Successful Early-Phase Development of mAb Drugs

• SGS Life Science Services

The first FDA-approved therapeutic monoclonal antibody (mAb) was muromonab in 1986, and since then, numerous mAb drugs have been approved, and many more are in the later stages of clinical development. In the main, mAbs are being developed against immunological and oncological targets, but their beneficial characteristics allow development of drugs for various therapeutic indications.

Since muromonab’s approval, there have been several milestones in mAb development, not least the approval of the first human mAb in the US, adalimumab (Humira®) in 2002. Table 1 shows the top five drugs by sales in 2018, and Humira is the top ranked – and notably four of the top five are monoclonal antibodies rather than small molecules.

Despite the opportunities offered by mAbs, they do have complex pharmacokinetic (PK) and pharmacodynamic (PD) properties compared to those of small molecule drugs; and it is essential that these properties are analyzed and well understood in early phase drug development. Designing first-in-human (FIH) clinical trials for mAb drugs can be challenging, and many issues have to be addressed early on, including the selection of a safe and appropriate starting dose, the choice of dose escalation steps, the planning of sufficient and correct follow-up procedures, and the necessary safety monitoring to take into account both the short-term infusion-related reactions and delayed PD effects. Table 2 highlights some of the specific characteristics of mAbs that differ from small molecule drugs.

Regulatory authorities look more rigorously at mAbs due to safety incidents in the past, and many of these drugs are considered to be high-risk medicinal products. Developing a robust early clinical development plan that includes appropriate justifications is crucial to assist the regulators in their evaluation, and reduce the risks in developing these products.

Early Clinical Development: Clinical Pharmacology

As with any trial, there are a number of pharmacological specifics that need to be considered when starting clinical development of mAb drugs. Safety is paramount in FIH trials, and so the selection of the starting dose and subsequent dose escalation steps have to be considered in a mAb drug FIH study. For mAbs, the dangers were highlighted in 2006, when a trial being conducted on behalf of Tegenero led to near-fatal consequences for the volunteers being administered a mAb under development. From this incident, there were a number of lessons learned that have helped to shape the conduct of studies, and the development of early-phase strategies.

The Tegenero Accident: Lessons Learned

In March 2006, the biologic drug theralizumab (TGN1412) underwent trials as a CD28 “superagonist” intended for the treatment of B cell chronic lymphocytic leukemia (B-CLL) and rheumatoid arthritis. The drug was administered as an intravenous infusion to the first healthy volunteer in its clinical trial program, with FIH dose as 0.1 mg/kg, which was estimated based on Cynamolgus monkey no-observed adverse-effect-level (NOAEL) data. Subsequently, six other subjects were administered TGN1412 and two with placebo at ten-minute intervals. Within 90 minutes, the subjects who had been administered the drug were suffering from a number of symptoms including headache, myalgia, nausea, diarrhea, erythema, and hypotension. They became critically ill between 12 to 16 hours post-dose, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation due to a cytokine storm.

Following the incident, several conclusions were drawn up to prevent a similar occurrence in the future:

• The mode of action is a determining factor when estimating the efficient/active dose.
• It is better to start with the lowest active dose than with the highest safe dose.
• The predictivity of animal models should be considered. In-vitro assays with human cell lines are suggested and should be carefully interpreted.
• In non-standard situations, and as per European Medicines Agency (EMA) guidelines, a ‘sentinel’ group approach is highly recommended in FIH single ascending dose (SAD).
• Clinical and PK/PD experts must be very careful in their planning to ensure that the correct data are analyzed from the sentinel group. The intention is to ensure any serious adverse event is identified in – and limited to - a single subject rather than affecting the entire cohort.
• Considering possible delayed adverse reactions (PD effect related to duration of target inhibition or target-mediated PK profile), an appropriate time interval should be defined between dose escalation steps, between sentinel groups as well for the follow-up at end of the trial.
• Modeling and simulation of human PK and PD profiles and their relationship from available preclinical data, as well as the use of physiologically-based PK (PBPK) modeling, should be considered as tools to help in the estimation of doses, human half-life, duration and time-points for different assessments and follow-up.

How to Manage PK Characteristics of mAbs During Early Development

The use of bioanalysis is absolutely key for successful PK studies. The bioanalytical features of mAbs that need to be taken into consideration when performing pharmacokinetic studies include the determination of an appropriate assay method (ELISA, bioassay, LC-MS, etc.), and in which matrices the study is to be performed (plasma, whole blood, etc.). Possible interference by anti-drug antibodies (ADAs) and the effects this may have need to be taken into consideration, as well as the stability of the mAb molecule in PK samples when subjected to light or variances in temperature. It is also important to think in advance about the nature of what the analysis is expected to show (drug bound to circulating target, unbound drug or total quantity of drug) and the effect of target concentration (patient versus human volunteer).

The first factor influencing PK to be considered is how the drug is to be absorbed by the body. This is determined by the drug’s route of administration, which will usually be either by intravenous, subcutaneous or intramuscular injection, as biologics exhibit low-tozero bioavailability when administered orally, and their intramuscular or subcutaneous bioavailability is generally in the region of 40 to 100%. Factors defining bioavailability such as dose, formulation, the charge of a mAb, species-specific factors, injection site, and subject specific physiological factors, need to be considered.

When dosing, it is important to consider what the therapeutic targeted dose will be, since large doses of biological drugs may not be feasible because the injectable volume by subcutaneous or intramuscular routes is limited, typically a maximum of 5 mL.

Biological drugs are usually absorbed into the body via the lymphatic system and absorption is slow. The maximum absorption is typically reached between one and eight days after subcutaneous or intramuscular dosing, so this must be considered when determining the appropriate approach for PK/PD sampling during the clinical trials.

In general, the distribution of a biologic within the body is limited due to the unusually large molecular weight of these molecules. This results in a typically low volume of distribution; the distribution within the body itself being mainly driven by convection, as compared to diffusion for small molecule drugs. When investigating the distribution profile of a mAb drug, properties such as the molecule’s charge, isoelectric point, glycan structure, and subject related specificities (weight, age, gender, genetic variants of neonatal Fc receptor (FcRn)/gamma Fc receptor (FcγR) etc.) should be taken into account.

Finally, to efficiently study the elimination of a mAb in human, special elimination pathways should be explored, such as:

1. Target-mediated drug disposition (TMDD), which is a nonlinear PK phenomenon whereby the drug-target binding and drug-target complex degradation result in dose-dependent changes in PK. TMDD should be assessed in preclinical PK studies and continued in a human SAD study. Appropriate PK analysis and correct interpretation is required, often by using complex mathematical PK/PD models.
2. Immunogenicity has the potential to affect both PK and PD properties and is considered as one of several possible elimination routes, the likelihood of which is difficult to predict from animals. Further complicating the analysis is that PD is impacted through PK. Factors influencing immunogenicity, such as humanization, the route of administration, dose and duration of treatment, species specificities, sensibility and timing of ADA testing, the nature of ADA (neutralizing or non-neutralizing) and appropriate ADA testing are to be considered and assessed in early phase trials with mAb drugs.
3. FcRn mediated recycling is another interesting phenomenon explaining the PK behavior of many mAb drugs. mAb drug affinity to FcRn should be studied at the preclinical stage, and information from these studies used in the design of later clinical trials. FcRn effects which result in a mAb having a longer than expected half-life is leading to opportunities for FcRn engineering. FcRn polymorphism may also result in inter-subject variabilities in healthy subjects and patients.

The combination of PK, PD and immunogenicity sampling schema should be adapted to assess the elimination specificities of each mAb drug, and at each clinical development level according to available information.

All of the above-mentioned PK factors highlight the facts that each complex situation requires a complex approach to trial design, implementation and data analysis.

Developing mAbs: Regulatory Aspects

There are several areas where there are regulatory differences between chemical and biological products: these include the chemistry, manufacturing and controls (CMC); non-clinical development; and scientific advice and regulatory agency meetings. In addition to these differences, mAbs are more complex products, and require a specific and tailored regulatory approach.

The CMC covers the manufacturing aspects of an investigational medicinal product (IMP) and governs the production of an investigational medicinal product dossier (IMPD). Specifics covered include the quality of batches, the composition of batches used for non-clinical testing, i.e., non-GMP batches, and the GMP batches used for clinical trials. The presence (or absence) of impurities in the batch needs to be justified, and the shelf life of a batch should be sufficient to support the duration of the study. In addition, it should be borne in mind that the manufacturing process influences the properties and performance of the product.

Non-clinical packages should be enough to support Phase 1 studies and it is important to consider the choice of animal species for nonclinical studies, as well as the drug’s dosage and the following of good laboratory practice (GLP). GLP must be undertaken for safety pharmacology studies, but it is not essential for efficacy studies. In Phase 1 studies, some non-clinical properties of the drug need to be considered, including the duration-repeated dose toxicity, drug carcinogenicity and genotoxicity, and the results of reproduction toxicology studies.

With respect to scientific advice and regulatory agency meetings, points that should be considered by drug developers are when is the best time to go for a meeting with a regulatory agency, and where is best to seek advice. In Europe, scientific advice is available from national authorities as well as the EMA. European national authority meetings usually take place before Phase 1 studies commence, and advice can be given on the non-clinical program, the design of a Phase 1 trial, validation of the testing strategy in a manufacturing program, and whether a study should be performed in healthy volunteers or in patients. In the US, a pre-Investigational New Drug (IND) meeting takes place with the FDA where the same topics can be discussed, which is a mandatory step before the submission of an IND. By asking the right questions at the right time, agencies can help developers draw up a clearly-defined path forward for the Phase 1 trial.

Conclusion

The development path of small molecule drugs is very well defined, and the clinical considerations with such drugs are well known. Biologics, including mAbs, have complex pharmacokinetic and pharmacodynamic properties in comparison to those of small chemical molecules, and ensuring successful clinical development of these drug products is dependent upon trial design and strategy. FIH trial study design is essential to support further clinical development and a well-designed CMC strategy is critical for success. The importance of engaging early with regulators cannot be overemphasized and learning from previous experiences is paramount to ensure safe, and effective trials yield the results that are needed to progress drugs through the clinical phases of development.

References

1. W Wang, EQ Wang and JP Balthasar; Clinical Pharmacokinetics of Therapeutic Monoclonal Antibodies, volume 84, 5, Nov 2008, www.nature.com/cpt
2. Lobo, E.D., Hansen, R.J. and Balthasar, J.P; Antibody pharmacokinetics and pharmacodynamics. J. Pharm. Sci. 93, 2645–2668 (2004).
3. Ron J. Keizer, Alwin D.R. Huitema, Jan H.M. Schellens and Jos H. Beijnen; Clinical Pharmacokinetics of Therapeutic Monoclonal Antibodies, Clin Pharmacokinet 2010; 49 (8): 493-507
4. Tang L, Meibohm B; Pharmacokinetics of peptides and proteins. Pharmacokinetics and pharmacodynamics of biotech drugs. Weinheim: Wiley-VCH Verlag GmbH and Co, 2006: 17-43.
5. Liang ZHAO, Tian-hua REN, Diane D WANG; Clinical pharmacology considerations in biologics development, Acta Pharmacologica Sinica (2012) 33: 1339–1347
6. Hoon Young Suh, Carl CPeck, Kyung-Sang Yu, Howard Lee; Determination of the starting dose in the first-in-human clinical trials with monoclonal antibodies: a systematic review of papers published between 1990 and 2013; Drug Design, Development and Therapy 2016:10 4005–4016
7. Aaron R. Hansen et al; Choice of Starting Dose for Biopharmaceuticals in First-in-Human Phase I Cancer Clinical Trials; Oncologist. 2015 Jun; 20(6): 653–659.
8. Adrian M. Senderowicz; Information Needed to Conduct First-in-Human Oncology Trials in the United States: A View from a Former FDA Medical Reviewer; www.aacrjournals.org Published OnlineFirst March 9, 2010; DOI: 10.1158/1078-0432.CCR-09-2766
9. Zou P, Yu Y, Zheng N, Yang Y, Paholak HJ, Yu LX, Sun D; Applications of human pharmacokinetic prediction in first-in-human dose estimation; AAPS J. 2012 Jun;14(2):262-81
10. Ryman et al; Pharmacokinetics of Monoclonal Antibodies; CPT Pharmacometrics Syst Pharmacol, 2017
11. Guideline on Immunogenicity assessment of therapeutic proteins; 18 May 2017 EMEA/CHMP/BMWP/14327/2006 Rev 1
12. Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products; 20 July 2017 EMEA/CHMP/SWP/28367/07 Rev. 1