While investors have been focusing their attention on palifosfamide and the upcoming phase III data, Ziopharm (NASDAQ:ZIOP) released some initial phase I data of Ad-RTS IL-12 in advanced melanoma (as well as announcing the dosing of patients in the phase II trial). In the two highest dosing groups, the company found that 5 out of 7 (71%) had a clinical response (some shrinkage of tumor). In addition, even though the drug was injected into specific tumors, the company reported that a systemic effect was observed (clinical response in tumors not injected with Ad-RTS IL-12). Finally, there was a correlation between T-cell immune responses and clinical outcome. While no dose limiting toxicity was reported, there were two serious adverse events (pyrexia and cytopenia). The phase I results were clearly positive enough from the company’s perspective to initiate a phase II trial, and while it is always difficult to interpret phase I data, it appears that the company’s enthusiasm is justified.
Ad-RTS IL-12 is part of the Intrexon technology licensed by Ziopharm for the treatment of tumors. The Intrexon technology allows for the modular creation of specific transgenes that contain unique combinations of promoter, expression, and regulatory modules. The key is that even when these transgenes are injected, they do not produce a biological effect. Intrexon has a Rheo Switch Therapeutic System™ (RTS) which allows an orally taken ligand to turn the gene on and off. When the transgene is activated by the RTS it produces the programmed mRNA, which then generates the desired protein. In essence, the Intrexon technology makes the individual the bioreactor, where they are able to produce the needed protein in precise amounts. This allows the use of effective therapeutic proteins that had previously been too toxic to take alone.
Ad-RTS IL-12 is used to produce interleukin-12 (IL-12), which is a protein known to trigger an immune response to cancer. In general, one would expect the immune system to recognize tumors as a foreign body and eliminate it, but the cancer microenvironment has a number of immunosuppressive characteristics that hinders this process. Il-12 is a pro-inflammatory cytokine that circumvents the immunosuppressive environment in a way that causes an immune response against cancer (for examples see Eisenring et al 2010 and Kerkar et al 2011). Despite the promise of using IL-12, it has been difficult to translate these effects into the clinic because of “dose-limiting toxicities, which included fevers, elevated hepatic enzymes, hemodynamic instability, and in some cases death” (Kerkar and Restifo 2012). Even if one could find a therapeutic window, it has also been found that treatment with IL-12 can exhaust the immune system making it ineffective. As such, researchers know that IL-12 can be an effective cancer immunotherapy agent, but have been unable to use it effectively.
It is within this context that Ad-RTS IL-12 seems like an intriguing approach to harness the known effectiveness of IL-12 without generating the toxic side effects or exhausting the immune system. The injection of Ad-RTS IL-12 into tumors has no immediate effect but when a patient takes the oral ligand activator, it triggers the in vivo production of IL-12 at the tumor site. The advantage, however, is that the amount of IL-12 can be modulated by the oral ligand. In other words, the RTS system allows for a measured production of IL-12 that can more efficiently find the best therapeutic levels. Ad-RTS IL-12 is essentially creating an IL-12 base immunotherapy that has a much better side effect profile without compromising effectiveness.
It is always difficult to judge what phase I results mean, so perhaps the more useful exercise is to examine the closest analog as a rough yardstick. The most obvious comparison is Yervoy (marketed by Bristol-Myers Squibb [NYSE:BMY]), which is an immunotherapy that has been recently approved for unresectable or metastatic melanoma. The labeled efficacy is based around overall survival, which is both the gold standard and not an uncommon measure in cancer immunotherapy. Yervoy is labeled with a statistically significant overall survival hazard ratio (OS HR) of 0.68 and a median OS of 10 months compared to 6 for the control arm. In terms of best response, Yervoy had a statistically significant better ORR than the control group with 0.2% complete response rate, 5.5% partial response rate, and 14.4% stable disease rate (20.1% disease control rate) as compared to 0.0%, 1.5%, and 9.6% (11.0% disease control rate) for the control.
It is an important detour to look at the difference between the effect on best response, which appears modest, and the effect on survival, which is clearly clinically significant. This is not unique to Yervoy but seems to be a characteristic of cancer immunotherapies as a class. A similar pattern was observed with Provenge (marketed by Dendreon [NASDAQ:DNDN]), where only 1 out of 341 patients saw a partial response but treatment increased the median overall survival by 4.1 months (25.8 months compared to 21.4 months). Mellman et al (2011) addressed this affect when noting that “the lack of tumour shrinkage, the criterion typically used to gauge the efficacy of cancer treatments, in the face of a survival benefit is surprising, but perhaps not unexpected for immunotherapy. As seen pre-clinically, an effect on pre-existing tumours due to immune manipulations can be delayed while an immune response develops.” In other words, the more common early sign of effectiveness (tumor shrinkage) does not adequately convey the ultimate effectiveness (overall survival) of cancer immunotherapies. This is not to say that higher response rates will not correlate with better survival when comparing across immunotherapy drugs, but that low response rates do not necessarily mean a drug is ineffective.
What makes the Ziopharm results interesting is that it is a cancer immunotherapy with a strikingly high response rate (71%). Of course, we do not yet know the breakdown of these responses, but even being conservative and assuming that the responses are simply stable disease or better, the trial resulted in a 71% disease control rate (compared to 20.1% for Yervoy). Of course, it is always a problem to compare between trials and that is especially the case when comparing a phase I trial to phase III. Perhaps the better comparison is between Ad-RTS IL-12 and the early Yervoy phase I trials in advanced melanoma, and even within this context Ad-RTS IL-12 stacks up quite well. The response rates generated by Yervoy in these trials had significant variation and ranged from 22% in Maker et al (2005) to 27% in Phan et al (2003) to 72% in Hodi et al (2008). In general then, even within the context of Yervoy early data, the Ad-RTS IL-12 results appear either significantly better or, at the very least, consistent with best Yervoy results.
Ziopharm obviously only released top-line data and noted that it plans on presenting the full data at a medical meeting. Given that we know that the response rates are quite positive, there are three additional factors that one should follow going forward. First is the duration of the response, which in some ways signals the depth of the response. Second is the survival of the patients, where this is the gold standard endpoint and will ultimately determine the probability of approval and commercial viability. Finally, it is important to monitor the side effect profile (which is relatively benign at this point) as this could be a major differentiator with Yervoy. While Yervoy is effective, it has numerous black box warnings related to severe side effects. An Ad-RTS IL-12 with similar efficacy without the side effects would be a significant improvement, and if the efficacy ends up better, then it is a clear winner and the market opportunity is quite large. Yervoy sales reached $514 million in its first year of launch and it is set to grow more both in the United States and abroad.
In general, Ziopharm’s Ad-RTS IL-12 data are early but clearly had an impressive signal. Its early efficacy appears better (or at least consistent) with early Yervoy data without the potential toxic side effects. Moving forward we need to focus on the duration of responses and how this translates into patient survival. If Ad-RTS IL-12 can simply match Yervoy on effectiveness while keeping the side effects low, then it will ultimately be a significant commercial threat. The potential increases even more if the efficacy results continue to remain at its current levels. As noted before, one needs to be careful when comparing trial results and not draw too many conclusions from phase I data; but there seems to be a clear signal, and investors should start paying more attention to Ad-RTS IL-12 as it has the potential to be significantly more successful than palifosfamide.