Integrated product development for ATMPs

By: Claes Buxfeldt and Dr Paula Salminkangas

In this article, published in the September issue of MedNous, Claes and Paula discuss why an integrated product development strategy for ATMPs is essential to meet both regulatory and HTA requirements.


Advanced Therapy Medicinal Products (ATMPs), which include cell and gene therapies and tissue engineered products, are a group of innovative products targeting diseases and conditions for which there are few, if any, effective treatments. The success of the first CD19 chimeric antigen receptor T cell (CAR T) products Kymriah and Yescarta against B-cell malignancies has raised the awareness of the high potential of ATMPs, but also shown the several challenges relating to their clinical use1. One of these challenges is the high prices asked by the manufacturers of these products, which are not always supported by national pricing and reimbursement bodies2.

In such cases, the discrepancy between a regulatory approval and a negative decision from a health technology assessment (HTA) body has raised concerns and questions from industry about how to ensure that an approved product also gets to the market and to patients. Many jurisdictions have created early access schemes and ways to communicate with regulatory and HTA bodies early on to ensure successful outcomes of both reviews3. However, the ATMP industry is facing challenges in both aspects.

The development of ATMPs has substantially increased with a focus on clinical trials in recent years. Several cell and gene therapy products have been authorised worldwide, most recently the CAR T product Tecartus from Kite Pharma Inc.4 in the US and Zolgensma for spinal muscular atrophy (SMA)5 in the EU.

Today there are more than 980 developers globally, the majority (78%) of whom are in North America and Europe.6 Over 1,000 clinical trials were underway worldwide at the end of 2019, two-thirds of which (64%) were in Phases 2 and 3. There has been a clear shift from early to late phase trials, as only four years earlier the majority of trials (> 90%) were in Phases 1 and 27. Since beginning of 2015, the overall number of ATMP clinical trials and ATMPs in Phase 3 has doubled, suggesting multiple new ATMPs will be approaching the marketing authorisation application stage in the next few years.

Today, the focus of ATMP development is heavily in gene therapy and genetically modified cells which constitute three-quarters of products in clinical trials. This is most probably due to the fast development of novel vectors and technologies, including genome editing. In addition, a lot of safety data has accumulated for certain gene therapy approaches (e.g. adeno associated virus vectors, AAV and lentivirus vectors, LVV), which reduces the regulatory burden before first clinical trials.

From an indication perspective, the majority of ATMP clinical trials (657/1066, 62%) 6 are in oncology, including leukaemia, lymphoma, and solid tumors, which may be explained by the great interest towards novel immunotherapies using genetically modified cells. In 2019, genome edited cells using the CRISPR/Cas9 approach proceeded to clinical trials both in the US and the EU8 and the first results from a trial studying an induced pluripotent stem (iPS) cell-derived product were reported in the EU 9.

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References :

  1. Mohty M., Gautier J., Malard F., et al. CD19 chimeric antigen receptor-T cells in B-cell leukemia and lymphoma: current status and perspectives. Leukemia 2019, 33: 2767–2778
  2. Jönsson, B., Hampson, G., Michaels, J., Towse, A., Graf von der Schulenburg, JM. and Wong, O. Advanced therapy medicinal products and health technology assessment principles and practices for value-based and sustainable healthcare. Eur. J. Health Econ. 2019, 20(3): 427–438
  3. Jörgensen, J. and Kefalas, P. Reimbursement of licensed cell and gene therapies across the major European healthcare markets. J Mark Access Health Policy 2015, 3: 10.3402/jmahp.v3.29321.
  4. FDA approved Cellular and Gene Therapy Products, https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products
  5. EU public assessment report for Zolgensma https://www.ema.europa.eu/en/medicines/human/EPAR/zolgensma
  6. Alliance for Regenerative Medicine: 2019 Regenerative Medicine Sector Report, available from https://alliancerm.org/sector-report/2019-annual-report
  7. 7.Alliance for Regenerative Medicine: Q1/2015 Regenerative Medicine Sector Report, available from https://alliancerm.org/wp-content/uploads/2018/04/ARM_Q12015_Data_Report_Web_Version.pdf
  8. CRISPR Therapeutics and Vertex Announce Progress in Clinical Development Programs for the Investigational CRISPR/Cas9 Gene-Editing Therapy CTX001, available from https://investors.vrtx.com/news-releases/news-release-details/crispr-therapeutics-and-vertex-announce-progress-clinical
  9.  Cynata Completes Clinical Study Report for Phase 1 Trial of CYP-001 in GvHD, available from https://www.globenewswire.com/news-release/2018/12/18/1668688/0/en/Cynata-Completes-Clinical-Study-Report-for-Phase-1-Trial-of-CYP-001-in-GvHD.html

 

 

Market access for immune-oncology products in the EU

By: Claes Buxfeldt, HTA Director at NDA Group

In this article, published in Volume 22 September 2020 of Pharmafocus, Claes Buxfeldt discusses key considerations in early development to succeed with market access for immune-oncology products in the EU.


Integrating market access considerations early into your development program saves money and the chances that your product will reach the market, or a premium at exit.

At NDA we work closely with development teams covering many disease areas. Reflective of the global pipeline, a large part of our time is spent helping clients with immune-oncology portfolios. Here we cover what activities should be considered in early development of new immune-oncology (IO) drugs to ultimately secure reimbursement or optimise the asset’s value. We also explore how IO treatments are different compared to other treatment options and important attributes to consider.

Background

Achieving regulatory approval by demonstrating your product’s appropriate benefit/risk profile is only one step to reach and treat patients. In many countries pricing and reimbursement bodies have additional requirements to be fulfilled. This includes demonstrating comparative effectiveness and value for money.

Immune-oncology (IO) therapies

Instead of targeting tumours directly, IO therapies engage the patient’s own immune system to stop them. This approach may offer a more effective treatment for some patients. Important characteristics of IO therapy include full tumour regression, often a more sustainable clinical outcome and improved health-related quality of life compared to standard chemotherapy. IO therapy often has a different side-effect profile and durability of response.

The development of targeted immune checkpoint inhibitors resulted in the first FDA approval in 2011 of Yervoy (ipilimumab – CTLA4 antibody) for melanoma. Additional studies of PD1/PDL1 antibodies have led to regulatory approval both as single agents and in combination with other agents. IO therapies are now approved by EMA and FDA in treating melanoma, lung, kidney, bladder, head and neck cancer.

Key distinctive features of IO therapies:
  • Immune-mediated mechanisms of action,
  • Significant and increased durability of response,
  • Unique kinetics enabling delayed response,
  • Potential for shorter treatment period,
  • Possibility of being “cured”,
  • Different, often more manageable, side-effect profiles,
  • Sometimes severe and systemic adverse effects,
  • Better health-related quality of life,
  • Flattening of the Kaplan Meier survival curve suggesting durable responses,
  • Administrated often in unique combinations of IO drugs.

Critical questions in developing IO therapies include targeting of those patients most likely to respond, combining IO therapies with other treatment options, mitigating related side-effects and reducing the resistance to therapies. How to practically use these therapies in an evolving health care environment and when to stop treatment are also important.

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