7:20 PM
Feb 15, 2019
 |  BioCentury  |  Product Development

ADCs’ inflection point

How fit-for-purpose ADCs could open the modality’s floodgates

Industry is writing a new rule book for antibody-drug conjugates that could take the modality beyond the one-size-fits-all approach that has limited its success. By 2Q20, late-stage data from at least four ADCs testing new combinations of payloads, linkers and targets could give the field a fresh burst of momentum.

The primary goal is to widen the therapeutic window, which has been the death knell of many ADC programs and has hindered uptake of marketed ADCs. FDA has approved four ADCs, and all carry black box warnings.

The consensus in the field is that companies must go beyond building pipelines on the back of single linker-payload combinations.

If successful, the next generation of ADCs will open up a range of indications beyond the reach of the early products.

But the rules for how to find optimal combinations of ADC components are only beginning to emerge.

Developers face an uphill battle because there are three dials to turn -- antibodies, linkers and payloads -- and each carries its own set of considerations for efficacy and toxicity.

For example, antibodies can deliver the cytotoxic payload to healthy cells, fail to penetrate dense solid tumors or fail to be internalized by tumor cells. Even if an ADC reaches the tumor and delivers its payload, the toxin can enter adjacent healthy cells and kill them -- a phenomenon known as the ‘bystander effect.’

Other challenges range from making linkers that only release the payload in the tumor to dialing in the appropriate potency of the payload.

Drug developers are addressing these issues by building large toolkits of different technologies in all three categories that can be mixed and matched to generate ADCs that solve specific problems. The goal is to tailor therapies to indications.

Over the next 18 months, Phase III and pivotal trial readouts will begin to show whether next-generation ADC approaches are up to the task (see Table: “Marketed and Late-Stage ADCs”).

These ADCs will serve as case studies for the hypothesis that the bystander effect can be flipped on its head by harnessing it to overcome heterogeneity in solid tumors.

Two will come from pivotal trials of second-generation HER2-targeted ADCs from Daiichi Sankyo Co. Ltd. and Synthon B.V., which are testing whether new payloads and linkers can widen the therapeutic window of Kadcyla ado-trastuzumab emtansine, the anti-HER2 ADC marketed by the Genentech Inc. unit of Roche (see Box: “A HER2 Case Study”).

These ADCs will serve as case studies for the hypothesis that the bystander effect can be flipped on its head by harnessing it to overcome heterogeneity in solid tumors. The idea is to extend an ADC’s reach to cells in the tumor that don’t express its target antigen, but the strategy involves careful threading of the needle between increased efficacy and toxicity.

Beyond these late-stage programs are a bolus of earlier stage programs that could sustain the momentum. These are being churned out by platforms that are applying new target selection and payload potency rules.

And an idea not yet in the clinic is to replace cytotoxic agents with targeted therapies, turning ADCs into immuno-oncology agents in their own right, rather than serving only as combination partners.

Table: Marketed and late-stage ADCs

At least 11 antibody-drug conjugates (ADC) are in pivotal trials or registration, poised to join the four already on the market. (A) AbbVie Inc. (NASDAQ:ABBV) discontinued the Phase III TAHOE trial of rovalpituzumab tesirine (Rova-T) plus topotecan to treat second-line small cell lung cancer (SCLC) due to shorter overall survival than produced by toptecan alone, but the Phase III MERU trial of Rova-T plus dexamethasone is continuing to enroll patients. (B) Daiichi Sankyo Co. Ltd. (Tokyo:4568) anticipates it will submit a BLA to FDA in FY20 ending March 31, 2021 based on data from a pivotal Phase II trial of [fam-]trastuzumab deruxtecan (DS8201) to treat HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to Kadcyla ado-trastuzumab emtansine, but has not announced when data are expected. Only the most advanced indication is shown for each product. Source: BCIQ: BioCentury Online Intelligence, PubMed, ClinicalTrials.gov, company websites

Microtubule inhibitors
Genentech Inc. / Roche (SIX:ROG; OTCQX:RHHBY) / Chugai Pharmaceutical Co. Ltd. (Tokyo:4519)Kadcyla ado-trastuzumab emtansineNon-cleavableHER2HER2-positive breast cancerMkt
Seattle Genetics Inc. (NASDAQ:SGEN) / Takeda Pharmaceutical Co. Ltd. (Tokyo:4502; NYSE:TAK)Adcetris brentuximab vedotinCleavableCD30Hodgkin disease, peripheral T cell lymphoma (PTCL), cutaneous T cell lymphoma (CTCL)Mkt
AbbVie Inc. (NASDAQ:ABBV) Depatuxizumab mafodotinNon-cleavableEGFREGFR-amplified glioblastomaPh III
Bio-Thera Solutions Ltd.

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