- Palifosfamide is a slight improvement over ifosfamide, but there is not a large market for the drug and higher cost will hinder clinical adoption.
- Darinaparsin is a substitute for arsenic compounds. As with palifosfamide, it is a "me-too" drug and will likely not be a clinical success.
- Ziopharm has partnered with Intrexon to develop a "synthetic biology" platform. There are many aspects that are not known and need to be understood for the development of successful therapies. Results from a Phase 1B melanoma trial were terribly disappointing. The therapy is unlikely to get approval in the next one or two decades.
Wednesday, June 29, 2011
Intrexon and Ziopharm's "Synthetic Biology" Platform More Abstract than Picasso's Art
Ziopharm Oncology (NASDAQ: ZIOP), a biotechnology company headquartered in NYC, has partnered with Intrexon to develop a "synthetic biology" platform to design a treatment for cancer. Ziopharm also has other candidates in various phases of clinical trials.
Its most advanced candidate is palifosfamide, which is a metabolite of ifosfamide. It is entering a Phase 3 trial called PICASSO. Ifosfamide is normally metabolized by the liver to 4-hydroxy ifosfamide, aldoifosfamide, and chloracetaldehyde (causes confusion). Intracellular conversion yields the active ifosfamide mustard and acrolein, which is a toxic molecule that causes bladder scarring (hemorrhagic cystitis). It is therefore required to administer MESNA with ifosfamide. ZIOP has designed palifosfamide to avoid the co-adminsitration of MESNA and reduce hemorrhagic cystitis. However, ifosfamide is not in extensive use and it is unlikely that the higher cost of palifosfamide will be enough to persuade oncologists to switch from ifosfamide + MESNA.
Ziopharm's other small molecule, darinaparsin, is an organic arsenic being investigated for the treatment of heptacellular carcinoma and hematologic malignancies. There probably is not a large enough market for arsenic products to generate large revenues as most investors has become accustomed to seeing from biotechnology firms.
The most interesting and disappointing project undertaken by Ziopharm is a partnership with Intrexon (notice the name is derived from intron and exon) to design a synthetic biology platform. This technology should be the hallmark of the companies. Synthetic biology is the introduction of genes that are not found in nature into a living system to produce useful products. A great example is that conversion of algae to produce diesel fuel. Utilizing synthetic biology for cancer treatment has the potential to be revolutionary. The companies have partnered to design a "synthetic biology" platform to combat cancer. The inserted gene can be controlled using a ligand that the patients swallows in pill form. This overcomes the biggest pitfall of not being able to control when the gene is expressed. However, the biodistribution of the ligand has to studied and any off-target effects are of concern.
However, deeper research into their studies reveals a that their "synthetic biology" appears to be no more than a euphemism for gene therapy. Gene therapy was once thought to be the next big thing, but it never worked and resulted in deaths. To date, Ziopharm and Intrexon have introduced a gene encoding interleukin-12 (IL-12) into dendritic cells. The goal is to induce dendritic cells to secrete IL-12. This will recruit and induce the immune system. This approach has some problems in itself. Dendritic cells are important immune cells, but they function by presenting antigens to T cells. To maximize efficacy, it would be wise to make dendritic cells present antigens associated with cancers such as Dendreon's Provenge and not change their functioning. Also, IL-12 will be secreted throughout the body. why not just inject the patient with IL-12? What other distal effects will this have? The procedure to modify the dendritic cells is time consuming, highly variable, and expensive. SOPs will need to be designed and implemented and training must be provided to all clinicians involved in treatment. Another disadvantage of the approach is that the modified dendritic cells are injected intratumorally. This will only treat visible tumors and miss micrometastases. Also, there is higher than normal probability of user error.
Another issue with the platform is the feasibility and mechanism of action. The scientific background and support for the platform seems shabby at best and is very abstract to any person including leading scientists to fully comprehend. In order for the ligand to work, the cell has to express a ligand-inducible transcription factor and a co-activation partner, termed RheoSwitch. The gene of interest is inserted using a replication incompetent adenoviral vector. The companies do not explain and probably cannot explain how the entire system works. It is virtually impossible to control where the genes will be inserted. Gene therapy always hanging the hanging cloud of carcinogenesis. This system does not alleviate that fear. Also, the companies do not disclose how the genes for the RheoSwitch are inserted into the cell and how the protein products are transcribed and how they find the promoter region of the target gene. The lifespan of these proteins and probability of stability of the genes are other unknown factors. Long term studies will need to be conducted to evaluate any future effects of modifying the genome. Biology is complex and this system adds to the complexity of treating diseases. Often the best solutions work through elegant and simple mechanisms.
Results from a Phase 1B trials in melanoma patients were very disappointing. Of 10 patients enrolled, no patients achieved a complete response, 1 had a partial response, 3 had stable disease, and 4 had disease progression. Two patients were not evaluable. This basically means that 50% of patients do not see any effect from receiving the medication. This is unacceptable given that melanoma These results cannot match the far superior results achieved by at least a half dozen other companies working on treatments for melanoma. Melanoma is very immunoresponsive when first treated with immunotherapies. It is not uncommon for melanoma patients to have complete regression of all melanoma nodules when initially treated. This adds to the disappointing results. Also, Ziopharm and Intrexon are in the newborn stage of the technology and ant meaningful progress is so far away that the Hubble telescope may be needed. The market will be loaded with therapies before Ziopharm and Intrexon can bring anything to market.
These are some of the issues with the "synthetic biology" platform facing Ziopharm and Intrexon. These companies are still far away from a viable product reaching the market. Ziopharm's other candidates are not blockbusters and will not generate huge revenues. It takes approximately $1 billion to bring a drug to market. The "synthetic biology" platform does not have a well-defined pathway and the costs of pre-clinical and clinical studies and failures will be higher than normal. Investors cannot expect palifosfamide and darinaparsin to help pay.