Synopsis

This presentation discusses clinical translation of novel agents. Firstly, the conventional diagnostic drug development pathway is outlined. Then six unconventional pathways are introduced and illustrated with examples from MR and other diagnostic imaging modalities.

Clinical Translation Overview

Novel agents are first characterised in vitro and, if promising, evaluated in animals, then translated into man. It seems difficult to justify the cost and ethical burden of chemistry and animal work, unless the ultimate goal is to improve human health.

Substances and devices introduced into the human body are strictly regulated by bodies such as CFDA (China), EMA (Europe), FDA (US), or MHLWPMDA (Japan). Approximately 95% of substances approved by regulatory authorities are therapeutic drugs. The rest are diagnostic drugs, mainly imaging contrast agents and tracers. Diagnostic imaging drugs have been approved for MR, CT/radiography, SPECT/scintigraphy, PET, ultrasound, and the optical imaging modalities.

Regulators have three concerns: Safety; Efficacy; and Quality. They need evidence that the medical benefits of the agent outweigh any risks or harms to patients who receive it, and evidence of consistent high manufacturing quality (Good Manufacturing Practice, GMP). Other diagnostic modalities which use innovative chemistries, e.g. immunohistochemistry or in-situ hybridisation, face lower regulatory burdens, because they do not expose patients to any risk of toxicity.

In Clinical Development the first milestone (translational gap 1) is regulatory approval to start clinical trials: Investigational Medicinal Product (IMP) or Investigational New Drug (IND) approval. The second milestone (translational gap 2) is regulatory approval to manufacture and sell the new agent: the Marketing Authorisation (MAA) or New Drug (NDA) Application approval.

A conventional pathway to market for new agents

1. A for-profit company acquires intellectual property (IP) to the agent, through either in-house discovery research or inlicensing;

2. The company raises funds for Development, either internally or from the financial markets;

3. The company demonstrates Safety and Efficacy (from clinical trial findings) and Quality (GMP) to regulators’ satisfaction;

4. Cost-effectiveness is often a fourth hurdle. The company must satisfy the payer that the benefit to patients (e.g. in Quality-adjusted Life Years, QALYs) outweighs the cost of the product e.g. in €/QUALY.

5. After regulatory approval, the company can sell the agent at a profit to radiologists or other healthcare professionals for diagnostic imaging of their patients. The company may only promote the product for indications approved by the regulator. Additional sales occur if the product is used “off-label” in other indications. Profits repay and reward the original investment. Most profit is made during the exclusivity period before patents expire.

6. If sales are low, the product is withdrawn from market.

7. If sales are high, generic competition may drive down prices after patent expiry.

8. Nanomedicines may retain effective exclusivity even after patent expiry because of confidential manufacturing "know-how".

Common contrast agents did follow this pathway^1,2, but there are challenges:

• Diagnostic agents, unlike therapeutics, do not benefit patients directly. Patients benefit indirectly if they are directed down a better care pathway. Hence it can be difficult to quantify the true benefit of a diagnostic to patients. If care pathways change (e.g. due to new treatments) the benefit of the diagnostic may disappear.
• Regulators have become more concerned about risks of chronic toxicity from diagnostic imaging agents. Identification of rare delayed adverse events needs large trials with long follow-up, increasing development costs.
• MR platforms change. Agents whose relaxivity is optimised at one field strength may become less effective as other field strengths are introduced.
• The capabilities of non-contrast MR increase continually, and may overtake the putative new capability offered by the new agent.
• Even if existing contrast agents are less specific than the new agent, if the old agents are sensitive and cheap (generic), they may out-compete the expensive new agent.
• Diagnostic imaging competes with other diagnostic modalities. It is difficult for MR to compete on cost or safety grounds with sensitive, specific and inexpensive biomarker modalities such as circulating free DNA in oncology.

In response to these challenges, several alternative pathways to impact have been devised.

A. “The non-proprietary NDA”

Here, for IP or other reasons, there is no prospect of exclusivity after approval, and therefore no incentive for investors to fund the development. Instead, development is funded by government agencies or entities who do not expect a direct financial return on their investment. This approach worked for PET tracers such as fludeoxyglucose-18-F (FDG^3,4).

B. “The everlasting IMP”

Similar to A, but with no intention of ever seeking marketing (MAA/NDA) approval and therefore no possibility of marketing for patient care. Instead, the agent is used under IMP/IND or similar authority solely in clinical trials. The substantial GMP costs are covered by the triallists. This is actually normal in PET, for example consider ¹¹C-raclopride⁵ or ¹⁸F-fluoromisonidazole⁶.

C. “Raiding the Pharmacopoeia”

Here, a foodstuff or drug previously approved in a different indication is adopted as an imaging contrast agent. There are many successful MR examples such as iopamidol⁷, ketamine⁸, oxygen^9,10, xenon¹¹, glucose¹², fructose¹³, or pyruvate¹⁴.

D. “Companion diagnostics”

Here, a proprietary therapeutic is co-developed with a proprietary imaging companion diagnostic. The regulatory authority requires that patients undergo the imaging diagnostic test before the therapeutic can be given. This case has favourable health economics, driven by the companion therapeutic. One disadvantage is that if the therapeutic development fails, it likely destroys the diagnostic development too. Imaging examples include: vintafolide plus etarfolatide¹⁵; [⁹⁰Y]-ibritumomab plus [¹¹¹In]-ibritumomab¹⁶; MM-302 plus [⁶⁴Cu]-MM-302¹⁷.

E. “Unrelated therapeutic indications”

Here, an investigational MR diagnostic agent also happens to have therapeutic potential in an unrelated indication, and so the agent can be developed as a therapeutic. A couple of MR examples are tempol (radioprotectant¹⁸) and ferumoxytol (chronic kidney disease¹⁹).

F. “Theranostics”

Similar to E, but now the agent is diagnostic and therapeutic in the same indication. An obvious opportunity in nuclear medicine (e.g. ¹³¹I-iodide²⁰), but capicitibine²¹ provides a possible MR example.

Conclusion

Acknowledgements

References

1. Pierre VC, Allen MJ, Caravan P. Contrast agents for MRI: 30+ years and where are we going? J Biol Inorg Chem. 2014;19(2):127-131. doi:10.1007/s00775-013-1074-5.

2. Zimmermann RG. Why are investors not interested in my radiotracer? The industrial and regulatory constraints in the development of radiopharmaceuticals. Nucl Med Biol. 2013;40(2):155-166. doi:10.1016/j.nucmedbio.2012.10.012.

3. Food_and_Drug_Administration_of_the_United_States_of_America. NDA 21-870 (2004)

4. Food_and_Drug_Administration_of_the_United_States_of_America. NDA 21-768 (2004).

5. Nord M, Farde L. Antipsychotic Occupancy of Dopamine Receptors in Schizophrenia. CNS Neurosci Ther. 2011;17(2):97-103. doi:10.1111/j.1755-5949.2010.00222.x.

6. Lee ST, Scott AM. Hypoxia Positron Emission Tomography Imaging With 18F-Fluoromisonidazole. Semin Nucl Med. 2007;37(6):451-461. doi:10.1053/j.semnuclmed.2007.07.001.

7. Longo DL, Dastrù W, Digilio G, et al. Iopamidol as a responsive MRI-chemical exchange saturation transfer contrast agent for pH mapping of kidneys: In vivo studies in mice at 7 T. Magn Reson Med. 2011;65(1):202-211. doi:10.1002/mrm.22608.

8. Doyle OM, De Simoni S, Schwarz AJ, et al. Quantifying the Attenuation of the Ketamine Pharmacological Magnetic Resonance Imaging Response in Humans: A Validation Using Antipsychotic and Glutamatergic Agents. J Pharmacol Exp Ther. 2013;345(1):151-160. doi:10.1124/jpet.112.201665.

9. Doyle FH, Gore JC, Pennock JM. Relaxation Rate Enhancement Observed in Vivo By NMR Imaging. J Comput Assist Tomogr. 1981;5(2):295.

10. O’Connor JPB, Boult JKR, Jamin Y, et al. Oxygen-Enhanced MRI Accurately Identifies, Quantifies, and Maps Tumor Hypoxia in Preclinical Cancer Models. Cancer Res. 2016;76(4):787-795. doi:10.1158/0008-5472.CAN-15-2062.

11. Albert MS, Cates GD, Driehuys B, et al. Biological magnetic resonance imaging using laser-polarized ¹²⁹Xe. Nature. 1994;370(6486):199-201. doi:10.1038/370199a0.

12. Walker-Samuel S, Ramasawmy R, Torrealdea F, et al. In vivo imaging of glucose uptake and metabolism in tumors. Nat Med. 2013;19(8):1067-1072. doi:10.1038/nm.3252.

13. Seegmiller JE, Dixon RM, Kemp GJ, et al. Fructose-induced aberration of metabolism in familial gout identified by ³¹P magnetic resonance spectroscopy. Proc Natl Acad Sci U S A. 1990;87(21):8326-8330.

14. Day SE, Kettunen MI, Gallagher FA, et al. Detecting tumor response to treatment using hyperpolarized ¹³C magnetic resonance imaging and spectroscopy. Nat Med. 2007;13(11):1382-1387. doi:10.1038/nm1650.

15. European Medicines Agency. EMA recommends approval of new treatment for platinum-resistant ovarian cancer together with companion diagnostic. 2014

16. Food_and_Drug_Administration_of_the_United_States_of_America. Ibritumomab Tiuxetan BLA approval 125019 of 19th February 2002.

17. Lee H, Shields AF, Siegel BA, et al. ⁶⁴Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer. Clin Cancer Res. 2017;23(15):4190-4202. doi:10.1158/1078-0432.CCR-16-3193.

18. Metz JM, Smith D, Mick R, et al. A phase I study of topical tempol for the prevention of alopecia induced by whole brain radiotherapy. Clin Cancer Res. 2004;10(19):6411-6417. doi:10.1158/1078-0432.CCR-04-0658.

19. Food_and_Drug_Administration_of_the_United_States_of_America. FERAHEME® (ferumoxytol injection), for intravenous use. HIGHLIGHTS OF PRESCRIBING INFORMATION (2009).

20. Avram AM. Radioiodine Scintigraphy with SPECT/CT: An Important Diagnostic Tool for Thyroid Cancer Staging and Risk Stratification. J Nucl Med Technol. 2014;42(3):170-180. doi:10.2967/jnumed.111.104133.

21. Chung YL, Troy H, Judson IR, et al. Noninvasive measurements of capecitabine metabolism in bladder tumors overexpressing thymidine phosphorylase by fluorine-19 magnetic resonance spectroscopy. Clin Cancer Res. 2004;10(11):3863-3870. doi:10.1158/1078-0432.CCR-03-0237.