Written by Modality Solutions
Posted on: January 21, 2020
2019 saw a resurgence of antibody-drug conjugates (ADCs) with seven new approvals and close to 100 investigational ADCs currently in pre-clinical and clinical trials i. On June 10, 2019, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Polivy™ (polatuzumab vedotin-piiq) by Genentech for the treatment of adults with diffuse large B-cell lymphoma ii. In January 2020, ADC Therapeutics announced an overall response rate that exceeded expectations for its Phase II clinical trials, clearing a big hurdle toward its first ADC pipeline iii.
Those therapeutics are just two examples of ADC therapies that are benefitting from the accelerated approval pathway the FDA granted this class of drug. Faster approvals coupled with increasing drug prices is expected to propel ADCs to a $7.5 billion market by 2025 – a compound annual growth rate of 17.7% for the next five years iv.
ADCs are designed to harness the targeting ability of monoclonal antibodies. Their three-component system is composed of a cytotoxic anticancer agent with a biodegradable linker to a monoclonal antibody v. The benefits of ADC therapy are the focused and targeted application of cytotoxic anticancer agents that maximize efficacy by discriminating between cancer and normal tissue, thus minimizing the damage to the surrounding healthy tissue.
Accelerated paths to approval and the unique challenges of ADC development and manufacturing cause additional cold supply chain hurdles. The starting point for any ADC manufacturing is the development of the parent mAb. Typically, mAbs destined for ADC production need additional optimization for robustness against the more demanding process conditions inherent in ADC processes. Recent studies indicate that ADC stability may be governed by properties stemming from both the antibody and the linker-toxin chemistry vi.
For example, the ADC trastuzumab emtansine (T-DM1) was subjected to several stress conditions including temperature, mechanical agitation, and repeated freeze and thaw. The stability assessment of the ADC compared to the parent monoclonal antibody showed clearly that T-DM1 is relatively less stable than its parent mAb. This was attributed to the presence of the drug-linker that is attached to the mAb vii.
The FDA published a regulator’s perspective on the challenges of ADC development in June 2018, specifically referring to the necessity of stability testing for the intermediates drug and linker as well as the final ADC drug product. The same perspective suggested freeze and thaw studies be included in stability testing viii.
Cold chain supply optimization depends on starting early to establish environmental monitoring needs for candidate mAbs as well as the linker/drug used in the ADC. Testing candidate mAbs for manufacturing robustness should be done in parallel with testing the effects of environmental hazards on the monoclonal antibody as it moves through the supply chain.
Specifically, stability data in relation to temperature, shock, vibration, and humidity during transport and storage should be evaluated as well as linker/drug intermediates stability testing, including freeze-thaw studies. Armed with this information, the ADC product could be modified for robustness to lower the supply chain risk. Early cold chain optimization is also an opportunity to eliminate penalties associated with delays in the supply chain during clinical trials and the FDA approval timeline.
Modality Solutions has been involved in providing optimized cold chain solutions for three of the ADCs currently on the market. We are your trusted partner, whether you are a CRO or biopharmaceutical innovator within North America or globally. Please call us for a free one-hour consultation should you have any questions. One of Modality Solutions’ cold supply chain experts will be glad to help.
viii https://cdn.ymaws.com/www.casss.org/resource/resmgr/mwdg/MWDG_0617_Shapiro_Marjorie.pdf, pg 57.