**9. Peptide Market and Clinical Trials**

As a class of drugs, peptides are increasingly important in medicine. The Food and Drug Administration (FDA) has seen a rapid increase in the number of new drug applications submitted for peptide drug products. The availability of generic versions of these products will be critical to increasing public access to these important medications. However, ensuring the quality and equivalence between generic and brand-name peptide drug products raises a number of challenges, and those challenges differ according to the type of peptide drug. For peptide drug products with a specifically defined sequence of amino acids, the challenge has been with impurities that may be inadvertently introduced during the production process that may affect a proposed generic drug's safety profile. Peptide-related impurities can be especially difficult to detect, analyze, and control because they usually have similar sequences to the drug itself. As per the current calculations, the market for peptide and protein drugs is estimated around 10% of the entire pharmaceutical market and will make up an even larger proportion of the market in the future. Since the early 1980s, more than 200 therapeutic proteins and peptides are approved for clinical use by the US-FDA [203].

Promising preclinical data led to clinical evaluation of a thiazole-containing linear pentapeptide, dolastatin 10 (**20**), isolated from sea hare as well as cyanobacterium. The potent antimitotic compound, dolastatin 10 (**20**), was evaluated in many phase I and phase II clinical trials for solid tumor, including a multi-institutional phase II clinical trial for soft tissue sarcoma treatment [204]. Dolastatin 10 (**20**) was withdrawn from clinical trials due to adverse effects such as peripheral neurophathy in cancer patients. Dolastatin 10 (**20**) was not found to be successful in human clinical trials, but it acted as a valuable source for a number of related compounds with clinical significance like ILX651, LU103793, and soblidotin [205,206]. Chemical modification efforts to reduce toxicity resulted in the synthesis of TZT-1027 (soblidotin or auristatin PE), a microtubule-disrupting compound, which entered a phase II clinical trial in patients with advanced or metastatic soft tissue sarcomas and lung cancer. Soblidotin has not progressed further beyond phase II clinical trials due to the associated hematological toxicities [207].

Although due to poor water solubility dolastatin 15 could not enter clinical trials, the investigations on this linear depsipeptide encouraged the development of its synthetic analogs like synthadotin and cematodin which have entered clinical trials. Preclinical studies confirmed the antitumor potential of the orally active microtubule inhibitor synthadotin against padiatric sarcomas. This depsipeptide has completed three phase II trials for the treatment of hormone refractory prostate cancer and metastatic melanoma that indicated toward the favorable toxicity profiles of synthadotin [208]. Another synthetic analog of dolastatin 15, cemadotin, underwent many phase I and phase II clinical trials against metastatic breast cancer and malignant melanoma. However, clinical trials were discontinued because of inconsiderable cytotoxicity caused by cemadotin in phase II trials and to acute myocardial infarction and neutropenia in phase I clinical trials [209].

Further modifications of soblidotin/auristatin E led to the development of monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF), each of which included a secondary amine at their N-terminus. MMAE and MMAF have been used as warheads to link monoclonal antibodies and are presently in many clinical trials for the treatment of cancer, and eventually various antibody-drug conjugates received FDA approval [210,211].
