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

BY MANDY JACKSON

Executive Summary

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

Gene therapies that program the body to make therapeutic antibodies, genetic surgery that replaces anatomical surgery and cell therapies designed to attack individual cancer patients’ tumors almost sound like science fiction, but in the eyes of Roche global partnering head James Sabry those types of innovations are the not-so-distant future of medicine.

Sabry, Spark Therapeutics Inc. chief scientific officer Federico Mingozzi and Harlan Robins, Adaptive Biotechnologies Corp. chief scientific officer and co-founder, discussed the future of regenerative medicines during an 8 June discussion of “Next-Generation Medicine: Cell and Gene Therapies and Beyond” as part of the Biotechnology Innovation Organization’s annual international meeting taking place 8-12 June online. Novel cell and gene therapies require risk-taking and partnership to move the field forward, the executives agreed.

Roche completed its $4.8bn acquisition of Spark late last year and kept the gene therapy developer intact as an independent subsidiary. (Also see “Roche/Spark Deal Clears FTC In A Sigh Of Relief For Pharma Dealmakers” - Scrip, 16 Dec, 2019.) Spark, whose most advanced research and development programs include gene therapies for hemophilia A and B, won the first-ever US Food and Drug Administration approval of a gene therapy with Luxturna (voretigene neparvovec) for a rare form of inherited blindness at the end of 2017.

Roche also is working with Adaptive, via its subsidiary Genentech Inc., through an early 2019 deal that gave the Seattle-based firm $300m up front with the promise of more than $2bn in potential milestone fees to develop T-cell receptor (TCR) therapies that target neoantigens specific to individual patients’ tumors. Adaptive uses its platform comprised of proprietary computational biology, software and machine learning technologies to develop diagnostics and therapeutics based on the adaptive immune system, including specific T-cell and B-cell responses to disease.

Sabry said Roche’s deals with Spark, Adaptive and other cell and gene therapy firms are emblematic of the big pharma’s view of health care in the future.

“We’re interested not in just the incremental improvements of antibody therapy or small molecule therapy currently used for human disease, but thinking beyond that to what could be the therapeutic modalities that will dominate therapeutic landscapes 10, 20 and 30 years from now,” he said. “It’s our view that if you look down that kind of a timeframe, that cell and gene therapy will not only be important parts of therapy but will actually dominate therapy, and that therapies like antibodies and small molecules, although they will still be around, will be less important health care than cell and gene therapies will be.”

Gene Therapy Advances: Better Vectors, More Diseases

Spark’s Mingozzi noted that Luxturna and the gene therapies approved since then all use adeno-associated virus (AAV) vectors to deliver the treatments, but Spark and others are looking at ways to improve AAV technology or develop new types of vectors to broaden the application of gene therapies to more and larger diseases. New ways of optimizing the nucleic acids delivered by AAV or other vectors so that they are more specific and controllable also are being explored.

AAV “has been proven very safe and very stable over time in terms of delivering therapeutic efficacy,” Mingozzi said, but noted that development of AAV-based gene therapies has been limited to monogenic diseases.

“My expectation for the future is to see more larger indications, more complex diseases,” he said. “When you establish the platform then you have enough confidence to move to diseases that are not simply the monogenic disorders, so the potential is really great.”

Among gene therapy companies also tackling some of these issues, Dyno Therapeutics Inc. recently emerged with a platform that uses artificial intelligence and machine learning to identify novel AAV capsids that may deliver gene therapy to tissues and organs that can’t be reached with current AAV technologies. It has partnered with Novartis AG and Sarepta Therapeutics Inc. to test its technology in specific disease areas. (Also see “Dyno Therapeutics Emerges With Novartis, Sarepta Deals For Novel AAV Capsids” - Scrip, 12 May, 2020.)

Italy’s Genespire launched earlier this year to develop gene therapies for primary immunodeficiencies and inherited metabolic diseases. It was spun out of the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and is working with SR-Tiget on novel gene editing and lentiviral vector technologies. (Also see “Genespire Glides Into Gene Therapy Space” - Scrip, 30 Apr, 2020.)

“What we have today [with AAV vectors] is great, because we can develop products,” Mingozzi said. “We have demonstrated that we can get all the way to have drugs based on the current platform, but we can do better and by improving the platform we can also open up to new indications.”

Conducting Genetic Surgery, Generating Antibodies In Vivo

Sabry said that in the future gene therapy firms may have a whole library of different delivery mechanisms at their disposal to deliver their genetic payloads into their targeted cells.

“And the genetic payload can be more than just a gene that sits outside the genomic DNA episomally,” he added. “It could be one that is truly targeted to integrate into the genome at the specific place where the disordered gene is, in essence opening up a whole field of genetic surgery that is very analogous to anatomic surgery where you go in and remove a diseased organ. Imagine, you go in and remove the diseased gene and you replace it with a normal gene.”

Sabry noted Spark’s ongoing research into gene therapies that could deliver instructions to the body for making its own therapeutic antibodies, which could replace monoclonal antibodies, like Roche/Genentech’s pioneering cancer medicines Avastin (bevacizumab) and Herceptin (trastuzumab). “There’s no reason that the liver couldn’t be the best way to make Avastin or Herceptin, for instance, if you could find ways to turn off the gene if you ran into trouble,” he said.

Turning tissues into biofactories is one area that Spark is exploring, Mingozzi acknowledged, including the ability of gene therapies to deliver an antibody systemically to the liver or to deliver the antibody across a barrier that limits efficacy of biologics today, like the blood-brain barrier. Expression of the antibody could be modulated or controlled via the gene therapy.

“I think that’s the leap in the technology that we need to do and is one of the points that we need to address to unleash the potential of the gene therapy technology,” Mingozzi said.

“Souping Up” And Personalizing Cell Therapies

Adaptive’s Robins noted that there are multiple angles the cell therapy field is progressing to improve the efficacy of engineered cells in cancer and other diseases.

“I think one way you can imagine this is souping up the cells themselves so you can make the cells more powerful,” he said. “Are there limits to that? I don’t think we’re anywhere near those limits, but every time you do that you’re opening up safety issues as well.”

However, Adaptive is going in another direction with Roche/Genentech to focus less on making cells more potent and more on tailoring them to each patient, which could redefine personalized medicine.

“Personalized medicine right now is effectively saying, ‘OK, we have a set of drugs that are sitting there on the shelf and we’re going to use diagnostics to determine which drug you should

use,’” Robins said. “What if instead we said, ‘Let’s look at this person, look at the patient, and actually make the right drug for this person in real time?’ What if you could give a personalized therapy for each person?”

Because of the way cells work together – including T-cells reengineered and given back to patients – Sabry said it may be possible in the future to develop integrated systems of cells that work together against diseases.

“Once we start to establish that normal immune regulation, then some of the concerns we have right now about either having these cell be too powerful or not powerful enough tends to go away, because all you’re doing is using the normal, very advanced regulatory systems that exist within the immune system to regulate the power and amplitude of the immune response,” he explained.

These kinds of treatments could replace small molecules and monoclonal antibodies over the next few decades, but only if big pharma and small biotechnology firms continue to take risks.

“There’s risk all over the future and we don’t know what it’s going to look like,” Sabry said. “That should never be a reason not to go down that path, especially for the large pharmaceutical firms that have the capital to do so. And in many ways, this should be part and parcel, I believe, of every large, revenue-positive pharmaceutical company to take chances and go into these risk spaces.”

He noted, however, that most cell and gene therapy technologies will originate from small companies, which can buy themselves time by partnering with big pharma.

“We’re all working very hard but it just takes time for complex breakthroughs in medicine to be discovered and developed,” Sabry said. “And that time requires a certain amount of capital breathing room and that’s what I think a lot of these collaborations give.”

Partnering To Progress Cell And Gene Therapy Innovations

Robins also noted the importance of partnering for Adaptive to advance its platform beyond diagnostics, where the company has two approved products, to patient-specific T-cell therapies.

He said “the horsepower you need to move further along down the food chain in terms of development for a therapeutic is much more intense in terms of just manufacturing, regulatory, commercialization, the clinical trials, etc., so there we were thrilled to be able to partner with Genentech/Roche and have their unbelievable horsepower to leverage for what we just don’t have the capabilities to do as of right now.”

Sabry noted that no company – not even Roche with a $12bn annual R&D budget – can do everything on its own. While big pharma companies actually are less likely to take big R&D risks than small biotech companies, he said Roche uses its partnerships to invest in innovation while sharing the risk. The pharma also gives its partners and acquired companies freedom to operate within their area of expertise.

Mingozzi said there is a lot of value for big firms that maintain expertise within a subsidiary company, like Spark, rather than integrating it into a much bigger organization.

“We remain like we were before – a young company, relatively small, well connected, very energetic,” he said, noting that as part of Roche, “we have more stability; we’re less exposed to the markets and our ability to raise funds.”

“Because we are able to maintain our culture then we can also now think of our outlook of the future as a little longer than a small public company where your goals are very well defined but tend to be shorter-term where you just need to bring to the finish line the candidates that are in your pipeline,” Mingozzi said. Robins noted that while Adaptive has big partners, it maintains its small company nimbleness that allows it to go after novel development programs, including COVID-19. To advance its initial work related to the novel coronavirus, Adaptive partnered with Amgen Inc. (Also see “Amgen, Adaptive Partner In COVID-19 Neutralizing Antibody R&D Effort” - Scrip, 2 Apr, 2020.)