View from the Top: Cell and Gene Therapy Successes and Promise

The following article is an excerpt from Nice Insight's Cell & Gene Therapy: 2023 Market Analysis, CDMO Pricing and Benchmarking report. You can find out more and order the report here.

 

Despite financial headwinds in 2022, the U.S. Food and Drug Administration (FDA) approved more cell and gene therapies than in any previous year. A higher number of approvals is expected in 2023, with the pace continuing to accelerate, including approvals for therapies that treat larger patient populations. Will the industry be able to make commercialization a reality? There are still many hurdles to overcome.

2022 was A Good Year

Worldwide, at least 24 gene and gene-modified cell therapies and 60 non-genetically modified cell therapies had been approved for clinical use by the end of 2022.¹ In the United States, two therapies were approved in just the fourth quarter of 2022 — Hemgenix for hemophilia B and Skysona for cerebral adrenoleukodystrophy — making it five for the year (Adstiladrin for bladder cancer, Zynteglo for beta thalassemia, and Carvykti for multiple myeloma are the others), which is more than the agency approved in any previous year.

2023 Shows Real Promise

The Alliance for Regenerative Medicine (ARM) expects 2023 to be even more exciting. In a January 2023 presentation, the organization’s CEO Timothy Hunt outlined five potential firsts that may occur, including approvals of a CRISPR-based gene therapy, an allogeneic T cell therapy, an adoptive cell therapy targeting a solid tumor, a gene therapy for Duchenne muscular dystrophy (DMD), and a total of five gene therapies in a single year.²

The list of anticipated regulatory decisions in the United States has quite a few entries.² Cell therapies that could receive FDA decisions soon include:

• afami-cel from Adaptimmume Therapies to treat advanced synovial sarcoma;
• CT-053, a chimeric antigen receptor (CAR)-T cell therapy from CARsgen Therapeutics to treat multiple myeloma;
• HPC Cord Blood from StemCyte, a cell therapy derived from unrelated donors for hematopoietic progenitor cell transplantation;
• tab-cel from Atara Biotherapeutics Inc. for the treatment of Epstein–Barr virus–associated post-transplant lymphoproliferative disease (EPV+PTLD) approved in the EU in 2022);
• omidubical from Gamida Cell for the treatment of hematological malignancies; and
• lifleucel, a tumor-infiltrating lymphocyte (TIL) cell therapy from Iovance for the treatment of metastatic melanoma.

Gene therapies that could potentially be reviewed by the FDA include:

• bb1111 from bluebird bio for the treatment of sickle cell disease;

• CTX001, a gene-editing therapy from CRISPR Therapeutics and Vertex Pharmaceuticals for the treatment of sickle cell disease and beta-thalassemia;
• fidanacogene elaparvove from Pfizer (formerly Spark Therapeutics) for hemophilia B;
• Roctavian from BioMarin for hemophilia A;
• Libmeldy from Orchard Therapeutics for metachromatic leukodystrophy;
• SRP-9001 from Sarepta Therapeutics for DMD;
• Upstaza from PTC Therapeutics for the treatment of aromatic l-amino acid decarboxylase (AADC) deficiency; and
• B-VEC from Krystal Biotech for the treatment of dystrophic epidermolysis bullosa.

A few of these cell and gene therapies are worth highlighting.³ B-VEC is a topical gene therapy for a rare skin blistering disorder that restores type VII collagen production by delivering functional copies of COL7A1 directly through patients’ open wounds. It would be the first gene therapy with a dermatological application. Its Prescription Drug User Fee Act (PDUFA) date is May 19, 2023. With a PDUFA date also in May 2023, SRP-9001 could be gene therapy to receive approval for the treatment of DMD. Afami-cel from Adaptimmune is interesting because it is a TCR-based cell therapy targeting a solid tumor, while lifleucel from Iovance could be the first TIL therapy to target solid tumors, and tab-cel, already approved in Europe, could be the first allogeneic T cell therapy to receive approval in the United States. And exa-cel from CRISPR and Vertex could be the first therapy approved that leverages ex vivo CRISPR gene editing.

Some candidates at early stages of development are also worth watching.³ Dutch biotech UniQure is expected to report follow-up data from patients dosed with AMT-130 later in 2023. This gene therapy would be the first for treatment of Huntington disease. Intellia, meanwhile, has two CRISPR/Cas9 gene-editing therapies (NTLA-2001 for the treatment of transthyretin (ATTR) amyloidosis with cardiomyopathy and NTLA-2002 targeting hereditary angioedema) that have shown promising results in clinical trials outside the United States, and the company plans to file investigational new drug applications (NDAs) to expand U.S. study sites for pivotal studies for both candidates. MCO-010 from Nanoscope is a gene therapy for treatment of retinitis pigmentosa and Stargardt disease and — if successful — would be only the second gene therapy for an inherited retinal disease.

Table 1. Approved Gene Therapies as of Q4 2022¹ 

Massive Clinical Trial Landscape

At the end of 2022, ARM had identified 2,220 clinical trials underway around the world, with 43% in North America, 38% in Asia-Pacific, and 18% in Europe.² Separately, the American Society of Gene + Cell Therapy reported a 7% increase in the pipeline (preclinical to pre-registration) of gene, cell, and RNA therapies in 2022.¹

The trials are being sponsored by just over 1,450 cell and gene therapy developers, which represents an 11% increase over 2021.² Over 250 new trials were started in 2022, with nearly half of them having sites in the APAC region. Nearly 10% of all trials are in phase III (202), and close to 60% have potential applications in prevalent disorders. Cancer remains the top target, accounting for 60% of all trials, with both liquid and solid tumors receiving equal attention.

In the gene therapy sector, ex vivo modification continues to predominate, accounting for nearly 75% of all candidates in development.¹ Of genetically modified cell therapies, CAR-T cells account for half of candidates in preclinical through pre-registration phases; natural killer (NK), macrophage, and various other cell types make up 32%.

The top indications for non-genetically modified cell therapies include non-oncology indications (~two-thirds) and rare diseases, with the top targets including acute respiratory distress syndrome, COVID-19 complications, graft-versus-host disease, and amyotrophic lateral sclerosis.¹

Strong Growth is Expected to Continue Beyond 2023

The number of active cell and gene therapies trials suggests that the rate of approvals will continue to increase. The Milken Institute estimates that 50–75 cell and gene therapies could receive approval in the United States by 2030.⁴ In addition, although cell and gene therapies account for only a little more than 1% of global biopharmaceutical sales, this segment of the market is predicted by Evaluate Pharma to expand at a compound annual growth rate (CAGR) of 46% — compared with a CAGR of just 5% for small molecule drugs and conventional biologics.⁵

If Commercialization is Truly Possible

Even if 50–75 cell and gene therapies receive FDA approval by 2030, questions remain as to whether they will achieve commercial success. Safety issues with different viral vector gene delivery vehicles that have occurred in the past few years must also be addressed. Demonstration of long-term safety and efficacy must be achieved as well.

One of the biggest challenges is the lack of sufficient manufacturing capacity, both internally and at contract development and manufacturing organizations (CDMOs), to meet the huge increase in demand for viral vector and cellular therapy production.⁶ Adding physical capacity will not be practical or able to fully solve the issue. Significant improvements in manufacturing efficiency will be essential.

Solutions to tackle this issue are being developed by modifying existing approaches for conventional biologics and identifying novel technologies using multidisciplinary (biology, engineering, physics, chemistry, and data science) approaches.⁷ Examples include nucleic acid formats and viral biosynthesis methods, non-viral gene therapy “printers,” cell therapy GMP “boxes,” microfluidics or encapsulation-based cell culture, in vivo cell therapy, non-chromatographic separations, advanced GMP cell sorting, and new optical methods for nanoscale analytics.

These improvements are also necessary to reduce the cost of these next-generation treatments, which carry prices of ~$500,000 per dose for gene-modified cell therapies and as much as $3 million per dose for gene therapies. Those prices have created concerns regarding reimbursement. Modernization of payment systems will be fundamental to enabling the commercial viability of cell and gene therapies.^2,5

To support the accelerated timelines associated with gene therapies, most of which receive at least one special designation from the FDA that includes greatly shortened review and approval periods, the development of accurate and reliable rapid analytical testing capabilities will also be key.⁶

Uncertainties in the regulatory framework for cell and gene therapies must also be eliminated and standardized approaches established so that developers of these complex products can have an understanding of regulatory expectations with respect to CMC requirements and the implementation of clinical trials.⁸ Recruitment and retention of participants for clinical studies and obtaining funding for those studies is becoming increasingly difficult as competition in an ever-more-crowded sector increases.⁹

Access to funding emerged as a real issue for many cell and gene therapies in 2022 and continues in 2023. The turbulent financial markets hit the entire biopharmaceutical industry in 2022, and cell and gene therapy developers were no exception. Continued investment (e.g., venture capital, public funding, mergers and acquisitions) will occur in 2023, but at a much slower pace and with more focus on later-stage companies that present lower risks.¹⁰ On the positive side, many big pharma companies have accumulated large cash reserves and will likely spend some of that money to refresh their pipelines with promising cell and gene therapy candidates, through acquisitions, licensing deals, and/or partnerships with small and emerging developers.

2023: A Pivotal Year for Cell and Gene Therapies

All signals in the cell and gene therapy market suggest that 2023 will be a pivotal year for the sector. The FDA is expected to review by far the largest number of cell and gene therapy biological license applications in a single year. The agency is also taking steps to boost its staff to support the dramatic increase in work it faces with respect to cell and gene therapies.² It is also taking part in dialogues around revamping the approval process so that the regulatory framework for cell and gene therapies better reflects the technologies in use today and into the future.⁹ At least 100 small and medium-sized companies are introducing technologies to boost the efficiency of manufacturing processes and working closely with therapy developers to ensure that they are fit for purpose.⁷ Discussions are ongoing among developers, insurers, and governments regarding new payment approaches.

At the same time, cell and gene therapy developers recognize that they face headwinds, and the most successful firms are taking effective steps to improve their business resilience in order to weather the turbulent times ahead as solutions for these many issues slowly emerge.¹¹ “Diversification, collaboration, and consolidation” are the watchwords for the year.

By the end of 2023, the industry hopes to have several key questions answered, including whether there will indeed be modernization of healthcare systems and payment options and whether patients will truly embrace cell and gene therapies as more products reach the market, with more of them treating diseases with larger patient populations. The answers to these questions will have implications for everyone from patients to payers and from cell and gene therapy developers to investors and will determine whether the market is able to truly realize its full potent

Table 2. 50 Top Cell and Gene Therapy Companies

References

1. Gene, Cell, & RNA Therapy Landscape Report: Q4 2022 Quarterly Data Report. American Society of Gene + Cell Therapy and Citeline (formerly Pharma Intelligence). 2022.
2. Hunt, Timothy D. “Cell & Gene State of the Industry Briefing.” Presentation. Alliance for Regenerative Medicine. 9 Jan. 2023.
3. Johnson, Victoria and Alicia Bigica. “10 Cell and Gene Therapies to Watch in 2023.” CGTLive. 24 Jan. 2023.
4. Choe, Sung Hee, Esther Krofah, and Allyson Conlin. “Cell and Gene Therapies: Looking Ahead to 2022.” Rep. Milken Institute. Accessed 15 Mar. 2023.
5. Pagliarulo, Ned. “5 questions facing gene therapy in 2023.” BioPharma 12 Jan. 2023.
6. Grote, James. “State of the Cell and Gene Therapy Market.” Pharma’s Almanac. 11 Oct. 2022.
7. Sylvestre, Julien and Philip Conti-Permanne. “Emerging technologies & companies in cell & gene therapy manufacturing.” Cell Gene Ther Insights. 8(11):1601–1649 (2022).  
8. “Mainstreaming cell and gene therapy – Realizing its potential.” BioPharma ICON. 28 Nov. 2022.
9. Dugan, Elizabeth. “Changing Cell & Gene Therapy Landscape and Implications on Clinical Trials.” Blog. Advanced Clinical. 20 Dec. 2022.
10. Lohr, Adam. “2023's Market Outlook For Cell And Gene Therapies.” Cell & Gene. 14 Feb. 2023.
11. Kakkaiyadi, Krishna and Angelika Gornikowska. “Cell and gene therapies: resilience the aim in 2023 amidst regulatory flux.” Out-Law Analysis. Pinsent Masons. 27 Jan. 2023.
12. Buntz, Brian. “50 leading cell and gene therapy companies.” Drug Discovery and26 Jul. 2022.
13. Buntz, Brian. “Caribou Biosciences announces positive CRISPR hybrid RNA-DNA data.” Drug Discovery and Development. 3 Sep. 2021.
14. Buntz, Brian. “How Cellares aims to transform cell therapy manufacturing.” Drug Discovery and Development. 26 Apr. 2022.
15. Buntz, Brian. “How Mission Bio is working to drive precision medicine.” Drug Discovery and Development. 10 Jun. 2022.