Can The Next Generation Drug Conjugates Revolutionize The Rare Disorder Domain?

Over the last two decades the pharmaceutical industry has observed a paradigm shift from conventional drug delivery strategies to more enhanced, potent, and targeted therapeutics. This led the researchers to find alternative pathways and drug delivery strategies to enhance the potent delivery of the drug to the site of action. As a result, in late nineties, the conjugation of drug with biological entities such as antibodies emerged as a possible solution for targeting earlier undruggable entities. However, it was not until 2000 when the first drug conjugate in the form of antibody drug conjugate (ADC) was approved by the USFDA. Unlike the conventional small molecule or biologics-based drugs, these new drug modalities utilize a targeting ligand, a linker, and a cytotoxic payload for targeted delivery to the site of action. In case of antibody drug conjugates, the developers utilized the antibody as the targeting ligand and link it with the small molecule drugs for therapeutic efficacy. The success of antibody drug conjugates (ADCs) for various oncological disorders paved the way for more efficient and formidable targeted therapeutic modalities which used conjugation technology. As a result, next-generation drug conjugates emerged as the possible successor to the antibody drug conjugates (ADC). Next-generation drug conjugates represent a notable outcome resulting from advancements in drug development processes. These novel conjugates incorporating diverse combinations of therapeutic modalities, have emerged as the promising and likely solution for rare disorders, including rare cancers.

Types of Next Generation Drug Conjugates

Similar to ADCs, the next generation drug conjugates utilize a targeting ligand, a linker and a payload for the targeted delivery. However, unlike it, which uses antibody as the targeting ligand, the next generation drug conjugates utilize various non-antibody-based targeting ligands, such as peptide, amino sugar, lipid, and small molecule as their targeting ligand. On the other hand, in place of drug, these next generation drug conjugates incorporate si-RNAs, oligonucleotide, antisense oligonucleotide, and radionuclide as its payload. The below figure illustrates the various synergistic combinations available with the next generation drug conjugates.

Different Types of Synergism Combinations Available With the Next Generation Drug Conjugates

Given the various combination available with the targeting ligand and the payload, various types of next generation drug conjugates, such as peptide drug conjugate, peptide oligonucleotide conjugate, peptide radionuclide conjugate, small molecule-drug conjugate (SMDC), ligand conjugated anti sense medicine (LICA), ligand medicated RNAi conjugate, peptide conjugated phosphorodiamidate morpholino oligomers (PPMO) have emerged in this domain.

Mechanism of Action of Next Generation Drug Conjugates

Similar to the antibody drug conjugates, these novel conjugates also utilize the targeting ligand to deliver the cytotoxic payload to the site of action. However, the major distinguishing difference between the ADCs and these novel conjugates lies in the uptake of these cytotoxic payload at the site of action. Owing to the various synergistic combinations, the next generation drug conjugates can carry si-RNAs, oligonucleotide or antisense oligonucleotide as their payload. Unlike, a small molecule or a biologic based drug, which works on the mechanism of cytotoxicity induction at the site of action, these conjugates insert their payloads directly inside the genetic material of the host cell. This results in altering the genetic makeup of the host cell, eliminating the root cause of the disease. For instance, ligand conjugated antisense medicines (LICA) insert their antisense oligonucleotide at that specific site of the host genetic material, the prime cause of the disease, thus silencing the faulty gene. Likewise, ligand mediated RNAi conjugate and phosphorodiamidate morpholino oligomers (PPMO) inserts a functioning si-RNA or an oligonucleotide in the place of the faulty genetic material. Given this unique mode of action, the next generation drug conjugates are now being evaluated as a possible solution for many rare and metabolic disorders.

Mode of Action of Next Generation Drug Conjugates

Current Activities In The Next Generation Drug Conjugate Domain

The Advanced Accelerator Applications (a Novartis company) was the first developer to use this novel concept of next generation drug conjugates. Lutathera® was the first conjugate within this domain to receive approval by the USFDA. Lutathera® is a peptide-radionuclide conjugate, which uses peptide as its targeting ligand and radionuclide as its payload for attacking the gastroenteropancreatic-neuroendocrine tumors. On the other hand, Givlaari®, developed by Alnylam Pharmaceuticals, is the second next generation drug conjugate to received regulatory approval. Givlaari®, also known as Givosiran, is a ligand mediated RNAi conjugate which utilizes N-acetyl galactosamine (GalNAc) sugar moiety as its targeting ligand and δ-aminolevulinic acid synthase 1 (ALAS1)-directed small interfering RNA for targeting the acute hepatic porphyria (AHP). Advanced Accelerator Applications (a Novartis company) and Alnylam Pharmaceuticals are the two developers that have approved next generation drug conjugates in its product portfolio. It is worth highlighting that there are several other developers that are actively evaluating drug candidates in this space. Examples of drug developers that have late-stage drug candidates to watch include Angiochem, Ionis Pharmaceuticals, Dicerna Pharmaceuticals, Geron and Arrowhead Pharmaceuticals. In fact, Ionis Pharmaceuticals has filed a new drug application for its drug, Eplontersen, which targets hereditary transthyretin amyloidosis (ATTRv-PN). On the other hand, a number of big pharma players, such as AstraZeneca, Genetech, Boehringer Ingelheim, Novartis, Eli Lilly, Merck, Novo Nordisk and GSK have collaborated with these next generation drug conjugate developers to gain entry into this domain. In fact, in November 2021, Novo Nordisk acquired Dicerna Pharmaceuticals, which currently possesses a pipeline of 13 next generation drug conjugates.

Key Advantages of Next Generation Drug Conjugates

The success of the next generation drug conjugate can be attributed to their clinical effectiveness, structural stability, limited side effects, targeted delivery of payload and deeper

Benefits of Next Generation Drug Conjugates

cellular penetration. Further, given the utilization of antisense technology for targeted delivery via si-RNA, oligonucleotide and antisense oligonucleotide as their payload, the next generation drug conjugates have emerged as a viable solution to many disease indications which were earlier considered undruggable. It is worth highlighting that a number of the next generation drug conjugates are using GalNAc as its targeting ligand, or si-RNA or oligonucleotides as its payload, have emerged as popular treatment option. For example, Givlaari® is the only treatment option and the only drug available in the market which act against the root cause of the acute hepatic porphyria. Similar observations can be drawn from other drug candidates, such as Oxlumo®. Owing to their novelty, the USFDA and the EMA have granted accelerated approvals to next generation drug conjugate. In addition to that, many other drug candidates which are currently in the clinical phase of development have been awarded with orphan and breakthrough designations.

Conclusion

The successful approval of Lutathera from Novartis® and Givlaari® from Alnylam Pharmaceuticals has increased the overall interest of the industry stakeholders. Further, given the ongoing pace of innovation in this field, a robust pipeline, coupled with the encouraging clinical trial results, and the continuous efforts of both industry and non-industry players, the next generation drug conjugates market is likely to witness significant growth during the coming decade.

Bottom Line

Keeping every trend in mind, Roots Analysis has provided complete information on market trends in next generation drug conjugate domain 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.