Cell and Gene Therapy Gathers Pace
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Next-generation therapeutics: cell and gene therapy gathers pace At one of its most exciting phases of growth, the cell and gene therapy market has gained momentum in dealmaking, product sales and big Brain light/Alamy Stock Photo Stock Brain light/Alamy pharma interest, all of which are analyzed in this feature. feature Paul Verdin and Lisa Urquhart Therapeutic approaches employing whole cells are not new—for is substantial ongoing work in oncology, the majority of programs example, techniques based on cultured autologous epidermal cells (65%) across the combined pipeline are in non-oncology indications. for burn treatment and chondrocytes for knee cartilage repair have The value picture reveals a similar overall distribution—indications been available for more than a decade. Gene therapy and other gene outside oncology account for 76% of the 2024 forecasted sales transcription and translation-targeted approaches such as RNA inter- value, and only three oncology indications are included in the top ference (RNAi) are a much more recent addition to the therapeutic 20 indications by 2024 forecast sales (Fig. 2). The top 20 list reveals a arsenal, and coupled with the high-profile arrival of chimeric antigen wide variety of indications, including SMA, amyloidosis, hemophilia receptor (CAR)-T cells are ushering in a new era for cell-based and A and B, sickle cell disease, Huntington’s disease and amyotrophic gene-based medicine. lateral sclerosis. Logically, nucleic acid approaches are on the whole These groundbreaking scientific advances have also brought with focused on those diseases with a clearer genetic basis, whereas cell them intense debate about payment models and affordability, add- therapies are being explored in oncology and those indications with ing fuel to the broader fire raging around drug pricing. Nonetheless, a more complex etiology. The indications attracting the biggest sales sell-side consensus forecasts from Evaluate Pharma project growth forecasts include those for which drugs have already been approved of the combined cell, gene and nucleic acid therapy market from (including DMD, NHL and SMA), helping to derisk forecasts. $1 billion in 2017 to $44 billion in 2024, resulting in a staggering 65% compound annual growth rate (Fig. 1). With such value at stake, this Participants in the cell and gene therapy field has been—and will likely continue to be—one of the most keenly In terms of the companies involved in the cell and gene therapy watched pharma segments for business development groups and space, thus far, major pharma has largely stayed on the periphery— industry observers alike in the next few years. only five companies that are considered established large pharma players are included in the top 20 by 2024 sales: Novartis, Gilead, Cell-based and gene-based medicine comes of age Biogen, Celgene and Takeda (Fig. 3). The top ranked company by In 2017, the first products harnessing CAR-T cells to treat cancer were forecasted 2024 sales is Sarepta, driven in part by the marketed approved by the US Food and Drug Administration (FDA)—Novartis’s Exondys 51 for DMD, but primarily through growth from a variety Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia and Kite of nucleic-acid-based pipeline programs including further exon- Pharma’s (now Gilead Sciences’) Yescarta (axicabtagene ciloleucel) for skipping antisense and gene therapy programs in muscular dystrophy. non-Hodgkin’s lymphoma (NHL). Shortly after in the same year, Spark Overall, Sarepta’s pipeline is forecasted to generate >$3 billion in Therapeutics’ Luxturna (voretigene neparvovec) became the first 2024 sales. FDA-approved in vivo gene therapy, for inherited retinal dystrophy. Then in 2018, the FDA approval of Alnylam Pharmaceuticals’ Onpattro 45 (patisiran), a pioneering RNAi therapy for polyneuropathy caused 43.7 by hereditary transthryetin-mediated amyloidosis, rounded off a 40 Gene therapy remarkable string of ‘firsts’ for cell-based and gene-based medicine. DNA and RNA therapeutics 35 13.6 There have also been notable approvals of oligonucleotide-based Cell therapy 31.9 therapies with antisense and exon-skipping mechanisms in the past 30 few years, including Ionis Pharmaceuticals’ Tegsedi (inotersen), also 25 9.4 for polyneuropathy caused by hereditary transthryetin-mediated 12.0 20.3 amyloidosis, Biogen’s Spinraza (nusinersen) for spinal muscular 20 5.7 8.9 atrophy (SMA) and Sarepta Therapeutics’ Exondys 51 (eteplirsen) for 15 11.9 Duchenne muscular dystrophy (DMD). Whereas the CAR-T approach sales ($ billions) Product 10 2.8 6.1 is somewhat different, and focused on oncology, the other approvals 6.9 16.8 1.0 4.4 4.1 12.0 represent major advances in the broader field of ‘regenerative medi- 5 2.7 0.03 0.2 3.5 7.6 1.3 1.0 cine,’ offering the prospect of major advances and perhaps even cures 0.2 2.0 0.6 2.7 1.1 4.5 0 2.3 for previously intractable diseases. 2017 2018 2019 2020 2021 2022 2023 2024 However, these recent catalysts might only be the tip of the iceberg. Evaluate’s analysis reveals >5,000 active research and development Fig. 1 | Sales growth trends of cell, gene and nucleic acid therapy products from 2017 programs for cell-based and gene-based medicine, and while there to 2024. Source: EvaluatePharma, March 2019. biopharmadealmakers.nature.com | June 2019 | B15 155 a Duchenne muscular dystrophy 4,021 7 Non-Hodgkin's lymphoma 3,872 Spinal muscular atrophy 884 3,290 Amyloidosis 2,614 Hemophilia A 1,730 Sickle cell disease 1,309 Multiple myeloma 1,237 Melanoma 1,073 Rare eye disorders (achromatopsia, choroideremia, Usher syndrome and Stargardt disease) 1,046 Huntington's disease 946 Phenylketonuria 911 Hemophilia B 856 Congestive heart failure 827 Amyotrophic lateral sclerosis 755 14 Graft-versus-host disease 735 Hyperlipidemia 686 Gastro-intestinal fistula 582 Thalassemia 573 2017 Dry age-related macular degeneration 504 2024 Sanfilippo syndrome (mucopolysaccharidosis III) 499 feature 0 1,000 2,000 3,000 4,000 5,000 Sales forecasts ($ millions) b Solid tumor indications 342 General cancer indications 273 Non-Hodgkin's lymphoma 113 General eye disorders 113 Other neurological indications 106 Acute myeloid leukemia 96 General blood malignancies 92 Multiple myeloma 80 Acute lymphocytic leukemia 78 Parkinson's disease 71 General cardiovascular indications 69 Duchenne muscular dystrophy 68 Melanoma 65 Diabetes, type I (juvenile onset) 65 Hepatoma (liver cancer) 62 Non-small-cell lung cancer 60 Glioblastoma multiforme 59 Amyotrophic lateral sclerosis 58 Retinitis pigmentosa 58 Bone repair and regeneration 57 0 50 100 150 200 250 300 350 400 Number of active R&D programs Fig. 2 | Top 20 indications in the field of cell, gene and nucleic acid therapies, based on 2024 sales forecasts and number of active R&D programs. R&D, research and development. Source: EvaluatePharma, March 2019. The top 20 list is populated by other smaller players that have allogeneic expanded adipose-derived stem cells targeted at gas- rapidly become well-watched names on the basis of their focus troenterology conditions—a deal that has delivered the larger on cell-based and gene-based medicine, including bluebird bio, group a marketed asset in Alofisel (darvadstrocel). The nucleic-acid- Alnylam, BioMarin Pharmaceutical and Spark—the announced based therapeutics landscape has been less of a target for standout acquisition of the latter by Roche in February, expected to close in acquisitions, but Biogen’s expanded tie up with Ionis is notable. Q2 2019, is proof that this area will continue to be closely watched Under the terms of the expanded 2018 deal, Biogen will pay Ionis by big pharma. a total of $1 billion upfront for a ten-year collaboration focused on developing antisense products for a range of neurological dis- Leading dealmakers eases. The collaboration builds on a relationship that successfully Other standout deals by major players in recent years include a num- delivered Spinraza to the market. And in April 2019, Regeneron ber of acquisitions and strategic collaborations that have already Pharmaceuticals’ announcement that it would invest $800 million yielded results (Table 1). Novartis’s 2018 acquisition of AveXis is the in Alnylam to collaborate on RNAi therapies across multiple disease biggest deal in gene therapy at $8.7 billion (an 88% share price pre- areas underlined the interest in this platform following the first mium), enabling the big pharma company access to technology and RNAi approval in 2018. a pipeline of assets in life-threatening neurological diseases, includ- Clearly many major players—as well as industry observers—have ing SMA. In cell therapy, the acquisitions of Kite and Juno by Gilead their eyes on cell-based and gene-based medicine as a new era ($11.9 billion) and Celgene ($9 billion), respectively, gave the larger in disease management and, potentially, cure. There is justifiable groups access to CAR-T platforms and advanced pipeline candidates. cause for excitement with the range and profile of regulatory suc- For Gilead, this has already delivered a marketed product in Yescarta. cesses in recent years. However, owing to the well-documented Outside oncology, Takeda announced in 2018 its intent to acquire but unsolved commercial challenges for such products once on TiGenix for $626 million, providing access to a platform based on the market, reasonable valuations are very difficult to measure. The B16 | June 2019 | biopharmadealmakers.nature.com 155 Sarepta Therapeutics 3,033 6 Novartis 2,787 bluebird bio 2,129 Alnylam Pharmaceuticals 2,128 7 Gilead Sciences 1,970 884 Biogen 1,694 Celgene 1,661 Moderna Therapeutics 1,586 Mesoblast 1,382 Autolus 1,291 BioMarin Pharmaceutical 1,210 Akcea Therapeutics 1,183 Spark Therapeutics* 964 The Medicines Company 877 Iovance Biotherapeutics 795 uniQure 790 WAVE Life Sciences 765 Abeona Therapeutics 727 2017 BrainStorm Cell Therapeutics 725 2024 Takeda 582 0 500 1,000 1,500 2,000 2,500 3,000 3,500 feature Sales forecasts ($ millions) Fig.