7:37 PM
Sep 13, 2018
 |  BC Innovations  |  Product R&D

Academia’s manufacturing problem

How gene therapy manufacturing bottlenecks are impeding academic translation

Editor's Note: This article was updated on Sep 14, 2018 at 6:32 PM PDT

With backups at academic manufacturing centers beginning to hamper translation of early stage gene therapies, pushing those who can afford it to CMOs, at least one non-profit has stepped in with a model to deliver the services on the cheap. But without more, the field may be slow to benefit from the next generation of gene therapies coming through.

Gene therapies are notorious for scale up issues that can hinder late stage trials or commercialization. However, manufacturing difficulties also extend to preclinical development, in particular in the transition from animal proof of concept to IND-enabling studies. The former does not require GMP-like vector, but the latter does.

Academic researchers typically have two options for obtaining high enough quality vector, and sufficient quantities, for IND-enabling work: use a specialized vector production core at a large academic institution, of which there are few; or compete with drug companies that are capable of paying more for limited manufacturing slots at CMOs.

With FDA’s first-ever approval of an in vivo gene therapy in December, Spark Therapeutics Inc.’s Luxturna voretigene neparvovec, the field is on the rise. Academic and industry researchers alike are pushing the modality’s horizons, moving gene therapies beyond the small volume compartment of the eye, where Luxturna is delivered, into larger organs and into indications that require systemic administration, which necessitates orders of magnitude more vector.

University production cores now have long lines that are pushing some researchers to seek more expensive CMO services, which in most cases requires dipping into grant money that isn’t allocated for that purpose.

NIH is still backing the search for new gene therapies, according to Jaysson Eicholtz, director of GMP operations at Nationwide Children’s Hospital. “We’re still seeing good NIH funding going to programs, but those dollars aren’t stretching quite as far,” he told BioCentury.

“Are CMOs going to be able to provide the material they need at a price they can afford, and at a timeline appropriate for innovative research?”

Kenneth Cornetta, Indiana University

At a joint FDA and National Center for Advancing Translational Sciences (NCATS) workshop held on Aug. 20 to discuss bottlenecks in gene therapy development, Jude Samulski, a pharmacology professor and director of the University of North Carolina at Chapel Hill Gene Therapy Center, called upon NIH to provide more funding for vector manufacturing so that researchers at smaller institutions or foundations won’t be left behind.

“If we end up with a structure of haves versus have nots, we will see a lot of orphan diseases not being tested because they won’t meet the commercial thresholds most companies have to play by,” he said. And many companies are not willing to pick up a gene therapy based only on animal POC.

The problem might ease as the field builds capacity and develops techniques to make vector manufacturing more efficient. In the meantime, at least one non-profit, Odylia Therapeutics, is offering alternative manufacturing support that could provide one solution. Still, as Odylia is focused on eye diseases, there’s a need for many others like it.

Preclinical pinch 

For gene therapies, manufacturing considerations remain one of the greatest challenges in preclinical development.

In remarks to the Alliance for Regenerative Medicine’s annual board meeting on May 22, FDA Commissioner Scott Gottlieb estimated that 80% of gene therapy product reviews are focused on manufacturing issues and the remaining 20% on clinical development -- the reverse of a typical product review.

University of California Berkeley professor David Schaffer told BioCentury it takes about six months to a year of preclinical work to flesh out gene therapy “release criteria,” the standards and assays used to determine whether different batches of vector consistently meet quality standards, plus an additional six months to a year to figure out how to scale the production process for Phase I studies.

Schaffer is also CSO of 4D Molecular Therapeutics Inc., which designs custom AAV vectors for its own gene therapies and for partner companies.

He said much of the work to develop release criteria can be re-purposed for additional therapies if those therapies have similar targets or vector scaffolds, suggesting the timeline can be sped up.

A proposal to get rid of Recombinant DNA Advisory Committee (RAC) reviews of gene therapies prior to clinical trial initiation also aims to save time (see “Sidebar: Moving On”).

Sidebar: Moving on

But Schaffer’s estimate does not include the wait to get vector made.

The problem is that while most academic institutions have facilities that can make vector that is good enough for preclinical proof-of-concept studies, only select centers can produce them with the quantity and quality needed for IND-enabling pharmacology and toxicology studies.

Although vectors do not have to meet GMP specifications for this purpose, researchers do need to demonstrate they are on the path to the eventual GMP versions that will be used in the clinic. In practice, this tends to motivate them to use an institution that can also make GMP vectors.

“You have to be able to paint a picture from a regulatory perspective of how you got from A to B to C to D,” said Schaffer.

Due to the increasing demand, the vector cores that meet those standards now have wait lists. For example, Indiana University’s vector production core, which makes retroviral and lentiviral vectors for preclinical and Phase I studies, has wait times stretching into 2020, Kenneth Cornetta, the core’s director and a clinical professor of Medical and Molecular Genetics at the university, told BioCentury.

“It continuously gets more challenging; the demand is very high right now,” he said.

The situation has worsened for U.S. researchers, as NIH support for academic production facilities has been unreliable, in part due to administrative hold-ups, said Cornetta. By contrast, the U.K., has been consistently funding gene therapy manufacturing since 2010 through its Cell and Gene Therapy Catapult.

The Gene Therapy Resource Program (GTRP) under NIH’s National Heart, Lung, and Blood Institute (NHLBI) used to subsidize vector production at three academic cores and provide investigators with resources like pharmacology and toxicology testing, immunology testing, and regulatory support. It also supported IND-enabling pharmacology and toxicology studies and early clinical trials at a fourth site.

“If we end up with a structure of haves versus have nots, we will see a lot of orphan diseases not being tested because they won’t meet the commercial thresholds most companies have to play by.”

Jude Samulski, UNC Chapel Hill

Under GTRP, which lapsed in 2017, academic investigators could apply for manufacturing slots that were reserved for intramural research.

Cheryl McDonald, a physician at NHLBI and director of GTRP, said the program is on hiatus and will likely resume in early 2019. She said the original contracts had expired and new ones have not yet been awarded. She declined to comment on whether GTRP will support the same core laboratories and vector grades as before the pause.

As a result, Indiana now allocates slots on a first-come, first-served basis, said Cornetta. “If folks have to wait on an NIH grant to be funded, that is a long process. We can’t just hold open slots like we did with GTRP.”

Restoring the program, without expanding it, will only partly solve the problem.

While demand at CMOs also is high, Nationwide’s Eicholtz said new and existing CMOs are working on extending their capacity to help ease the crunch.

But CMO services come with a cost that academic investigators haven’t historically had to write into their grants.

“The concern for Phase I research institutions is, are CMOs going to be able to provide the material they need at a price they can afford, and at a timeline appropriate for innovative research,” asked Cornetta.

A non-profit solution 

At least one non-profit is taking action now to address the academic bottleneck.

Odylia is aggregating early stage gene therapies for ultra-rare inherited retinal diseases and shepherding them from animal POC to human trials, where industry is more willing to pick them up. The Boston-based non-profit was founded in 2016 by biotech entrepreneur Scott Dorfman and two non-profits: Massachusetts Eye and Ear and Usher 2020 Foundation Inc.

After Dorfman’s twins were diagnosed with Usher syndrome, he created Usher 2020 to search for a cure. One of its programs generated animal data showing it could slow loss of sight caused by USH1C mutation, but he was unable to find a pharmaceutical partner to take it forward.

He created Odylia to push translation of gene therapies for highly rare indications where industry seldom starts programs.

By gathering several programs under one roof, Odylia aims to leverage volume, as well as its non-profit status, to keep costs down.

“It’s bridging the gap between early discovery and IND-enabling preclinical work where these projects have trouble moving forward,” VP and CSO Harrison Brown told BioCentury.

“If we end up with a structure of haves versus have nots, we will see a lot of orphan diseases not being tested because they won’t meet the commercial thresholds most companies have to play by.”

Jude Samulski, UNC Chapel Hill

Brown said Odylia outsources development to a network of CMOs and CROs, with which it has negotiated discounts. It has a deal with its sponsoring organization Lonza Houston Inc., an affiliate of Lonza Group Ltd., for discount vector manufacturing and reserved manufacturing slots.

Both Lonza and Odylia have rights from Massachusetts Eye and Ear to use the Anc80 AAV platform for gene therapies. Odylia’s license covers indications with fewer than 3,000 patients in the U.S.; Lonza’s covers more prevalent indications.

“We were able to get in with them because they have a vested interest in Anc80,” he said.

Odylia’s pipeline contains five gene therapies; the most advanced candidate is RPGRIP1, an Anc80 vector encoding the gene for RPGRIP1. Brown said Odylia has full rights to RPGRIP1 from Mass Eye and Ear, and plans to advance it into the clinic to treat Leber congenital amaurosis (LCA) within 18 months.

Brown said Odylia is agnostic to the source of the therapy and that the non-profit’s pipeline includes candidates sourced both from academia and industry, as well as from its own vector platform under sponsorship by patient advocacy groups. He declined to specify the source of Odylia’s other four disclosed programs, which deliver the genes USH1C, USH2A, RDH12 and CLRN1.

Odylia aims to de-risk pharma programs through its “adopt-a-gene” program, in which it in-licenses a deprioritized preclinical therapy and does the work to get it into the clinic. Donations from the partner cover development costs. The partner gets claw-back rights or right of first refusal to license the program back again at any time it wishes. Odylia is eligible for royalties.

“In the worst case they made a donation to rare disease research, and in the best case they can get a drug ready for BLA at a fraction of the cost they can do internally,” said Brown.

Odylia is also putting together a precompetitive consortium to streamline gene therapy development by crafting common protocols for small preclinical and clinical development programs, and common procedures for the CMC section of INDs.

“It may be different for each AAV serotype, but if you can find the best manufacturing practices and best release criteria practices, that would greatly streamline that section,” he said.

The consortium, which Odylia hopes to kick off in March, will include CMOs and CROs, industry members, academics, patient advocates and regulatory experts.

Brown said Odylia eventually hopes to tackle gene therapy indications beyond the eye.

In the short term, however, some of the hardest hit academic programs will be those for other ultra-rare diseases, in particular those which require large amounts of vector because they target larger volumes of cells and tissues.

That impact could bear on neurological and muscular disorders, where early stage trials have involved some of the highest vector doses, and where the next wave of gene therapy innovations is building.

Companies and Institutions Mentioned 

Alliance for Regenerative Medicine, Washington, D.C.

Audentes Therapeutics Inc. (NASDAQ:BOLD), San Francisco, Calif.

Cell and Gene Therapy Catapult, London, U.K.

4D Molecular Therapeutics Inc., Emeryville, Calif.

Indiana University, Indianapolis, Ind.

Lonza Group Ltd. (SIX:LONN), Basel, Switzerland

Massachusetts Eye and Ear, Boston, Mass.

National Center for Advancing Translational Sciences (NCATS), Bethesda, Md.

National Institutes of Health (NIH), Bethesda, Md.

National Heart, Lung, and Blood Institute, Bethesda, Md.

Nationwide Children’s Hospital, Columbus, Ohio

Odylia Therapeutics, Boston, Mass.

Spark Therapeutics Inc. (NASDAQ:ONCE), Philadelphia, Pa.

University of California Berkeley, Berkeley, Calif.

University of North Carolina at Chapel Hill, Chapel Hill, N.C.

University of Pennsylvania, Philadelphia, Pa.

U.S. Food and Drug Administration (FDA), Silver Spring, Md.

Usher 2020 Foundation Inc., Atlanta, Ga.


CLRN1 - Clarin 1

RDH12 - Retinol dehydrogenase 12

RPGRIP1 - Retinitis pigmentosa GTPase regulator interacting protein 1

USH1C - Usher syndrome 1C

USH2A - Usher syndrome 2A

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