Alipogene tiparvovec

In February this year, the biotech company Humacyte announced its decision to go public, marking its shift from a clinical-stage company to a commercial one. The company, which develops regenerative human tissues that can be implanted in any patient without the need for immunosuppressive drugs, is expected to hit the market with a value of $1.1bn. “We believe our universally implantable regenerative human tissue will be a disruptive technology with the potential to transform medicine,” says Humacyte CEO Dr Laura Niklason. “We are creating engineered off-the-shelf replacement tissue, which can be implanted in anyone. Longer-term, the technology has the potential to create solutions for complex organ disease, including replacement bioengineered organs.” Rather than going down the IPO route, the company chose to go public via a special purchase acquisition company (SPAC), Alpha Healthcare. This has allowed it to engage investors more thoroughly – educating them on the platform and its groundbreaking possibilities. It represents a benchmark in the field of regenerative medicine. “I think this recent SPAC transaction really validates our approach and how far regenerative medicine has come,” says Niklason. “I’ve been in the cell therapy and regenerative medicine space for several decades, and when I started, it really did seem like science fiction. Now, we are at a point with advancements in cell biology and tissue engineering where this is becoming science fact.” The hype and the reality Although technologies of this kind have been talked up for years, it is only recently that they have started to become commercially viable. For all the hype around stem cell treatments, tissue engineering and next-generation cell and gene therapies, relatively few patients have benefited to date. Worldwide, there are 64 approved advanced therapy medicinal products (ATMPs), including 34 cell therapies, 20 gene therapies and ten tissue engineering products. While not a trivial figure, it is far eclipsed by the number of products that have entered clinical development and stalled there. The route to market is complex, time-consuming, expensive and highly regulated, and even for those products that do succeed, few have the potential to become blockbusters. Just 15 ATMPs have been approved in Europe, of which four have already been withdrawn from the market. One of these was the gene therapy Glybera, indicated for patients with an ultra-rare genetic disorder. Because the patient population was so limited (only 31 people worldwide had been administered Glybera as of 2018), it didn’t have much chance to become commercially successful and gained infamy as a million-dollar drug. Global Data Pharma Decode the future to profit from faster, more informed decisions Powered by GlobalData's proprietary intelligence, our free Pharma Data Packs provide essential insights across a variety of key themes disrupting the market that keep CEOs awake at night. Find out more Many new ATMPs face issues around manufacturing know-how, pricing reimbursement and market access, meaning they struggle to make the leap from laboratory sensation to commercial reality. It’s for this reason, then, that many companies in the field are working to find strategies to unlock these products’ potential. Overcoming the challenges One of these is OriBiotech, a cell and gene therapy (CGT) manufacturing company based in London and New Jersey. It has developed a flexible platform that automates CGT manufacturing, allowing therapeutics developers to bring their products to market at scale. The company hopes to launch its platform in H2 2022, following a Series B funding round this year. “I don’t think the clinical or scientific case for cell and gene therapies needs to be made further,” says OriBiotech CEO Jason Foster. “As an industry, we have proven that we can create cures for devastating cancers and rare diseases like leukaemia, multiple myeloma, spinal muscular atrophy and others. “What remains to be proven is the market access and commercialisation case – can we manufacture these products at a high enough throughput and low enough cost to make them widely available for patients?” The good news is that CGT manufacturing is being talked about more widely, especially since the start of the Covid-19 pandemic. “Right now we have cures for cancer that patients can’t get access to, which can’t end soon enough, in my view,” says Foster. “With the advent of technology platforms like Ori’s, we can begin to tackle these scalability challenges over the next 12-24 months.” The industry is also starting to work together to overcome access challenges. Orgenesis, a global biotech, has brought together what it calls a POCare Network – a network of patients, doctors, industry partners, research institutes and hospitals worldwide, who want to bring new therapies to market in a harmonised way. After identifying promising new CGTs and adding them to its pipeline, the company works to develop these products across its network. The idea is to make CGTs more affordable at the point of care. “The commercial viability of these products is dependent on the industry’s capability to go through a paradigm shift,” says Orgenesis CEO Vered Caplan. “Just as the software industry became widely commercially available once the proper hardware was developed and reduced in pricing, so will this industry expand its availability once the right infrastructure is put in place.” He adds that while surviving the pandemic has been an uphill battle for early-stage companies, many later-stage companies may actually have benefited from the rising glory of biotech. “The vaccine industry is closely related to cell and gene therapies, with many of the most advanced products being cancer vaccines,” he says. “This has reflected positively on our industry. In addition, the economic crisis and the erratic behaviour of the financial markets have shifted investors’ appetites.” A bright future for regenerative medicine Miguel Forte, CEO of Belgian biotech Bone Therapeutics, is equally sanguine about the prospects for regenerative medicine. The company develops cell and biologic therapies within orthopaedics, among other areas, and has a number of products in clinical trials. “A lot of developments have taken place in the field recently, and renewed scientific and technical confidence should support growth,” says Forte. “Regenerative medicine needs to bring a value proposition that is industrially viable, with good willingness to pay from stakeholders. This is increasingly happening, so investment will follow from venture capitalists as well as from big pharma.” As an example, his company’s lead product, ALLOB, takes stem cells from the bone marrow of healthy donors and turns them into bone-forming cells. The product is in mid-stage clinical trials for patients with difficult tibial fractures, but might ultimately be used within other orthopaedic indications too. “The ALLOB product is allogeneic, sourced from healthy donors, and produced in a scalable way,” says Forte. “Since it’s cryopreserved, it’s off-the-shelf. This delivers a product that is competitive from a cost and use perspective. We are poised to see more and more of these approaches reaching the market. I would predict that we will see products reaching the market significantly over the next five to ten years, if not before.” Massimo Dominici, CEO of Italian biotech Rigenerand, points out that there are still large pockets of unmet need in regenerative medicine. He thinks the market will soon benefit from new manufacturing techniques, harmonised regulation and cost reductions, all of which will push these products closer towards the pharma mainstream. And he doesn’t hold back when it comes to his own goals for the future. “We will have allogeneic CAR-lymphocytes produced on a large scale and autologous CAR-lymphocytes manufactured on the weekend and infused on Monday,” he says. “A dream? Considering the evolution of technologies and the current biotech investments, I do not think so.”

About five years ago, George Church and his new postdoc, Ying Kai Chan, sat hunched over a laptop in the genetics pioneer’s Harvard office and stared in bewilderment at an old paper. The paper documented early trials for Glybera, the first and at the time only gene therapy approved anywhere on the planet. Less than three dozen patients ever received it, but in the years before Luxturna and Zolgensma, it gave researchers an example they could point to for gene therapy actually working. Chan and Church, though, were shocked to see that researchers running clinical trials had given patients a battery of high dose immunosuppressive drugs often reserved for organ transplants, names like mycophenolic acid and cyclosporine. And when they biopsied patients’ muscles, they were filled with T cells, suggesting an immune response in action. The results were particularly surprising because Glybera used the viral vector AAV, a delivery system that had led to a resurgence in gene therapy precisely because it was commonly believed to evade the immune overreaction that doomed the field in the 90s. “There are so many people working on gene therapy now and even when you tell them, oh, ‘Did you know cyclosporin was used? Did you know all these things were used?’ People are like, ‘Huh, what?” Chan told Endpoints News. “Glybera was the poster child, but it seems people didn’t appreciate how much immunosuppression was required.” Chan trained as a viral immunologist and he came into the Church lab with an intuition that viral vectors, those hollowed out and souped up gene taxis, were still viruses and still treated by the body as such. Gradually, the field has come around to his view. Multiple monkey studies showed that high doses of AAV could be toxic for certain neurons, results that companies have reluctantly accepted. And last year, three deaths in a high-dose trial heightened AAV safety concerns, even if those have yet to be linked conclusively to an immunologic reaction. Meanwhile, Chan has been working on new methods of cloaking AAV to make it safer and reduce the need for immunosuppressants. This week, he, Church, and a larger team at the Wyss Institute published the work in Science Translational Medicine , showing how weaving specific strands of human DNA into the vector can neutralize one of the body’s key defenses against foreign invaders. “It was very much inspired by nature,” Chan said. One of the first ways gene therapy pioneer Jim Wilson showed the body could react to AAV was through a set of sentinels called toll-like receptors. These sentinels provide one of the immune system’s first layers of defense, sounding an alarm if they detect anything that appears foreign. That means, though, that normal cells need a way of telling the receptors they’re safe — an encryption key that only human cells know. That encryption key is encoded in a few strands of DNA on the ends of telomeres, those paperclip-shaped strands at the end of chromosomes that are sometimes implicated in aging. Chan incorporated those strands into the DNA of an AAV2 vector, the serotype used in Luxturna. When the vector is injected, the strands should bind to the toll-like receptors throughout the body and tell the receptors not to sound any alarm. When the team injected it into the muscles, liver and eye of pig and mouse models, it triggered a markedly reduced immune reaction than a traditional vector, Chan reported in STM. The results add to a suite of new technologies emerging out of labs across the country to combat AAV immunogenicity. Wilson’s lab has offered a way of using microRNAs — short strands that minimize expression of a particularly gene in a given cell — to mitigate the neural effects. And Dyno Therapeutics, a Church lab spinout, uses engineering and machine learning to come up with wholly new vectors, with the hopes of finding some that can avoid the immune system. Chan has now helped launch a new company, teaming with ARCH and a couple other VCs to form Ally Therapeutics, a still-in-stealth biotech that tries to minimize the immunogenicity of viral vectors. Still, he acknowledges that he had hoped for more sweeping results than he ultimately had. Although his technology successfully tamped down the immune response in pigs and mice, the results were less profound in monkeys. Chan’s team injected the vector into non-human primates’ eyes, a part of the body where much of the immune system can’t enter and, consequently, toll-like receptors are acutely important. They saw improved safety when they administered beneath the retina, but injecting it directly into the vitreal jelly at the center of the eye still triggered significant inflammation. Intravitreal injection is important for tackling several conditions and for more broadly making ocular gene therapies safer and easier to deliver, as only eye surgeons can administer sub-retinally. The new paper, though, is just version 1.0 of the approach, Chan said, and they’ve come up with significant improvements since. More broadly, the field has a long way to go. Animal models, for example, are still poor predictors of the immune response in humans, making translation difficult and putting big holes in safety tests. A vector that appears immune-silent in monkeys could still trigger reactions in humans and vice versa. Although their role in animals is well-documented, it’s still not clear how great a role toll-like receptors play in the human response to AAV. Still, Chan says they accomplished what they set out to do: They improved the vector and, in the process, helped the field wake up to an issue that for years went overlooked. “There are still challenges,” Chan said. “What we really wanted to accomplish was to raise awareness, as well as come up with a promising solution. I would say we made progress on both fronts.”