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Exposure–disease response analysis of natalizumab in subjects with multiple sclerosis

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Abstract

Natalizumab, a human immunoglobulin monoclonal antibody that targets α4β1/α4β7 integrin, is an effective therapy approved for the treatment of multiple sclerosis (MS). The objective of this analysis was to develop a population exposure–response model utilizing gadolinium-enhancing (Gd) lesion count data from four clinical studies and annualized relapse rate (ARR) data from three clinical studies. The natalizumab exposures were derived for the individuals using a population pharmacokinetic model. A log-linear exposure effect on Gd lesion count and ARR adequately characterized the relationship between exposure and disease response. In the case of the Gd lesion count model, a bimodal model that distributed subjects into two subpopulations based on low or high baseline Gd lesion count provided a superior goodness of fit. The mean (95% confidence interval) slopes from the exposure–Gd lesion count model and exposure-ARR model are −0.0903 (−0.100, −0.081) and −0.0222 (−0.026, −0.015) (mg/L)−1, respectively. From these slopes, it can be inferred that both Gd lesion count and ARR decrease with increasing exposure to natalizumab in MS subjects. Model-based simulations demonstrated that although reductions in Gd lesion count and ARR were observed with lower doses (75, 150, or 200 mg), only the dose of 300 mg every 4 weeks (q4w) was associated with an ARR ≤0.25 and was considered clinically effective. The results from the exposure-Gd lesion count and exposure-ARR models thus support the appropriateness of the approved natalizumab dose (300 mg q4w) in MS subjects.

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Acknowledgements

All named authors meet the International Committee of Medical Journal Editors criteria for authorship for this manuscript and take responsibility for the integrity of the work as a whole. Biogen (Cambridge, MA, USA) provided funding for editorial support in the development of this manuscript; Joshua Safran of Ashfield Healthcare Communications (Middletown, CT, USA) copyedited and styled the manuscript per journal requirements. Biogen reviewed and provided feedback on the manuscript to the authors. The authors had full editorial control of the manuscript and provided their final approval of all content. We would like to thank Dr. Yaming Hang and Dr. Xiao Hu on their valuable input on model development and implementation in NONMEM. Partial results from this analysis have previously been presented at the 32nd congress of the European Committee for Treatment & Research in Multiple Sclerosis (ECTRIMS; September 14–17, 2016, London, UK).

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Authors and Affiliations

  1. Systems Pharmacology, Biogen, 14 Cambridge Center, Cambridge, MA, 02142, USA

    Kumar Kandadi Muralidharan & Ivan Nestorov

  2. Clinical Development, Biogen, Cambridge, MA, USA

    Deb Steiner, Dan Mikol & Jacob Elkins

  3. Global Medical Affairs, Biogen, Cambridge, MA, USA

    Diogo Amarante & Pei-Ran Ho

  4. Global Biomarker Discovery and Development, Biogen, Cambridge, MA, USA

    Meena Subramanyam

Authors
  1. Kumar Kandadi Muralidharan
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  2. Deb Steiner
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  4. Pei-Ran Ho
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  5. Dan Mikol
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  6. Jacob Elkins
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  7. Meena Subramanyam
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  8. Ivan Nestorov
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Contributions

Dr. MS facilitated bioanalytical analysis of serum natalizumab concentration and α4-integrin saturation interpretation of laboratory data and provided access to PK-PD data. Dr. DM facilitated the transfer of MRI and ARR data. KKM and Dr. IN developed and interpreted the PK-PD and exposure–response models. Additional feedback on sections involving clinical interpretation, and discussions were provided by Dr. DM, Dr. P-RH, Dr. DA, Dr. JE and Dr. DS, KKM wrote the manuscript. Dr. IN, Dr. MS, Dr. P-RH, Dr. JE, and Dr. DS approved the final version.

Corresponding author

Correspondence to Ivan Nestorov.

Ethics declarations

Conflict of interest

This analysis was funded by Biogen. Drs. Muralidharan, Steiner, Ho, Elkins, Subramanyam, and Nesterov are employees of and hold stock and/or stock options in Biogen (Cambridge, MA, USA). Drs. Amarante and Mikol were employees of and held stock and/or stock options in Biogen during completion of this work. Dr. Mikol is now an employee of Amgen; Amgen was not in any way associated with this work.

Ethical approval

All studies were sponsored by Biogen and were conducted in accordance with the principles of the Declaration of Helsinki and the International conference on Harmonization Guideline for Good Clinical Practice.

Informed consent

Written informed consent was obtained from all subjects.

Additional information

Dr. Amarante passed away during the development of this manuscript, and though he qualified for authorship per ICMJE criteria, he was not able to provide final approval. The authors gratefully acknowledge his contributions to the analyses in and development of this manuscript.

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Muralidharan, K.K., Steiner, D., Amarante, D. et al. Exposure–disease response analysis of natalizumab in subjects with multiple sclerosis. J Pharmacokinet Pharmacodyn 44, 263–275 (2017). https://doi.org/10.1007/s10928-017-9514-4

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  • DOI: https://doi.org/10.1007/s10928-017-9514-4

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