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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Optimising the path to market for ATMPs

A two part webinar series

Together with Cirio Advokatbyrå would like to invite you to our two-part interactive webinar series, Optimising the path to market for ATMPs.

ATMPs, Advanced Therapy Medicinal Products, are an increasing and diverse group of innovative products. They are complex  products with unique development challenges, and several have shown very promising efficacy results in treating highly debilitating diseases and conditions. However, the prices of the first approved ATMPs have been high and not always supported by the national pricing or reimbursement bodies or other payers.

This interactive webinar series will focus on the challenges of ATMP development and market access with case examples of approved products. The option of an integrated product development to cover both regulatory and HTA expectations will be presented, together with information on regulatory, HTA and market access support available for ATMP developers.

Session 1: Integrated Product Development for ATMPs to meet Regulatory and HTA requirements

Date: 22nd September

Time: 11am – 12pm CET

Session 2: Models for realizing ATMP- value

Date: 29th September

Time: 11am – 12pm CET

Our panelists are available to answer questions at the end of each session. You can ask your questions during the webinar or send them in advance to denise.stromquist@ndareg.com


Click here to book your place today!



Panelists 

Paula Salmikangas: Director of Biopharmaceuticals and ATMP, NDA Group

Paula joined NDA in 2017 from her position as a Research Professor at the Finnish Medicines Agency (2003-2017). She has served as a member of the EMA Committee for Advanced Therapies (CAT) from 2009 to 2017 and as the Chair of the CAT 2014-2017. She has also been the Chair of EMA CPWP and a member of the BWP. Her main areas of expertise are biological medicinal products, especially advanced therapy medicinal products and CMC aspects of biopharmaceuticals.

Steffen Thirstrup: Director NDA Advisory Board, NDA Group

Steffen joined NDA in 2013 from his position as head the Division for Medicines Assessment and Clinical Trials at the Danish Health and Medicines Authority where he alos acted as Danish member of the Committee for Human Medicinal Products (CHMP) at the EMA. Steffen excels at advising companies on their development strategies to meet expectations of regulatory agencies around the world. He applies his skills to a broad range of therapeutic areas and have successfully helped numerous clients interact with regulatory agencies throughout the stages of development and during regulatory review.

Anders Burén: Senior Counsel, Cirio Advokatbyrå

Anders specialises in strategic collaborations in the pharmaceutical industry and in regulatory law. He advises on Swedish and international aspects of agreements of all kinds governing research, development and commercialisation in the pharmaceutical industry and on product approvals, marketing and other regulatory considerations. Anders has previous experience as Assistant General Counsel for the AstraZeneca Group’s transaction lawyers based outside the US. Before that he was Assistant General Counsel for the Group’s lawyers based in Sweden.

Per Hedman:  Partner, Cirio Advokatbyrå

Per Hedman is head of Cirio’s Life Science, Health and Food practice – the Biological team. Per advises companies in all aspects of their business and legal affairs, including regulatory advice, R&D arrangements (such as non-disclosure, material transfer, clinical trial and joint development agreements), commercial relationships (such as manufacturing, supply and distribution agreements), M&A (such as product acquisitions and spin-outs, domestic and cross border), capital-raising transactions (debt and equity), and IPO:s and other capital market transactions.


To learn more about NDA’s ATMP capabilites click here