The next generation drug conjugate is relatively a new concept. This novel modality emerged when pharmaceutical developers used non-antibody-based entities as targeting ligand to develop targeted therapeutics. Similar to the structure of the antibody drug conjugates, these next generation drug conjugates use a non-antibody-based targeting ligand, a cytotoxic payload and a linker. However, the key distinction between an antibody drug conjugate and this conjugate lies in the mechanism of action and targeting efficiency. Various types of next generation drug conjugates, such as peptide receptor radionuclide therapy (PRRT), GalNac conjugates, peptide drug conjugates, peptide oligomer conjugate, ligand conjugated anti sense medicine (LICA) and peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) have emerged as the direct competitors to the ADCs. Let us dive deep to understand how it all began.
Entry of the First Peptide Receptor Radionuclide Therapy into the Market
Advanced Accelerator Applications (now part of Novartis), Oncopeptides, Endocytes, and Alnylam Pharmaceuticals were pioneers in adopting this innovative concept. Endocyte, a US-based company, gained widespread recognition in 2012 by collaborating with Merck to advance next generation drug conjugates that employed small molecules as targeting ligand and small molecule-based drugs as payload. Their flagship product, Vintafolide, utilized a small molecule targeting ligand to specifically target folate receptors found in ovarian cancers. Endocyte also developed other small molecule drug conjugates for the treatment of cancer and renal disorders. Moreover, they employed the concept of peptides as targeting ligand and radionuclide as payload to target prostate specific membrane antigen (PSMA) receptors for treating prostate cancer. Unfortunately, the initial success was short-lived as the products did not progress beyond phase III clinical trials, leading to the delisting of the products from the market and, consequently termination of their partnership with Merck. Subsequently, in mid-October 2018, Novartis acquired Endocyte, leveraging their prostate cancer product for further development.
In 2018, the French-based Advanced Accelerator Applications, a subsidiary of Novartis, achieved a significant milestone by obtaining the FDA approval for its product Lutathera®, a next-generation drug conjugate designed for GEP-NET (Gastroenteropancreatic Neuroendocrine Tumors). Lutathera® is a peptide-radionuclide conjugate, alternatively also known as peptide receptor radionuclide therapy (PRRT), comprising a peptide as its targeting ligand and the Lutetium 177 radionuclide as its therapeutic payload. This combination allows it specifically to target the somatostatin receptors (SSTR) expressed in GEP-NET. It is worth noting that Novartis, which acquired the PSMA targeting peptide-radionuclide conjugate or PRRT from Endocyte, subsequently entrusted Advanced Accelerator Applications with its further clinical development. This product was named Pluvicto® and uses a PSMA targeting peptide in conjunction with the Lutetium 177 radionuclide as its payload to treat prostate cancer. Pluvicto® received the FDA approval in March 2022 and the EMA approval in December 2022. It is noteworthy that despite facing challenges related to supply and quality issues in the manufacturing process during the fiscal year 2022, both Lutathera® and Pluvicto® achieved substantial sales revenue. For example, Pluvicto® generated USD 271 million in revenue during FY 2022, while Lutathera® earned USD 475 million.
The Swedish pharmaceutical company, Oncopeptides was another developer which tapped into the next generation drug conjugate domain. PEPAXTO® (also known as melflufen) was a peptide-drug conjugate which uses aminopeptidase targeting peptide and an alkylating agent to target myeloma cells. In February 2021, PEAXTO® was awarded accelerated approval by the FDA, thereby becoming the first peptide-drug conjugate to get regulatory approval. However, the success was cut short, when in October 2021, PEPAXTO® was withdrawn from the market when the drug’s phase III OCEAN study showed toxicity issues in adult patients. Other prominent next generation drug conjugate developers are included in the figure below;
Approval of GalNAc Conjugates in Recent Years
Endocyte’s attempt to tap into the new domain led many developers to look for other synergistic combination available for the next generation drug conjugates. Over the past decade oligonucleotide therapeutics emerged as a prominent therapeutic modality. Within them, the use of GalNAc (N-acetylgalactosamine) as a targeting ligand with the oligonucleotide emerged as a viable solution to many disease indications. GalNAc molecule as the targeting ligand has affinity to attach to the asialoglycoprotein receptor (ASGPR) of the liver cells, thereby opening up a new avenue for oligonucleotide therapeutics. Alnylam Pharmaceuticals was the first company to develop the next generation conjugate, wherein GalNAc is conjugated to aminolevulinate synthase 1 targeted si-RNA. Givlaari® (developed by Alnylam) became the first next generation GalNac conjugate to receive the FDA approval for the treatment of acute hepatic porphyria (AHP) in November 2019. This drug candidate has been developed using the oligonucleotide technology. Building on the success of Givlaari®, Alnylam successfully received the approval and commercialization of the other three next generation GalNAc conjugates. These include Oxlumo® (for the treatment of primary hyperoxaluria type 1), Leqvio® (for the treatment of hypercholesterolemia) and Amvuttra® (for the treatment of hATTR amyloidosis) in 2020, 2021 and 2022, respectively by the FDA. It is worth highlighting that Leqvio® (also known as Inclisiran), a GalNAc conjugate was acquired by the Medicine Company (a subsidiary of Novartis) from Alnylam Pharmaceuticals in 2018 for the further clinical development and global commercialization. In fact, it is worth highlighting that many stakeholders and industry players have claimed that Leqvio® (Inclisiran) is likely to be a potential blockbuster drug.
The rapid success of Alnylam prompted several developers to develop next generation drug conjugate utilizing the concept of conjugating oligonucleotides. With robust pipeline of 17 drug candidates from Ionis Pharmaceuticals, 13 from Dicerna Pharmaceuticals and 21 from Suzhou Ribo Life Sciences indicates the underlying potential within this domain.
Entry of big Pharma Players in GalNAc Conjugates Space
The acquisition of Advanced Accelerator Applications, Endocyte and The Medicine Company by Novartis and the subsequent approval of Lutathera®, have increased the overall interest of the stakeholders within this domain. Several big pharma players have collaborated with the next generation drug conjugate developers to gain entry within this domain. For instance, Dicerna’s drug candidate, Nedosiran, another GalNAc conjugate is considered as the direct competitor for Oxlumo®, was acquired by Novo Nordisk in November 2021. Further examples of big pharma players forging strategic partnerships with next generation drug conjugate developers include AstraZeneca, Roche, GSK, Eli Lilly, Boehringer Ingelheim and Janssen. Below is the year-wise distribution of the partnership inked within this domain by various stakeholders.
Rise in Interest of Stakeholders for Peptide Receptor Radionuclide Therapy and GalNAc Conjugates
The rise in interest by the big pharma players is further accompanied by rise in publications and within this domain. For instance, more than 400 publications have been published within this domain since 2018. Interestingly, majority of these publications were focused on peptide-radionuclide conjugates or more popularly known as peptide receptor radionuclide therapy or PRRT. It is worth highlighting that more than 75% of the articles published were focused on the PRRT, followed by GalNac conjugates and ligand mediated RNAi conjugates. The rise in the number of publications signifies the rising interest of the stakeholders within this domain. The below figure gives a glimpse of the trend of the publications from 2018 to H1 of 2023.
In addition to the rise in publications, the number of grants awarded in this domain has increased steadily in the last four years. More than 150 grants have been awarded within this domain from 2018. A significant rise in grants was observed in 2022, where more than 64% of all the grants awarded within this domain since 2018 have been awarded in that year. It is worth highlighting that the National Cancer Institute (NCI) emerged as the leading funding institute center. Interestingly, close to 60% of all the grants awarded within this domain have been awarded by NCI alone. The below figure gives a glimpse of the trend of the publications from 2018 to H1 of 2023.
Keeping every trend in mind, Roots Analysis has provided complete information on market trends in the next generation drug conjugate in its report titled, Next Generation Drug Conjugates Market, 2023-2035. The research report has some of the very recent and precise activities listed for the clients to help them make better decisions. Further, it presents current and future opportunity trends associated with the global plasma fractionation market, for the time period between 2023 and 2035.