The rise of genomics and advanced therapeutics

The rise of genomics technologies over the past two decades has enabled the high-throughput interrogation of the entire human genetic complement.¹For around $1,500, it is now possible to determine the sequences of your chromosomes, and this data can be mined for genetic mutations that cause disease and affect drug response. We can also now interrogate the whole human exome, which reveals which genes are actively being converted into their protein products at a particular time or under specific conditions (such as healthy vs. diseased states).

Such technologies have also facilitated the advent of a whole new field of human therapeutics. These “advanced therapy medicinal products” (ATMPs) offer significant promise for the treatment of diseases and injuries that currently have no cure.ATMP包括三种类型的治疗学: gene-based, cell-based, and tissue-engineered medicines. Gene therapies consist of synthesized genetic fragments administered as a therapeutic. Cell therapies consist of cells or tissues that are modified and then introduced into the body to treat specific diseases. Tissue-engineered medicines also contain cells or tissues, but these have been modified to enable the repair, regeneration or replacement of tissue.

在本文中，我们查看了获得市场访问的不同ATMP，并分享了从Dr. Anastasia WiseandDr. Ebony Maddenfrom the National Human Genome Research Institute (NHGRI美国国立卫生研究院 - 领导该组织的组织Human Genome Project。

The very first ATMPs

atmps首先留下了自己的印记再生医学, specifically for joint repair.⁴1997年，Genzyme的Carticel®成为第一个FDA-approved ATMP, around a decade before the term became standardized. Carticel® was a cell therapy used to regenerate articular cartilage in the knee. It comprised cartilage cells called chondrocytes that were cultured from the patient’s tissue sample, and then implanted back into the patient. In 2009, a similar product calledChondroCelect® by TiGenix was the first ATMP to be approved by the European Medicines Agency (EMA) in the EU. In the first indication of how genomics information would drive ATMPs, ChondroCelect® used gene expression profiling of cultures prior to implantation to increase the likelihood of success.⁵

However, in 2016, TiGenix withdrew ChondroCelect®. This may have been due to competition withMaci®是Carticel®的第三代，组织工程版本，分别在2013年和2016年批准了EMA和FDA。MACI®由在生物膜上培养的软骨细胞组成，然后植入该膜。这种创新需要植入的复杂手术较少，并使MACI®成为FDA批准的第一个组织工程ATMP。但是，此后，MACI®被标记为欧盟制造地点关闭后悬挂在欧洲市场上。⁶

The impact of genomics-guided ATMPs in oncology

Besides the ever-growing list of known癌基因, there are still many rare genetic variants of unknown significance.⁷Screening for such variations and correlating these with cancer risk, prognosis, and responsiveness to approved or candidate drug treatments is only feasible with NGS-based technologies.

“我认为将基因组或外显子组测序纳入临床护理是基因组学引导疗法中最令人兴奋的发展，因为经常发现不在当前的基因组面板上，这些变体可能使患者处于疾病风险或可能有助于理解患者的风险治疗患者的最佳方法。” Madden博士说。

Furthermore, such screening can uncover predictive biomarkers of adverse drug reactions, which can potentially reduce the burden of drug toxicity.¹Such information is increasingly used to stratify patients in clinical trials to improve the chances of clinical efficacy, reduced toxicity, and eventual regulatory approval.⁷These benefits provided by genomics are, of course, true for non-cancer ATMPs as well.

Indeed, genomics technologies have been key in uncovering new opportunities for cancer treatment; the largest proportion of ATMP applications and approvals to date have been cancer therapeutics.⁸ATMP方法固有的“精度肿瘤学”是在正确的时间向合适患者提供正确药物的概念。⁹Gene therapy ATMPs are particularly suitable for treating the early stages of cancer when there is less genetic variation among the cancer cells, while cell-based immunotherapy ATMPs are most effective against tumors, which tend to have more unstable genomes.

Challenges facing the success of current and future ATMPs

尽管ATMP具有很大的希望，但该领域仍面临许多困难。批准后不久，几个ATMP已从市场上撤出，尽管多年的努力和费用将其带到那里。的确，仅在欧盟，在2009年至2017年之间进入临床试验的约500个ATMP中，只有十个已获得营销授权，其中只有6个仍在市场上。¹⁰其中许多花了20多年的发展。

ATMPS忍受了报销挑战，严格的监管要求以及高昂的开发，制造和授权维护成本。^11,12Many ATMPs are developed for rare or very rare disorders meaning that the demand is low and the unit cost is high. In addition, ATMP clinical trials typically comprise small sample sizes and single-arm trial designs, leading to increased payer uncertainty.⁸Madden博士评论说：“我相信该领域进步的最大挑战在于学习需要哪种证据来实现临床准则。科学文献充满了成功结果的基因组医学研究，但是提供者，机构和付款人通常也需要具有成本效益的证据，并且通常不想从当前的临床准则中脱颖而出。”

Furthermore, many ATMPs require a sample from the patient prior to production (which means that companies must routinely deal with biological variation), high levels of expertise to manufacture, and some require high levels of surgical skill to ensure their success. These challenges all add to increased cost and commercial risk. For rare diseases particularly, Dr. Anastasia Wise says, “One of the greatest challenges to genomic-guided therapeutics for n-of-1 conditions is the development of a scalable process that would allow for lessons learned from other development efforts to be applied to new conditions.”

For example, the much-publicized gene therapy,Glybera®, which broke pricing records with treatment costing €1.1 million per patient, was approved by the EMA in 2012 for familial lipoprotein lipase deficiency. However, in 2017, uniQure decided not to renew marketing authorization because of high manufacturing and authorization maintenance costs versus low patient demand (1–2 patients per million).^13,14Glybera was only ever prescribed to one individual before being withdrawn.

Exciting times ahead for ATMPs

Several initiatives have, however, recently been put forward to boost the number of approved and commercially successful ATMPs. In October 2018, the European Commission and EMA announced a joint action plan for fostering future ATMPs.¹⁵The EMA is also encouraging the development of ATMPs through its PRIority MEdicines (PRIME) scheme.

In the UK, the Cell and Gene Therapy Catapult was recently set up to encourage innovations in cell and gene therapy.¹⁶Their resources include 1,200 m2 of laboratory space and over £51 million of funding. The UK government has also sponsored the formation of a network of Advanced Therapy Treatment Centers to ensure that patients receive the benefit of ATMP innovations via their national health service.¹⁷

In the US, the FDA has implemented, among others, the突破疗法designation, theRegenerative Medicine Advanced Therapyprogram, theINTERACTprogram, andnew guidanceissued in July 2018 specifically for gene therapies.

在不久的将来，许多ATMP可能会进入市场。尽管ATMP开发中固有的临床证据通常是限制的，但ATMP的潜在优势可能会越来越多地迫使付款人提供访问权限，并且患者将继续对政客和政策制定者施加压力。⁸Long-term follow-up, post-launch studies, and escrow agreements may all be needed to ensure success. Without preemptive action, the very sustainability of health insurance may come into balance. However, genomics technologies will, no doubt, play an increasingly important role in developing ATMPs and ensuring their future success.

参考：

1)Gong, J., Pan, K., Fakih, M., Pal, S., Salgia, R. Value-based genomics.Oncotarget。2018;9(21):15792–15815. doi:10.18632/oncotarget.24353.

2)Fellmann, C., Gowen, B.G., Lin, P.C., Doudna, J.A., Corn, J.E. Cornerstones of CRISPR-Cas in drug discovery and therapy.Nature reviews. Drug discovery。2016;16(2):89–100. doi:10.1038/nrd.2016.238.

3)Baliou, S., Adamaki, M., Kyriakopoulos, A., et al. CRISPR therapeutic tools for complex genetic disorders and cancer (Review).国际肿瘤学杂志。2018;53(2):443–468. doi:10.3892/ijo.2018.4434.

4)Mao, A.S., Mooney, D.J. Regenerative medicine: current therapies and future directions.Proceedings of the National Academy of Sciences of the United States of America。2015;112(47):14452–14459. doi:10.1073/pnas.1508520112.

5)Negoro，T.，Takagaki，Y.，Okura，H.，Matsuyama，A。通过细胞疗法修复关节软骨修复临床试验的趋势。NPJ Regenerative medicine。2018;3:17. doi:10.1038/s41536-018-0055-2.

6)Closure of EU manufacturing site for MACI. European Medicines Agency. 19 November 2014. (https://www.ema.europa.eu/documents/referral/maci-article-20-procedure-closure-eu-manufacturing-site-maci_en.pdf)

7)Burris, H.A., Saltz, L.B., Yu, P.P. Assessing the value of next-generation sequencing tests in a dynamic environment.美国临床肿瘤学教育学学会。2018; 38：139–146。doi：10.1200/edbk_200825。

8)Hanna, E., Rémuzat, C., Auquier, P., Toumi, M. Advanced therapy medicinal products: current and future perspectives.Journal of market access & health policy。2016;4: 10.3402/jmahp.v4.31036. doi:10.3402/jmahp.v4.31036.

9)Subbiah, V., Kurzrock, R. Challenging standard-of-care paradigms in the precision oncology era.Trends in Cancer。2018;4(2):101–109. doi:10.1016/j.trecan.2017.12.004.

10)Advanced therapy medicinal products (ATMPs) and ATMP regulation. European Medicines Agency. 8 March 2018. (https://www.ema.europa.eu/documents/presentation/presentation-module-4-advanced-therapy-medicinal-products-atmps_en.pdf)

11)ten Ham, R.M.T., Hoekman, J., Hövels, A.M., Broekmans, A.W., Leufkens, H.G.M., Lungel, O.H. Challenges in advanced therapy medicinal product development: a survey among companies in Europe.Molecular therapy. Methods & clinical development.2018;11:121-130. doi:10.1016/j.omtm.2018.10.003.

12)Abou-el-Enein，M.，Elsanhoury，A.，Reinke，P。克服欧盟市场先进疗法面临的挑战。Cell Stem Cell。2016;19(3):293–297. doi:10.1016/j.stem.2016.08.012.

13)uniQure announces it will not seek marketing authorization renewal for Glybera in Europe. uniQure. 20 April 2017. (http://uniqure.com/GL_PR_Glybera%20withdrawal_FINAL_PDF.pdf)

14)Lipoprotein Lipase Deficiency (LPLD). National Organization for Rare Disorders. (https://rarediseases.org/physician-guide/lipoprotein-lipase-deficiency-lpld/)

15)The potential of advanced therapy medicinal products in Europe. Health Europa. 2 August 2018. (https://www.healtheuropa.eu/potential-advanced-therapy-medicinal-products-europe/87548/)

16)Thompson, K. Cell and gene therapies set to revolutionise the healthcare system. Innovate UK. 19 September 2017. (https://innovateuk.blog.gov.uk/2017/09/19/cell-and-gene-therapies-set-to-revolutionise-the-healthcare-system/)

17)McKay，I。T细胞在癌症上呼唤T-EME？英国创新。2018年9月3日。