfusions per year. In these patients, gene therapy-derived HbAT87Q supported total Hb levels ranging from 8.8–14.0 g/dL at last visit.

These are complemented by data from the first SCD patient that shows them to be free from vaso-occlusive crises at nine months after CTX001 infusion. In total, the companies say, five patients with beta-thalassemia and two patients with SCD have been treated to date with CTX001 and all have successfully engrafted. CTX001 exploits the fact that both inherited hemoglobinopathies – caused by mutations in the β-globin gene – can be tackled by increasing the expression of fetal hemoglobin (HbF) in patients.

CRISPR Therapy For CRISPR Therapeutics/Vertex’s CTX001, the new results are from a just a handful of patients in two Phase I/II studies (CLIMB-111 and CLIMB-121) but they hint at the novel treatment’s potential for producing durable therapeutic effects; the safety results also augur well so far.

Fetal hemoglobin produced by an unborn baby gradually gives way to the adult form during the six months before and after birth, and as only adult hemoglobin contains the disease-causing mutations, symptoms of these diseases do not appear until the hemoglobin switching has occurred.

The CLIMB-111 study in TDT became the first industry-sponsored clinical trial of a CRISPR gene editing therapy when it was launched in 2018, and the companies say the new data show clinical proof-of-concept for CTX001 in this disease. SC123803

But individuals who have a rare benign hereditary condition where they continue to produce fetal hemoglobin into adulthood, and who also have beta-thalassemia or SCD, have reduced or no disease symptoms, because their fetal hemoglobin substitutes for the diseased adult hemoglobin.

Lead author Haydar Frangoul of the Sarah Cannon Research Institute said the encouraging data,

The CRISPR Therapeutics/Vertex therapy takes advantage of this phenomenon. The treatment

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involves isolating a patient’s CD34+ hematopoietic stems cells from their blood, editing them using CRISPR/Cas9 to increase fetal hemoglobin expression, and then returning the edited cells to the patient. Over time, the stem cells start to produce red blood cells with increased levels of fetal hemoglobin to reduce or eliminate patient’s symptoms. Despite the small number of patients to date, analysts have deemed the data highly encouraging and say they bode well for the program as a whole. CTX001 has already been designated a regenerative medicine advanced therapy (RMAT) by the FDA and has both US and EU orphan drug status, plus an FDA fast-track designation for both SCD and TDT. The updated data for patient 1 in CLIMB-111 shows that at 15 months after CTX001 infusion, the patient was transfusion independent and had total hemoglobin levels of 14.2 g/dL, fetal hemoglobin of 13.5 g/dL, and F-cells (erythrocytes expressing fetal hemoglobin) of 100.0%. Bone marrow allelic editing was 78.1% at six months and 76.1% at one year. Before treatment, the patient had a transfusion requirement of 34 units of packed red blood cells per year. At five months after CTX001 infusion, patient 2 – who before therapy needed 61 units of packed red blood cells per year – was transfusion independent and had total hemoglobin levels of 12.5 g/dL, fetal hemoglobin of 12.2 g/dL and F-cells of 99.4%. Strong SCD Data In sickle cell disease, updated data from the first patient in the CLIMB-121 study showed that at nine months after CTX001 infusion, the patient was free of VOCs, was TI and had total hemoglobin levels of 11.8 g/dL, 46.1% fetal

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hemoglobin, and F-cells of 99.7%. Bone marrow allelic editing was 81.4% at six months. Previously, this patient had seven VOCs and five packed red blood cell transfusions per year. None of the patients had serious adverse events deemed to be related to the treatment. Analysts at Jefferies said the key biomarker data show efficient gene editing and engraftment, adding in a 12 June note that the trajectory of patient 2’s fetal hemoglobin levels out to five months was in line with patient 1’s, demonstrating some consistency. “Overall, these data support BCL11A editing in bone marrow CD34+ cells with sustained engraftment potentially supportive of long-term clinical efficacy.” CRISPR Therapeutics CEO Samarth Kulkarni said, “With these new data, we are beginning to see early evidence of the potential durability of benefit from treatment with CTX001, as well as consistency of the therapeutic effect across patients.” Vertex’s CEO Reshma Kewalramani called the data “remarkable.” Other Therapies Until recently, there were no approved treatments for SCD, but 2019 brought two to the market: Novartis AG’s P-selectin antagonist, Adakveo (crizanlizumab), which treats crisis precipitated by vaso-occlusion in sickle cell anemia; and Global Blood Therapeutics Inc.’s Oxbryta (voxelotor) an allosteric modifier of hemoglobin oxygen affinity, which allows red blood cells to deliver oxygen more efficiently. Neither product tackles the underlying cause of the disease. For beta-thalassemia, Acceleron Pharma Inc./ Bristol-Myers Squibb Co.’s erythroid maturation agent Reblozyl (luspatercept) was first approved in the US last November for the treatment of anemia in TDT patients.

Other similar therapies under development include Sangamo Therapeutics Inc./Sanofi’s BIVV-003 for SCD, and ST-400 for TDT, which use Sangamo’s proprietary zinc finger nuclease genome-editing technology platform.

China’s Shanghai Bioray Laboratory is developing a gamma-globin reactivated autologous hematopoietic stem cell therapy for TDT, which uses a CRISPR/Cas9 gene editing system and is in Phase I/II.

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Japan To Reimburse Zolgensma – But At Lower Price Than US

BY IAN HAYDOCK Executive Summary Novartis gene therapy gets insurance coverage at record price although small patient population will limit system costs.

Japan’s regulatory authorities have decided to grant reimbursement to Novartis AG/AveXis Inc.’s gene therapy Zolgensma (onasemnogene abeparvovec) under the national health insurance scheme, marking a watershed in drug pricing in the country, although the annualized cost will be less than many other big-selling products. The decision also suggests a continued willingness in Japan to support novel therapies and gene therapies in particular, following the reimbursement of the first such product last year. At the equivalent of around $1.56m per administration (at current exchange rates) for the one-time only therapy, the final Japanese price of around JPY167m comes in substantially below its roughly $2.1m price tag in the US, where Zolgensma was launched in May 2019 and Novartis has offered various pay-over-time and outcomes-based pricing schemes.

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Even so, it will be by far the most expensive single-unit price given to any medicine in Japan, surpassing the roughly JPY33.5m per dose awarded to another Novartis product, the CAR-T drug Kymriah (tisagenlecleucel) for leukemia/ lymphoma, a year ago. Given the differences from the US in drug insurance, provision and payment systems, Japan’s health system usually reimburses the full cost of a drug at the official price once this has been agreed, as opposed to the negotiations with multiple payers that take place in the US. However, while patient co-payments are usually set at 30% of under Japan’s NHI scheme, there is a government-supported cap on out-of-pocket costs for very expensive treatments above a certain threshold, as well as support schemes for pediatric care administered by local authorities. Following an October 2018 filing, an advisory panel to Japan’s ministry of health, labour and welfare recommended Zolgensma for spinal muscular atrophy (SMA) type 1 in children aged under two years this February, which led to a formal final approval on 19 March. The therapy has “sakigake” (pioneering therapy) and orphan status in Japan, which confers expedited review for high-need products, although the review time was extended in apparent relation to the manipulation of preclinical safety data during the global development program, which came to light at Novartis last year. Pricing Mechanisms Following discussions with Novartis, the reimbursement of Zolgensma was approved by the Central Social Insurance Medical Council (Chuikyo), which advises the health ministry, on May 13, with the product to be added to the NHI

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tariff on 20 May this week, allowing nationwide commercial launch. Japan has a complex drug price calculation scheme, which for novel products with an existing comparator is usually based on daily costs plus a range of other available premiums which take account of medical need and innovativeness, and also a cost comparison with other major markets, which may result in adjustments. Given that Biogen Inc.’s antisense oligonucleotide Spinraza (nusinersen) became the first therapy for SMA in Japan when it was launched in August 2017, Zolgensma’s proposed price was based on this product, which is reimbursed at JPY9.4m per vial and is usually administered two or three times a year for multiple years. The calculated cost was then raised in consideration of various factors such as usability and efficacy, and Zolgensma’s sakigake status. Policies, Concerns Japan has in general shown a policy willingness to reimburse new modalities of treatment such as cell and gene therapies, with AnGes Inc./ Mitsubishi Tanabe Pharma Corp.’s Collategene (beperminogene perplasmid) becoming the first gene therapy in the country to be paid for by the NHI scheme in August 2019. But the rising unit cost of new drugs, however effective, has been in the political and public spotlight since 2016, after Ono Pharmaceutical Co. Ltd.’s immuno-oncology blockbuster Opdivo (nivolumab) was approved for non-small cell lung cancer. Budget pressure eventually led to the product’s price being halved and there have been further reductions since. Zolgensma’s high unit price has also already attracted some negative attention from medical

groups and there would seem to be a need for the authorities and Novartis to address the benefits and lifetime costs of the therapy. Meanwhile, Novartis has had to deal with a backlash against a “lottery-style” managed access program for the product outside the US. Small Patient Population SMA1, an ultra-rare disorder caused by bi-allelic mutations in the survival motor neuron 1 (SMN1) gene, leads to a decrease in motor neurons, muscle wasting and respiratory problems. It is a designated intractable disease in Japan, affecting around 850 people in total. But the pediatric population aged 0-9 years numbers only around 30 and Zolgensma is expected to be given to just 15-20 patients annually given its age range restrictions.

and probably less than JPY4bn annually. By comparison, Chugai Pharmaceutical Co. Ltd. ’s anticancer Avastin (bevacizumab), one of the top-selling conventional drugs in Japan, logged reported sales of JPY95.6bn last year. Companion Diagnostic Free Until Reimbursed Zolgensma can be administered only to patients confirmed negative for anti-AAV9 (adenoassociated virus 9) antibodies by tests through an approved diagnostics, which Novartis Japan said would be offered for free until any NHI reimbursement is granted. The MEBCDX AAV9 serum-based ELISA test was approved in late April and released by the Medical and Biology Research Institute, Inc. on 7 May, with testing outsourced to Japanese firm LSI Medience Co., Ltd. The test uses technology licensed from US firm Quest Diagnostics Inc.

Despite the high unit cost, the total expense to Japan’s medical system will therefore be limited

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Gene Therapy eBook

Articles inside

Japan To Reimburse Zolgensma – But At Lower Price Than US

Medicare’s CAR-T Payment Change Helps the Entire Regenerative Medicine Field ... A Little Bit

Gene Therapies Will Be A Bigger Cost Issue In 2021, PwC Predicts

Sickle Cell And Beta-Thalassemia Bend To Gene Manipulation By CRISPR/Vertex And Bluebird

China Inc. Eyes Gene Therapy In Post-Coronavirus Growth Trajectory

In Vivo’s Quick Guide To Gene Therapy

Introduction

The Future Of Medicine: Cell And Gene Therapies Take The Lead

Top US FDA Official Says New ‘Playbook’ Needed For CMC Reviews Of Gene Therapy Products