Cell, gene and RNA therapies have been widely adopted by the major pharma players. While their growth is tremendous (52% CAGR up to 2026), they will only account for up to 7% of total market size by 2026. 

The US Food and Drug Administration’s (FDA) website currently references 23 approved cell and gene therapies, including six CAR-T products, the most recent of which was Johnson & Johnson Carvykti for multiple myeloma. (Also see “Janssen/Legend Plan Phased US Launch For BCMA-Targeting CAR-T Carvykti” – Scrip, 28 Feb, 2022.) Other advanced modalities, such as RNA therapeutics, were at the center of the COVID-19 pandemic with up to $50bn in sales reported in 2021 for Pfizer Inc.’s and Moderna, Inc.’s messenger RNA (mRNA) vaccines. 

Reflecting their transformative nature, the 52% CAGR forecast over the next five years for advanced modalities is the highest across all approaches (from $7bn in sales in 2021 to around $57bn in 2026), see Exhibit 2. Nonetheless, small molecules are still predicted to
account for 44% of the total pharmaceutical market. Traditional modalities including antibodies are unlikely to be replaced any time soon.

Unsurprisingly, the mRNA COVID-19 vaccines are still predicted to dominate (even though their sales are expected to come down to $11bn in 2026), followed by Novartis AG’ PCSK9 siRNA Leqvio, the AAV9-based gene therapy Zolgensma,and the newly approved CAR-T Carvytki.

Looking at today’s net present value (NPV) for assets with value up to $2bn, 10 out of 24 are not yet approved or marketed. Some are expected to bring novel modalities to the market, CRISPR Therapeutics AG’ CTX001 for example, along with Crispr/Cas9 gene-edited cell therapy targeting BCL11A for sickle cell disease, Intellia Therapeutics, Inc.’s NTL-2001 an in vivo application of CRISPR for the treatment of transthyretin-related hereditary amyloidosis, Fate Therapeutics, Inc., Inc.’s natural killer (NK) cell therapy FT516, and red blood cell therapeutics such as those used by Rubius Therapeutics, Inc.’ RTX240.

Adoption Of Advanced Modalities By Top 18 Biopharma Companies

The top 18 biopharma companies have already placed heavy bets on those novel modalities. All the major pharma players are actively pursuing them through their BD activities, with a range of four to twelve advanced modalities identified. One limitation of the analysis is that many biopharma companies have also built internal groups limiting systematic analysis as data is not publicly available. Novartis, Takeda Pharmaceutical Co. Ltd., and Roche Holding AG appear to lead the pack when it comes to diversification of investments.

Adoption of RNA technologies is wide. Deals among the top 18 were identified for 12 companies when it comes to mRNA alone and 16 out of 18 have deals in place when it comes to small interfering RNA (siRNA) vs antisense oligonucleotides (ASO) where deals were only identified for 11.

For mRNA, following the massive success of COVID vaccines the next step will be to unlock the cancer vaccine space as these are ideal combo partners for classical immune-oncology drugs such as checkpoint inhibitors or CAR-T cells. Roche and Sanofi have partnerships in place with BioNTech SE to develop mRNA cancer immunotherapy candidates. Merck & Co., Inc. also had struck a deal with Moderna back in 2018 but more recently cut ties for the early phase KRAS vaccine. For siRNA, Novartis finalized the acquisition of The Medicines Company for $9.7bn in 2020 for its PCSK9, Leqvio, approved in 2021 with peak sales expected above $4bn.

More recently, Novo Nordisk A/S acquired RNAi platform company Dicerna Pharmaceuticals, Inc. for $3.3bn in November 2021, following a broad collaboration agreement focused on liver targets initiated in 2019. For ASOs, most of the deals identified were in connection with Ionis Pharmaceuticals, Inc., which recently claimed a PCSK9 win after suffering multiple setbacks over the last year and a half. By contrast, big pharma companies seem to have dropped out of the miRNA space, a class of small non-coding RNA molecules, responsible for RNA silencing and post-transcriptional regulation of gene expression.

While miRNA was in development for the last two decades with deals in early 2010s, the technology faced technical hurdles when it came to delivery and dosage. The GlaxoSmithKline Pharmaceuticals Ltd. and AstraZeneca PLC alliances with Regulus Therapeutics Inc. were terminated in 2015 and 2017, respectively. Regulus also had a co-development deal with Sanofi in June 2010 but was forced to hand it over to Sanofi back in November 2018 for a small down payment of $7m and $40m of potential milestones. A few players are left in the field but overcoming technical hurdles will be essential before big pharma companies show interest again.

Cell Therapy Gains Momentum But Some
Players Stay Away

Fourteen of the top 18 biopharma companies have deals in place for CAR-T. Two large acquisitions were observed in the space: Gilead Sciences, Inc./Kite Pharma, Inc.for $11.9bn and Celgene Corporation/Juno Therapeutics Inc. for $9bn. Interestingly, an additional barrier was just cracked in April 2022 with Gilead’s Kite scoring a landmark approval for Yescarta in second-line treatment for lymphoma, roughly doubling the market size in US. The challenge for cellular therapies is access to earlier lines of treatment due to their challenging safety profiles.

Before its acquisition of Juno Therapeutics in 2018, Celgene had already invested $1bn upfront in a 10-year agreement with the firm. Novartis built internal capabilities at first by partnering with the University of Pennsylvania back in 2012 for a seven-year R&D alliance
that resulted in the approval of Kymriah in August 2017. These deals struck early on can help gain internal knowledge on those complex technologies and provide a foundation for BD activities when reviewing new platforms, assets, or M&A.

The next frontiers for cell therapy will be the establishment of allo-CAR-T (with or without edits) and advancement into solid tumors. However, the allo-field has also been plagued by clinical holds. For example, Allogene Therapeutics Inc.’s clinical hold due to chromosomal abnormalities observed was eventually lifted in January 2022, and Celyad Oncology SA had to put clinical studies on hold for its NKG2D CAR T cell, CYAD-101, after the deaths of two patients with similar pulmonary findings. Notably, a few players have not made any major deals in the space including Biogen, Inc., Boehringer Ingelheim GmbH and AstraZeneca. Possibly in part because the advances of the field, which is now extremely competitive, are complex to navigate and require internal expertise. In addition, manufacturing and commercial challenges are still a hurdle. Other companies might also have placed bets on alternative modalities such as bispecific antibodies, a modality more familiar to large antibody companies. Bispecifics share similitudes to CAR-T since they also target lymphocytes and other immune cells to redirect them to specific antigens on solid or liquid tumors, but the targeted patient population might differ due to considerations around their safety profile and potency. Amgen, Inc.’s Blincyto, the first CD3 T cell engager (BiTE), was approved back in 2014 ahead of Kymriah, a CD19 CAR-T in 2017.

While deals in the TCR-T space were identified in 10 out of 18 companies, there was no major acquisition even though the first TCR-T cell therapies are already advanced. Adaptimmune Therapeutics plc’s afami-cel has revealed positive interim data and the company is looking
to submit registration in 2022, with peak sales expected below $200m due to its initial focus on rare cancer. Adaptimmune has a collaboration with Genentech, Inc. on five targets but also deals with Astellas and GSK. A landmark in the field of TCR therapies was also achieved in January 2022, with approval of the first TCR from Immunocore, Ltd.’s tebentafusp for uveal melanoma, an reminder that alternative modalities directly competing with cell therapies exist.

CAR-NK is an emerging modality with Phase II data showing response rates comparable to CAR-T with a cleaner safety profile. As NK cells do not express a T cell receptor and will not elicit graft-versus-host responses going allogeneic is easier than with CAR-T, whereby modifying or knocking out the TCR first is required. While questions remain on durability of response, there might be opportunities for multiple dosing. The last three years have seen several big pharma (Bristol Myers Squibb Company, Janssen Pharmaceuticals Inc., Merck and Sanofi) engaging with CAR-NK partners. Nkarta revealed its first clinical data for its off-the-shelf NK cell therapies in April 2022. SC146277. Among five AML patients who received three doses of 1 billion or 1.5 billion NK cells, three complete responses were observed. Nkarta’s stock more than doubled on the news.

For all the modalities previously discussed, a significant effort is also ongoing to boost cGMP production facilities both within pharma and the CDMO industry.

In Vivo Setbacks

CAR-T cell manufacturing protocols are usually based on ex vivo viral transduction followed by T cell expansion and activation steps. The fact that we have currently six approved CAR-T products is a testimony to the maturity of ex vivo gene therapy.

For gene editing, the top 18 biopharma companies have not fully embraced the technology yet – less than half have deals in place and no major M&A has taken place. This may be because intellectual property around gene editing is controlled by a limited number of players and the existing deals are often exclusive for specific therapeutics areas.

Bayer AG invested early by establishing a joint venture with CRISPR Therapeutics, Casebia, which focuses on hematology/autoimmune diseases. (Also see “Bayer Bids To Be A Winner In Cell & Gene Therapy” – Scrip, 8 Dec, 2020.) Bayer invested €300m and had opt-in rights for two products at IND submission. The management of Casebia was handed over to CRISPR in 2019. Novartis, Gilead, Pfizer, and Biogen signed up with Sangamo for its Zinc Finger Nuclease (ZFN) based approach. The first generation of gene editing (CRISPR/CAS9, ZFN, megaTAL, ARCUS) approaches in vivo has reached Phase III with CRISPR’s CTX-001 in sickle cell anemia, which is anticipated to become a blockbuster.

While the majority of the top 18 companies also had deals for AAV-based therapies, recent events have highlighted the limitations of the technology. AAVs are currently dominating the field of vector-based in vivo gene therapy, with deals made by Novartis, Roche, Astellas and Bayer within the last four years. (Also see “Novartis Goes Big On Gene Therapy With $8.7bn AveXis Acquisition” – Scrip, 9 Apr, 2018.) (Also see “Roche $4.8bn Buy Sparks Hemophilia Gene Therapy Race “ – Scrip, 25 Feb, 2019.) (Also see “Bayer Boosts Gene Therapy Presence With AskBio Buy” – Scrip, 26 Oct, 2020.) (Also see “Astellas To Pay $3bn For Gene Therapy Company Audentes” – Scrip, 3 Dec, 2019.)

The field is currently at a crossroads due to the multiple safety signals observed in recent years leading to clinical holds, patient deaths and the promise of what was once “one and done” disappearing.

Delivery And Targeting

When it comes to in vivo application, for mRNA and in vivo gene therapy, the pipeline is primarily centered around liver, eye, CNS and musculoskeletal with LNPs and AAVs traditionally used as delivery systems. Expanding to new therapeutic areas requires solving two challenges:
spatial localization and targeting of specific cells. In addition, physical limitations render some organs less amendable to targeting. Optimization efforts of AAVs and LNPs are currently on-going, including novel approaches based on active targeting.

Unlocking The Solid Tumor Space

In the case of cell therapies, most of the successes so far have been in hematological malignancies. Unlocking the solid tumor space will require the cells to reach the site of the tumor, overcoming a hostile environment and finding highly cancer-specific targets to minimize on-target, offtissue toxicities.

Safety

Applications of RNA therapeutics for diseases with high prevalence have been demonstrated. However, for mRNA most applications outside vaccines will require repeat dosing and the safety has not yet been cleared for that.

In the gene therapy space, multiple companies have seen clinical holds recently due to abnormal findings, toxicity concerns or deaths in clinical trials When it comes to gene editing, the FDA recommends at least 15 years of long-term follow-up after product administration and monitoring of any off-target editing.

For CAR-T, severe toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have been the major cause of concern but can be managed much better now with anti-IL6 and are generally not viewed as major obstacles anymore for those targeting CD19 or BCMA. Safety due to on-target off-tissue expression can be a formidable challenge especially in solid tumors. For
example, expression of oncogene Her-2 is specific enough for antibodies but for CAR-T a massive cytokine storm in an undesired tissue or organ can quickly turn out to be fatal. Therefore, the mantra in this field has been “dose low – go slow”.

Common Diseases

Gene editing and gene therapy have yet to successfully penetrate the common disease market. Given the current price of the existing gene therapies, as we extend to high prevalence diseases, how long can the system sustain such price policy and where is the breaking point? In addition, the larger market will require to address multiple genes/disrupted biological pathways at the same time, requiring combination therapies or novel approaches.

When it comes to in vivo gene therapy or gene editing, is the vision of application as cure for non-life-threatening complex diseases even realistic in the mid-term? The safety, delivery and multiplexing requirements makes it currently a long-term vision. There could be some indications where gene therapy might leverage existing products and act as a replacement. Of particular interest would be to monitor Regenxbio Inc.’s RGX-314 for wet AMD, pushing with AbbVie Inc. the vision of “one and done” version of Eylea. But even there, the safety concern is strong.

Manufacturing

Manufacturing challenges span across the different modalities – upscaling LNP production has been a significant issue during the COVID-19 pandemic, and gene therapy with AAVs have been hindered by the presence of empty capsids that makes dosing in clinical trials more challenging. Logistics and costs associated with an autologous CAR-T approach are also a hurdle preventing broad adoption. There is currently a shortage of manufacturing capacity and the CDMO industry has a long waiting time before taking on new projects.

Knock-Out For Gene Editing

The CRISPR system is based on a defense system against bacteriophage infection that allowed the bacteria to produce RNA segments that attach to specific regions of the infecting DNA and cut it into pieces. Therefore, the system has been fundamentally evolved to perform knock outs. Precise knockins remained challenging with low efficiency, but a new generation of gene therapy/gene editing technologies is in active development ranging from nuclease free approaches to base editing and large insertion, via gene writing.

Long-Term Expression

The long-term data from AAVs indicate a loss of potency over time, which was one of the concerns for BioMarin Pharmaceutical Inc.’s Valox in hemophilia, where factor VIII levels seemed to decline over time. This has also implications when it comes to pricing of those therapies given that we might not be in a “one-and-done” scenario, and the presence of neutralizing antibodies makes repeated dosing challenging. In addition, in pediatric diseases, since cells are dividing, integration will likely be required.

Persistence of CAR-T cells has been a significant limitation as well. For example, in the case of B-cell acute lymphoblastic leukemia (ALL) approximately half of all patients, following anti-CD19 or anti-CD22 CAR-T cell therapy, relapsed within 12 months. CD19-positive relapse is also driven by CAR-T cell exhaustion, immunogenicity against CAR-T, essentially impacting the ability of the cells to remain and do their job.

Implications For Biopharma

Investment into novel modalities is by nature a risky business and this is especially true when it comes to advanced modalities which contain a myriad of subelements to optimize and require keeping up with the atest innovations. Support and understanding at the
highest level of the organization is required to push it forward. Moreover, success requires internal expertise to make multiple educated investments, as a one-off deal is not sufficient. For collaborations, the ability to develop projects somewhat independently without the constrains of the parent organization’s objectives also seem an essential factor.

There are still opportunities when it comes to novel modalities including:
• new cell types (γδ T cells, CAR-M) for oncology or other therapeutics areas
• novel RNA technologies emerging (circular RNA, tRNA, RNA editing),
• new generation of gene therapy/gene editing technologies and,
• original approaches (epigenome editing, for example).
In that context, connection to venture capitalists, trained to spot early innovation, provides additional support coupled with a pragmatic approach of spreading the bets across various technologies to reduce risks might be required.