Clinical trials, phase II

Year is year of launch in the U.S. market unless indicated. Pre-Cl = preclinical, Ph III = phase III clinical trials, and Ph II = phase II clinical trials (status as of Feb. 1990). 

The majority of promising drug candidates emerging from marine natural products research to date are potential cancer treatments. Six anti-cancer compounds that are either marine natural products or synthetic analogs of marine natural products have made it to clinical trials. The first of these compounds to enter clinical trials was didemnin B (43), one of a family of cyclic depsipetides isolated from the Caribbean tunicate Trididemnum solidum Didemnin B was advanced to Phase II clinical trials for treatment of small cell lung cancer, myeloma, prostate cancer, and melanoma. Unfortunately, no favorable responses were found so the compound has been withdrawn. Crude extracts of another Caribbean tunicate, Ecteinascidia turbinata, showed extremely... 

Interference with specific cell-cell and cell-matrix adhesion mechanisms is another rapidly advancing approach to therapeutically interfere with angiogenesis. Antagonistic antibodies (Vitaxin) to the integrin heterodimer av 33 have been shown to act on the blood vessels of tumors but not on the resting organ vasculature. Vitaxin demonstrated some promise in Phase II clinical trials. 

PPAR5 Ubiquitous Potent TG- and LDL-C-lowering and potent HDL-C-raising increased oxidative disposal of fatty acids in adipose and skeletal muscle thermogenesis weight loss Fatty acids, eicosanoids (fatty acids derived from VLDL particles ) GW501516 currently in Phase II clinical trials Dyslipidemia, obesity atherosclerosis ... 

Bryostatins are another class of compounds that bind to the Cl domain and result in acute activation of PKC. However, unlike phorbol esters, these marine natural products have antitumor effects. Bryostatins are currently in phase II clinical trials and show promise as anticancer drugs, particularly when combined with other adjuvant therapy. 

KC706 stabilizes the inactive conformation of the mitogen-activated protein kinase p38a, a protein kinase involved in inflammatory reactions and cardiovascular functions. KC706 therefore holds the potential to treat conditions such as rheumatoid arthritis, psoriasis, inflammatory bowel disease and cardiovascular disease. This compound is currently being tested in phase II clinical trials with patients suffering from rheumatoid arthritis. 

Ragweed SC/Pollinex Quatro Agonist Allergic rhinitis (Ragweed) Phase II clinical trials... 

A Agonist Melanoma Phase II clinical trials... 

Resiquimod (R-848) Agonist Genital Herpes Phase II clinical trials discontinued... 

The NRRI 2 -C-methylcytidine (Fig. 4ab) has in its oral prodrug form (NM 283, valopicitabine) acceded into phase II clinical trials in chronic HCV-infected patients. 

Compound 34 (BCZ-1812, RWJ-270201, peramivir) showed selective inhibition of influenza virus sialidases over bacterial and mammalian sialidases (Babu et al. 2000 Bantia et al. 2001 Sidwell and Smee 2002). Successful inhibition of influenza virus infectivity in vitro (Smee et al. 2001) and upon oral administration in vivo [mice (Bantia et al. 2001) and ferrets, reviewed in Sidwell and Smee 2002] led to human clinical trials of orally administered peramivir (Barroso et al. 2005). While orally administrated peramivir successfully completed animal studies and Phase I and Phase II clinical trials, in which the compound was showing neither major side effects nor toxicity (Sidwell and Smee 2002), preliminary results of the Phase III trials (June 2002) demonstrated no statistically significant difference in the primary efficacy endpoint, possibly due to low bioavailability (Barroso et al. 2005). 

The development of nucleic acid-based therapeutics is not as straightforward as researchers had initially anticipated. Stability, toxicity, specificity, and delivery of the compounds continue to be challenging issues that need further optimization. In recent years, researchers have come up with intricate solutions that have greatly improved the efficacy of potential antisense, ribozyme, as well as RNAi-based therapeutics. Clinical trials for all these types of nucleic acid-based therapeutics are underway. So far, data from several trials and studies in animal models look promising, in particular, the therapies that trigger the RNAi pathway. However, history has shown that compounds that do well in phase I or phase II clinical trials may still fail in phase III. A striking example is the nonspecific suppression of angiogenesis by siRNA via toII-Iike receptor 3 (Kleinman et al. 2008). It will become clear in the near future which compounds will make it as a new class of antiviral therapeutics. 

Emerit, J., Pelletier, S., Tososni-Verlignue, D. and Mollet, M. (1989). Phase II clinical trial of copper zinc superoxide dismutase (CuZnSOD) in treatment of Crohn s disease. Free Rad. Biol. Med. 7, 145-149. 

The definitive identifieation of a therapeutie raison d etre for H3 antagonists will happen in the elinie. A handful of H3 ligands are reported to have entered elinieal testing. ABT-834 entered Phase-I trials for the indieation of cognitive disorders in May 2003 but no news has been reported since that time. GT-2331 (11) was approved for Phase-II clinical trials in 1999 but no news has been reported since then [4]. At this point, there are no data available to assess the therapeutic potential in human disease (See Table 5.1). 

The safety of the cocaine vaccine TC-CD in former cocaine abusers has been evaluated in a Phase I clinical trial, and it was determined that the vaccine was well tolerated with dose-related increases in antibody levels.65 Two Phase II clinical trials have now been conducted.66,67 The vaccine was again well tolerated and subjects reported a reduction in cocaine s reinforcing effects. The antibody levels were detectable after the second dose, peaked at 8 to 12 weeks, and remained elevated for up to 6 months preliminary findings indicated a negative association between antibody level and cocaine use. Other anti-cocaine vaccines in development include a blocking antibody (ITAC-cocaine) and a monoclonal catalytic antibody (15A10). 

Probably the most widely adopted and well-known method for estimating the likelihood of a compound (drug) being well absorbed is the rule-of-5 described by Lipinski and co-workers [1]. In analyzing 2245 compounds from the World Drug Index (WDI) database that were either considered for, or entered into, Phase II clinical trials, these authors developed the following rules ... 

TRPV1 is a nonselective cation channel predominantly expressed in sensory neurons and activated by capsaicin, heat (>42°C), pH (<5.4), and noxious stimuli. Several compounds have advanced into clinical development and have been extensively covered in recent reviews [5,34—39]. Among these, MK-2295 (structure not disclosed), AMG 517 (38), SB-705498 (39), and GRC-6211 (structure not disclosed) have reportedly encountered safety issues [35]. In phase II clinical trials with MK-2295, patients experienced an increase in core body temperature... 

At least four clinical candidates including GSK-256073 [112], MK-0354 [102], MK-1903 [113], and INCB-19062 [91], and one preclinical candidate MK-6892 [77] have been reported. Neither the structure of GSK-256073, nor the clinical data, has been reported. In Phase II clinical trials, neither GPR109A partial agonist MK-0354, nor the full agonist MK-1903 showed substantial lipoprotein effects, and both candidates were discontinued. INCB-19062 is targeted to a type II diabetes indication based upon the related role of FFA to insulin sensitization in type II diabetes, and the robust FFA lowering effect observed in a Phase I clinical trial devoid of FFA rebound. 

Currently, there are a number of systemic and intestine-selective MTP inhibitors, including lomitapide (23, BMS-201038, AEGR-733), implitapide (24), JTT-130, SLx-4090, and R-256918 (latter three structures not disclosed) believed to be in active development [60]. In a meta-analysis of three Phase II clinical trials, lomitapide as monotherapy or in combination with ezetimibe, atorvastatin, or fenofibrate significantly reduced LDL cholesterol (up to 35% as monotherapy and 66% in combination with atorvastatin) and was well tolerated with less than 2% discontinuation due to abnormal liver function [61]. Lomitapide has also been granted orphan drug status for the treatment of homozygous familial hypercholesterolemia [59]. Results of a Phase II study of JTT-130 for type 2 diabetes are expected in August 2010 [59,60]. 

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