The Development of Somatuline Autogel®: An Interview with Joël Richard, Vice President Peptides, Ipsen

By Andy Lewis, CRS Director at Large

Somatuline Autogel® is a ready-to-use sustained release formulation of the peptide lanreotide with a unique and innovative controlled release mechanism. Andy Lewis interviewed Joël Richard, VP Peptides at Ipsen, on the background of its development, how it works, and how it is manufactured.

Q         What makes lanreotide a good candidate for a sustained release formulation?

A         Lanreotide is a potent somatostatin analogue used for the treatment of acromegaly. In acromegaly, the anterior pituitary produces abnormally high levels of growth hormone, often as a result of a tumour of the pituitary gland. The excess growth hormone results in the continued and abnormal growth of the tissues of the body in adulthood. The symptoms are therefore the results of this excessive growth and include large facial bones, large hands, large feet, excessive sweating, fatigue, a large jaw and tongue, and widely spaced teeth. Lanreotide blocks the production of growth hormone by the pituitary gland. Due to its short half-life and the fact that endogenous growth hormone is secreted throughout the day, sustained elevated plasma levels of lanreotide provide the best suppression of growth hormone secretion—making it an ideal candidate for a controlled release formulation.

Q         A PLGA microparticle formulation was already developed prior to Autogel®. What spurred the development of Somatuline Autogel®?

A         Ipsen has considerable experience in developing PLGA and PLA peptide microparticle formulations, using a variety of different manufacturing technologies, so this delivery system was the natural first choice for our needs. The microparticle formulation developed (Somatuline LA®) not only demonstrated the versatility of PLGA formulations for peptide delivery but also was most important because it showed that when lanreotide is delivered at elevated levels for prolonged periods it is safe and effective. As part of the company’s product development pipeline, work was already underway on enhanced formulations that improved various features of the final product. In particular, a formulation was desired that could be injected subcutaneously, was ready to use, and provided longer periods of coverage.

Q         Why wasn’t another PLGA formulation developed?

A         While PLGA or PLA formulations have been shown to be highly effective, with many success stories, there are a number of limitations. In this case, the dose of peptide required to provide coverage for a month made development of a microparticle formulation challenging, and the acceptability of an implant was questionable. Thus, while various options were investigated, an innovative approach was required.

Q         What was the technology behind Somatuline Autogel®, and who led the team that developed it?


Somatuline nanotubes


A         As more experience formulating the peptide was obtained, it was observed that under certain conditions the peptide became a semisolid. This remarkable and somewhat unexpected observation prompted further investigation into what exactly was causing it to happen. After extensive work by the team led by Roland Cherif-Cheikh and Céline Valéry in collaboration with Franck Artzner (from CNRS, Rennes, France), it was determined to be due to assembly of the peptide into nanotubes. These nanotubes are composed of 26 helicoidal, laterally assembled filaments. These filaments are themselves formed from two different protofilaments (one internal to the nanotube, one external) made up of dimer building blocks in antiparallel β-sheet networks stabilised by hydrogen bonding. The two protofilaments interact via π-π stacking of the aromatic side chains to form the filaments that make up the nanotubes.

The key finding was not only how to control this process but that it is reversible, and following injection or when put in dilute solution, peptide monomers are slowly released from the ends of the nanotubes. Following extensive development and characterisation, a formulation and a manufacturing process were developed that released the peptide in vivo over a period of a month. Somatuline Autogel® was the first marketed sustained release formulation produced via peptide self-assembly. Following the initial observation, the pharmaceutical development of Somatuline Autogel® at Ipsen took about eight years, obtaining its first approval in 2001.



Q         What advantages does Somatuline Autogel® have?

A         Unlike microparticle formulations, Somatuline Autogel® can be injected subcutaneously and can be presented as a prefilled syringe. As there are no complicated resuspension procedures—such as those required by other technologies—there is less potential for errors or issues with injectability, and it is potentially suitable for self-administration by patients. Furthermore, a one-month coverage is achieved from a single injection.

Q         What advice would you give to young scientists at the start of their career?

A         Actually, two pieces of advice:

  • Look outside the box (i.e., away from classical ideas, formulations, and processes). 
  • In France we have an expression, “Il faut toujours essayer de voir le bon côté de la médaille,” which means “Always try to see the golden side of the medal.” In other words, think positive and take advantage of what you observe: with Autogel®, an a priori drawback (gel formation, viscosity) was transformed into a key advantage for sustained release.

Q         Are there any relevant or interesting papers that you would recommend?

A         Pouget, E, Fay, N, Dujardin, E, Jamin, N, Berthault, P, Perrin, L, Pandit, A, Rose, T, Valéry, C, Thomas, D, Paternostre, M, Artzner, F. Elucidation of the self-assembly pathway of lanreotide octapeptide into b-sheet nanotubes: Role of two stable intermediates, J. Am. Chem. Soc. 132(12): 4230-4241 (2010). doi:10.1021/ja9088023

Valéry, C, Artzner, F, Robert, B, Gulick, T, Keller, G, Grabielle-Madelmont, C, Torres, M-L, Cherif-Cheikh, R, Paternostre, M. Self-association process of a peptide in solution: From b-sheet filaments to large embedded nanotubes, Biophys. J. 86(4): 2484-2501 (2004). doi:10.1016/S0006-3495(04)74304-0

Valéry, C, Pouget, E, Pandit, A, Verbavatz, J-M, Bordes, L, Boisdé, I, Cherif-Cheikh, R, Artzner, F, Paternostre, M. Molecular origin of the self-assembly of lanreotide into nanotubes: A mutational approach, Biophys. J. 94(5): 1782-1795 (2008). doi:10.1529/biophysj.107.108175

Further Information

For a video of the self-assembly of lanreotide into nanotubes, see