Synta Pharmaceuticals (SNTA) may look like the typical American biotech company: A promising phase III compound, which is, of course, partnered with a pharma giant, two agents in early clinical stages, a list of failed trials, and an alarming cash burn rate. Nonetheless, the story behind the company’s lead product, elesclomol, is shaping up as one of the most interesting events in oncology in recent years. Elesclomol is currently in a registrational phase III trial for metastatic melanoma, a major achievement by itself, however, if successful, this trial will mark two events on a historical scale.
The first and more immediate title elesclomol might claim is being the first chemotherapy agent to show benefit in metastatic melanoma in over 30 years. In fact, since the only approved agent for this condition has never shown benefit in a placebo controlled trial in accordance to current standards, elesclomol might be viewed as the first ever chemo agent to show a clear benefit in metastatic melanoma.
The second achievement, which is more impressive and potentially rewarding, is the introduction of a novel class of anti-cancer therapy: Oxidative stress elevation. Just as Gleevec® and Avastin® marked the birth of tyrosine kinases inhibition and anti-angiogenesis as important concepts in cancer treatment, elesclomol might be the first drug in a long dynasty of oxidative stress inducing drugs useful for the treatment of a wide range of malignancies.
Oxidative Stress And Cancer
Oxidative stress is a state in which there is a high level of reactive oxygen species (ROS) within a cell. ROS, which are produced by every living cell as a by-product of its metabolism, are highly reactive entities that can interact and damage biological components such as DNA and proteins. In normal cells, the production and neutralization of ROS is tightly regulated by several defense mechanisms. These mechanisms include enzymes and vitamins, generally termed antioxidants as well as specialized repair proteins whose role is to contain ROS and their hazardous effect. Therefore, in normal cells there is a balance between ROS and antioxidants. A disruption of this balance in which ROS outnumber antioxidants leads to a state of oxidative stress. This state implies that a cell cannot cope with the amount of ROS, which in turn cause damage to cellular components. When the oxidative stress reaches a certain threshold a cell usually “commits suicide” through a process termed apoptosis (programmed cell death).
Since cancer cells originally derive from healthy tissues, they are almost identical to normal cells. Therefore, the fundamental mission in developing anti-cancer treatments is finding a trait that distinguishes between cancer and normal cells, and use this difference for killing the former. Cancer cells, for example, typically divide at a faster rate than normal cells, so most anti-cancer compounds utilize this difference by blocking the process of cell division. Another characteristic of advanced cancer is the formation of new blood vessels (angiogenesis), a process which rarely occurs in the adult body, leading to a whole class of compounds that utilize this difference for damaging cancer cells while sparing normal ones.
A growing body of evidence suggests that cancer cells operate at a substantially higher level of oxidative stress than normal cells, mainly due to fast proliferation and a low level of antioxidant activity. High levels of oxidative stress have been even suggested as a mechanism that helps cancer cells to proliferate and spread. Although this does not represent a normal state, there is a fairly wide range of oxidative stress levels in which cancer cells can function without reaching a threshold that will trigger programmed cell death. Nevertheless, cancer cells are much closer to that breaking point and because they have impaired anti-oxidant abilities, a relatively modest increase in oxidative stress may push cancer cells over the edge, and force them to commit suicide. This concept can serve as a basis for a novel type of anti-cancer treatment: a drug which elevates oxidative stress in all cells, indiscriminately, but has a much stronger effect on cancer cells. This is exactly the proposed mechanism of action of elesclomol.
Judging by the emphasis Synta’s management places on oxidative stress, one might wrongly conclude that elesclomol was developed specifically for the purpose of inducing oxidative stress. The truth is that until recently, nobody had a clue with respect to elesclomol’s mechanism of action, and the term “oxidative stress” entered the company’s lexicon only a year ago. Elesclomol was originally picked out of a library of compounds after a process of screening, in which it showed anti tumor effect against a broad spectrum of cancer cells. More importantly, the drug seemed to be harmless towards normal cells and when added to other chemotherapy compounds, it augmented their activity without increasing toxicity. These promising qualities made elesclomol an obvious candidate for further development, even though its mechanism of action was not understood at the time.
It is common to think that most chemotherapy agents kill cancer cells directly by intervening with crucial processes, but the truth is that most anti-cancer therapies kill cancer cells by forcing them to commit apoptosis. Although there are multiple pathways to achieve this effect, from growth signals disruption to DNA damage, the ultimate goal is the same. Oxidative stress elevation leads to apoptosis by a novel pathway, which might even bypass chemotherapy resistance and thus make chemo-resistant tumors chemo-sensitive. Elesclomol was particularly effective in sensitizing melanoma cell lines, one of the most chemo-resistant types of cancer.
Melanoma is the deadliest form of skin cancer, accounting for the vast majority of skin cancer related deaths. Similar to other cancers, in early stages of the disease, melanoma can be cured by surgery. However, in its advanced stages, melanoma is one of the deadliest cancers and is associated with very poor prognosis. The median survival time of patients with metastatic melanoma has not changed much for the past 30 years, due to a lack of effective treatments, thus melanoma can be regarded as the most underserved oncology market. The best indication for how desperate things are is the fact that upon diagnosis of metastatic melanoma, many physicians prefer enrolling patients into clinical trials, instead of using available therapies.
Metastatic melanoma patients can be given numerous chemotherapy treatments, but only one of them, dacarbazine, has been specifically approved for the treatment of metastatic melanoma more than thirty years ago, based on an objective response rate of 20-25%. Today, however, dacarbazine achieves a response rate of 7-12%, due to a change in criteria for evaluating responses. In addition, dacarbazine was never shown to prolong survival in a randomized trial, leading some investigators to claim that if it were to enter the clinic today, dacarbazine would not be approved for the treatment of melanoma. A myriad of other chemo drugs, including some of the most effective oncology agents were evaluated vs. or in combination with dacarbazine but none of them managed to show any improvement. Therefore, all available chemo agents for advanced melanoma can be viewed as equally effective (or equally ineffective, as some might say) in treating the disease. The only agent that has shown some sort of benefit is the cytokine, IL-2, which was approved in 1998. IL-2 leads to a long-lasting response in 5-7% of patients, and to a curative effect in a fraction of these patients. However, IL-2 is not commonly used due to its very narrow spectrum of activity and severe side effects, which necessitate long hospitalization periods and can sometimes be fatal.
The bleak landscape in melanoma leads to an intrinsic “catch 22”. On the one hand, this is a field with a huge unmet medical need after decades of stagnancy, so every drug that proves to be even slightly effective would be immediately embraced as the new standard of care, with no real competition. On the other hand, what are the odds to demonstrate a real benefit in a disease where all phase III trials have failed to date? The terrible success rate in melanoma implies that by default, investors should never bet on any melanoma drug no matter how promising it seemed in phase II trials, however, elesclomol may be an exception to the above rule. The elesclomol data derives its strength from a statistically significant difference in Progression-free survival (PFS) observed in a previous phase II, so it may be saved from the fate of other drugs that had showed very promising results in phase II single arm trial. While there is no guarantee that the ongoing elesclomol phase III trial will replicate the success of the phase II trial, it is currently the most promising agent for treating metastatic melanoma.
A phase II trial that shows a statistically significant benefit is quite a rare event in oncology because in order to show a difference there must be, by definition, a control arm, which is absent from most phase II clinical trials in oncology. The purpose of phase II trials is to screen therapies for further testing in large, controlled phase III trials, by looking at end points such as tumor shrinkage or extended survival. Results are then compared to historical data from similar patient populations, and based on this comparison, a decision whether to promote the candidate to a phase III trial is made. This pattern is considered the common way to evaluate investigational oncology drugs because it represents a trade-off between cost, time and reliability. Uncontrolled trials are smaller, cheaper, shorter and easier to conduct, while controlled studies produce results which are more indicative of real-life performance but are expensive and longer. However, the phenomenon of promising phase II studies followed by costly and catastrophic phase III trials has become a hallmark of cancer drug development, which suffers from one of the poorest success rates in the pharmaceutical industry. This has led some to advocate for a paradigm shift in the way oncology phase II trials are conducted. The Street’s Adam Feuerstein addressed this issue in one of his recent columns. Although I disagree with Feuerstein’s take on Cell Genesys’ (CEGE), he clearly has a point in his criticism of the company. Companies like Cell Genesys often prefer to launch large expensive phase III trials based on limited data from small uncontrolled studies, rather than doing comparative phase II trials with a placebo arm.
In metastatic melanoma the crisis is perhaps the most evident, as there has not been a single phase III trial that managed to show improved PFS or overall survival for decades. One of the most resounding failures was that of Onyx Pharmaceutical’s Nexavar®, which failed to show any benefit in a recently published phase III trial. What makes this case so frustrating is the unprecedented PFS data Nexavar demonstrated when combined with paclitaxel and carboplatin in a single arm phase II. The combination led to a median PFS of 8.8 months, an unprecedented number that had never been seen in metastatic melanoma phase II trials. These results led to a phase III trial in second line melanoma patients, but it failed to show any significant difference in terms of PFS, overall survival or response rate. In fact, median PFS in the phase III trial was less than half of the median PFS in the phase II single arm trial, which included a fairly large number of patients (101 patients). In another phase II trial, Nexavar was combined with dacarbazine, this time in a randomized placebo-controlled study. Top line results from the trial were presented at last year’s annual meeting of ASCO and showed a strong trend (almost statistically significant) in PFS in favor of Nexavar + dacarbazine but the placebo arm had a better overall survival. More recently, Medarex (MEDX) and Pfizer (PFE) announced their melanoma drug candidates, ipilimumab and tremelimumab did not meet their primary endpoints in their registrational trials. While Pfizer prematurely halted its trial after an interim analysis review, Medarex and its partner, Bristol-Myers Squibb, decided to file for regulatory approval based on what they defined as encouraging signs which stemmed from “the totality of data”.
Bearing all this in mind, it is hard not to get excited with a drug candidate that finally shows a statistically significant improvement in a randomized, controlled trial. Nonetheless, Synta’s elesclomol had its share of criticism regarding some issues that arose from the phase II data. Another question that has to be asked is whether at a market cap of $250 million and 9 months before the phase III trial results, Synta is a “Buy”.
I will try to address these issues in the next article.
Author is long CEGE.