Category Archives: Genetic Therapy

Inherent Complexity

The inherent complexity of viral vector-based products, due to their physical size, formulation, and the fact that they often utilize a combined drug targeting/delivery vehicle function, makes their physical and biological characterization highly challenging from a regulatory perspective. Consequently, a fallback approach is adopted where the product is defined by the manufacturing process. This approach then makes the introduction of potentially product-impacting process changes difficult to implement and by default, the process becomes locked down within the early stages of development, severely restricting the scope for process improvement and scale up.

Classical process scale up tends to be via a vertical approach, with a focus on increasing the size of single operations (such as fermentation vessels) while keeping similar labor levels, subsequently achieving reduction in cost. This approach is valid if the process is well understood and amenable to linear scale up. The reality is that a large number of the key operations in the production of viral vectors are neither well characterized nor easily scaled. Lack of time and analytical tools will eventually direct developers to take a more horizontal approach to process scale up.

It seems likely that scale up will be based on limited vertical scale up, with multiple and overlapping production streams, potentially exploiting options around the adoption of closed single-use production systems to maximize outputs from production facilities. While this may not be the most efficient approach with regard to labor and facility costs and end-product testing, it is likely to be the only realistic option for many product development groups.

It is inevitable that some process changes will need to be introduced, for example, the requirement to replace purification of vectors by ultracentrifugation, as these processes are perceived as not only being unscalable, but also as highly operator-dependent with regard to yield and purity. The challenge becomes how engineers replace this type of operation. From a regulatory perspective, the key is an understanding of the critical quality attributes (CQAs) that impact product safety, purity, and potency; the critical process parameters (CPPs) required to control them; and the availability of the tools to measure CPPs.

This approach then, in theory, will allow process development groups to develop strategies for introducing and verifying the impact of desired process changes. However, the successful process development of these legacy processes will be dependent on the availability of suitable in-process and final-product assays. There is a clear regulatory, as well as operational, need for drug developers to invest in the analytical tools required to achieve greater understanding of AAV vectors and the processes used to make them for the products to receive commercial licensing.

The production of vectors through transient production routes entails a complex materials supply chain. At the front end is the supply of plasmid DNA constructs used to generate the vectors; clearly the quantities required will not only increase proportionally with the increased scale of vector manufacturing, but also, the associated quality requirements will be increased, moving from materials made to traceable standards to those made to GMP-grade standards (Figure 2). For early-phase development, non-GMP-grade plasmids may be used for the production of material for proof-of principle clinical studies. However, this may not be the case for commercial vectors, where GMP-grade plasmids may be required. One consequence of this will be the potential need for manufacturers to align with suppliers that have large-scale GMP capabilities to ensure the timely and secure delivery of plasmid supplies to support late clinical and commercial production.

At the end of the supply chain is the production of the viral vector drug product. For early-stage development, relatively little focus is given to either the product formulation or the filling process. There is often good reason for this, as material for such development studies is in very short supply, with all available material often directed into clinical studies to demonstrate product efficacy.

The result of this is that the basic formulations used in early-stage development are carried forward into late-stage trials, with the products 0.2-m filtered and hand filled into glass vials and stored at 80C.

Future development activities in the AAV field will need to be focused on identifying formulations that provide long-term stability, potentially moving to +28C storage, and generating meaningful stability data. Fully defining the drug product manufacturing process will also ensure the retention of product titers and activity throughout the manufacturing process, including activities such as inspection and labeling.

In conclusion, we are in exciting times with a number of these potentially life-changing products coming through to clinic. However, if we are to bring these products efficiently to the market, developers will need to adopt pragmatic and informed solutions for the manufacturing challenges that lie ahead.

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Manufacturing of AAV Vectors for Gene Therapy - Genetic Engineering & Biotechnology News

Dimension Therapeutics is winnowing out 25% of its staff as it concentrates on three gene therapy programs, including one partnered with Bayer that has the potential to generate some badly needed milestone cash.

The biotech says it has enough revenue in hand to operate for another year, adding that it can extend the runway out to the end of 2018, provided it bags about $15 million in cash in its deal with Bayer. Three years ago Dimension inked a $252 million pact with Bayer, with $20 million of that upfront.

Annalisa Jenkins

Counting milestone money in your business plan isnt likely to generate much confidence among investors, especially after some disappointing results and evidence of liver toxicity for its initial lead gene therapy for hemophilia B in January crushed the biotechs stock price. DTX101 which faced more advanced competitors with better data has now been shoved out of the spotlight.

The biotechs market cap has now shrunk to $38 million.

The lead program in the clinic now is DTX301 for rare cases of ornithine transcarbamylase (OTC) deficiency. The biotech is lining up two more programs for INDs, including DTX201 allied with Bayer.

Dimension was one of several gene therapy companies to get started with a technology licensing deal with ReGenX, a spinoff from the University of Pennsylvania which is working with AAV technology developed by scientific founder James Wilson.

Our key focus is to deliver initial data from our ongoing Phase I/II clinical trial for DTX301 in OTC deficiency, advance two proof-of-concept studies for glycogen storage disease type Ia (GSDIa) and hemophilia A, the latter in collaboration with Bayer, and advance our unique HeLa 2.0 manufacturing platform, says CEO Annalisa Jenkins. We believe we can deliver these important objectives in 2017-2018 with our current financial position.

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Hammered on a gene therapy setback, Dimension cuts staff and circles the wagons - Endpoints News

U.K. firm NightstaRx raised $45 million in a Series C financing round to support continued clinical development of its pipeline of retinal gene therapies, including a pending Phase III study with lead candidate NSR-REP1 for treating choroideremia. The new funds will also be used to support an ongoing Phase I/II study with NSR-RPGR in patients with X-linked retinitis pigmentosa (RP), and a proposed Phase I/II trial with a gene therapy product targeting an inherited form of macular dystrophy. Nightstar projects starting the macular dystrophy clinical trial during late 2018.

Investors in the Series C round included Nightstars existing investors Syncona and New Enterprise Associates (NEA) and new investors Wellington Management Company and Redmile Group. As an original investor in Nightstar, our goal from day one was to build a global gene therapy leader with the capability of developing multiple programs for inherited retinal diseases, commented Chris Hollowood, Ph.D., chairman of the board of Nightstar and chief investment officer of Syncona, which is funded by The Wellcome Trust. We welcome Wellington Management and Redmile Group as investors and look forward to working with them and NEA to fulfill Nightstars potential.

Founded in 2014 by researchers at the University of Oxford, Nightstar is developing a pipeline of one-time potentially curative treatments for rare inherited retinal diseases. Lead candidate NSR-REP1 is an adeno-associated virus (AAV) vector-based gene therapy in development for treating choroideremia, a rare X-linked inherited retinal dystrophy for which there are currently no disease-modifying therapies. The AAV vector is administered by injection under the retina, using standard surgical procedures performed under local anesthetic. Nightstar says a Phase I/II study carried out by the University of Oxford confirmed long-term benefits of the treatment including vision improvement or stabilization.

The firms AAV-vector-based NSR-RPGR gene therapy for X-linked RP is designed to deliver a normal copy of the RP GTPase regulator (RPGR) gene, which Nightstar says is mutated in more than 70% of cases of X-linked RP. The procedure similarly involves injecting the gene-carrying vector under the retina. The ongoing Phase I/II study with NSR-RPGR was started in March.

Nightstar has ongoing collaborations with the University of Oxford, the Bascom Palmer Eye Institute, and the Institute for Ophthalmic Research, Tbingen University Hospital. In February, the firm inked a collaboration with Netherlands-based Preceyes to develop a subretinal drug delivery technology based on the latters high-precision robotic device for ocular surgery.

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NightstaRx Raises $45M to Fund Phase III Study with Retinal ... - Genetic Engineering & Biotechnology News (blog)

Xconomy Boston

Gene therapy offers the potential for a long-lasting, if not permanent, treatment for an inherited disease, but cells that divide rapidly, such as those in the liver, present a thorny problem. Because of how they insert themselves in the cells, some forms of gene therapy get diluted as the cells divide.

Its a particular problem in growing children. Cambridge, MA-based LogicBio says it has developed a workaround by combining gene editing with gene therapy. The firm has raised $45 million in additional capital to help bring this technology into human testing, and it is moving from California to the LabCentral shared incubator space in Cambridges Kendall Square.

LogicBio calls its technology GeneRide. The company says its approach can transfer genetic material to specific sites to repair a faulty genetic sequence. The companys focus is metabolic disorders that affect the liver in children. Published research shows that metabolic disorders of the liver can progress to injury affecting other organs. In rare cases, the severity of the disease requires a pediatric liver transplant.

If GeneRide works as the company envisions, the gene therapy would offer a one-time treatment that avoids side effects.

London-based Arix Bioscience (LSE: ARIX) led the Series B round of investment, which was joined by new investors OrbiMed, Edmond De Rothschild Investment Partners, Pontifax, and SBI Japan-Israel Innovation Fund. Earlier investor OrbiMed Israel Partners also joined in the latest investment. In total, LogicBio says it has raised approximately $50 million in financing to date.

Gene therapy remains largely experimental. UniQure (NASDAQ: QURE) received the Western worlds first gene therapy approval in 2012 for alipogene tiparovec (Glybera), a treatment for a rare metabolic disorder. But earlier this year, the company, split between the Netherlands and Lexington, MA, announced it would not seek renewal of its conditional approval, set to expire in October. Patient demand for the drug was limited and the company did not expect that to change.

The first U.S. approval could come soon. Philadelphia-based Spark Therapeutics (NASDAQ: ONCE) is awaiting an FDA decision on a gene therapy for an inherited form of blindness. Cambridge-based Bluebird Bio (NASDAQ: BLUE) last week released early data from a Phase 3 study in patients with beta-thalassemia, a rare blood disorder.

The technologies underlying LogicBios approach were developed at Stanford University by company co-founders Mark Kay, Adi Barzel, and Leszek Lisowski. In addition to its Cambridge site, the company also has scientists in Tel Aviv, Israel.

Frank Vinluan is editor of Xconomy Raleigh-Durham, based in Research Triangle Park. You can reach him at fvinluan [at] xconomy.com

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LogicBio Lands $45M for Gene Therapies in Rare Pediatric Diseases - Xconomy

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

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