Searching for Success
The failure of Corgentech's (www.corgentech.com) edifoligide (E2F Decoy) in Phase III trials led to the company's decision to cease development of the drug, which had been in development with Bristol Myers Squibb to prevent vein graft failure following coronary artery bypass graft surgery.
Corgentech will continue to pursue development of its other transcription factor decoys, oligo drugs focused initially on the treatment of inflammatory diseases and cancer.
Producing oligos for Corgentech's E2F clinical trials was a major focus of the manufacturing activity at Avecia Biotechnology's (www.avecia.com) Grangemouth, Scotland facility. Following the release of the negative study results, Avecia announced the closing of its Grangemouth site. It is consolidating its oligo manufacturing activities at its facility in Milford, MA.
Recently, Avecia entered a manufacturing agreement with Pfizer to produce clinical and commercial quantities of the active pharmaceutical ingredient for ProMune, an anticancer drug licensed to Pfizer by Coley Pharmaceutical Group. Avecia will focus on process development and optimization, scale-up, and process validation in applying its solid-phase amidite technology to produce ProMune.
Driving efforts to make large-scale cGMP synthesis of oligos more efficient and cost effective is the continued hope that DNA drugs now in the development pipeline will establish themselves as effective therapeutics in the clinic and in the marketplace.
Coley's lead compound is one such drug. ProMune is an agonist of Toll-like receptor (TLR) 9 and is in late Phase II clinical studies for the treatment of advanced non-small cell lung cancer, malignant melanoma, and cutaneous T-cell lymphoma.
ProMune is composed of unmethylated, synthetic CpG sequences that mimic a pattern of nucleotides commonly found in the DNA of bacteria and viruses, and it can bind to and activate TLR 9 to induce a T-cell and B-cell based immune response against malignant cells.
Other oligo drugs in development include Hybridon's (www.hybridon.com) IMOxine, a second-generation synthetic oligonucleotide agonist of TLR 9.
In April, Hybridon presented data from two preclinical studies in tumor models that demonstrated the drug's antitumor activity and its ability to enhance the effects of chemotherapy, radiation, and antibody therapy and to enhance the immunological response to and antitumor activity of peptide cancer vaccines. IMOxine is currently in a Phase II trial as a monotherapy to treat patients with renal cell carcinoma.
Dynavax Technologies (www.dynavax. com) is developing short, immunostimulatory DNA sequences for three clinical indications: linked to allergens for the treatment of allergies and asthma; linked to antigens to enhance prophylactic and therapeutic vaccines and immunotherapy of cancer; and as treatments for infectious and inflammatory diseases.
In March, Dynavax reported data from a Phase I trial of its AIC ragweed allergy immunotherapeutic showing a clinically significant improvement in symptoms and a reduction in medication usage compared to placebo. The company anticipates initiating a pivotal Phase III trial in early 2006 and hopes to begin a supportive Phase II trial in a pediatric indication in the first half of 2005.
At its large-scale oligo manufacturing plant in Cincinnati, OH, Girindus (www.girindus.com) produces REP 9, Replicor's (www.replicor.com) lead antiviral drug candidate. REP 9 is an oligo drug designed to combat viral infections such as HIV, hepatitis B, herpes, respiratory syncytial virus, influenza, and Ebola virus. Girindus is applying its solution-phase synthesis technology to produce oligos at ton scale.