Overall, we’ve seen and heard big predictions for advanced therapy approvals and INDs. In fact, at the beginning of 2019 the FDA commissioner at the time, Scott Gottlieb, predicted the agency would be receiving more than 200 INDs per year by 2020 and approving 10-20 cell and gene therapies a year by 2025.
CAR-T therapies, specifically, have gone from zero to hero in an incredibly short period of time. Back in 2011/12, the team at the University of Pennsylvania (UPenn) working on what was to become Kymriah could only get enough funding together to run clinical trials on three patients. Due to the alliance with Novartis and some incredible outcomes data later, CAR-T trials and funding have exploded.
In reality, we’ve still not seen this promise translate to an influx of new therapeutics. The advanced therapies industry has seemingly stalled and not gathered the expected momentum. 2019 saw just two approvals (Zolgensma and Zynteglo) and Takeda’s Alofisel was ‘approved to a certain extent’ by the EMA.
This is coupled with many challenges accompanying the approvals we have seen in recent years. Zolgensma’s success has been overshadowed by data inaccuracies. In addition, Health Technology Assessment bodies have refused or delayed recommending several products and various manufacturing setbacks have delayed other launches and to provide sufficient market supply. A pertinent example of which is Kymriah®.
Ever since Kymriah was approved by the FDA in August 2017, this expensive and difficult-to-manufacture cell therapy has given Novartis many challenges despite hopes it would result in blockbuster sales. Back in a 2018 Q2 investor call, Novartis confirmed that it was facing out of specification production issues that have since plagued the commercial success of Kymriah.
One of the reasons for this could have been the fact that Novartis was the first big pharma to get cell therapy to commercial approval in the US; they had to create multiple procedures and protocols specific for cell therapy within the company to complete the launch and manage a highly complex supply chain. Besides, challenges in establishing appropriate release specifications for the final product may have also been impactful.
In contrast, Kite is a much smaller and dynamic biotechnology company, that appears to have more easily adjusted to cell therapy manufacturing requirements.
Anne Kerber, Vice President, Head of Clinical Development, EU, at Kite, a Gilead Company, shares her experience of developing in-house manufacturing to ease the major bottleneck of manufacturing associated with CAR-Ts.
“In cell therapy, clinical advances are closely tied to innovations in manufacturing. Kite’s focus on in-house manufacturing has helped us scale our commercial and clinical operations without sacrificing the level of excellence required, which has allowed us to have more control over the process from early development through to commercialisation.
Our European manufacturing site in the Netherlands will be key for our ability to manage global clinical trials in Europe, and in partnership, we can manage the ongoing trial supply for Yescarta (axicabtagene ciloleucel) and pipeline products, including end-to-end manufacturing in Europe of Axi-cel.
Another example of this is our facility under construction in Oceanside, California, in the U.S, which will be dedicated to the development and manufacturing of viral vectors. Viral vectors are a critical starting material in the production of cell therapies and will complement our commercial and clinical facilities. Pursuing our own viral vector capabilities will allow for accelerated process development of current CAR T and future pipeline therapies. This type of vertical integration is key for us as we progress our clinical pipeline.”
All of this illustrates that CAR-Ts and other advanced therapies are very challenging to manufacture and bring to market. Not only that but we must now also consider, what impact Covid-19 will have on pending approvals, future approvals and pipelines overall?
This article will explore the current CAR-T landscape, commercialisation barriers and some technology-based solutions.
A closer look at the CAR-T landscape
Let’s examine the clinical pipeline more closely, we will need to apply some assumptions, as data does not always specify which trials are CAR-T but we can get a snapshot of current activity.
The headlines are that there are currently 625 cell therapy and 496 gene therapy companies worldwide. In 2019, cell therapy companies raised $5.1bn, whereas gene and gene-modified cell therapy companies raised $7.6bn.
According to clinicaltrials.gov there are currently 1,114 CAR-T trials worldwide with the majority in early phases and either taking place in the USA or China. A more detailed analysis follows:
- 627 in early phase I or phase I
- 310 in phase II
- 38 in phase III
- 29 in phase IV
Table 1. Regional CAR-T trials, source: clinicaltrials.gov, please note that studies with multiple locations are included in each region containing the location
In terms of this pipeline coming to fruition, there are two CAR-T products nearing approval, two nearing filing and five in regulatory fast track pathways:
- Nearing approval
- BMS’s lisocel for large B cell lymphoma – FDA
- Kite/Gilead’s KTE-X19 for mantle cell lymphoma – FDA and EMA
- Nearing filing
- Bluebird/BMS’s ide-cel for multiple myeloma – FDA
- Poseida Tx’s P-BCMA-101for mantle cell lymphoma – FDA
- Currently in fast track regulatory pathways
- RMAT: 1 CAR-T out of 11 products (CARsgen’s CT053)
- PRIME: 4 x CAR-Ts out of 10 products (BMS’s JCAR125 | Miltenyi’s MB-CAR2019.1 | CARSgen’s CT053 | Janssen’s JNS-68284528)
Will this increase in new biotechs and phase I and II trials truly translate through to treatments for patients? It may be a premature moment to really answer this question, but we can see some positives and relative progress, plus a lot of promise in early clinical pipelines.
However, there are challenges in getting to market and getting therapies to patients after approval, which could be attributed to some significant bottlenecks, such as logistics of individual patient dose manufacturing, raw material back-logs, inefficiencies in production and challenges in optimising the already approved processes.
Usman Azam, President and CEO at Tmunity Therapeutics gave us his thoughts on what needs to be done to ease CAR-T clinical bottlenecks.
“With the growing arsenal of tools and enablers (e.g. single-cell RNA, nanostring technology), an urgent focus on decoding the microenvironment using these enablers and really characterising why T-cells work or don’t in certain patients is critical to optimising clinical outcomes, especially in solid tumours.”
So, perhaps a timelier question is "what next…?"
Continuing to evolve
What is the next major hurdle the industry should be focusing on in order to improve and innovate around CAR-T manufacturing?
Dr Bruce Levine, Barbara and Edward Netter Professor in Cancer Gene Therapy at the University of Pennsylvania commented:
"If we're going to see the potential of CAR-T therapies that is currently in clinical pipelines realised as therapies that are available to patients globally, our industry needs a combination of factors that includes manufacturing improvements but also concerns the wider infrastructure of the industry.
We need trained, expert talent at all levels, potency improvements for solid tumour applications and more patients to be treated with allogeneic approaches to show potency. The same is true for iPSC.”
The need to economically embed flexibility into CAR-T manufacturing is paramount, especially to be able to scale up or scale out as needed. Collaboration is a key characteristic of the advanced therapies industry, so what can we expect from across the ecosystem of biotechs, tools providers, bioprocessing experts and more?
Louis van de Wiel, Vice President, Site Head, EU Manufacturing at Kite, a Gilead Company, expands on how his team have innovated and worked together to improve the flexibility of CAR-T manufacturing.
“At Kite, we continue to set the bar in manufacturing, with a rapid, reliable median 29-day turnaround time from leukapheresis to product release of Yescarta in Europe. The challenge for us – and for the industry as a whole – is to scale that level of manufacturing excellence as everyone continues to become more global. We’ve been able to continue to increase the scale of our response to patient needs with the recent European approval of our manufacturing facility in the Netherlands.
Cell therapy manufacturing is a ‘team sport’ because of the close partnerships across functions and the speed at which we need to move. Cross-functional work is essential to maximising flexibility and continuing to innovate. At Kite, the relationships that our tech ops team built with our clinical research and process development team early on laid a strong foundation for execution and innovation. If the initial strategy is built right, the leap into the clinic and then into commercial is much more straightforward. This process has been successful with our currently approved cell therapies, as well as other products currently in the clinic. By working together cross-functionally, cell therapies can be brought faster to patients.”
Another crucial piece of the puzzle is the technology and manufacturing community. The right kind of innovation here requires collaboration.
One such manufacturing leader, WuXi Advanced Technologies (WuXi ATU), has recently developed a fully integrated closed CAR-T cell therapy platform with the aim to help accelerate the timeline for cell and gene therapy development, manufacturing and release while providing greater predictability.
We asked Tatiana Golovina, who is the Senior Director of Cell Therapy at WuXi Advanced Therapies what tech and tools providers can do to help innovators ease CAR-T bottlenecks and progress clinical pipelines.
“Genetically modifying T-cells with Chimeric Antigen Receptors (CAR)s is currently the most popular approach to manufacture tumour-specific T-cells. However, these therapies carry high clinical safety risks which depend on many factors, such as cell therapy technology types, manufacturing process and product characteristics with many cell-based therapies being highly experimental. Therefore, there is a need in the field for platform development to ensure manufacturing processes consistency, predictability and product control, to decrease the cost of manufacturing, enable manufacturing scalability and automation, secure raw material supply and build sufficient and cost-efficient testing systems. WuXi Advanced Therapies’ closed CAR-T platform is an ‘equipment vendor blind’ combination of ‘industry-leading in the field’ methodologies and off-the-shelf characterised materials.”
WuXi Advanced Therapies, as a CDMO, is world-class to provide a fully integrated solution for clients who may not have certain or all CMC capability. In other words, clients could just bring their gene of interest to WuXi ATU, and then WuXi ATU could leverage established platforms and production and testing capabilities to produce, test and release plasmids, viral vectors and CAR-T drug products in a timely manner to fulfil the clients' different phases of clinical and commercial demands. In addition, the established CAR-T centres of excellence in both US and China, where predominant CAR-T product developments are taking place, can also readily support Innovators locally in the US and China.
 Source: Alliance for Regenerative Medicine Annual Report & Sector in Review Report https://alliancerm.org/sector-report/2019-annual-report/