Antibody-Drug Conjugates (ADCs) are an exciting new class of drugs that offers clinical benefits to a wide range of cancers. Unlike immune modulating monoclonal antibodies (mAbs) such as checkpoint inhibitors, the mAb role in an ADC serves as a carrier and targeting agent to deliver cytotoxic molecules to a tumor. Over a dozen ADCs have been approved by the FDA1 and it represents a highly active segment of M&A within pharma with an estimated market growth from $8.58 billion in 2023 to $25.34 billion in just the next 5 years.2
However, a number of challenges exist for these new drug conjugates:
- The Drug to Antibody Ratio (DAR) needs to be relatively modest (typically in the single digits) as any greater small molecule binding to the antibodies would affect their conformational integrity, antigen binding sites and aggregation risk in vivo.
- For antibodies with high target affinity, the availability of target antigens near blood vessels may restrict further distribution of these drugs away from blood vessels and deeper into tumors due to rapid, tight antigen binding referred to as “binding site barrier.”3
- DARs can vary from 0 to 8 in Kadcyla and Adcetris as well as other commercial ADCs. Additional heterogeneity can arise in vivo when the ADC undergoes biotransformation before it reaches the target, resulting in multiple species with varying DARs. These different DAR species can each have distinct pharmacokinetics behaviors.4
- Adverse related events for these ADC drugs can be high with a mean occurrence of 46.1% for ≥3 adverse events (maximum was Seagen’s Adcetris at 72.9%). Treatment was completely discontinued, on average, in 13.2% of patients.5
Vesselon’s novel co-formulation of gas lipid microspheres and self-assembling liposomes, targeted and activated by commercial ultrasound, would be an ideal adjunct to any of these ADC drugs. First, our FDA-approved Imagent® drug can be co-formulated on-site with any ADC without any change to the ADC manufacturing, packaging, dosing or method of administration. Second, the ADC biodistribution to the tumor can be elevated by ≥ 2–4X via our sonoporation and tissue modulation modes of action at the cellular level, using biophysics to push ADCs deeper into the tumor and to counteract effects such as efflux pumps. Third, encapsulation in the gas lipid microspheres and self-assembling liposomes would provide additional protection from de-conjugation and catabolism of the ADCs that invariably occurs in vivo prior to reaching the target.
In effect, Vesselon would fundamentally improve the therapeutic index of any ADC to a remarkable degree — without having to alter the ADC molecule in any way. Clinical trials can progress rapidly as the same approved ADC doses can be used with Imagent (which is also approved for human use in another clinical indication).
The benefits to patients would be materially significant. At the same initial doses, patients would get far more active dose directly to their tumors with less systemic exposure, improving clinical impact. For those many patients who experience adverse events leading to dose interruption, lower doses can be implemented sooner while maintaining the same level of tumor target bioavailability as a full dose. For example, in the registrational trials for Padcev for urothelial cancer from Seagen, all documented over 60% of patients having to discontinue treatment due to adverse events. A third to half of patients had to reduce dose to continue treatment.6
The market implications for Vesselon’s innovation could be profound. Without changing the ADC molecule, a Vesselon co-formulation could increase utilization by 20% for patients already being prescribed the product. Incremental efficacy metrics could be demonstrated in straightforward clinical trials using the same-dose registrational trials as a guide which would propel a Vesselon-co-formulated ADC far above any competition in the same indication.
From a franchise management perspective, a Vesselon-ADC-co-formulation would create new patent life to any ADC. Interestingly, the potential to extend mAb patents via subcutaneous formulations is highly improbable for ADCs due to the potential reactions to cytotoxic payloads and off-target toxicities mediated by immune cells in the skin, which may cause local deposits of cytotoxic material.(7)
Vesselon is decidedly on the cusp of a new generation of co-formulated entities that will benefit patients and clinicians, but also franchise managers who have the difficult task to help outcomes, avoid toxicity and increase revenues at the same time.
- AxisPharm: ADC List
- Mordor Intelligence: Industry Report
- Lucas AT. Factors Affecting the Pharmacology of Antibody–Drug Conjugates. Antibodies 2018,7;10
- Kamath 2016. Challenges and advances in the assessment of the disposition of antibody-drug conjugates. Biopharm. Drug Dispos. 37: 66–74 (2016)
- Zhu Y. Treatment?related adverse events of antibody–drug conjugates in clinical trials: A systematic review an meta?analysis. Cancer. 2023;129:283–295
- Padcev — enfortumab vedotin Package Insert
- Lucas Ibid.
Vesselon develops patentable drug co-formulations with a platform consisting of an FDA-approved, biophysically activated lipid microsphere and self-assembling liposomes. These co-formulations safely make targeted cells and tissues more receptive to therapeutic drugs and produce unprecedented levels of efficacy.
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