FDA issues draft regulatory guidance for antibody conjugated drugs, these points deserve attention

In recent years, antibody-drug conjugates (ADC), as a new type of molecule, have made waves in the pharmaceutical industry

Introduction to ADCs

As its name suggests, an ADC molecule consists of two parts: one is an antibody or antibody fragment that recognizes a specific antigen target on the surface of the target cell (such as a tumor-specific antigen), and the other is a small molecule drug called a payload , often cytotoxic

Ideally, after an ADC molecule enters the body, the antibody portion of it binds to the target cell

In order to help the pharmaceutical industry better develop ADC molecules, the FDA has released a draft of this guidance, which highlights some of the FDA's considerations for clinical pharmacology and some recommendations for ADC molecule development

ADC Dosing Strategy

The FDA pointed out in the draft guidance that since the ADC molecule itself consists of antibodies and cytotoxic drugs, the optimal dosage strategy needs to take into account the differences in the pharmacokinetics and pharmacodynamics of antibody drugs and loaded drugs

In first-in-human studies, the FDA strongly recommends selecting a broad dose range and selecting multiple different dose levels in early-stage clinical trials (eg, Phase 1 or Phase 2 expansion cohort studies) for Assess the safety and activity of ADC molecules

The FDA also mentioned that some internal and external factors (such as kidney or liver damage, or drug interactions) can also affect the choice of dose

Bioanalytical Methods

In first-in-human studies, the FDA recommends quantification of ADCs, their components, and any active metabolites

The FDA also noted that if a decision was made not to analyze a particular ingredient, there would need to be specific considerations and justifications

The following is a specific analysis of some specific cases:

Organ damage studies: ADC molecules, unconjugated payloads, and active metabolic components need to be measured

QTc assessment: Generally, it is sufficient to measure the unconjugated load as well as the active metabolite

For drug-drug interaction studies: If the bioanalytical method is sensitive enough to find systemic exposures with low unconjugated loads, then measurement of unconjugated loads as well as active metabolites is sufficient

For analysis of pharmacokinetic comparability (eg, comparing changes due to changes in manufacturing processes or changes in dosage form): the concentrations of ADC molecules and their components should be measured

Dose/Exposure to Response Relationship

In addition to evaluating the relationship between the dose and response of the ADC, the relationship between exposure and response needs to be evaluated in order to understand the safety and efficacy of the ADC molecule, its components, and active metabolites.

In addition, if the antibody-bound target itself is easily detached, and a considerable degree of the target enters the systemic circulation, the analysis of the relationship between exposure and response should only consider ADC molecules and/or total molecules that do not bind to the detached and entered circulation target.

Intrinsic factors to consider

The FDA's draft guidance states that factors such as kidney or liver damage, body weight, age, and gender may affect the exposure of ADC molecules, their components, and potentially active metabolites

The first is organ damage
.
Unconjugated payloads as well as active metabolites are cleared by the kidneys or liver, so impaired function of these two organs can alter drug exposure, potentially affecting the safety and/or efficacy of ADC molecules
.
For example, for the use of antibody fragments, as well as ADC molecules whose entire molecular weight does not exceed 69 kDa, they may be cleared by the renal pathway
.
In addition, changes in ADC exposure levels were also observed in some patients with impaired hepatic function
.
It is precisely for these reasons that in the development of ADCs, the FDA recommends that evaluation work should be done well
.

Then there are some factors related to genetics
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For example, some gene variants, and/or some expression of antibody targets, may affect the patient's response to ADC molecules
.
In addition, some metabolic enzymes in the liver, as well as transporters, may also affect the metabolism and transport of uncoupled loads, thereby affecting the metabolic rate
.
Finally, functional genetic variation of the Fc-gamma receptor can affect its binding to IgG molecules, thereby altering antibody-dependent cytotoxicity—one of the mechanisms by which ADC molecules work
.

other considerations

The FDA also cites other considerations in the draft guidance, such as the need for a QTc assessment to see if the ADC molecule prolongs the QT interval of the heartbeat—something the unconjugated load of the ADC molecule may have an effect on
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In addition, developers also need to evaluate the potential immune response of ADC molecules
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This includes the immune response brought by the antibody, but also the immune response brought by the load, or the linker
.

Finally, the FDA's draft guidance also mentions drug-drug interactions
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When developing ADC molecules, in vitro drug interaction analysis needs to be incorporated to understand the potential risks of unconjugated payloads and active metabolites
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In addition, FDA recommends further in vivo interaction analysis based on the results of in vitro assays
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The FDA also listed some scenarios where drug-drug interaction analysis is recommended: other drugs share the same target as the ADC molecule; other drugs may interfere with or inhibit the binding of the ADC molecule to the corresponding receptor; immunosuppressants are used, and the ADC molecule Pharmacokinetics are affected by immunogenicity
.

In general, the dose of ADC may not be easily adjustable
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Developers therefore need to understand whether other drugs can be safely combined with ADC drugs
.

Summarize

As a class of therapies that has recently gained a lot of attention, ADC molecules are also one of the development priorities of many companies
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Understanding the FDA's draft guidance can help better design and execute development programs
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Of course, the FDA's draft guidance is only a suggestion, not a regulatory requirement, so it is for reference only
.

References:

[1] Clinical Pharmacology Considerations for Antibody-Drug Conjugates, Retrieved February 11, 2022, from https://