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. 

  • 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. 



    I am not sure you were at the meeting in NYC. See above for a different point of view. Did you hear Dr. Read say "Vaccine -like effect"---not sure where you came to the conclusion that it would only treat visable tumors. Also, these melanona patients had already failed other forms of treatment(you failed to mention that) so where is your justification to say the results were very disappointing???

    Methinks you might be short?? If so, I sincerely hope you cover soon.

  2. Thanks for your comment. First, I have no position on the stock and do not plan to initiate one. The author of the article you mention is long on ZIOP. The author just summarizes the presentation at NYC. The author is also not a scientist. I was at the NYC meeting and spoke to several scientists and all of us were not impressed.

    Of course the speakers will not mention anything negative about their approach. They may impress those who are not scientists, but they cannot support their science nor explain the mechanism to those of us who work in the area.

    ZIOP and Intrexon champion that they are designing faster methods for drug development. What are other companies doing? Do you think that they like slow and expensive drug development processes? The best available methods are high throughput screening and RNA interference to learn gene-protein function. There's nothing in ZIOP and Intrexon's approach that will accelerate the drug development process in the next decade.

    The approach to use a viral vector to insert a gene into cells is not new and has been tried thousands of times. Read about Jesse Gelsinger, who died due to a massive immune attack induced by a viral vector. There is public resistance against gene therapy. This opened the door for RNA interference as a substitute.

    Also, I have been working on development of cancer vaccines for last 3 years. I have read clinical and pre-clinical studies for cancer vaccines and drugs that stimulate the immune system. If you look at the results from Vemurafenib, Yervoy, or Allovectin, you'll notice how much superior they are compared to ZIOP's candidate. Yervoy is already approved and the 2 other drugs are at a more advanced stage than ZIOP.

    A new drug candidate is almost always treated in patients who have failed current forms of treatment. That's not an excuse for poor results.

    The reason that "synthetic biology" platform only treats visible tumors is simple. The DNA is injected intratumorally. You can only inject where you see a tumor. If all the cells in the tumors are transfected and begin secreting IL-12, they will be targeted and may be killed. Untransfected tumors are not detected or killed in any way.

  3. YERVOY was approved with about a 26% overall response rate; a fact you can check. Yet you describe a 50% response rate for ZIOPHARM's AD-IL-12 as "unacceptable." That seems a bit odd; really a total misread. Apparently you are unaware of the YERVOY response rate, or you just choose to overlook bad facts give YERVOY is FDA approved? (Bad if you are parroting the arguments of the shorts).

    Also -- from its label: "YERVOY (ipilimumab) can cause serious side effects in many parts of your body which can lead to death."

    The side effect profile for YERVOY appears more toxic with SAEs leading to death, and its response rate is well under 50%!

    Separately, you don't seem to understand that palifosfamide is a less toxic, hopefully safer version of ifosfamide with comparable efficacy. The problem with ifos is not its clinical response performance; but rather is its toxic side effect profile. The Phase II palifosfamide study in Soft-Tissue Sarcoma was judged a "best of ASCO."

    etc. etc.

    This analysis is just a cheap shot at ZIOPHARM (and Intrexon) and lacking the scientific rigor you purport to attain as "oracle of pharma."

    You are an oracle in your own mind, but that is about it. The shorts create a net buying opportunity to the extent they can pass garbage on as fact.

  4. My argument not in favor of palifosfamide is that soft tissue sarcoma is a rare cancer; it accounts for 1% of all cancers. I don't see it generating the revenues to fund all of the other projects. The biggest boost would have been good results from oral palifosfamide therapy, which was in Phase 1. The study has been suspended ( Oral therapy would be a big plus for the treatment for other cancers for which palifosfamide showed good in vitro activity.

    The Yervoy results were from Phase 3 trials, not Phase 1b as with AD-IL-12. It is typical that Phase 1 and 2 trials yield better results than Phase 3 due to various factors including increased heterogeneity of the study population. ZIOP includes Stable Disease (SD) as part of overall/objective response (OR); the standard is to use only complete response and partial response when calculating OR.

    Also, Yervoy is the 1st drug approved for the treatment of unresectable or metastatic melanoma. Therefore, it has a lower bar than future drugs because patients have no other viable options. Vemurafenib from Plexxikon/ Roche is poised to set a very high bar. However, this drug can be used in only in patients with a BRAF mutation (~60% of melanoma patients).

    The target population for Yervoy is very sick. They have no other options and the median survival is less than 1 year. Possible death due to SAEs is found on the labels of many chemotherapeutics. Deaths from Yervoy are due to T-cell mediated immune reactions. Successful treatment with AD-IL-12 will include T-cell mediated immune reactions since IL-12 induces T-cell maturation and differentiation. The adenoviral vector can also induce T-cell mediated immune response. Phase 1b trials are short and will not reveal longer term toxicities seen in Phase 3 trials.