This article will discuss the
development of Poniard’s lead drug, picoplatin, for the treatment of small cell
lung cancer (SCLC). A General introduction for picoplatin can be found in the first
part of this article.
As a novel platinum compound, picoplatin seems to be the ultimate “platform” product, with potential application in multiple indications, including some of the most lucrative oncology markets. Nevertheless, the only chance Poniard has to generate sales from this product in the next 4-5 years lies in a relatively modest indication - Small Cell Lung Cancer (SCLC).
SCLC accounts for 13%-15% of all lung cancer diagnosed in the US (32,000 cases in 2007). When diagnosed early, the disease is curable with surgery in some patients, however, in most cases, patients either develop recurrent disease or are diagnosed at an advanced stage. The common treatment for SCLC is a platinum-containing chemotherapy regimen, which typically leads to a very high response rate, however, the vast majority of patients eventually relapse, thus creating a second line market of around 70 thousand patients in developed nations. Although this market represents a rather small market for picoplatin, it can certainly be viewed as the most underserved one.
Because virtually all second line SCLC patients are “platinum relapsed”, they are not considered suitable for additional platinum therapies. These patients can be divided into (i) sensitive (ii) resistant and (iii) refractory patients. Sensitive patients are those who respond to platinum treatment but have the disease progress after 2-3 months. Resistant patients have disease relapse within 2-3 months after the end of treatment. Refractory patients are those who progress during platinum therapy.
For sensitive patients, there is currently only one approved drug, GSK’s topotecan (Hycamtin®). Topotecan was originally approved as an IV treatment, but recently, an oral version of the drug received FDA approval, after showing comparable activity. For the refractory/resistant group, there is no current approved therapy, making it an obvious, yet challenging indication.
By the time Poniard retained rights to picoplatin, the drug had been evaluated in SCLC patients in a small trial with clear signs of clinical activity. Picoplatin led to a median survival of 27 weeks in resistant/refractory patients. Sensitive patients had even better median survival of 36 weeks, which compares favorably with the 25-26 weeks topotecan achieves in this patient population.
Based on theese data, the company decided to designate picoplatin for refractory/resistant patients, despite the good performance in sensitive patients, as the former group represents a substantial portion of second-line SCLC patients and has very limited treatment options. Therefore, Poniard decided to narrow picoplatin’s target market twice: It first decided to focus on second-line SCLC as opposed to first line patients, and then it chose to focus on the resistant/refractory subgroup. It still remains to be seen whether focusing on this patient population was the right strategy for advancing picoplatin. On the one hand, it is always easier, cheaper and faster to get a drug approved for an indication with no real alternative in the market. On the other, it may be more difficult to show a statistically significant clinical effect in refractory/resistant patients, not to mention the decreased market size.
Poniard launched a phase II trial in mid 2005 for the evaluation of picopatin vs. topotecan in refractory/relapsed patients. The trial was not well received by physicians and patients, who were unwilling to accept the topotecan arm, which at the time was considered ineffective and toxic for refractory/resistant patients. Consequently, in January of 2006 the company amended the trial protocol, and aborted the topotecan arm. Despite the setbacks, the 70-patient trial confirmed the prior trial with a response rate of 10% and a median overall survival of 27 weeks. This trial paved the way for a registration double blind randomized phase III trial, which was launched in May 2007.
Because there is no approved therapy for resistant/refractory SCLC patients, the phase III trial, dubbed SPEAR (Study of Picoplatin Efficacy After Relapse), uses best supportive care (BSC) as a reference arm. BSC is a general term for treatments given to prevent, control, or relieve complications and side effects of a disease. Although it may vary on a case by case basis, BSC usually includes pain relief agents, antidepressants and blood transfusions. In a recent study published in 2006, resistant/refractory patients who were treated with BSC arm had a median survival of only 14 weeks, making the picoplatin data quite compelling.
The SPEAR trial is expected to enroll 400 platinum resistant/refractory patients, who will be randomized to receive picoplatin+BSC or BSC alone. Of note, no chemotherapy is allowed in the BSC arm, and the study is powered at 90% to show only a 50% difference in survival, as opposed to the 90% theoretical difference observed in the phase II trials. In the SPEAR trial, the definition of resistant disease is more flexible, as it includes patients whose disease has relapsed up to 180 days after first line therapy (as opposed to 60-90 in previous trials). Regardless of the basis for this inconsistency, it should not create any registrational hurdles since the trial protocol was developed in agreement with the FDA and is conducted under a SPA (special protocol assessment). In fact, this may broaden the addressable market for picoplatin at the expense of topotecan.
The company originally expected to have results already in late 2008, but delays in site openings pushed the date forward to the middle of 2009, so the drug could hit the market as soon as 2010. This may put the company in a delicate position as it is expected to run out of cash around mid 2009. A possible way out is signing a partnership deal for picoplatin with a large pharmaceutical company, based on data from other clinical programs such as the phase II trials in colorectal or prostate cancer.
