(52e) Autologous Cancer Therapies:How Can We Handle the Complexity of the Supply Chain?

Autologous
Cancer Therapies:

How
can we handle the complexity of the supply chain?

Maria M. Papathanasiou, Nilay Shah

Dept. of Chemical Engineering, Centre
for Process Systems Engineering (CPSE), Imperial College London SW7 2AZ,
London, U.K

In August
2017, the U.S. Food and Drug Administration made a historic approval of the
first autologous, cell-based cancer therapy, changing the future of cancer
therapies. Novartis’ Kymriah, is an autologous Chimeric Antigen Receptor (CAR)
T-cell therapy for B-cell acute lymphoblastic leukaemia (ALL) and is the first
therapy to open the road towards innovative cancer therapies. Following that
Kite’s Yescarta was approved by FDA in October 2017, indicated for the
treatment of adult patients with relapsed or refractory large B-cell lymphoma
after two or more lines of systemic therapy. Due to their highly promising
results [1], the CAR T-cells are
currently experiencing a tremendous growth with more than 200 clinical trials
in place globally (data as presented in ClinicalTrials.gov).

Unlike
common pharmaceutical products, those therapies are of autologous nature,
suggesting 1:1 business and/or manufacturing models, where the drug is
manufactured based on the patient’s own cells (Figure 1) [2]. The latter increases
the complexity both of the production process, as well as of the reimbursement
strategies that need to be established. Such products are of highly sensitive
nature, requiring special handling, while their manufacturing process involves
a plethora of steps that need to be well-coordinated. Moreover, due to their
high specificity and complex lifecycle, CAR T-cell therapies are characterized
by high manufacturing costs that are reflected by excessive end-prices for the
patients (approximately $400.000 per patient). Consequently, CAR T-cells are
currently considered elite-type products that cannot be accessed by all patient
groups and are very challenging to reimburse.

Figure 1 Current CAR T-cell process/distribution steps
along with some of the key bottlenecks and challenges.

Apart from the
afore-mentioned challenges .CAR T-cell therapies are currently following a hand-to-hand
logistics model that will prove to be insufficient once they become available
to bigger patient populations. Therefore, the pharmaceutical industry is urged
by the regulators to establish robust supply chain models that will be able to
support full-scale commercialization as those therapies become available.

In this work, we focus
on the investigation, design and comparison of alternative supply chain models
that will be able to ensure: (i) lower costs, (ii) return time optimization,
(iii) scalability and (iv) risk mitigation in cases of supply shortages and/or
high demand. We present and discuss alternative distribution solutions and
their impact on the cost and regulations associate with those therapies, as
well as challenges associated to adverse events (e.g. extreme weather
conditions). We focus on decisions related to: (i) number of clinical sites,
(ii) number of manufacturing sites, as well as (iii) location of sites.
Moreover, we investigate the establishment of intermediate collection sites to
serve as de-bottlenecking solutions between the clinical and manufacturing sites.
The impact of all presented alternatives on the Net Present Value (NPV) of the
therapy is assessed, along with potential challenges related to the associated
regulatory environment.

Acknowledgments

Funding from the UK
Engineering & Physical Sciences Research Council (EPSRC) for the Future
Targeted Healthcare Manufacturing Hub hosted at University College London with
UK university partners is gratefully acknowledged (Grant Reference:
EP/P006485/1). Financial and in-kind support from the consortium of industrial
users and sector organisations is also acknowledged.

References

[1]       S.
L. Maude et al., “Tisagenlecleucel in Children and Young Adults with
B-Cell Lymphoblastic Leukemia,” N. Engl. J. Med., vol. 378, no. 5, pp.
439–448, 2018.

[2]       B. L.
Levine, J. Miskin, K. Wonnacott, and C. Keir, “Global Manufacturing of CAR T
Cell Therapy,” Mol. Ther. - Methods Clin. Dev., vol. 4, no. March, pp.
92–101, 2017.