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Forty years after the accidental discovery of their anti-cancer properties, platinum based compounds represent one of the most important classes of oncology drugs. Platinum compounds are effective in treating a wide array of malignancies including lung, ovarian and colorectal cancers. Cisplatin was the first approved platinum drug (1978) followed by carboplatin (1989) and oxaliplatin (2002), which together generated annual worldwide sales of approximately $3 billion in 2007. These drugs exert their antitumor activity by binding to DNA and interfering with DNA replication, ultimately leading to cell death.

Despite their impressive activity, platinum drugs suffer from two primary drawbacks. The first drawback is the appearance of undesirable side effects and toxicities. Cisplatin often leads to kidney toxicity, while carboplatin and oxaliplatin often lead to bone marrow and nerve toxicities. The most urgent safety issue is the nerve toxicity caused by the use of oxaliplatin in colorectal cancer, as it sometimes forces physicians to stop the administration of the drug. The second drawback of platinum compounds is the emergence of platinum resistance in most patients during or following treatment. These patients stop responding to treatment after an initial response within several months of initial treatment. Moreover, some cancers are inherently resistant to platinum even before being exposed to platinum drugs. Fortunately, many resistance mechanisms tumors utilize to block the anti-cancer effect of platinum drugs have now been elucidated, and this knowledge will hopefully provide the basis for the development of the next generation of platinum drugs.

 

Efforts to develop novel platinum agents are currently very modest, with only a handful of compounds in the clinic. Throughout the 90’s, hundreds of compounds have been screened but this effort resulted in only one approved agent, Sanofi-Aventis’ (NYSE:SNY) oxaliplatin. Consequently, the pharmaceutical giants abandoned the field, leaving it to smaller companies such as Spectrum (NASDAQ:SPPI) and Poniard (OTCPK:PARD). The recent disappointing data from Spectrum’s Satraplatin in prostate cancer only increased the negative sentiment towards experimental platinum compounds. At the moment, Poniard’s picoplatin is the only platinum drug in phase III, with results expected in the middle of next year.

   

Efforts aimed at introducing novel platinum drugs focus mainly on three fronts. First, there is a need to expand the use of platinum drugs to additional types of cancers. The most evident example of that is the use of oxaliplatin for the treatment of colorectal cancer, which is resistant to cisplatin or carboplatin. Second, there is a need to decrease side effects and make platinum based therapy more tolerable. A good example for that is the introduction of carboplatin for circumventing the kidney toxicity associated with cisplatin. Carboplatin has been shown to have similar efficacy profile as cisplatin but with more acceptable side effects. Third, since the majority of tumors that respond to platinum eventually develop resistance, there is a need to develop second line platinum drugs. Poniard’s picoplatin is currently being evaluated in three clinical programs, each representing one of the above approaches. Picoplatin is in a registrational phase III trial in small cell lung cancer [SCLC] patients who are resistant to available platinum therapies. It is also being evaluated in colorectal cancer as a safer alternative to oxaliplatin and in hormone-refractory prostate cancer [HRPC], which is considered resistant to all marketed platinum compounds.

 Picoplatin (as well as satraplatin) both emerged from an academic/pharmaceutical collaboration between the UK Institute of Cancer Research (ICR) and Johnson Matthey, the same collaboration which led to the development of carboplatin in the 80’s. The drug was rationally designed to overcome some of the mechanisms of resistance developed by tumors, such as fast inactivation and secretion by tumor cells, and indeed demonstrated strong activity in preclinical models of platinum resistant tumors. In addition, picoplatin showed evidence of an extended spectrum of antitumor activity. In 1998, AnorMed, a spin out of Johnson Matthey, licensed the drug to AstraZeneca (NYSE:AZN). Three years and thirteen clinical trials later, AstraZeneca decided to return picoplatin (then called ZD0473) back to AnorMed, claiming the drug did not prove to be active enough, especially among platinum-resistant ovarian patients. AnorMed struck a new licensing deal with Poniard (then called NeoRx) for picoplatin in 2002 and sold it all rights to the product in 2004 in return for milestone payments and up to 15% of future sales.  Regardless of the outcome of ongoing picoplatin trials, it is clear that either AstraZeneca or Poniard made a serious mistake. If picoplatin proves to be effective in only one or two indications, AstraZeneca missed a potential blockbuster drug that could have become the new gold standard for platinum therapy. If picoplatin fails, Poniard’s existence as an independent company will be at risk, since it is the only clinical stage drug in the company’s pipeline. One thing is certain: Poniard’s decision to buy the drug was much riskier than AstraZeneca’s decision to abandon it. 

When a company such as AstraZeneca dumps a drug candidate after so many clinical trials, including phase II evaluations, it does not bode well for the potential of the compound. However, the drug did have single agent activity (even if sometimes modest) in both platinum-resistant and platinum-sensitive cancers. Results from the long list of clinical trials of picoplatin presented at annual meetings of ASCO in 2001 and 2002 showed clear clinical activity, including multiple complete responses in patients with ovarian cancer previously treated with platinum:

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 CR (complete response), PR (partial response), SD (stable disease)

The most pertinent conclusion that can be drawn from the above table is that picoplatin is active to some extent in a broad spectrum of malignancies. Obviously, the objective response rate (or the lack of it) is not outstanding, but it is certainly something to begin with, especially when considering that the blockbuster drug oxaliplatin achieved a single agent activity of 10% in second line colorectal cancer. Importantly, picoplatin has a well studied safety profile and seems very safe with respect to kidney and nerve toxicities, in contrast to the marketed platinum drugs. Moreover, picoplatin proved safe in multiple combinations with drugs such as gemcitabine, paclitaxel and docetaxel. This attribute is crucial because virtually all approved platinum drugs are given in combination with other cytotoxic agents.

Taken together, this data implies that Poniard did not make such a terrible deal after all, and recent clinical data further validates this assumption. All the above trials are small, open-label uncontrolled studies and as such should be approached with skepticism. Even if picoplatin is active in several types of advanced cancers, this does not necessarily imply that the clinical response can be translated into an extension of progression-free or overall survival in larger trials. Nevertheless, picoplatin’s huge, mostly genericized addressable market, the scarcity of new effective chemotherapeutic compounds and the fact it has not been partnered yet make Poniard an attractive investment at this point of time.

 

Poniard is expected to report data from multiple trials this weekend at the ASCO annual meeting. The most important trial in terms of market potential is a randomized, controlled trial in metastatic colorectal cancer. The purpose of this trial is showing that picoplatin leads to similar activity but lower prevalence of nerve toxicity compared to oxaliplatin . The company recently announced it has completed accrual for the trial, but it will probably have only preliminary data at ASCO. Nevertheless, this early data might serve as a basis for a lucrative global partnership deal for picoplatin.

The next articles will deal with picoplatin’s ongoing clinical development.

 

Disclosure: Author has a long position in PARD 

Source: Poniard Pharmaceuticals: Platinum Rediscovered (Part I)