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License To IL-12: Finding A Potentially New Therapeutic Window

|Includes:OncoSec Medical Incorporated (ONCS), ZIOP

Immunotherapy is an increasing important treatment option particularly in metastatic melanoma as seen with the recent approval of Yervoy (marketed by BMY), although there has already been treatment with IL-2. It has long been the goal of researchers to utilize cytokines as an anti-cancer treatment but it has been difficult to find a proper therapeutic window (see Cohen 1995 for some of the difficulties). The goal of immunotherapy is to create a systemic response, often with the use of cytokines, to affect the risk of metastatic disease and progression. Immunotherapy is quite broad with many targets including a very effective IL-12. The problem with IL-12, however, is not effectiveness but it is related to significant toxicities. Both Ziopharm (NASDAQ:ZIOP) and OncoSec (NASDAQ:ONCS) are developing ways to utilize IL-12 while minimizing its toxic effects (I should also note that there is a private company [EGEN Incorporated] working on using IL-12 in ovarian cancer). I have previously examined early data from Ziopharm in metastatic melanoma and talked more broadly about the import of IL-12. In addition, I touched on both the science behind OncoSec and its approach to using IL-12 in an earlier post. Within the past month both Ziopharm and OncoSec have provided updated data, where the OncoSec data was associated with their metastatic melanoma program and Ziopharm an extension into breast cancer.

To briefly summarize the Ziopharm approach it is to insert an adenoviral vector, Ad-RTS-mIL-12, expressing IL-12 under the control of RheoSwitch Therapeutic System. The expression of IL-12 is triggered by the ingestion of a small molecule activator ligand. This strategy attempts to avoid the adverse events by carefully controlling the expression of IL-12. Additional data was presented at AACR highlighting the potential effectiveness of the combination of palifosfamide and Ad-RTS-mIL-12. While the earlier study was done in metastatic melanoma, there should be some read-through from this trial into the general mechanism of action.

The pre-clinical trial looked at the effect of various treatment regimes (solo and combinations of Ad-RTS-mIL-12 and palifosfamide) on the growth of breast cancer in a mouse model. For the mice that received the vehicle (control group), it took an average of 13 days for the tumor to quadruple in size. In terms of treatment with just Ad-RTS-mIL-12, you see a clear dose response (where higher doses of the activator ligand increases the amount of IL-12 expressed). The tumor quadrupling time for activator ligand doses of 10 mg/mm, 30 mg/mm, 75 mg/mm, and 150 mg/mm was 19, 17, 20, 23 days, respectively. The only dosing regime that does not follow the dose response is the 30 mg/mm. When palifosfamide (40 mg/mm) was added to the 30 mg/mm dose, however, it considerably increased the time to quadrupling of the tumor to 25 days and was further increased 26 days with a 120 mg/mm dose of palifosfamide. Outside of simply the effect of tumor growth, you saw similar results on the percent of mice alive at day 35. For the activator ligand doses of 10 mg/mm, 30 mg/mm, 75 mg/mm, and 150 mg/mm the percent of mice alive at day 35 were 10%, 10%, 20% and 30% respectively. In addition, adding the 40 mg/mm or 120 mg/mm doses of palifosfamide increased that percent to 50% and 30%.

It is always difficult to compare pre-clinical data to actual clinical data in patients but the ZIOP presentation provides two important pieces of information. First, and most importantly, there is a correlation between the dose and the response. Obviously the 30 mg/mm dose was the outlier but, in general, you saw higher doses of the drug related to a slowing of tumor growth and an extension of survival. Second, this reads into the use of IL-12 in general as this is once again shown to be an effective cytokine. What the study does not show is whether there can be a therapeutic window in humans and whether the Ziopharm approach can find it. This is where OncoSec comes into play with its data. While OncoSec cannot inform us on the Ziopharm approach, it can provide data on whether a therapeutic window in humans can be found.

In an earlier post, I went through the basic science behind OncoSec (ONCS.BB) and its lead programs. In general, the goal of Immunopulse is to increase the permeability of cancer cell walls to enhance the uptake of a plasma encapsulated IL-12 coded DNA. Immunopulse is an attempt to more effectively deliver the IL-12 DNA to cancer cells while sparing the healthy ones in the hope of minimizes the adverse events. I highlighted some of the previous results in the first article but the company has recently provided updated data from the phase II trial in metastatic melanoma (to watch the presentation see here).

In general, there are two pieces of information that we should focus on in the data. First is the local response. In other words, these patients have a number of lesions and Immunopulse is used on small portion of them and the local response is simply how these targeted lesions respond to the treatment. Second, and perhaps more importantly, is the distant response. In order to be competitive and have a long term effect on the patients, the treatment needs to generate an immune response that affects distant legions as well. Obviously the distant effect will be much smaller but generating this type of response is a clear indicator that the treatment is stimulating the immune system in the desired manner. In fact, the associate medical director at HemOnc Today was commenting on the approach and specifically noted: "This is an interesting approach, but this is local therapy. The problem with melanoma is metastasis, some of which cannot be treated locally. The key to the success of this treatment would be regression of nontreated lesions, as well." So what does the data show?

The interim results had data on 13 patients. The presentation (seen at 13:19 into the video) had information on the specific patients that were part of the interim analysis and provides the best look at both the local and distant responses. In terms of the best local response (the legions targeted with the Immunopulse treatment) 5 patients received a complete response, 6 had a partial response, 1 had a stable disease, and 1 had progressive disease. This equates to an overall best response rate of 85% for treated tumors, which is impressive but in some ways expected. In addition, these responses were seen quite early in the treatment with most patients receiving their best response by day 30 and all by day 60. Overall, the data seems clear in that the treated lesions are being affected.

In terms of the distant response, there were only 4 patients who were in the trial long enough to be coded at day 180. Of these 4 patients, 2 had a complete response, 1 had a stable disease, and the last was progressive. It should be noted that of the 4 that made it to 180 days only two of them were actually evaluated in term of the primary endpoint of distant response and of those one had a complete response and the other stable disease. What is interesting is looking at the local response and how it might correlate with the distant response. For instance, of the two patients with complete distant response only one had a complete local response (the other had a partial response). The patients with progressive distant response and stable disease both had complete local responses. While these are small numbers, it is not yet clear the relationship between local and distant responses but one would expect a positive correlation to develop.

While the efficacy results look promising, there also seemed to be a significant number of patients who went "off study." It is not immediately clear from the presentation the reason so many patients went off the trial. If you then look at some of the descriptions of the results, however, it is noted that 6 had progressive disease and one left the study for an undisclosed reason. It seems then that these "off study" patients are those whose local disease progressed and therefore did not make it to the primary endpoint evaluation of distant response (one of them left study for an unknown reason). Of course, these are patients who are being examined months after treatment stopped, so it would be expected that some progressed but if you assume that the locally progressive disease would lead to distant progression then actually overall rate of response falls to 25% (2 of 8). In general, however, a significant portion of the locally treated legions have durable responses where 45% of the treated legions continued to have a response at month 6 (see 13:21 into the presentation).

Aside from signs of efficacy, the side effect profile was relatively clean. There were 18 treatment emergent adverse events but these were generally mild. There were no grade 3 or 4 adverse events and only a few grade 2 (fatigue, erythema and maculopapular rash). What is interesting about the side effects is that two of the most severe (keeping in mind that grade two is not particularly severe) are likely related to the activation of the immune system. In other words, the adverse events are also providing some evidence that the drug is working as predicted and even the fatigue could be related to immune system activity.

In general, the interim results are showing some efficacy both in terms of local and distant effects. This is a small trial to begin with and we only have data from a portion of the patients but it seems as if the treatment is working as expected. The OncoSec and Ziopharm data are both important pieces of the puzzle in that they are slowly building a case that a therapeutic window for IL-12 can be found. In addition, while much of the clinical data is in metastatic melanoma, it could be the case that it can be used more broadly. Unfortunately, the data do not provide much guidance as to which approach will ultimately succeed (if either) but despite being early, these are two programs that are certainly worth following.

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Stocks: ONCS, ZIOP