Phase I development

How important is chirality Based on the percentage of chiral compounds entering phase I development in the last year, the importance of chirality varies greatly between companies. In one case, all phase I candidates were chiral, in another, just 5%. In the recent past, some discovery groups were deliberately avoiding chiral molecules to circumvent perceived complications. 

After establishing the safety and kinetic properties of the investigational drug in Phase I, development moves into the intended patient population. Phase II studies are typically safety and efficacy studies conducted in the target patient population. 

Figure 3. Photograph of Phase I development CVI furnace in assembly.

Preclinical and Phase I development work is crucial in that it determines the merit of further development or. 

It is currently in Phase II clinical trials for relapsed ovarian, lung, breast and pancreatic cancer. PMOl 183 is also undergoing Phase I development in combination with other chemotherapies and in haematological tumours. PharmaMar on August 20, 2012 receives FDA orphan drug design ation (ODD ) for PMOl 183 for the treatment of ovarian eaneer [126, 134, 135]. 

Kallus, K.W., Batbarino, M., and VanDarmne, D. (1998). Integrated Task and Job Analysis of Air Traffic Controllers Phase I Development of Methods (HUM. ETl.STOl.lOOO-REP-03). Bmssels Eurocontrol. 

Pavlou SP, Weston DP (1983) Initial evaluation of alternatives for development of sediment related criteria for toxic contaminants in marine waters, Puget Sound. Phase I. Development of conceptual framework. Tech Rep JRB Associates, Bellevue, WA. 

FIGURE 9.2 Histograms showing the number of new drag entities entering phase I clinical development (blue bars), and concomitantly the number entering phase III development as a function of year. Adapted from [2]. 

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

A large and rapidly growing number of clinical trials (phase I and phase II) evaluating the potential of DNA vaccines to treat and prevent a variety of human diseases are currently being performed ( http // clinicaltrials.gov) however, there is yet no licensed DNA vaccine product available for use in humans. The clinical trials include the treatment of various types of cancers (e.g., melanoma, breast, renal, lymphoma, prostate, and pancreas) and also the prevention and therapy of infectious diseases (e.g., HIV/ABDS, malaria, Hepatitis B vims, Influenza vims, and Dengue vims). So far, no principally adverse effects have been reported from these trials. The main challenge for the development of DNA vaccines for use in humans is to improve the rather weak potency. DNA vaccines are already commercially available for veterinary medicine for prevention of West Nile Vims infections in horses and Infectious Hematopoetic Necrosis Vims in Salmon. 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

In infectious disease compounds such as ANA975 (phase I trials) and Resiquimod (phase II trails) have been developed to target Hepatitis C and genital herpes, respectively. DRS954 is a TLR-7 and 9 antagonist in pre-clinical trials for Systemic Lupus Erythematosus (SLE). 

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. 

As inhibitors of certain enzyme reactions and apoptosis related to the development of cancer (Naasani et al, 1998 Yang et al, 2001), specifically by selective induction or modification of phase I and phase II metabolic enzymes so as to increase the formation and excretion of detoxified metabolites of carcinogens. 

In pharmaceutical and medical device development, clinical trials are classified into four main phases designated with Roman numerals 1,11, III and lY The various phases of development trials differ in purpose, length and number of subjects involved. Phase I trials are conducted to determine safe dose levels of a medication, treatment or product (National Institutes of Health, 2002). The main purpose is often to determine an acceptable single dosage - how much can be given without causing serious side-effects. Phase I trials will also involve studies of metabolism and bioavailabity (Pocock, 1983). The sample size of a Phase 1 clinical trial is usually small, ranging from 10-80 subjects (National Institutes of Health, 2002 Pocock, 1983). 

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