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Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

Conference Insight

ISCT 2019 Commercialization Signature Series

Miguel Forte

ISCT staged its third Signature Series conference session at the Phacilitate Cell & Gene Therapy World 2019 event in Miami In January this year. Through these events, the ISCT provides the opportunity for the corporate membership to meet face-to-face, to network, and to discuss key topics and issues around which ISCT seeks to provide thought leadership on an ongoing basis.

DOI: 10.18609/cgti.2019.087
Citation: Cell & Gene Therapy Insights 2019; 5(5), 743-757.
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Introduction: Miguel Forte

The ISCT Commercialization Committee Signature Series, having now completed its 3rd edition in 2019, is becoming an established major event for the cell and gene therapy industry community.

The promise of cell and gene therapy products are now providing tangible value to patients as more and more products are gaining market authorization globally. The current reality requires us to deal with these great opportunities and challenges to enable the launch and adoption of cell and gene therapy products. This was well reflected in the topics of this year’s ISCT Commercialization Signature Series as we addressed “Patients First: Achieving Global CGT Adoption”

It is a good place to be as we discuss the commercial use of these products and start to see the benefit being delivered to a larger number of patients. Delivery of these products in the market has to deal not only with aspects of product development, production and distribution but also issues involved with market access in terms of reimbursement, physician and patient adoption. The text below highlights the presentations and discussions around these topics that took place at this year’s Signature Series, attesting to the excellent level of engagement of the ISCT industry community.

The Signature Series continues to represent a unique opportunity for ISCT industry members to network with key opinion leaders and address the defining issues in the field to develop strategies that drive the commercialization of advanced therapies for the benefit of patients. As an added benefit to the regular Commercialization Committee teleconferences, this event is an opportunity to have a lively discussion and deliver thought leadership in this exciting field. The title of this year’s event: “Patients First: Achieving Global CGT Adoption”, reflects the stage of the field, and focuses on addressing the challenges and opportunities of increasing numbers of products being used to treat patients in a regulated commercial environment.

These events are becoming recognized as a fun and productive opportunity to engage with peers, both academic and industry, in a face to face meeting where thought leadership discussions take place. I trust that these recurrent events and the written summary here delivered now will keep the members of the ISCT industry community fully engaged and eager to continue participation and membership. This will enable us to continue, within and beyond ISCT, to live up to our mission of facilitating the translation of cell and gene therapy products to patients with unmet medical needs.

ISCT Signature Series events provide the opportunity for the corporate membership of ISCT to meet face-to-face, to network, and to discuss key topics and issues around which ISCT seeks to provide thought leadership on an ongoing basis.

This past January, the ISCT staged a Signature Series conference session at the Phacilitate Cell & Gene Therapy World 2019 event in Miami. The focus was on 3 broad areas:

1. The business of cell & gene therapy: state of the financial markets
2. Getting the product to the patient: global manufacturing strategies
3. Overcoming cell & gene therapy adoption barriers: positioning clinical evidence and pricing models for success

The business of cell and gene therapy

Reni Benjamin, Managing Director, Senior Biotechnology Analyst, Raymond James Financial, Inc.
Dr Reni Benjamin provided the introductory Keynote, ‘Investors’ perceptions of the CGT space.

Dr Benjamin firstly reflected upon a tumultuous 2018 for biotech financial markets overall, strong performance and positivity over the first three quarters giving way to uncertainty and a downturn in Q4. However, the message was that overall, the biotech investment environment remains robust: 2018 saw both a record amount of cash injected into VC funds – some US$21 billion – and a record amount of IPO funds raised (although not from a record number of IPOs, suggesting that individual IPO funds raised were relatively high).

What factors are driving this investment?

  • An aging population and consequent rise in incidence of chronic diseases (it is estimated that by 2030, 50% of the US population will have one or more CDs)
  • Record amounts are being spent on R&D innovation but as a percentage of income, pharma is actually investing less and less in internal R&D efforts. The patent cliff is the key driver, sharpening focus on internal cost-cutting whilst building topline through increased collaboration and acquisition – good news for the biotech sector. M&A activity continued at quite robust levels in 2018 – about $100 billion in activity in total – and although this activity tends to ebb and flow naturally, there remained more than $500 billion cash readily available for deals at the end of the year.
  • Improving clinical development strategies and trial designs. More Phase 1 products are progressing to market than ever before.
  • An improved regulatory environment. Accelerated development pathways are generally panning out so far in their aim to drive innovation to market ad there were a record number of biotech product approvals in 2018. (A word of caution here, though: much credit for this was given to Dr Scott Gottlieb’s administration of the US FDA, which has of course since come to an end).
  • A continuation of the sector’s trend to not just focus on traditional, ‘big ticket’ markets and indications, such as the major cardiovascular diseases. Investment in technologies targeting orphan drug indications has remained high, for example, as the rare disease area has demonstrated its potential to generate significant revenues.
  • Positive newsflow: the high amount of M&A activity and positive clinical data readouts have driven valuation increases and bode well for the biotech sector overall.


Dr Benjamin stressed that markets are not just driven by these fundamentals, but by potentially more volatile, less predictable elements such as investor sentiment. Even so, despite the biotech space being in something of a trough currently, the fundamentals are in place to allow for a positive turnaround to occur through the course of 2019.

Regenerative medicine as an overall sector has performed exceedingly well over the past 5 years, rewarding investors with a 188% return overall during this period. In 2018, there was a positive return of about 19% overall, driven by key events such as Celgene’s acquisition of Juno Therapeutics and Novartis’s acquisition of Avexis. Additionally, several key approvals occurred in 2017/18 and sales of approved products started to outperform analysts’ and investors’ expectations, (especially YESCARTA). The VC investment trend continued upwards in 2018, there were 8 IPOs in the space for $1.2 billion total funds raised, and follow-ons were significant – close to $5billion in total gross proceeds (though mostly in the first 3 quarters).

However, Dr Benjamin pointed out that Wall Street splits regenerative medicine into 3 main areas and it is important to consider the performance of each of these individually:

1. Stem cells (eg. bone marrow, MSCs, etc.) The stem cell area did surprisingly well in 2018, boasting 17% growth – however, this growth is almost entirely attributable to the better-than-expected revenues achieved by one company – Vericel. Without this, the picture is less positive and overall, the past 5 years have seen a 50% negative return on investment in this particular field.
2. Cellular therapies (eg. CAR T cell immunotherapies). An astonishing 371% return over the past 5 years, including 41% in 2018, ensures investor interest and activity in this space will likely remain very high for the foreseeable future. $2 billion was raised in 2018 for CAR T cell therapies and other related approaches.
3. In vivo gene therapy (eg. AAV vector-driven gene therapy). Another huge success story in investors’ eyes, with a 310% return over the past 5 years. It was notable that the first half of 2018 was better than second half, with some negative impact from newsflow such as the Chinese CRISPR controversy. Overall, though, US$3.5 billion investment in 2018 was very positive.

In summary, Wall Street loves the regenerative medicine field overall, although the stem cell area is a significantly different story unless you have a product that is generating revenues. The maturing regulatory and vibrant M&A environments, and newly accelerated clinical development pathways are all major positives for investors. The following are aspects that investors find particularly exciting looking ahead to 2019 and beyond:

1. The amount of newsflow to come out. For example, ARM recently reported at JP Morgan that there are now over 1,000 clinical trials active in the space as of the end of 2018
2. Investors love the typically premium pricing of novel cell & gene therapies, which make even ultra-rare diseases a commercially viable proposition. While reimbursement is discussed a lot by investors, until there is really concerted pushback from payers, it will not be at the top of the list of investors’ worries. With that said, the likes of bluebird bio and Spark Therapeutics are wisely and strongly committed to discussing and developing potential new models.
3. The regulatory environment continues to look positive, with estimates from the FDA of 10-20 regenerative medicine approvals in 2019.

Again, a word of caution: the source of the above estimate was Dr Scott Gottlieb, who has since departed his role as Commissioner of the US FDA – a sign that even individual events can potentially impact investor confidence considerably. In reality, any of the above three aspects could prove to be a double-edged sword for the regenerative medicine field in 2019.

Dr Benjamin went on to discuss some of the key elements that can still scare Wall Street when considering a cell & gene therapy company investment:

  • Manufacturing. Novartis’s difficulties with Kymriah have driven this issue home of late.
  • The regulatory environment, although positive currently, can always swing the other way – it remains a point of concern for investors.
  • Clinical data and development approach/trial design.
  • Investment track record and cash reserves
  • The specific commercial opportunity always has to be spelled out to investors (even if you think you are going to sell your business before commercialisation, you need to be able to show investors you have done the work!)
  • Keen awareness of the competition is a must.


Audience Questions
Have you seen any trend in terms of the specific methods of financing changing since the downturn in Q4 2018? In a risk averse climate, investing is based mainly on equity – you will only really see a change in IPOs when there is a market downturn, although you might also see more alternative vehicles like reverse mergers appearing – pubic companies that have failed and have no real pipeline, but that are sitting on cash reserves, might become attractive sources of financing for small private companies that may look to reverse merge into those funds.

  • Reni:: For companies that have already gone public, the number 1 rule is that unless you are generating revenues, stay away from debt!

Do investors see the mooted high prices of immunotherapies as realistic?

  • Reni: Generally, investors are now quite used to this sort of pricing and the ever-increasing costs of these novel therapies that help to drive it. As mentioned previously, until they see any real pushback from payers, they will not be too concerned. Pharma and biotech does need to do a better job of communicating where there will be major cost savings to healthcare as a result of these disruptive products, however. It is up to pharma and biotech to remind not so much investors but Congress that if these therapies work, there will be really significant cost savings to the system in the long run.

SESSION 1: Getting the product to the patient: global manufacturing strategies

Chair: Derek Hei, Senior Vice President of Manufacturing, Quality & Regulatory, Bluerock Therapeutics
Presenters: Dan Shoemaker, CSO, Fate Therapeutics; Luca Alberici, CBO, MolMed; Amy DuRoss, CEO & co-Founder, Vineti; Simon Ellison, Cell & Gene Therapy Service Director, World Courier.

Session 1 was wide-ranging, exploring manufacturing strategies for both autologous and allogeneic cell & gene therapy products, as well as the issues and challenges on the minds of developers as they progress towards commercialisation

The rise of gene-edited allogeneic cell therapy approaches

Clearly, manufacturing and CoGs issues remain with autologous approaches, a key reason for which is the requirement to work with generally low quality, variable starting material from patients. While allogeneic approaches remove issues presented by unhealthy donors and offer potential Cost of Goods benefits, challenges remain – for example, in terms of the need to genetically manipulate a very heterogenous set of cells derived from different donors.

Fate Therapeutics’ approach, where the NK cells are derived from an iPSC stem cell line, served to illustrate allogeneic cell therapy’s potential to address such obstacles; an unlimited cell source producing NK cells that are highly amenable to complex gene editing strategies results in a very uniform starting material. Looking to the future, gene editing also holds the key to migrating such approaches into solid tumours by helping to overcome challenges presented by the tumor microenvironment.

Outsourcing vs. manufacturing in-house

With over a thousand cell & gene therapy clinical trials currently underway around the world, manufacturing capacity limitations are a very real obstacle to progress in the sector. The fact that the majority of current cell therapy approaches are autologous in nature exacerbates this problem and will lead to bottlenecks.As both an in-house novel cell therapy developer and a CDMO, MolMed offered insights and “do’s and don’ts” on either side of the outsource vs. in-house equation: close networking with raw and starting material suppliers is key, as is securing a second source of critical materials to ensure supply chain robustness; keeping analytics development in-house is key given the complexity of cell & gene therapy products.Perhaps the single greatest challenge at this point in time is that most early phase trials still use academic manufacturing centers, which can raise both quality and capacity issues. CMOs/CDMOs are working hard to bridge the quality gap to commercial production, and to add significant, much-needed capacity.

The critical importance of manufacturing and supply chain standardization

Standardization can only occur when the connection points in a cell & gene therapy supply chain are made and cemented with robust partners.Companies such as Vineti, which provides a manufacturing and delivery standardization software solution to automate workflows around chain of identity, chain of custody and chain of condition, are key to ultimately extending cell & gene therapy’s access to more patients. It is important to note, however, that this is not solely a challenge that belongs to autologous products – allogeneic products will also require the same kind of supply framework.An important issue of current concern is the lack of standardized labelling across different supply chain and manufacturing steps and territories. There is now a concerted effort to push for globally standardized label sets.

Are we really ready to launch CGT products in logistical terms?

Logistics in the cell and gene therapy space is the critical connection between manufacturing and patients. It is evolving rapidly with World Courier for example now delivering advanced therapies to over 2,000 clinical sites, globally. However this growth brings challenges such as not all dewars fit on all flights, or the need to maintain airline security whilst avoiding x-ray exposure.

These challenges are being proactively overcome, but planning is key to ensure robust logistics platforms are created. To support this planning, two key points were offered:

    1. Apply a Logistics by Design framework. This creates a risk-based analysis of a planned supply chain and enables therapy developers to build, test and optimise their logistics platform through clinical trials, ready for commercial launch;
    2. Utilize your logistics vendors as experts – they have been doing it for years.

Audience Questions

How are we going to cope with the proliferation in products coming to market in terms of the various demands on capacity, logistics, raw materials and scale-up?

The major current drive towards allogeneic products will drive more efficient, effective scale-up. Once the biology is locked down, the prospect of a move towards controllable manufacture is an exciting one.A key challenge is that people continue to operate in silos and are still not communicating with each other sufficiently. Standardization is a part of the solution, especially around data and logistics to streamline systems.Technology improvements are needed – for instance, to further enable vector production scale-up. However, in cell processing where the process ideally needs to be closed and automated, it will be more difficult to achieve. There are simple methods available to standardize manufacturing sites and make them more professional, such as creation of a one-stop-shop web portal for key supply chain items. Simplification is the key.

SESSION 2: Overcoming cell & gene therapy adoption barriers: positioning clinical evidence and pricing models for success

Chair: Professor Gerhard Bauer, Director of the UC Davis Institute for Regenerative Cures’ Good Manufacturing Practice
Presenters: Dr Richard Maziarz, Medical Director, Blood & Marrow Transplant & Cellular Therapy Program, Oregon Health and Science University
Professor Mehrdad Abedi, Physician, Division of Hematology and Oncology, University of California Davis
Peter Olagunju, Vice President, Global Patient Operations, bluebird bio

This session focused on challenges beyond manufacturing and the supply chain: how will we ensure that cell & gene therapy products will actually benefit patients in the commercial setting? Pricing and reimbursement are clearly front and centre in this discussion, but there is also much to be done in terms of educating clinicians regarding product administration, and hospital staff in general regarding product handling as well as ongoing patient monitoring requirements for these ‘living drugs’.

Is the market prepared to adopt cell & gene therapies? A clinician’s view

US$1.3 trillion is spent per annum on healthcare in the US. 20% of this is spent on 1% of patients, with 50% overall spent on 5% of patients, promoting the questions of when do you treat a patient, and with what? Waste in US healthcare delivery (defined as healthcare services that do not add value or improve an outcome) is high – some US$750 billion per year of healthcare delivery could be optimised – and pricing failure (where price is higher than the value of a therapy) is a major contributor to this. But who decides what constitutes ‘value’? The issue is that it’s very much in the eye of the beholder.

Dr Maziarz pointed out that recent ICER assessments that compared CAR T cell immunotherapy to standard drugs in terms of quality-adjusted life years (QALY) produced results that ranged from high value in paediatric indications to only just qualifying for the pharmacocopiea in adult large cell lymphoma.

From the clinician’s point of view, it is important to look at the break-even point for a therapy. At the local level, you have to be aware of the payer pool – is it private (therefore pre-authorisation is allowed) or government? Is it outpatient vs. in-patient? Only the sickest of the sick will break even with in-patient care due to bundling.

Is the market prepared to adopt cell & gene therapies? A physician’s view

Overall, public perception of gene therapy is still quite negative. However, desperate patients are beginning to ask for gene therapy options and increasingly, patients look on regenerative medicines as ‘alternative therapies’ versus traditional drugs, which they often view as poison. Patients are becoming more familiar with the field, but there are still battles to be fought – for example, against the stem cell clinic ‘bad actors’, which will hurt the whole field. Academia needs to play a bigger role in fighting this threat, alongside the FDA.

Professor Abedi commented that high cell & gene therapy prices do not particularly matter to him as a physician due to the fact that:

    1. These are curative products, and
    2. Prices will drop eventually.

Provenge was also expensive but offered minimal efficacy, and yet it was still prescribed and reimbursed. For Medicare and Medicaid, if you are cured and can still pay insurance fees, it will make economic sense in the long run, and the cost of chronic disease drugs over the course of a lifetime will only go up. A one-time, curative approach can still be cost effective if it spares a lifetime of treatment with increasingly expensive chronic disease interventions.

Are we ready for commercial cell & gene therapy today? We need infrastructure, but we have been doing things like stem cell transplants and cell/blood banking for a long time – there are structures and expertise that can be leveraged. Models such as that employed by the Alpha Clinics, where networks of clinics maintain an infrastructure which allows them to run multiple trials with large numbers of patients entirely in-house, point to the future.

How to optimise the patient’s experience? An industry perspective

Providing integrated, personalised support at the point of care will be a crucial differentiator in cell & gene therapy. Mr Olagunju shared some keys to achieving this:

  • Know who your stakeholders are: they are the patients, but also various healthcare providers and patient family members, too – this is a key differentiator not just for clinical outcomes but also uptake.
  • Understand how you can augment existing hospital systems: what are their needs? How to create a seamless, integrated support system? How to communicate in real-time with a hospital or institution to confirm a schedule for an individual patient in a streamlined, efficient process? (Avoiding stalls in the patient pathway is an important a cost saver).

Focusing on apheresis collection, it is clear that variability patient-to-patient is key. Bluebird bio has focused on apheresis collection centres to try to address this issue, creating a genuinely circular supply chain rather than a linear one. Phenotyping, collection counts, process yields… sources of variability can be numerous. Some are cell/patient-based but others, including the individual apheresis technician, the collection technology or the bioprocess technology, can be more easily mitigated. Co-developing best practices with collection centres and collaborating with apheresis companies to customise protocols is crucial.

bluebird bio maintains no fewer than eight apheresis nurses on internal staff purely to support those apheresis nurses at the centres who are doing the actual collections. They have identified ‘moments that matter’ and educate the collection centres and nurses about these. They are present at first collection to hand-hold. It is important to realise that these centres may be dealing with 50 different clinical protocols at any one time, so this hands-on approach is vital. The nurses are seen as the face of bluebird bio at these collection centres and they spend 8–10 hours with a patient – bluebird bio needed to invest heavily in this aspect and have done so. Their goal is to create a ‘white glove experience’ for all their stakeholders, using IT systems for support and integration where necessary. Ongoing training and education will also be key.

Audience Questions

Are Medicare patients gaining access to the approved CAR T cell immunotherapies in practice? Is financial engineering working in that context?

  • Yes, MediCare patients are getting CARTs and centres are trying to do this in the outpatient setting.
  • Some centres are restricting CART to commercial-only and not managing Medicare. Some centres are treating Medicare patients but are saying there is a ‘drift’ from trials – those centres are saying the Medicare patients have to fully meet the requirements to qualify for a CART clinical trial.
  • Medicare is being heavily lobbied by ASH, ASCO and others about moving up their process. In the in-patient setting, there has been a plea for the drug cost to be a ‘pass-through’, but it is not the case at the moment. The product that has the safety profile to allow outpatient treatment is likely to win at the moment, even if it is not as efficacious as a competitor which must be given as an in-patient intervention.

The 2019 Commercialization Signature Series is supported by ISCT Industry Patron and Partner Members:

The 2019 Commercialization Signature Series AttendeesMehrdad Abedi, University of California Davis, Sacramento, CA, United States Behnam Ahmadian Baghbaderani, Lonza, Houston, TX, United States Luca Alberici, MolMed, Milan, Italy Julie Allickson, Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States Nina Bauer, BioInsights, London, United Kingdom Gerhard Bauer, University of California Davis, Sacramento, CA, United States Reni Benjamin, Raymond James & Associates, New York, NY, United States Bryan Choi, Strategic Center for Regenerative Medicine, Seoul, Korea (South) Albert Cooksey, ICS Connect, Dallas, TX, United States Amy Duross, Vineti, San Francisco, CA, United States Simon Ellison, World Courier, London, United Kingdom Mark Flower, Be The Match BioTherapies, Minneapolis, MN, United States Miguel Forte, Zelluna Immunotherapy, Rixensart, Belgium Maya Fuerstenau-Sharp, Sartorius Stedim Biotech, Goettingen, Germany Philip Gotwals, Novartis, Cambridge, MA, United States Namir Hassan, Zelluna Immunotherapy, Oslo, Norway Derek Hei, BlueRock Therapeutics, Madison, WI, United States Matt Hemstreet, Terumo BCT, Lakewood, CO, United States Tamie Joeckel, Vineti, San Francisco, CA, United States Robert Jones, Cryoport, London, United Kingdom Lisa Kretzschmar, FUJIFILM Irvine Scientific, Irvine, CA, United States Sandy Kuligowski, Thermo Fisher Scientific, Grand Island, NY, United States Bruce Levine, University of Pennsylvania, Philadelphia, PA, United States Ainslie Little, BlueRock Therapeutics, Toronto, ON, Canada April Lynch, Vineti, San Francisco, CA, United States Nuno Madeira do Ó, Cell & Gene Therapy Catapult, London, United Kingdom Aby J Mathew, BioLife Solutions, Inc., Bothell, WA, United States Richard Maziarz, Oregon Health & Science University, Portland, OR, United States Chris McClain, Be The Match BioTherapies, Minneapolis, MN, United States Ruth McDermott, Sartorius, Royston, United Kingdom Bill Milligan, Steminent Biotherapeutics, Vancouver, BC, Canada Jennifer Moody, BlueRock Therapeutics, Toronto, ON, Canada Delara Motlagh, Terumo BCT, Lakewood, CO, United States Mara Neal, Cook Regentec, Indianapolis, IN, United States Benjamin Nelson, Fresenius Kabi, Lake Zurich, IL, United States Peter Olagunju, bluebird bio, Cambridge, MA, United States So Ra Park, SCRM, Seoul, Korea Brian Poole, ISCT, Vancouver, BC, Canada Patrick Rivers, Aquilo Capital, San Francisco, CA, United States Christian Rouldan, HCATS, Allendale, NJ, United States Dan Shoemaker, Fate Therapeutics, San Diego, CA, United States Nathan Smith, Cell Therapies Pty Ltd, Melbourne, Australia Madeline St. Onge, ISCT, Vancouver, BC, Canada Phil Vanek, GE Healthcare – Life Sciences, Marlborough, MA, United States Scott Wolkcho, Fate Therapeutics, San Diego, CA, United States

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