Developing a Gene Therapy with Transformative Potential for Patients with Recessive Dystrophic Epidermolysis Bullosa – Drug Discovery &…

The term butterfly children sounds pleasant but refers to a harsh reality: children with epidermolysis bullosa, or EB, an inherited, genetic blistering skin disorder, are born withskin as fragile as a butterflys wings.

EB affects all races, ethnicities and both genders, and has no cure. According to the Dystrophic Epidermolysis Bullosa Research Association of America, every year about 200 children are born with EB in the United States.

There are several types of EB. The most common type of severe EB is recessive dystrophic epidermolysis bullosa, or RDEBa progressive, devastatingly painful and debilitating disease that affects up to ~2,500 patients in the U.S. and often leads to death. RDEB causes severe blistering and areas of missing skin in response to any kind of friction, including normal rubbing and scratching.

Cause of RDEB

RDEB is an autosomal recessive, inherited skin disease caused by null mutations within the type VII collagen gene (COL7A1). The mutations cause an absence or reduction of functional collagen VII (COL7), which make up anchoring fibrils that maintain binding of the epidermis to the dermis. The disease is characterized by a mechanical fragility and repeated blister formation in the sub-lamina densa at the level of the structurally defective anchoring fibrils.

Development of a New Gene Therapy

Fibrocell, a gene therapy company, is applying its distinctive autologous fibroblast technology to develop FCX-007, its candidate for the treatment of RDEBand potentially the first investigational therapy to target the underlying cause of the disease.

FCX-007 is being developed in collaboration with Intrexon Corporation, a leader in synthetic biology.

FCX-007 is an autologous dermal fibroblast genetically modified to express functional COL7 that is missing or deficient in RDEB patients. Transduced with a lentiviral vector containing COL7A1, FCX-007 is injected directly into the papillary dermis of blisters and wounds where the COL7 protein could enable formation of anchoring fibrils to hold the layers of skin together. The goal of the therapy is to provide high levels of functional COL7 directly to the affected areas while avoiding systemic distribution. This localized therapeutic approach is compatible with the unique biology of each individual patient.

The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to FCX-007 for the treatment of Dystrophic Epidermolysis Bullosa, which includes RDEB; likewise, the FDA granted both Rare Pediatric Disease and Fast Track Designations to FCX-007 for the treatment of RDEB.

A poster presented at the American Society of Human Genetics Annual Meeting in October 2015 addressed the preclinical development of FCX-007 for the treatment of RDEB. As noted in the poster, in vitro product development data indicates that cGMP scale FCX-007 cells express full-length COL7 exhibiting the proper trimeric structure, size and binding functionality.

Production of the lentiviral vector (LV-COL7) was successful, resulting in an infectious titer of ~9 x 106 IU/mL. The integrated transgene copy number per cell was dependent on the virus dose. FCX-007 was produced by expanding fibroblasts from skin biopsies, transducing with the vector, followed by subsequent expansion, harvest and cryopreservation. The COL7 expression from the FCX-007 cells was confirmed by ELISA and Western Blot as well as qRT-PCR and immunofluorescence staining.

The structure of expressed COL7 was confirmed to be predominantly trimeric by immunoprecipitation/SDS-PAGE/Western blot analysis. The COL7 produced from the FCX-007 cells was demonstrated to be functional by binding to Laminin332 in an in vitro binding assay as well as by correction of the hypermotility phenotype of RDEB cells in an in vitro migration assay.

The presentation also reported in vivo results from a preclinical animal model evaluating FCX-007 in RDEB and normal human skin xenografts implanted onto the dorsum of immunodeficient SCID mice. The grafts consisted of human fibroblasts and keratinocytes in a bilayer. The goals of the study were to confirm persistence, distribution and localization of COL7, and to evaluate any potential for product toxicity or vector biodistribution.

The composite RDEB skin grafts were injected intradermally with 1 x 106 FCX-007 cells and analyzed by immunofluorescent staining with human COL7 specific antibodies. Localization of COL7 was observed in composite grafts 10 days post-injection. Positive control grafts generated from normal keratinocytes and fibroblasts showed intense COL7 staining and negative control grafts did not show COL7 staining at baseline measurements.

In a follow-up toxicology/biodistribution study, FCX-007 was well tolerated up to six months post-administration.

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Developing a Gene Therapy with Transformative Potential for Patients with Recessive Dystrophic Epidermolysis Bullosa - Drug Discovery &...

Tapping gene therapy potential for inherited retinal diseases – ModernMedicine

Reviewed by Edwin M. Stone, MD, PhD

Though gene therapy technology already exists to treat most inherited retinal disease, the current challenge is to drive down the costs of implementing the technologythus availing more patients with the benefits of treatments and possibly prevent inevitable visual deterioration.

Edwin M. Stone, MD, PhD, recounted the case of a 14-year-old boy with an inherited eye disease who was born deaf and received bilateral cochlear implants during the first years of his life. The boys visual acuity levels were 20/25 and 20/32 in the right and left eyes, respectively. Despite good visual acuity, more recently, he had been having difficulty seeing in dim light.

A Goldmann perimetry evaluation showed normal responses to large, bright stimuli. However, there was some restriction at the 12e and 14e isopters, explained Dr. Stone, director, Stephen A. Wynn Institute for Vision Research, and professor, Department of Ophthalmology and Vision Sciences, University of Iowa, Iowa City.

A fundus examination showed that both discs were normal and the vessels were slightly constricted. Some pigmentation was present in the midperipheral retina.

Based on these findings, deafness at birth, and retinitis pigmentosa at the beginning of the second decade of life, the patient was given a diagnosis of type I Usher syndrome. Molecular testing showed the presence of the two most common mutations in the USH1C gene, i.e., Val72Val (a splice variant) and Thr78insC.

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Tapping gene therapy potential for inherited retinal diseases - ModernMedicine

Gene Therapy Biotech AveXis Targets SOD1 ALS – ALS Research Forum

A delivery for ALS? AveXis is currently using the gene therapy vector NAV AAV9, developed by REGENXBIO in Maryland, to deliver its experimental gene therapy for SMA into the spinal cord. The approach, which aims to increase levels of SMN, is beginning to show signs of benefit including motor function according to interim phase 1 results presented by Nationwide Childrens Hospitals Jerry Mendell and colleagues at the 2017 meeting of the American Academy of Neurology in Boston. [Image: National Human Genome Research Institute.]

AveXis is one step closer to developing a potential gene therapy for SOD1 ALS. The gene therapy company, based in Cleveland, Ohio, announced this month it has obtained the rights to develop treatments for ALS using REGENXBIOs gene therapy delivery vehicle. The emerging vector, derived from adeno-associated virus 9 (AAV9), is being increasingly utilized to deliver potential therapies into the CNS for neurological diseases.

The strategy is one of a growing number of potential gene therapies for SOD1 ALS that aims to reduce levels of misfolded SOD1 in the CNS and in the muscles by silencing the expression of the SOD1 gene (see May 2017 conference news). The approach is being developed by a research team led by Nationwide Childrens Hospitals Brian Kaspar in Ohio, who is also AveXis chief scientific officer and scientific founder (see December 2015 conference news; Thomsen et al., 2014; Foust et al., 2013).

The delivery vehicle, known as NAV AAV9, forms the basis of AveXis experimental gene therapy for the motor neuron disease spinal muscular atrophy (SMA). The strategy, known as AVXS-101, is currently being evaluated at the phase 1 stage at Nationwide Childrens Hospital as a treatment for Type 1 SMA, the most severe form of the disease. The approach builds on previous studies in 2009 led by Institute of Myologys Martine Barkats in France and Brian Kaspar in the United States, which found that AAV9 could cross the blood-brain barrier and therefore, could be used to potentially treat motor neuron diseases (seeDecember 2008news;Duque et al., 2009;Foust et al., 2009).

Meanwhile, Martine Barkats, in collaboration with Maria Grazia Biferi, in France is using a different approach in hopes to treat SOD1 ALS (see May 2017 conference news). The strategy, which uses a related gene therapy delivery vehicle known as AAV10, also aims to reduce motor neuron toxicity by silencing the expression of the SOD1 gene. The strategy is currently being optimized and is at the preclinical stage. The researchers are now developing a similar strategy in hopes to treat C9orf72 ALS, the most common form of the disease.

***

To learn more about gene therapy and its potential for ALS, check out our recent news feature: A New Potential Gene Therapy Delivers A Key Milestone.

References

Thomsen GM, Gowing G, Latter J, Chen M, Vit JP, Staggenborg K, Avalos P, Alkaslasi M, Ferraiuolo L, Likhite S, Kaspar BK, Svendsen CN. Delayed disease onset and extended survival in the SOD1G93A rat model of amyotrophic lateral sclerosis after suppression of mutant SOD1 in the motor cortex. Neurosci. 2014 Nov 19;34(47):15587-600. [PubMed].

Foust KD, Salazar DL, Likhite S, Ferraiuolo L, Ditsworth D, Ilieva H, Meyer K, Schmelzer L, Braun L, Cleveland DW, Kaspar BK. Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. Mol Ther. 2013 Dec;21(12):2148-59. [PubMed].

Duque S, Joussemet B, Riviere C, Marais T, Dubreil L, Douar AM, Fyfe J, Moullier P, Colle MA, Barkats M. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol Ther. 2009 Jul;17(7):1187-96. [PubMed].

Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2009 Jan;27(1):59-65 [PubMed].

Further Reading

van Zundert B, Brown RH Jr. Silencing strategies for therapy of SOD1-mediated ALS. Neurosci Lett. 2017 Jan 1;636:32-39. [PubMed].

Tora MS, Keifer OP Jr, Lamanna JJ, Boulis NM. The challenges of developing a gene therapy for amyotrophic lateral sclerosis. Expert Rev Neurother. 2017 Apr;17(4):323-325. [PubMed].

AAN2017 aav9 c9orf72 disease-als gene therapy SOD1 vector

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Gene Therapy Biotech AveXis Targets SOD1 ALS - ALS Research Forum

Newly Designed Viral Vectors Could Lead to Improved Gene Therapies – Bioscience Technology

For many patients, participating in gene therapy clinical trials isnt an option because their immune system recognizes and fights the helpful virus used for treatment. Now, University of Florida Health and University of North Carolina researchers have found a solution that may allow viruses used for gene therapy to evade the bodys normal immune response.

The discovery, published in the Proceedings of the National Academy of Sciences, is a crucial step in averting the immune response that prevents many people from taking part in clinical trials for various disorders, according to co-author Mavis Agbandje-McKenna, Ph.D., a professor in the University of Florida College of Medicine department of biochemistry and molecular biology and director of the Center for Structural Biology.

During gene therapy, engineered viruses are used to deliver new genes to a patients cells. While the recombinant adeno-associated virus, or AAV, is effective at delivering its genetic cargo, prior natural exposure to AAV results in antibodies in some people. As many as 70 percent of patients have pre-existing immunity that makes them ineligible for gene therapy clinical trials, Agbandje-McKenna said.

The findings provide a road map for designing virus strains that can evade neutralizing antibodies, said Aravind Asokan, PhD, an associate professor in the department of genetics at the University of North Carolina School of Medicine, who led the study.

University of Florida first identified the structural footprints where pre-existing antibodies interact with the virus, using an cryo-electron microscope. The UNC researchers then evolved new viral protein shells. Using serum from mice, rhesus monkeys, and humans, the researchers showed that the redesigned virus can slip past the immune system.

This is the blueprint for producing AAV strains that could help more patients become eligible for human gene therapy. Now we know how to do it, Agbandje-McKenna said.

While the findings prove that one variation of AAV can be evolved, further study in preclinical models is needed before the approach can be tested in humans. Next, the immune profile of one particularly promising virus variant will need to be evaluated in a larger number of human serum samples, and dose-finding studies are needed in certain animal models. Researchers may also need to study whether the same virus-manipulating technique can be used in a broader range of gene therapy viruses, Agbandje-McKenna said.

Although human gene therapy remains an emerging field and has yet to reach patients on a wide scale, researchers elsewhere have used AAV therapy to successfully treat hemophilia, a blood-clotting disorder, in a small trial. It has also been or is now being studied as a way to treat hereditary blindness, certain immune deficiencies, neurological and metabolic disorders, and certain cancers.

The latest findings are the result of more than 10 years of studying the interactions between viruses and antibodies and a long-standing collaboration with Asokan, who heads the synthetic virology group at the UNC Gene Therapy Center.

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Newly Designed Viral Vectors Could Lead to Improved Gene Therapies - Bioscience Technology

Gene therapy by the numbers – BioPharma Dive

Gene therapies have been in clinical development for decades, a winding, stop-and-start path toward transforming science's understanding of the genome into commercial therapies. Strimvelis, a gene therapy made by the British pharma GlaxoSmithKline and approved in Europe last year, will be a high-profile test of the viability of selling cures to a tiny handful of patients.

A broader pipeline, though, backs up an emerging field that could soon begin delivering new therapies to patients in need. Biotechs like Spark Therapuetics and BioMarin have promising gene treatments in late-stage development, and big pharmas like Pfizer and GlaxoSmithKline are active in exploring market opportunities in the space.

Only two gene therapies for inherited diseases have been approved for commercial sale in the Western world, both in Europe.

UniQures Glybera was the first to market, authorized under a five-year conditional approval for treatment of an ultra-rare genetic disorder known as familial lipoprotein lipase deficiency. Yet, Glyberas $1 million price tag and low demand (only one patient was ever treated) meant the therapy never gained any traction. In April, UniQure decided against seeking renewal of its marketing authorization when it lapses this October.

Gene therapy got some new momentum after GlaxoSmithKline won approval from the European Commission in May 2016 for Strimvelis, an ex-vivo stem cell gene therapy for a disease called ADA-SCID, perhaps better known as the "bubble boy" disease.

GlaxoSmithKline

Strimvelis is considered the first outright cure for a genetic disease, although its not known if the 100% survival rate seen in clinical trials will persist over a lifetime. Median duration of follow-up at the time of approval was seven years.

The cost of Strimvelis.

Cures dont come cheap. GlaxoSmithKline priced Strimvelis at 594,000 ($669,000), which after Glyberas $1 million pricetag and Strimvelis' better efficacy profile, was actually lower than what some had expected.

With more gene therapies in development, pricing will be a critical problem to solve for drugmakers seeking to commercialize genetic fixes particularly against the backdrop of the ongoing debate over how to price and value drugs.

One-time treatments that promise to deliver cures will clearly be priced higher than existing therapeutics. But its not just the high cost that will be an issue. If a drugmaker markets a cure with all costs paid upfront, the insurer and patient will hold the risk if the gene therapy stops working after, say, 10 years.

In addition, when patients in the U.S. are free to move from insurer to insurer as they change jobs and move through life, why would one insurer pay $500,000 or $1 million upfront if that patient is free to change insurance?

Estimated number of patients affected by ADA-SCID in Europe each year.

ADA-SCIDs ultra-rare nature underscores the challenge of successfully marketing a gene therapy. While some rare diseases have a sizable enough patient population to support a product commercially, others like ADA-SCID occur so infrequently that even a cure like Strimvelis might not actually make much money for GlaxoSmithKline.

The shelf life of freshly transduced cells for treatment with Strimvelis.

With Strimvelis, stem cells are taken from a patients bone marrow, inserted with a correct copy of the ADA gene using a viral vector, and then infused back into the patient, who has received low dose chemotherapy to improve engraftment.

Due to the limited window of time for infusion, GlaxoSmithKline only offers Strimvelis at the San Raffaele Hospital in Milan, Italy, which is near a cell processing laboratory.

While production and dosing procedures for other gene therapies will be different, manufacturing and logistical challenges are weightier than with small molecules or even biologics.

Since the drug is a patients own modified cells, chain of custody and supply chain visibility are crucial. Managing treatment at its own center simplifies things, but also makes it more difficult for patients to access treatment.

In 2003, the Food and Drug Administration temporarily halted 27 gene therapy trials amid safety concerns.

While Strimvelis and a full pipeline of gene therapies in testing have buoyed optimism in the field, progress from gene therapies hasnt been a straight line.

The FDA decided to suspend the 27 studies, which represented around 15% of the total number of gene therapy trials then underway, after two children developed leukemia-like symptoms in a French study. The new concern followed the 1999 death of Jesse Gelsinger, who had reacted to a gene therapy he received for a metabolic disorder.

The number of worldwide clinical trials for gene therapy or gene-modified cell therapy, according to numbers cited by the Alliance for Regenerative Medicine (ARM) in an annual report.

Thirty-one are in Phase 3, reflecting the progress in clinical development. Spark Therapeutics, for example, recently completed an application submission for U.S. approval of voretigene neparvovec in patients with a type of inherited retinal disease. The therapy, developed in collaboration with Pfizer, is one of the most high-profile candidates in the U.S.

Other well-known names such as BioMarin and Bluebird Bio are also making progress on treatments for beta thalassemia and hemophilia A, respectively.

Total amount of global financing for gene and & gene modified cell therapy companies raised last year, according to ARM.

That figure includes sums raised by a variety of means such as upfront payments, IPOs, venture rounds and partnerships.

Much of the work developing gene therapies has been driven forward by biotech companies, but big pharmas are starting to notice too.

Last summer, Pfizer put down $150 million upfront to acquire Bamboo Therapeutics, with another $495 million in milestones to shareholders lined up. More recently, the pharma giant paid $70 million upfront with $475 million in milestones to work with Sangamo Therapeutics on its hemophilia A gene therapies.

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Gene therapy by the numbers - BioPharma Dive

Saturday’s letters: Hit-and-run, Frontier, gene therapy, Braves – Sarasota Herald-Tribune

Hit-and-run story makes police look really inept

You have got to be kidding me.

A serious crime is committed (hit and run) with substantial bodily injury and property damage. When reporting the accident, the injured party says the person responsible has fled the scene, and the dispatcher asks: Do you still want an officer to respond?

Really? That must have instilled great confidence that a professional investigation was under way.

The initial responding officer fails to collect and protect physical evidence. Fortunately, the family of the injured party does. That's the extent of it for 16 days, until a complaint is made to the mayor.

The next officer on the case is able to identify the owner of the other vehicle. That person does not cooperate. So that's the end of it. Really? You can't bring him in for questioning?

Put Tom Lyons on the case and he will get it done really.

John Corning, Venice

Frontier not profiting from 'bogus billing'

The implication in Tom Lyons June 12 column that Frontier Communications somehow profits from customer billing issues is untrue and unjustified.

As with any company, our customers are our lifeblood. Our intent, in every interaction, is to provide reliable communications services.

When we let a customer down, we are accountable and do our best to fix the problem as quickly as possible. We offer sincere apologies and remedy the issue, making the customer whole. Often this includes credits for the customer quite the opposite of benefiting from bogus billing.

Frontier has made solid improvements over the past year and we will continue to sharpen our service. We live in and support the communities we serve, and our only goal is to be better.

Melanie Williams, Senior Vice President-Operations, Florida, Frontier Communications

Gene therapy article strikes home for reader

Regarding the June 6 article on the gene therapy of Stefanie Joho:

This article is very close to my heart. My husband Steve was diagnosed with cancer in 2005 and has been a patient since 2009 of Dr. Richard Brown, an oncologist at Florida Cancer Specialists in Sarasota.

In November 2015, Steve's chemotherapy was no longer effective. We were fearful and feeling desperate. Ironically, Jimmy Carter's remarkable life-saving treatment with a new immunology drug Keytruda (Merck pharma) was in the forefront of the news.

At Steve's next appointment, we told Dr. Brown that we had learned through a friends son, a breast cancer researcher, that Merck wanted to test Keytruda on other cancers. Dr. Brown, always Steve's advocate, told us that the practice had already discussed Steve. He would contact Merck.

It was determined Steve was a candidate and would qualify for the trial. He enrolled immediately. The rest is history!

The drug "suppressed a mutation" in his DNA. It attacked the cancers growth. Steve is no longer in the trial. He continues to receive an infusion treatment every three weeks and so far, so good!

Happily, life goes on and we owe a debt of gratitude to all the selfless researchers who have opened a new frontier in cancer treatment. Dr. Brown revealed that more options will be coming as they make new discoveries.

Good luck and long life to Stefanie!

Donna Jablo, Lakewood Ranch

Atlanta Braves play with taxpayers' money

In their quest for a cushy deal on their spring training facility, the Atlanta Braves were rebuffedby Palm Beach County and twice by Collier County, but have been welcomed with open arms by the easy marks in Sarasota County.

The pending deal will be another screw job unleashed on taxpayers by politicians offering huge subsidies to billionaire owners and multimillionaire players.

According to reports in the Herald-Tribune and elsewhere, the amount of public taxpayer money potentially allocated is:

$20 million from the Florida Sports Foundation, which, thanks to the Legislature and governor, is taxpayer-supported and hands out grants to special-interest groups like the Braves.

$22 million from the county tourism tax, which is paid by guests who stay in hotels and motels and largely used to fund special-interest groups rather than go into general revenues to benefit overburdened taxpayers. According to the Herald-Tribune, the requested amount is below the amount that would require public-referendum approval.

$300,000 a year paid by North Port for maintenance.

Also, West Villages is donating land worth $7 million to $9 million and paying for improvements.

Now, as reported in the Herald-Tribune, the county administrator and financial management officer suggest that a millage increase may be in store.

They play and you pay.

William Allen, Longboat Key

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Saturday's letters: Hit-and-run, Frontier, gene therapy, Braves - Sarasota Herald-Tribune

Alternative pricing models a fantasy for gene therapies? – BioPharma Dive

Once upon a time, gene therapy was thought to be the miracle of science that was going to change everything. After safety issues and patient deaths, that didnt work out quite like the industry had hoped.

Yet, 20 years later, the next generation of gene therapies is coming of age. These drugs so far have proven to be safer and more effective, but are raising new issues around cost. Many of the gene therapies being developed have the potential to be one-time treatments begging the question, how do you pay for something that could cure you after one dose?

This is the conundrum facing Spark Therapeutics, the West Philadelphia biotech poised to bring the first gene therapy to the U.S. market. Spark recently submitted an application to the Food and Drug Administration for voretigene neparvovec, a one-time gene therapy for the treatment of patients with vision loss due to confirmed biallelic RPE65 mutation-associated retinal disease a rare genetic disorder that causes blindness. The company completed its rolling Biologics Licensing Application on May 18 and is awaiting confirmation from the FDA that it has been accepted. An approval could come by mid-2018 or earlier.

Spark CEO Jeff Marrazzo has said publicly that the company has been having conversations with payers and is prepared to take on the challenge of drug pricing.

"We founded Spark in 2013 and began thinking about it 2011. I spent five years working in government, working on matters of healthcare reform before there was the Affordable Care Act, so I have some perspective on at least from a government and policy perspective what people are thinking about. And with respect to Spark, none of our conversations about getting patients access began after someone increased a price, or someone tweeted about it or wrote an article about it. We were having these conversations long before any of that," said Marrazzo at the BIO CEO conference in New York on Feb. 14.

While the company has been thinking about pricing for some time, Spark has been mum about how it actually intends to the price voretigene neparvovec.

"With respect to gene therapy, I think it really has the potential to reframe what we are talking about, and [move the conversation toward] talking more about health than healthcare. What we talk about and pay for, specifically on a transactional basis, is healthcare, and more and more thats how we are reimbursed. I think what we need to move to is to paying more toward health," added Marrazzo.

"Were engaging in productive conversations with payers, both private and public, and are encouraged by the discussions so far. Were finding that theres broad agreement that the current payment system is not designed to reward the long-term value created by gene therapy," added Marrazzo in an email to BioPharma Dive.

Marrazzos hope that a new path with alternative pricing models can be created may be an overly optimistic one. U.S. payers have been slow to adopt new pricing models for other drug classes. Even outcomes-based pricing models are still few and far between.

"Gene therapies are single, one-time interventions with the potential to deliver sustained, life-altering benefits to patients, families and healthcare systems. At this early stage, we are exploring potential payment, distribution and reimbursement models where we might address budgetary concerns or be paid for performance to further align with the potential long-term benefits of our investigational therapies. Clearly, different gene therapies may call for different pricing models in different markets," said Marrazzo to BioPharma Dive.

Jeff Marrazzo at BIO CEO

Lisa LaMotta, Editor BioPharma Dive

If Europe is any indication, alternative pricing models for gene therapies are not on the horizon. The first gene therapy hit the EU market in 2012, brought to patients with an ultra-rare disease by small biotech UniQure. Glybera (alipogene tiparvovec) was priced at about $1 million for a treatment a single treatment like what Spark offers. Reportedly, it was only ever used on one patient and while that patient has been reportedly doing well, Glybera was a commercial failure. UniQure opted not to renew the drugs marketing authorization in the EU in April, finally abandoning all effort into the therapy.

The failed Glybera experiment makes it clear that one-time administration gene therapies cannot follow the typical rare disease-pricing model. For the last several years, rare disease drug makers have been able to price their therapies at a higher rate upwards of $300,000 annually in many cases due to the extremely small patient populations and the lack of other available treatments. While this isnt ideal, most patients dont pay the full cost due to rebates and discounts, and the small patient populations mean there is less burden on the healthcare system overall. This pricing model is increasingly coming into question as drug makers develop more and more rare disease treatments, and the costs continue to climb.

Alternative pricing models have been proposed for one-time, or extremely long-acting, therapies such as those currently being developed for hemophilia. While these models are purely theory at the moment and likely far from reality, there has been talk of putting patients on a payment plan, having them make payments on a one-time treatment like a mortgage. The model would rely on the premise that as long as a patient continues to be healthy, they pay towards the treatment (at least for a set number of years or once a certain price cap is reached).

Yet, Spark has backed away from making concrete comments on the topic. The company has eluded and analysts believe it will stick with a single high price tag as per the typical rare disease model.

"Part of whats important to understand, we can come up with all sorts of various alternatives, but we have [to propose] an alternative that the other party can accommodate and succeed with. We dont want to have an approval and then waste time trying to come up with the perfect payment model," said Marrazzo at BIO CEO.

Until the agency grants an approval, the public is unlikely to get more details on the price for voretigene neparvovec. In the meantime, Spark is prepping its launch. The company has started a patient and physician education plan, as well as a genetic testing initiative.

Through a program dubbed ID YOUR IRD, the company is providing free, simple and fast access to genotyping. In addition, the medical field team is working to locate previously identified inherited retinal disease (IRD) patients at leading eye institutions.

"We have invested in disease education and built strong relationships with the patient advocacy community, demonstrating Sparks commitment to improving patient care through new models of diagnosis, delivery and access," Marrazzo added."Weve proactively engaged with regulators throughout the development of investigational voretigene neparvovec. In parallel, weve had many conversations with payers and experts both in the United States and in Europe to characterize the burden of disease and consider carefully the value that investigational voretigene neparvovec may provide."

Even if commercialization preparation goes well, payers may push back. Other rare disease drugs that have reached the market lately have not gotten the warm reception that they expected.

For instance, Sarepta Therapeutics recently approved Duchenne muscular dystrophy drug Exondys 51 (eteplirsen) is not being received well by payers, despite a patient population of children that has advocated for the drug for years. Several major insurers have refused to cover the drug or only cover it on a limited basis that makes a $300,000 a year treatment very hard to afford.

For Spark and other gene therapy drugmakers that follow, there will be an uphill battle as they enter an environment rife with public criticism about drug pricing.

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Alternative pricing models a fantasy for gene therapies? - BioPharma Dive

French Biotech Reports Sight Restoration thanks to Gene Therapy – Labiotech.eu (blog)

GenSight has announced Phase I/II data revealing that its gene therapy technology can restore sight in patients suffering from a rare mitochondrial disease.

GenSight Biologics develops gene therapies targeting degenerative diseases that cause blindness. The French biotech has now announced very promising results from its lead candidate, GS010, after 2 years of following patients treated with the gene therapy in an ongoing Phase I/II trial. Thetreatment targets Leber hereditaryoptic neuropathy (LHON), a rare genetic disease for which there is no curative treatment.

Patients sight was evaluated using the ETDRS test, the one consisting on recognizing increasingly smaller letters that most of us have done at some point in our life. Those patients treated with GS010 showed a statistically significant improvement in the number of letters they were able to recognize over time, especially in those that were treated within two years after their diagnosis. Detailed results after 96 weeks of follow-upare now pending publication in a peer-reviewed journal.

TE: treated eye; UTE: untreated eye

According to GenSight, 95% of LHON cases are caused by mutations in the genes that encodes the NADH dehydrogenase complex, which is involved in ATP metabolism within mitochondria. Since it affects amitochondrial gene, the disease is maternally inherited. GenSight is particularly focusing on patients with a mutation in the ND4 gene, which accounts for 70% of LHON cases in Europe and North America and up to 85% in Asia.

GenSight is already running two Phase III studies in Europe and the US evaluating GS010 in patients with the ND4 mutation that have been affected by LHON for a year or less.We are now less than a year away from Phase III efficacy data, and more than ever committed to find a cure for patients and their families affected by this devastating condition, said Bernard Gilly, CEO and co-founder of Gensight, in a statement. Philip recently interviewed him regarding his impressive track in biotech as both a serial entrepreneur and a partner at the VC firm Sofinnova.

So far, GenSight seems to be the only biotech developing a gene therapy for this disease. Ocular disorders are often rare,which leads most companies in the field to focus on age-related macular degeneration instead, which has a significantly higher prevalence. The French biotechs pipeline also includes GS011, a gene therapy to treat the ND1 mutation in LHON, still in the early research stage. The company is also working in GS030, an optogenetic gene therapyto introduce a protein that can respond to light with the aim of restoring sight in patients with retinitis pigmentosa, currently undergoing preclinical investigation.

Images via HQuality / Shutterstock; GenSight

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French Biotech Reports Sight Restoration thanks to Gene Therapy - Labiotech.eu (blog)

A new wave of gene therapies ready to hit US shores – BioPharma Dive

Gene therapy has finally made it over the hump.

After decades of research and some devastating setbacks, major technical hurdles have been overcome, opening up the long-anticipated promise of this field. A new approval has buoyed interest, pipelines are bubbling with new candidates and big investments are being made.

Two gene therapies have hit the European market and the first is expected to hit the U.S. market as early as next year. Beyond that, there is a growing pipeline rapidly coming forward.

All this is fueling high hopes of actual cures for previously incurable diseases and big profits. So whats the rub?

The first ever approved gene therapy was Shenzhen SiBiono GenTechs Gendicine, a recombinant Ad-p53 gene therapy for head and neck cancer, which launched in China in 2004. But it was Glybera's (alipogene tiparvovec) approval in fall 2012 that sparked investor interest in gene therapy. For a while that drug reigned as the most expensive treatment in history, costing more than $1 million per patient.

Glybera turned out to be a disappointment due to the high price tag. The drug restores lipoprotein lipase enzyme activity in patients with LPL deficiency (an ultra rare disease), but the drug comes with the severe side effect of pancreatitis. After use by only one patient and five years on the European market, maker uniQure chose not to seek renewal of its European approval this fall and is not pursuing U.S. approval.

Despite the failure of Glybera, GlaxoSmithKlines Strimvelis has further fueled investor interest with its approval in Europe in May 2016.

Strimvelis treats severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency. It is estimated that about a couple dozen children per year are diagnosed with ADA-SCID in the U.S. and Europe combined. One year on the market, the British pharma has confirmed that one patient has been treated with the drug. "A patient has been treated with Strimvelis and others have been referred and are currently being assessed for eligibility to receive the drug," GSK spokesperson Anna Padula told BioPharma Dive.

After the Glybera debacle, GSKs experience with Strimvelis will be telling, but there are also some up-and-coming gene therapies that may teach us more.

Gene therapy was originally regarded as one of those "no-brainer"approaches to curing genetically caused diseases. After all, if the DNA is broken, why not just fix it? Unfortunately, it turned out to be much more complicated.

Many of the challenges are around how new DNA is incorporated. One choice is to inject a viral vector attached to a payload that naturally integrates its genetic material into that of the patients. The other choice is to remove the patients cells, modify them, and return them, a process known as ex vivo therapy.

One of the early fears was that DNA would incorporate in the wrong place thereby not fixing the error, as well as creating a new one. That turned out to be a real worry with some of the first vectors, reinforced by early gene therapy treatments for SCIDS that led to T-cell leukemia in some treated boys. At least one of those boys died from the cancer they developed.

Further, there was the tragedy of Jesse Gelsingers death at the University of Pennsylvanias Institute of Human Gene Therapy in 1999. Eighteen-year-old Gelsinger was taking part in a trial aimed at treating ornithine transcarbamylase deficiency, but just days after receiving the therapy he died of massive organ failure, likely sparked by an immune reaction to the adeno-viral vector used.

Then there were treatments that just didnt work. Avigens gene therapy worked well in animals, producing adequate Factor IX levels for several years in models of hemophilia. But in clinical trials, only one patient responded, and that response lasted only four weeks. The patient, as one observer noted, had "touched the rainbow" only to watch it fade from view.

Beyond efficacy, manufacturing is still a challenge. "But we are getting better at that and in the selection of indications," said Scott Burger, principal at Advanced Cell and Gene Therapy. Because gene therapy is such a young field, Burger noted that "long-term monitoring of patients will be key." The boys who developed leukemia in the early SCID trial were all diagnosed a couple of years after treatment.

Every field has its ups and downs, but these tragic events left gene therapy with tremendous baggage. Still, some dogged proponents have soldiered on, and the news now more than a decade later seems to be getting a lot better.

"A new generation of vectors have dramatically improved the prospects for this field," said Geoff MacKay, President and CEO of AvroBio. "There are now hundreds of gene therapies that are in trials and many of them are a one time cure."

News about promising gene therapies in the clinic is sprouting up all the time.

BioMarin has a gene therapy for hemophilia A in Phase 2b. "We are far ahead in the development process and could potentially market the first gene therapy for this condition," said company spokesperson Debra Charlesworth. "The physician and patient community will be looking for strong clinical data," she added. "In addition we have commissioned a gene therapy manufacturing facility that will come online in the middle of this year."

GSK has a license to develop multiple new gene therapies with Fondazione Telethon and Ospedale San Raffaele, the same groups that helped produce Strimvelis. The agreement covers six additional treatments, including one for metachromatic leukodystrophy and one for Wiskott-Aldrich Syndrome. Padula reports that both of these are in clinical trials.

The next wave of gene therapies will focus on rare diseases like hemophilia and even inherited forms of blindness.Spark Therapeutics, for example,recently submitted a Biologics License Application (BLA) with the FDA for voretigene neparvovec, a gene therapy for the treatment of vision loss due to biallelic RPE65 mutation-associated retinal disease.

And Pfizer has inked deals with both Spark and Sangamo for gene therapies to treat different forms of hemophilia. Meanwhile, Biogen spin-off Bioverativhas picked up two gene therapies from Sangamo.

Scientific challenges remain considerable, though, and pricing will clearly be one of the biggest hurdles for gene therapies going forward. "Todays challenges are all around building a viable business model," said MacKay. That has not dampened enthusiasm for the blossoming field that has been rising and falling out of favor for at least two decades.

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A new wave of gene therapies ready to hit US shores - BioPharma Dive

Gene therapy hope for allergies and asthma – BioNews

Life-threatening allergies and asthma could one day be treated by a single injection, say researchers who have successfully treated mice using gene therapy.

Dr Ray Steptoeofthe University of Queensland in Australia and colleagues 'turned off' the immune system's memory of an allergen in mice, suggesting that it could be possible for a single treatment to permanently stop the cause of allergic reactions, rather than just managing the symptoms.

The immune system's memory is the underlying cause of both asthma and allergies, as immune cells incorrectly recognise and 'remember' allergens as being potentially dangerous, andmount an immune response. Repeated exposure to an allergen can cause increasingly severe and potentially fatal reactions. However, it is extremely difficult for potential therapies to contend with the permanence ofimmune memory.

The researchers worked with mice who were allergic to a protein found in egg white. They first inserted a gene which regulates the egg white protein into blood stem cells then transplanted these modified stem cells into the allergic mice. Transplanting the modified stem cells was enough to remove the mice's immune memory of the egg white protein as an allergen, meaning that the animals were no longer sensitive to the protein.

'We have now been able "wipe" the memory of these T-cells in animals with gene therapy, de-sensitising the immune system so that it tolerates the protein,' said Dr Steptoe. 'This research could be applied to treat those who have severe allergies to peanuts, bee venom, shell fish and other substances.'

But the findings should be treated with some caution, given the early stages of the research, note some. Professor Adnan Custovic at University College London told The Independent: 'A mouse model is not the same as a human model We can cure allergies in mice but we cannot do it in humans the mechanisms are not identical. Only time will tell whether this approach will be a viable one.'

The researchers are now working on making the treatment simpler and safer and it is hoped that human trials could begin in as little as five years.

Asthma is a major public health issue with some 5.4 million people in the UK with the condition; costing the NHS 1 billion annually. As allergies play a significant role in around 75 percent of asthma cases, as well as affecting the 44 percent of British adults who have at least one allergy, there is a need to produce effective, long-term treatments for these conditions.

The research was published in JCI Insight.

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Gene therapy hope for allergies and asthma - BioNews

Steroids may up effectiveness of AAV-based gene therapy | Latest … – Daily News & Analysis

Glucocorticoid steroids, such as prednisone, may improve effectiveness of AAV-based gene therapy by reducing immune response, according to a recent research.

The study of gene transfer using adeno-associated virus (AAV)-based gene delivery into skeletal muscle of rhesus macaques showed that oral prednisone reduced immune responses to AAV that can weaken expression of the therapeutic transgene over time.

Animals given prednisone before the gene therapy had a 60% decrease in immune cell infiltrates, mainly comprised of cytotoxic T cells, according to the study.

Megan Cramer, The Ohio State University, Paul Martin, The Research Institute at Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, and coauthors also reported that AAV-treated muscles had higher levels of a biomarker called PD-L2, which can induce programmed T-cell death.

"Prednisone is frequently used in conjunction with AAV gene therapy in the hope of blunting harmful immune responses to the AAV capsid. However, very little is known about the precise immune mechanisms involved in its use, or even if it is beneficial with various different routes of AAV administration," said Editor-in-Chief Terence R. Flotte.

The research appears in Human Gene Therapy.

(This article has not been edited by DNA's editorial team and is auto-generated from an agency feed.)

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Steroids may up effectiveness of AAV-based gene therapy | Latest ... - Daily News & Analysis

Steroids may up effectiveness of AAV-based gene therapy … – Business Standard

ANI | Washington D.C. [USA] June 11, 2017 Last Updated at 13:42 IST

Glucocorticoid steroids, such as prednisone, may improve effectiveness of AAV-based gene therapy by reducing immune response, according to a recent research.

The study of gene transfer using adeno-associated virus (AAV)-based gene delivery into skeletal muscle of rhesus macaques showed that oral prednisone reduced immune responses to AAV that can weaken expression of the therapeutic transgene over time.

Animals given prednisone before the gene therapy had a 60% decrease in immune cell infiltrates, mainly comprised of cytotoxic T cells, according to the study.

Megan Cramer, The Ohio State University, Paul Martin, The Research Institute at Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, and coauthors also reported that AAV-treated muscles had higher levels of a biomarker called PD-L2, which can induce programmed T-cell death.

"Prednisone is frequently used in conjunction with AAV gene therapy in the hope of blunting harmful immune responses to the AAV capsid. However, very little is known about the precise immune mechanisms involved in its use, or even if it is beneficial with various different routes of AAV administration," said Editor-in-Chief Terence R. Flotte.

The research appears in Human Gene Therapy.

(This story has not been edited by Business Standard staff and is auto-generated from a syndicated feed.)

Glucocorticoid steroids, such as prednisone, may improve effectiveness of AAV-based gene therapy by reducing immune response, according to a recent research.

The study of gene transfer using adeno-associated virus (AAV)-based gene delivery into skeletal muscle of rhesus macaques showed that oral prednisone reduced immune responses to AAV that can weaken expression of the therapeutic transgene over time.

Animals given prednisone before the gene therapy had a 60% decrease in immune cell infiltrates, mainly comprised of cytotoxic T cells, according to the study.

Megan Cramer, The Ohio State University, Paul Martin, The Research Institute at Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, and coauthors also reported that AAV-treated muscles had higher levels of a biomarker called PD-L2, which can induce programmed T-cell death.

"Prednisone is frequently used in conjunction with AAV gene therapy in the hope of blunting harmful immune responses to the AAV capsid. However, very little is known about the precise immune mechanisms involved in its use, or even if it is beneficial with various different routes of AAV administration," said Editor-in-Chief Terence R. Flotte.

The research appears in Human Gene Therapy.

(This story has not been edited by Business Standard staff and is auto-generated from a syndicated feed.)

ANI

http://bsmedia.business-standard.com/_media/bs/wap/images/bs_logo_amp.png 177 22

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Steroids may up effectiveness of AAV-based gene therapy ... - Business Standard

Bioventure AnGes MG tries again to market Japan’s first gene therapy – Nikkei Asian Review

TOKYO -- AnGes MG expects to apply in October for approval to manufacture and market a treatment for severe blockage of the arteries in the legs that could become the first commercial gene therapy product in Japan.

The Japanese biopharmaceutical startup grew out of the work of researchers at Osaka University. If the treatment is approved, partnerMitsubishi Tanabe Pharmacould begin sales as soon as next year.

Known as beperminogeneperplasmid,the product is injected directly into the feet, where it promotes the regeneration of blood vessels. It is meant to alleviate the symptoms of critical limb ischemia, a condition marked by reduced blood flow to the extremities, leading to pain and even gangrene.

AnGesestimates that its gene therapy would be suitable for around 10% of the 100,000 to 200,000 people in Japan who suffer from this condition. The alternative is surgery, which places a much heavier burden on the patient.

This will be the second time that AnGessubmits beperminogenefor approval from Japan's health ministry. The company withdrew the first application after more data was found to be needed.

AnGesis more optimistic this time because in November 2014 the health ministry introduced a conditional early approval system for regenerative medicine and gene therapies as part of the government's policy to make Japan a leader in advanced medicine.Under this fast-track system, a company can conditionally release a product and collect additional data while the treatment is in use, later submitting that data to win formal approval.

AnGeshas been conducting domestic clinical trials on beperminogenesince 2014 to take advantage of the new system. The therapy was developed in 1995 by Osaka University'sRyuichi Morishita and his team.

(Nikkei)

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Bioventure AnGes MG tries again to market Japan's first gene therapy - Nikkei Asian Review

A new gene therapy may help fight against an incurable form of breast cancer – Hindustan Times

A small study presented at the worlds largest cancer conference found treating patients with the drug olaparib could slow cancer growth by three months and be less toxic for patients with inherited BRCA-related breast cancer. A type of inherited and incurable breast cancer that tends to affect younger women could be targeted by a new gene therapy, researchers have found. However, researchers have said there was not enough data to say whether patients survived longer as a result of the treatment.

We are in our infancy, said Dr Daniel Hayes, president of the American Society of Clinical Oncology and professor of breast cancer research at the University of Michigan. This is clearly an advance; this is clearly proof of concept these can work with breast cancer. Does it look like its going to extend life? We dont know yet, he said.

The drug is part of the developing field of precision medicine, which targets patients genes to tailor treatment.

It is a perfect example of how understanding a patients genetics and the biology of their tumor can be used to target its weaknesses and personalize treatment, said Andrew Tutt, director of the Breast Cancer Now Research Centre at The Institute of Cancer Research.

Olaparib is already available for women with BRCA-mutant advanced ovarian cancer, and is the first drug to be approved that is directed against an inherited genetic mutation. The study was the first to show olaparib can slow growth of inherited BRCA-related breast cancer. The drug is not yet approved for that use.

People with inherited mutations in the BRCA gene make up about 3% of all breast cancer patients, and tend to be younger. The median age of women in the olaparib trial was 44 years old.

BRCA genes are part of a pathway to keep cells reproducing normally. An inherited defect can fail to stop abnormal growth, thus increasing the risk of cancer. The study examined the effectiveness of olaparib against a class of BRCA-related cancers called triple negative. Olaparib is part of a class of four drugs called PARP-inhibitors that work by shutting down a pathway cancer cells use to reproduce.

Patients who received olaparib saw cancer advance in seven months, versus four months for only chemotherapy. (Shutterstock )

The study from Memorial Sloan Kettering Cancer Center in New York randomly treated 300 women with advanced, BRCA-mutated cancer with olaparib or chemotherapy. All the participants had already received two rounds of chemotherapy.

About 60% of patients who received olaparib saw tumors shrink, compared with 29% of patients who received chemotherapy. That meant patients who received olaparib saw cancer advance in seven months, versus four months for only chemotherapy.

Researchers cautioned it is unclear whether olaparib extended life for these patients, and that more research was needed to find out which subset of patients benefit most from olaparib.

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A new gene therapy may help fight against an incurable form of breast cancer - Hindustan Times

Lonza plugs EU cell and gene therapy manufacturing gap through PharmaCell buy – BioPharma-Reporter.com

The acquisition of Dutch commercial cell and gene therapy maker PharmaCell places Lonza as the leading CDMO in the space, the firm says.

The deal sees Switzerland-headquartered contract development and manufacturing organisation (CDMO) add the assets and staff of PharmaCell to strengthen its cell and gene therapy offerings.

We had a manufacturing gap in the European market, especially related to products requiring regional manufacturing like the new immunotherapy products, Andreas Weiler, head of Emerging Technologies at Lonza, told Biopharma-Reporter. The acquisition of PharmaCell helps bridge that gap.

Financials details were not divulged but the deal sees Lonza add a 1,400m2 multiple product facility in Maastricht, The Netherlands and a 4,800m2 cell therapy manufacturing plant nearby in Geleen to its personalised medicine manufacturing network.

Lonzas current cell and gene therapy capabilities are located in Tuas, Singapore and at its site in Walkersville, Maryland (which recently received a US FDA warning letter ). The CDMO is also constructing a facility set to open this year at its Houston, Texas site with 14,000m2 of space dedicated to cell and gene therapy manufacturing.

And with the addition of PharmaCell, Lonza is now the leading contract development and manufacturing organisation offering an international cell and gene therapy manufacturing network, spanning the US, Europe and Asia, Weiler told us.

PharmaCell

The European CDMO was targeted due to its expertise in autologous products, where cells and genes are taken, engineered and then placed back into the patient. This complements our current allogeneic cell manufacturing offerings, Weiler said.

PharmaCell has won a number of contracts to make both clinical and commercial volumes of such therapies, including deals with Orchard Therapeutics and Lion Biotech , both announced this year.

The firm also made European supply of Dendreons prostate cancer therapy Provenge (Sipuleucel-T) until Dendreons buyer Valeant withdrew the Marketing Authorisation in 2015.

Last year, the firm reported sales of around 11m ($12.3m).

Weiler said Lonzas acquisition will have no impact to current contracts. PharmaCell is now part of Lonza and the new legal entity name is Lonza Netherlands, B.V. The name change has no impact on existing contracts.

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Lonza plugs EU cell and gene therapy manufacturing gap through PharmaCell buy - BioPharma-Reporter.com

VBL Wins $2.5M Grant to Progress Pivotal-Stage Anticancer Gene Therapy – Genetic Engineering & Biotechnology News

VBL Therapeutics won an ILS8.75 (approximately $2.5 million) grant from the Israel Innovation Authority to support continued clinical development of the firms lead Phase III-stage gene therapy ofranergene obadenovec (VB-111). The antiangiogenic candidate is being evaluated in a pivotal Phase III GLOBE study in patients with recurrent glioblastoma (rGBM) under an FDA Special Protocol Assessment. Phase II studies with VB-111 have previously been carried out in patients with platinum-resistant ovarian cancer and differentiated thyroid cancer indications.The gene therapy is administered as an IV infusion once every two months.

VBL says the grant will fund clinical trials and development activities for the 2017 calendar year. The continuous financial support for the VB-111 program is an important contribution to our ability to execute on our plans into 2019, as we prepare for the commercialization of VB-111 and establish our new manufacturing site, commented Dror Harats, M.D., CEO at VBL Therapeutics. We believe this nondilutive grant for the VB-111 program underscores the confidence that the Innovation Authority has in our technology and its potential for commercialization.

Vascular Biogenics Ltd., operating as VBL Therapeutics, is developing a portfolio of anticancer and anti-inflammatory programs based on its proprietary Vascular Targeting System (VTS) and lecinoxoidplatforms. VB-111 is an antiangiogenic, adenovirus 5 vector-based gene therapy developed using the VTS technology.

VBL is, in addition, developing a series of orally available, small-molecule lecinoxoid compounds that exhibit immune modulating anti-inflammatory properties for treating chronic immune-related conditions. An exploratory Phase II study with lead lecinoxoid candidate VB-201 indicated that the compound reduces vascular inflammation in atherosclerosis. DuringApril, VBL separately presented data from a retrospective analysis of Phase II studies indicating that oral administration of VB-201 reduces levels of liver enzymes. The firm said the data support the potential use of lecinoxoids for liver-related indications, including nonalcoholic steatohepatitis (NASH).

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VBL Wins $2.5M Grant to Progress Pivotal-Stage Anticancer Gene Therapy - Genetic Engineering & Biotechnology News

Breakthrough Gene Therapy Approach Raises Hopes For Patients With Blood Cancer – Wall Street Pit

Multiple myeloma (also known as plasma cell myeloma) is a cancer of plasma cells, specifically, the kind of white blood cell that produces antibodies to help fight infection. Based on statistics from the National Cancer Institute, its currently one of the fastest growing cancer types the second for men and the third for women. In the U.S. alone, it is estimated that 30,280 new cases will be diagnosed this year, and 12,590 cases will turn out to be fatal.

Since the year 2000, a total of nine drugs have been approved as treatments for multiple myeloma. But the drugs cant be considered as cures because even with the treatment, only around 50% of patients live up to 5 years after being diagnosed with the disease. Thankfully, that might soon change.

A few days ago, at the American Society of Clinical Oncology conference held in Chicago, doctors reported about the success of a new treatment for multiple myeloma called CAR-T (short for Chimeric Antigen Receptor-T) therapy an individualized treatment that makes use of blood filtering and genetic reprogramming.

The process works by removing immune system cells called T cells from a patients blood, after which, the filtered blood is modified to contain a cancer-targeting gene, then re-injected into the patient to seek and destroy cancer cells. Its being called a living drug a one-time treatment designed to permanently alter cells that multiply in the body, turning those cells into an army of cancer-fighting cells.

In the clinical trial led by Dr. Wanhong Zhao associate director of hematology at The Second Affiliated Hospital of Xian Jiaotong University in Xian, China 33 out of 35 patients responded positively within two months of the treatment, with some patients responding as early as 10 days after the first injection (three separate injections were given in a span of more than a week).

So far, 19 of the patients are currently well beyond the timeframe needed for full efficacy assessment by the International Myeloma Working Group (IMWG) consensus. In other words, it is now reasonable to conclude if complete remission has been achieved in a patient or not. And the results are: 14 are now in complete remission, 4 have achieved very good partial remission, and 1 is in partial remission.

In terms of side effects, most experienced typical ones such as fever, low blood pressure and difficulty in breathing. Only 2 patients experienced severe side effects, though such were temporary and easily manageable.

As Dr. Zhao said: Although recent advances in chemotherapy have prolonged life expectancy in multiple myeloma, this cancer remains incurable. It appears that with this novel immunotherapy there may be a chance for cure in multiple myeloma, but we will need to follow patients much longer to confirm that.

Following the success of this small clinical trial, the researchers are now planning a bigger trial involving 100 patients. Early next year, they are also planning a similar run in the U.S.

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Breakthrough Gene Therapy Approach Raises Hopes For Patients With Blood Cancer - Wall Street Pit

News from the AAN Annual Meeting: Gene Therapy Found to Benefit Infants with SMA Type 1 in Open-Label Trial – LWW Journals

Collins, Thomas R.

doi: 10.1097/01.NT.0000520852.35562.83

Features

In a new gene therapy trial, infants with spinal muscular atrophy survived longer without adverse events and achieved developmental milestones. Independent experts said the therapy should be studied and compared with the recently-approved drug, nusinersen.

BOSTON All 15 infants treated with gene therapy for spinal muscular atrophy type 1 (SMA-1) survived past the age at which 75 percent of untreated infants typically die or need at least 16 hours a day of ventilation support, according to results of an open-label phase 1 trial reported here in April at the AAN Annual Meeting.

The event-free survival of the infants to at least 13.6 months shows the promise of the proprietary gene therapy known as AVXS-101, for Avexis, the Illinois-based manufacturer that funded the study.

The drug uses an adeno-associated virus 9 AAV9 to deliver a fully functioning survival motor neuron gene to the patient's cells.

Researchers also found that all nine infants born at least 20 months before the January data cut-off reached the 20-months' time point. All of the patients in the trial are alive, and only one has required 16 or more hours per day of ventilator support at 28.8 months, according to the researchers.

The United States Food and Drug Administration (FDA) granted the drug breakthrough therapy status, which will mean faster review, in July.

Jerry R. Mendell, MD, FAAN, the principal investigator of the current study, said SMA-1 is nearly always fatal for children. Dr. Mendell, who conducted the first gene therapy studies on the treatment and developed the neuromuscular gene therapy program at Nationwide Children's Hospital in Columbus, OH, noted that a 2014 study in Neurology, conducted to establish the natural history against which potential therapies could be measured, found that only 25 percent of children with SMA-1 survive without permanent ventilation beyond 13.5 months. And only 8 percent of untreated infants live beyond 20 months.

In the current study, 12 of the 15 children were given the high dose of the drug. All of these infants have reached at least one milestone, and most have achieved several milestones, such as bringing their hands to their mouths, head control, and sitting. Two children stand and walk independently, and eight can talk.

These are milestones that are essentially never achieved in untreated children, said Dr. Mendell, who reported he has no financial interest in the drug.

None of them ever learn to talk and as they approach their death march, they can no longer feed except by G-tube and they basically live in a vegetative state, he said. And all that has changed dramatically.

Dr. Mendell emphasized the importance of early treatment. The two best patients in our clinical trial were those who were treated very early, and they very rapidly reversed their course; they are now walking, he said. Many of the patients in the trial were treated early because they have a family history [for SMA] and were recognized prenatally. That is what facilitated the study and also what will make a difference in the long run.

He added: I'm hoping the results of this study will allow for newborn-screening for this disease. That will provide a pathway for early treatment.

Last year, the FDA approved the new SMA drug nusinersen, an antisense oligonucleotide therapy, which uses targeted RNA binding to boost production of a protein in which SMA patients are deficient. Dr. Mendell said it's possible that the two drugs could work well together, although this hasn't been evaluated yet.

What we all wonder about on the gene therapy side and on the oligonucleotide side is whether these treatments could be complementary, he said. We'll know the answer to that because some of our patients have requested opportunity to move to nusinersen.

He noted that is an option for patients after their two-year enrollment commitment is reached.

In a review of the abstract, Brent L. Fogel, MD, PhD, FAAN, associate professor of neurology and human genetics at the University of California, Los Angeles, said the results sound promising, and he agreed that the therapy should be compared with nusinersen.

Given the recent success of the FDA-approved antisense oligonucleotide therapies which increase production of SMN protein by altering the splicing of the endogenous SMN2 gene, rather than replacing the damaged SMN1 gene it would be important to compare the risk and benefit between the two approaches to determine the optimal treatment for patients with SMA, who previously had none at all, he said.

He said that other clinical questions remain, as well. It would be of key interest to know what cells the virus is targeting, the resulting gene expression initially and whether that is maintained, and if any side effects are observed as the patients are followed over time, Dr. Fogel said. This would have implications for similar future therapies in other neurogenetic disorders.

Kathryn J. Swoboda, MD, director of the neurogenetics program at the Massachusetts General Hospital for Children, who was a site leader in the multi-center trial on nusinersen, noted that the evidence of gene therapy's efficacy is limited in scope, at least for now.

It's a viral-derived vector, she said, referring to the AAV-9 used in the gene therapy trial. It's a common virus that people are ultimately exposed to so they produce antibodies with time. So the proof that it works is only in babies right now, she said

If you take a young baby with SMA, those are where the phenomenal results are. Even if you took a 9-month-old or an 8-month-old or a 7-month-old with a severe form of disease, it didn't do much, because by then they've already had devastating loss of motor neurons. So we don't know how this would be tolerated in older patients and adults, and we don't have the capacity to make enough virus to deliver it to those patients at this point, and so it's going to take some additional time to do those studies.

The approval of nusinersen could complicate the future of trials on gene therapy, she said.

You've already got an approved drug and how do you design those trials? Do you say they can't get a drug we know might help them? And what if the therapy for gene therapy doesn't work? A back-up plan to start the approved therapy later could mean it might to be too late to respond, she said.

I think there's a lot to think about from an ethical perspective.

News of new therapies for the disease has drawn tremendous demand for SMA treatment from around the world, she said.

We've gotten calls from parents of newborns, prenatal cases, all the way up to 70-year-old patients who want something because it's a progressive disease, she said. And even though it's slowly progressive after a certain point, you're still losing something continuously over time.... They don't even care if it's a major improvement. They just want to stay where they are.

Nonetheless, the path forward is not clear, she said.

Does this cure? Do we have a cure yet? No. We have a really promising set of therapies that are so above anything we've seen for neurodegeneration that it's tremendously exciting. But it doesn't mean that it makes it easy to figure out how to do this.

. AAN Annual Meeting Abstract CT.003: Mendell J, Al-Zaidy SA, Shell R, et al. AVXS-101 phase 1 gene therapy clinical trial in SMA type 1: Event free survival and achievement of developmental milestones. http://bit.ly/genetherapy-abstract.

. AAN Annual Meeting Abstract CCI.002: Kuntz N, Farwell W, Zhong ZJ, et al, on behalf of the ENDEAR Study Group. Nusinersen in infants diagnosed with spinal muscular atrophy (SMA): Study design and initial interim efficacy and safety findings from the phase 3 international ENDEAR study. http://bit.ly/nusinersen-abstract

. Sign up for the video link to the plenary here: http://aan.informz.net/AAN/pages/17_AMOD_Form.

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News from the AAN Annual Meeting: Gene Therapy Found to Benefit Infants with SMA Type 1 in Open-Label Trial - LWW Journals

Nationwide Children’s spins out fourth gene therapy company this one is staying in Central Ohio – Columbus Business First


Columbus Business First
Nationwide Children's spins out fourth gene therapy company this one is staying in Central Ohio
Columbus Business First
Nationwide Children's Hospital has spun out its fourth gene therapy startup to result from decades of research and millions in investment in manufacturing equipment and commercialization personnel.

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Nationwide Children's spins out fourth gene therapy company this one is staying in Central Ohio - Columbus Business First

Allergy Breakthrough with Gene Therapy – Anti Aging News

Posted on June 6, 2017, 6 a.m. in Allergy Gene Therapy Immune System

Using gene therapy, scientists have been able to 'turn-off' the immune response which causes allergic reaction in animals.

It might soon be possible for a single treatment to provide life-long protection against harsh allergies including asthma. An immunology research team at The University of Queensland led by Professor Ray Steptoe has figured out how to disable the immune response that triggers allergic reactions. The research team operates out of the university's Diamantina Institute. Professor Steptoe's lab is situated at the Translational Research Institute. The research was funded by the National Health and Medical Research Council and the Asthma Foundation. The research team's findings are published in JCI Insight.

The Basics of Allergies and Asthma

When an individual has an allergy or a flare-up of asthma, the symptoms he experiences stem from immune cell reactions to proteins within the allergen. Allergies and asthma recur over and over again as the immune cells, referred to as T-cells, gradually create a type of immune memory. As a result, they resist treatments. Steptoe and his research team are now capable of wiping the memories of T-cells in animals. They have successfully done so with gene therapy that desensitizes the immune system to allow for the tolerance of pain.

About the Breakthrough

Steptoe's research team made use of an experimental asthma allergen. They took blood stem cells, inserted a gene that regulates the allergen protein and put it into the recipient. These engineered cells generated new blood cells. The protein is expressed in these new blood cells. Specific immune cells are targeted in order for the allergic response to be turned off.

The experimental asthma allergen worked so effectively that it is possiblethe research could be used to treat those who suffer from traditional allergies to foods. Examples include allergies to nuts, shellfish, bee venom and an array of other substances. Professor Steptoe indicates the findings will soon be subjected to additional pre-clinical investigation. The next step is to replicate the results with human cells in a lab setting.

The Goal of Gene Therapy in the Context of Allergies

Professor Steptoe states the end goal is to make use of single injected gene therapy rather than repeated short-term treatments that attempt to reduce allergy symptoms. Such short-term treatments are successful in some instances and unsuccessful in others.

Professor Steptoe's team has not reached the point where gene therapy is as straightforward as receiving a flu jab yet his group is hard at work on making it as simple and safe as possible. Their aim is for gene therapy to be used on an extensive cross-section of those plagued by allergies and asthma as well as those who endure potentially deadly food allergies. It is possible that a completely safe one-off style gene therapy treatment for traditional allergies, asthma, and food allergies will be available in the near future.

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Allergy Breakthrough with Gene Therapy - Anti Aging News