Advanced Accelerator Applications

Last updated
Advanced Accelerator Applications
Industry Pharmaceuticals
Founded2002 (2002)
Headquarters Saint-Genis-Pouilly, France
Key people
 Sidonie Golombowski-Daffner, Chairperson and President
ProductsGluscan, Dopaview, Fluorochol/Aaacholine, Netspot, Somakit Toc
Number of employees
>1000
Parent Novartis
Website adacap.com

Advanced Accelerator Applications (AAA or Adacap) is a France-based pharmaceutical group, specialized in the field of nuclear medicine. [1] The group operates in all three segments of nuclear medicine (PET, SPECT and therapy) to diagnose and treat serious conditions in the fields of oncology, neurology, cardiology, infectious and inflammatory diseases. [2]

Contents

In late October 2017, Reuters announced that Novartis would acquire the company for $3.9 billion, paying $41 per ordinary share and $82 per American depositary share representing a 47 percent premium. [3] On January 22, 2018, Novartis AG announced the successful completion of the tender offer by its subsidiary, Novartis Groupe France S.A. [4]

History

AAA was created in 2002 by Italian physicist Stefano Buono to exploit a patent from the European Organization for Nuclear Research (CERN). [5]

AAA currently has a total of 31 sites in 12 countries, including: 19 production facilities in 8 countries (in Europe and the U.S.) that manufacture targeted radioligand therapies and precision imaging radioligands, and 6 sites with R&D activity.

In October 2017, Novartis announced that it intended to acquire the company for US$3.9 billion. [6] [7] The acquisition was completed in January 2018. [8]

In January 2024, AAA announced plans to expand manufacturing capabilities and build additional RLT supply facilities in Sasayama, Japan, and Haiyan, Zhejiang, China. [9]

In August 2024, Siemens Healthineers bought the diagnostic arm of Advanced Accelerator Applications that specialises in producing radioactive chemicals used for cancer scan for more than $224 million. [10]

Products

AAA has a portfolio of diagnostic and therapeutic applications and products in the fields of Molecular Imaging and Therapy. [11] The group's portfolio of radiopharmaceuticals includes radioactive agents for positron emission tomography (PET) imaging as well as single-photon emission computed tomography (SPECT) diagnostic products. [12]

Lutathera

The company's lead product is LUTATHERA, a Lutetium Lu 177 dotatate labeled somatostatin analogue peptide, [13] a theragnostic cancer product being developed to treat certain gastro-entero pancreatic neuroendocrine tumors (GEP-NETs). [14] It selectively targets over-expressed somatostatin receptors while also giving off gamma emissions to allow physicians to visualize where in the body both the drug and the tumor are. It was approved by the FDA in January 2018 for GEP-NET. [15]

Approval

Lutathera, also known as lutetium Lu 177 dotatate, is a target treatment drug for patients with GEP-NETs. [16] Its approval for Advanced Accelerator Applications was announced on January 26, 2018, by the US Food and Drug Administration. [17] Lutathera is most notable as the first FDA approved peptide receptor radionuclide therapy (PRRT) to combat GEP-NETs. [18]

GEP-NETs

GEP-NETs are rare groups of cancer that continue to proliferate, regardless of initial therapy treatments. [16] They are present in areas affected by pancreatic or gastrointestinal cancers; specifically, the pancreas, stomach, intestines, colon and rectum. [17]

Use

Lutathera is used to combat pancreatic and gastrointestinal cancers that do not respond well to common chemotherapeutical treatments; namely for patients with somatostatin receptor-positive GEP-NETs. [16] [17] These receptors are commonly found on tumors located in the foregut, midgut, and hindgut. [19]

Mechanism

Lutathera is a radioactive drug consisting of a tyrosine-containing somatostatin analog Tyr3-octreotate (TATE) attached to the chelating agent tetraazacyclododecanetetra-acetic acid (DOTA). [20] Attached to the dotatate is the radioactive marker Lu-177, a radioisotope. [16] The dotatate binds to the GEP-NET positive somatostatin receptor cells commonly present on neuroendocrine tumors. [16] [20] After binding to the receptor, Lutathera enters the cell and uses its radioactive property to damage DNA. [16] This mechanism effectively triggers apoptosis of cancerous tumor cells. As a result, studies found that 16% of patients being treated with Lutathera experienced either complete or partial tumor shrinkage. [16]

Studies

FDA approval of Lutathera was ultimately supported by two clinical studies. [17] NETTER-1, a Phase 3 study, was a randomized clinical trial which included patients with a severe form of somatostatin receptor-positive NETs. [16] [18] The study compared Lutathera treatment with a standard dose of octreotided LAR against a high-dose of octreotide LAR. [16] Researchers measured tumor growth after the course of the treatment, also known as progression-free survival. [17] The study concluded that patients who were treated with Lutathera lived substantially longer compared to those who only received the octreotide treatment. [16] They experienced a 79% reduction in death and cancer progression. [18]

The Netherlands study gathered several patients with somatostatin receptor-positive tumors, including patients with GEP-NETs. [16] The study found that 16% of patients with GEP-NETs, who were treated with Lutathera, experienced complete or partial tumor shrinkage. [16] As a result, a pre-planned interim overall survival analysis found that Lutathera treatment lead to a 48% reduction in risk of death. [18]

Common Grade 3-4 Adverse Reactions

Common problemsSymptoms/ReactionsPercent of patients affected
Nausea5%
Vomiting7%
Hyperglycemia4%
Hypokalemia4%
Liver problems
Increased Gamma-Glutamyl Transferase20%
Elevated AST5%
Increased ALT4%
Tumor bleeding
Swelling (edema)
Tissue injury (necrosis)
Bone Marrow problems
Myelodysplastic syndrome2%
Acute leukemia1%
Kidney problems
Kidney failure2%
Neuroendocrine hormonal crisis
Hypotension1%
Bronchospasm
Myelosuppression1%
Lymphopenia44%
Anemia
Thrombocytopenia
Leukopenia
Neutropenia
Cardiac problems
Myocardial infarction1%
Cardiac failure2%
Embryo-Fetal Toxicity
Causes harm to unborn fetuses
Temporary Infertility
May cause infertility

[16] [17] [18] [19]

Advances

Lutathera is a major technological advancement for the detection of tumors. Diagnostic imaging that relies on dotatates can now rely on Lutathera to locate somatostatin receptor-positive tumors by tagging them with its radioactive component. [16] This tagging of tumors will allow them to become more visible during positron emission tomography (PET) scans. [16] With LU-177 dotatates, more somatostatin receptor-positive GEP-NET patients can be identified for treatment of the disease. [16]

LysaKare

LysaKare received a marketing authorisation valid throughout the EU on 25 July 2019. [21]

LysaKare protect the kidneys from radiation damage during cancer treatment with a radioactive medicine called lutetium (177Lu) oxodotreotide. LysaKare is for use in adults and contains the active substances arginine and lysine. [21]

Pipeline

AAA has a broad pipeline of products in development, including several theragnostic pairings for oncology indications.

NETSPOT and SomaKit TOC are novel kits for radiolabeling somatostatin analogue peptides to help diagnose somatostatin receptor-positive NET lesions. Each kit has received orphan drug designation from both the EMA and the FDA. [22] [23]

99MTc-rhAnnexin V-128, a SPECT investigational candidate for the diagnosis and assessment of apoptotic and necrotic processes, which are present in a number of pathological conditions in oncology and cardiovascular disease, as well as in autoimmune disorders. 99MTc-rhAnnexin V-128 is currently in a Phase I/II trial for the diagnosis of rheumatoid arthritis and ankylosing spondylitis, as well as several Phase II studies in cardiovascular, cardio-oncology, and pulmonary indications.

177Lu-PSMA-617 and 68Ga-PSMA-617 are in development to treat, image, monitor and stage prostate cancer. PSMA-617 is a ligand of prostate-specific membrane antigen (PSMA) expressed on the majority of prostate tumor cells. 177Lu-PSMA-617 also known as lutetium (177Lu) vipivotide tetraxetan is being developed to treat prostate cancer by binding to PSMA-617. In June 2021 it was granted a breakthrough therapy designation. [24] 68Ga-PSMA-617 is under development as a complementary diagnostic candidate.

CTT1057 is an 18F-labeled investigational diagnostic candidate in development for PET imaging of prostate cancer. CTT1057 is a phosphoramidate-based peptide, which specifically binds to Prostate-Specific Membrane Antigen (PSMA), expressed on the majority of prostate tumor cells.

177LuNeoBOMB1 and 68GaNeoBOMB1 are new generation antagonist bombesin analogs in development to treat, image, monitor and stage gastrin-releasing peptide receptor (GRPR)-expressing malignancies, such as such as gastrointestinal stromal tumors (GIST), prostate cancer and breast cancer. 177LuNeoBOMB1 is a therapeutic candidate and 68GaNeoBOMB1 is its complementary diagnostic candidate.

Millburn site

In 2016, AAA opened a light manufacturing and distribution site in Millburn, NJ, a residential town in North Jersey. [25] When the site was first purchased, it caused substantial concerns among local residents. [26] Per the requests of Millburn Residents, the Township Committee hired a nuclear/radiology expert to re-assess the appropriateness of opening a radioactive manufacturing site in the residential area. [27] The expert concluded that the proposed operations at AAA are safe and pose no hazard to the citizens of Millburn. [28] [29]

Related Research Articles

Radionuclide therapy uses radioactive substances called radiopharmaceuticals to treat medical conditions, particularly cancer. These are introduced into the body by various means and localise to specific locations, organs or tissues depending on their properties and administration routes. This includes anything from a simple compound such as sodium iodide that locates to the thyroid via trapping the iodide ion, to complex biopharmaceuticals such as recombinant antibodies which are attached to radionuclides and seek out specific antigens on cell surfaces.

A radioligand is a microscopic particle which consists of a therapeutic radioactive isotope and the cell-targeting compound - the ligand. The ligand is the target binding site, it may be on the surface of the targeted cancer cell for therapeutic purposes. Radioisotopes can occur naturally or be synthesized and produced in a cyclotron/nuclear reactor. The different types of radioisotopes include Y-90, H-3, C-11, Lu-177, Ac-225, Ra-223, In-111, I-131, I-125, etc. Thus, radioligands must be produced in special nuclear reactors for the radioisotope to remain stable. Radioligands can be used to analyze/characterize receptors, to perform binding assays, to help in diagnostic imaging, and to provide targeted cancer therapy. Radiation is a novel method of treating cancer and is effective in short distances along with being unique/personalizable and causing minimal harm to normal surrounding cells. Furthermore, radioligand binding can provide information about receptor-ligand interactions in vitro and in vivo. Choosing the right radioligand for the desired application is important. The radioligand must be radiochemically pure, stable, and demonstrate a high degree of selectivity, and high affinity for their target.

A gallium scan is a type of nuclear medicine test that uses either a gallium-67 (67Ga) or gallium-68 (68Ga) radiopharmaceutical to obtain images of a specific type of tissue, or disease state of tissue. Gallium salts like gallium citrate and gallium nitrate may be used. The form of salt is not important, since it is the freely dissolved gallium ion Ga3+ which is active. Both 67Ga and 68Ga salts have similar uptake mechanisms. Gallium can also be used in other forms, for example 68Ga-PSMA is used for cancer imaging. The gamma emission of gallium-67 is imaged by a gamma camera, while the positron emission of gallium-68 is imaged by positron emission tomography (PET).

<span class="mw-page-title-main">Neuroendocrine tumor</span> Tumors of the endocrine and nervous systems

Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung, and the rest of the body.

<span class="mw-page-title-main">Glutamate carboxypeptidase II</span> Enzyme

TAH molecule, also known as N-acetyl-L-aspartyl-L-glutamate peptidase I, NAAG peptidase, or prostate-specific membrane antigen (PSMA) is an enzyme that in humans is encoded by the FOLH1 gene. Human GCPII contains 750 amino acids and weighs approximately 84 kDa.

Copper-64 (64Cu) is a positron and beta emitting isotope of copper, with applications for molecular radiotherapy and positron emission tomography. Its unusually long half-life (12.7-hours) for a positron-emitting isotope makes it increasingly useful when attached to various ligands, for PET and PET-CT scanning.

<span class="mw-page-title-main">Octreotide scan</span> Type of medical imaging

An octreotide scan is a type of SPECT scintigraphy used to find carcinoid, pancreatic neuroendocrine tumors, and to localize sarcoidosis. It is also called somatostatin receptor scintigraphy (SRS). Octreotide, a drug similar to somatostatin, is radiolabeled with indium-111, and is injected into a vein and travels through the bloodstream. The radioactive octreotide attaches to tumor cells that have receptors for somatostatin. A gamma camera detects the radioactive octreotide, and makes pictures showing where the tumor cells are in the body, typically by a SPECT technique. A technetium-99m based radiopharmaceutical kit is also available.

<span class="mw-page-title-main">Lutetium(III) chloride</span> Chemical compound

Lutetium(III) chloride or lutetium trichloride is the chemical compound composed of lutetium and chlorine with the formula LuCl3. It forms hygroscopic white monoclinic crystals and also a hygroscopic hexahydrate LuCl3·6H2O. Anhydrous lutetium(III) chloride has the YCl3 (AlCl3) layer structure with octahedral lutetium ions.

Indium-111 (111In) is a radioactive isotope of indium (In). It decays by electron capture to stable cadmium-111 with a half-life of 2.8 days. Indium-111 chloride (111InCl) solution is produced by proton irradiation of a cadmium target in a cyclotron, as recommended by International Atomic Energy Agency (IAEA). The former method is more commonly used as it results in a high level of radionuclide purity.

<span class="mw-page-title-main">DOTA-TATE</span> Eight amino-acid long peptide covalently bonded to a DOTA chelator

DOTA-TATE is an eight amino acid long peptide, with a covalently bonded DOTA bifunctional chelator.

<span class="mw-page-title-main">Edotreotide</span> Chemical compound

Edotreotide (USAN, also known as (DOTA0-Phe1-Tyr3) octreotide, DOTA-TOC, DOTATOC) is a substance which, when bound to various radionuclides, is used in the treatment and diagnosis of certain types of cancer. When used therapeutically it is an example of peptide receptor radionuclide therapy.

A PSMA scan is a nuclear medicine imaging technique used in the diagnosis and staging of prostate cancer. It is carried out by injection of a radiopharmaceutical with a positron or gamma emitting radionuclide and a prostate-specific membrane antigen (PSMA) targeting ligand. After injection, imaging of positron emitters such as gallium-68 (68Ga), copper-64 (64Cu), and fluorine-18 (18F) is carried out with a positron emission tomography (PET) scanner. For gamma emitters such as technetium-99m (99mTc) and indium-111 (111In) single-photon emission computed tomography (SPECT) imaging is performed with a gamma camera.

<span class="mw-page-title-main">Peptide receptor radionuclide therapy</span> Type of radiotherapy

Peptide receptor radionuclide therapy (PRRT) is a type of radionuclide therapy, using a radiopharmaceutical that targets peptide receptors to deliver localised treatment, typically for neuroendocrine tumours (NETs).

Lutetium (<sup>177</sup>Lu) chloride Radioactive compound used for radiopharmaceutical labeling

Lutetium (177Lu) chloride is a radioactive compound used for the radiolabeling of pharmaceutical molecules, aimed either as an anti-cancer therapy or for scintigraphy. It is an isotopomer of lutetium(III) chloride containing the radioactive isotope 177Lu, which undergoes beta decay with a half-life of 6.64 days.

Lutetium (<sup>177</sup>Lu) oxodotreotide Chelate of Lu-177 with dotatate, a peptide derivative bound to a DOTA molecule

Lutetium (177Lu) oxodotreotide (INN) or 177Lu dotatate, brand name Lutathera, is a chelated complex of a radioisotope of the element lutetium with dotatate, used in peptide receptor radionuclide therapy. Specifically, it is used in the treatment of cancers which express somatostatin receptors. It is a radiolabeled somatostatin analog.

Copper (<sup>64</sup>Cu) oxodotreotide Radioactive diagnostic agent used in PET scan to localize tumors

Copper (64Cu) oxodotreotide or Copper Cu 64 dotatate, sold under the brand name Detectnet, is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adults.

Gallium (<sup>68</sup>Ga) gozetotide Radiopharmaceutical medication

Gallium (68Ga) gozetotide or Gallium (68Ga) PSMA-11 sold under the brand name Illuccix among others, is a radiopharmaceutical made of 68Ga conjugated to prostate-specific membrane antigen (PSMA) targeting ligand, Glu-Urea-Lys(Ahx)-HBED-CC, used for imaging prostate cancer by positron emission tomography (PET). The PSMA targeting ligand specifically directs the radiolabeled imaging agent towards the prostate cancerous lesions in men.

Lutetium (<sup>177</sup>Lu) vipivotide tetraxetan Radiopharmaceutical medication

Lutetium (177Lu) vipivotide tetraxetan, sold under the brand name Pluvicto, is a radiopharmaceutical medication used for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC). Lutetium (177Lu) vipivotide tetraxetan is a targeted radioligand therapy.

<span class="mw-page-title-main">Somatostatin receptor antagonist</span> Class of chemical compounds

Somatostatin receptor antagonists are a class of chemical compounds that work by imitating the structure of the neuropeptide somatostatin. The somatostatin receptors are G protein-coupled receptors. Somatostatin receptor subtypes in humans are sstr1, 2A, 2 B, 3, 4 and 5. While normally expressed in the gastrointestinal (GI) tract, pancreas, hypothalamus, and central nervous system (CNS), they are expressed in different types of tumours. The predominant subtype in cancer cells is the ssrt2 subtype, which is expressed in neuroblastomas, meningiomas, medulloblastomas, breast carcinomas, lymphomas, renal cell carcinomas, paragangliomas, small cell lung carcinomas and hepatocellular carcinomas.

<span class="mw-page-title-main">Somatostatin inhibitor</span> Class of pharmaceuticals

Somatostatin receptor antagonists are a class of chemical compounds that work by imitating the structure of the neuropeptide somatostatin, which is an endogenous hormone found in the human body. The somatostatin receptors are G protein-coupled receptors. Somatostatin receptor subtypes in humans include sstr1, 2A, 2 B, 3, 4, and 5. While normally expressed in the gastrointestinal (GI) tract, pancreas, hypothalamus, and central nervous system (CNS), they are expressed in different types of tumours. The predominant subtype in cancer cells is the ssrt2 subtype, which is expressed in neuroblastomas, meningiomas, medulloblastomas, breast carcinomas, lymphomas, renal cell carcinomas, paragangliomas, small cell lung carcinomas, and hepatocellular carcinomas.

References

  1. ↑ PrivateEquityWire, "Advanced Accelerator Applications completes fundraising", Feb 18th, 2014
  2. ↑ Il Sole 24 Ore, "Dal Cern and Biopark canavese", March 12th, 2014
  3. ↑ Miller, John (3 November 2017). "Novartis to buy French cancer specialist AAA for $3.9 billion". Reuters. Archived from the original on December 5, 2020.
  4. ↑ "Novartis Completes Tender Offer for Advanced Accelerator Applications" (Press release). Novartis. 23 January 2018.
  5. ↑ AdnKronos," Research: from Rubbia to AAA, great success for an Italian physicist with European company". March 19th, 2010.
  6. ↑ Wirtschaftswoche (30 October 2017). "Advanced Accelerator Applications: Novartis kauft Krebsspezialisten für 3,9 Milliarden Dollar". www.wiwo.de (in German). Retrieved 2022-08-20.
  7. ↑ Larsen, Peter Thal (2017-10-30). "Novartis Makes a Deal That Should Go Down Easy". The New York Times. ISSN   0362-4331 . Retrieved 2024-08-26.
  8. ↑ "Novartis completes tender offer for Advanced Accelerator Applications S.A. and announces commencement of subsequent offering period". Novartis. Retrieved 2024-08-26.
  9. ↑ Staff, G. E. N. (2024-01-24). "Novartis Automates New Radioligand Therapy Production Plant". GEN - Genetic Engineering and Biotechnology News. Retrieved 2024-08-26.
  10. ↑ "Siemens Healthineers boosts cancer imaging with €200mn Novartis deal". www.ft.com. Retrieved 2024-08-26.
  11. ↑ "Advanced Accelerator Applications Nuclear Medicine Glossary". Archived from the original on 2015-04-13. Retrieved 2015-04-15.
  12. ↑ "Medicaldevicedaily.com, "AAA to increase clinical trials of MNM diagnostic products", Febr 19th, 2014" (PDF). Archived from the original (PDF) on 2014-04-08. Retrieved 2014-04-07.
  13. ↑ Larsen, Peter Thal (30 October 2017). "Novartis Makes a Deal That Should Go Down Easy". The New York Times.
  14. ↑ Warner, Jeremy L; Fitts, Austin; Warner, Jeremy (6 May 2021). "Lutetium Lu 177 dotatate (Lutathera)". HemOnc.org. Retrieved 14 August 2022.
  15. ↑ FDA approves Lutathera for gastroenteropancreatic neuroendocrine tumors Jan 2018
  16. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "FDA Approves New Treatment for Neuroendocrine Tumors". National Cancer Institute. 8 February 2018. Retrieved 2018-05-26.
  17. 1 2 3 4 5 6 Commissioner, Office of the. "Press Announcements - FDA approves new treatment for certain digestive tract cancers". www.fda.gov. Retrieved 2018-05-26.
  18. 1 2 3 4 5 "Advanced Accelerator Applications Receives FDA Approval for Lutathera® for Treatment of Gastroenteropancreatic Neuroendocrine Tumors | Novartis". Novartis. Retrieved 2018-05-26.
  19. 1 2 "For Patients - Lutathera". Lutathera. Retrieved 2018-05-26.
  20. 1 2 "NCI Drug Dictionary". National Cancer Institute. Retrieved 2018-05-26.
  21. 1 2 "LysaKare EPAR". European Medicines Agency (EMA). 26 August 2024. Retrieved 26 August 2024.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  22. ↑ Devicespace.com, "Advanced Accelerator Applications Receives Orphan Drug Designation From FDA And European Medicines Agency For Gallium-68 DOTATATE For Use In Patients With Gastro-Entero-Pancreatic Neuroendocrine Tumors" Archived 2014-04-08 at the Wayback Machine . 3 March 2014.
  23. ↑ News Medical, "AAA gets orphan drug designation status for radiopharmaceutical, Gallium-68 DOTATATE". 4 March 2014.
  24. ↑ Parsons, Lucy (2021-06-21). "Novartis' radioligand therapy granted US Breakthrough Therapy Designation". PharmaTimes Online. Retrieved 2021-07-10.
  25. ↑ Danielle Desisto. "Millburn manufacturing site safely produces cancer-fighting drug".
  26. ↑ "Concerns raised about proposed cancer drug factory in Millburn"
  27. ↑ Cecilia Levine. "Nuclear meds expert hired". The Record. 7 May 2015.
  28. ↑ Jonathan Sym. "Advanced Accelerator Application Investigation Results: Risks Are "Close To Zero Without Being Zero" Says Expert". Tap Into Millburn/Short Hills. 18 February 2016.
  29. ↑ Harry Trumbore. "Expert says radiopharmaceutical factory proposed for Millburn is safe" . 11 February 2016
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