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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. (To be discussed in part 3 of this article).

Picoplatin’s Potential Competitors

Due to its small size, the market for SCLC is not very active, in contrast to the lucrative market of non-small cell lung cancer [NSCLC] that garner a great deal of attention from every major pharmaceutical company. Niche markets are often targeted by smaller companies who seek to get their foot in the door, generating initial proof-of-concept for the product as well as a modest stream of revenues. Exelixis’ (NASDAQ:EXEL) XL184, which recently entered pivotal trial in medullary thyroid cancer [MTC], and Infinity’s (NASDAQ:INFI) IPI-504 which is expected to enter a pivotal trial for gastrointestinal stromal tumors [GIST] this year are good examples for this trend. Both drugs may be applicable in larger indications, but the companies decided to initially target niche markets.

The competitive landscape in the resistant/refractory SCLC market made it a suitable route to commercialization for small biotechs such as Poniard. Because there is no currently approved drug for this indication, picoplatin’s chances of showing a survival benefit and getting approved seem fairly high, while the overall market is still substantial. There are estimated to be 70,000 SCLC patients in developed courtiers who relapse following initial chemotherapy with a platinum agent. Around 40,000 of these patients fall under the definition “refractory/relapsed” as defined in the SPEAR trial. Assuming an average drug cost of $10,000 per patient (the cost of topotecan for the recommended 4 cycle treatment), picoplatin’s addressable market in developed countries is around $400 million. If picoplatin becomes the standard of care in resistant/refractory patients, it will likely be used off-label in sensitive patients as well.

Unfortunately, with the recent emergence of two potential competitors, Poniard might find out that turning picoplatin into the standard treatment for refractory/relapsed SCLC is more challenging than expected.

The first potential competitor is oral topotecan. The drug was developed with the goal of replacing IV topotecan for the treatment of second line sensitive SCLC patients, in order to provide them with a more convenient option. The trial compared oral topotecan combined with BSC vs. BSC alone, and showed a benefit in median survival (26 weeks vs. 14 weeks), similarly to the IV version of the drug. This trial led to the approval of oral topotecan only for sensitive SCLC patients, so allegedly it should not pose any threat to picoplatin. However, almost a third of the patients in the trial were refractory/resistant, and apparently these patients, who were traditionally considered non-responsive to topotecan, have actually responded quite well to the drug with a median survival of 23.3 weeks. This set of data might encourage GSK to try and get oral topotecan approved for resistant/refractory SCLC patients as well, even though the company has not disclosed any plans of doing so (yet). Furthermore, the results may encourage physicians to use topotecan for resistant/refractory patients even before approval. The lead investigators of the study left little room for speculation as they wrote:

This study suggests that with oral topotecan the benefits of therapy outweigh the risks in all patient groups and therefore all subgroups of patients with relapsed SCLC (sensitive or resistant) should now be considered for this treatment.

Phase III trials tend to result in shorter survival, compared to uncontrolled phase II trials, so if history is of any indication, picoplatin will probably have a lower benefit in the phase III trial compared to the 27 weeks in the phase II trial. Results may be slightly better than expected because the SPEAR trial includes some patients who had a better response to first line platinum therapy, but in general, it is possible that picoplatin will have only a slight or no advantage over oral topotecan. Assuming that picoplatin and oral topotecan have comparable survival benefits, picoplatin will have to prove advantageous based on other factors, such as, patient convenience, safety profile and financial feasibility.

Oral topotecan has definitely the upper hand in terms of ease of administration, as it can be taken as a pill. In addition, Poniard does not have the worldwide marketing and distribution resources GSK does, which should make worldwide market penetration challenging without a large partner. Picoplatin, on the other hand, seem to have a much better safety profile, as topotecan leads to a substantially higher incidence of severe side effects and a 6% mortality rate.

On top of the obvious quality of life issue, an unfavorable safety profile translates into additional medical costs that can sometimes overshadow the direct costs of the drug, and on that front, Poniard should have plenty of ammunition to throw at topotecan.

Over the past years, several studies evaluated the associated cost of topotecan’s toxicity in second line ovarian cancer patients, a setting that mirrors to some extent second line SCLC. In several different studies, the cost of topotecan was compared to that of another chemo agent, lyposomal doxorubicin, (Doxil) which has a similar efficacy. The graph below summarizes some of the data from the cost analysis studies.

topo-and-doxil.PNG

Although there is some degree of inconsistency among the studies and the associated costs, they all demonstrate the economic implications of severe side effects. Topotecan was cheaper in all studies, but its toxicity-associated costs were substantially higher and made it less economically feasible. Of note, all the studies above involve IV topotecan, but the oral version seems to have a similar safety profile. For the same reason, the cost of administration is not included in the analysis.

The pertinent conclusion is that if picoplatin shows a comparable or even slightly worse efficacy profile, health insurers will prefer it over topotecan, based on financial considerations. The superior safety profile should also help picoplatin gaining acceptance among physicians and patients, many of whom are old and frail and consequently cannot tolerate intensive therapies.

Amrubicin

Picoplatin’s second potential competitor is Celgene’s (NASDAQ:CELG) amrubicin, which is already approved in Japan for the treatment of lung cancer. Celgene gained access to amrubicin as a result of the Pharmion acquisition, which held the exclusive rights for the drug in the US and Europe, after acquiring San Diego-based Cabrellis. Amrubicin is currently in a registrational phase III trial, where it is being evaluated against topotecan among second-line SCLC patients, sensitive and resistant/refractory. Interestingly, results from the trial are expected to arrive in 2010, one year after the expected results from the picoplatin study.

Amrubicin previously demonstrated unprecedented clinical activity in several single arm clinical trials in Japan, with an overall survival above 40 weeks in second line SCLC. There was, however, some skepticism with respect to the reliability of these impressive results, which stemmed from ambiguous results in other trials as well as from the fact that amrubicin had never been evaluated outside of Japan. At this year’s ASCO annual meeting, three studies in second line SCLC were published, including two comparative trials in which amrubicin was evaluated head-to head with topotecan.

One randomized trial (#8040), run by Celgene in the US, compared amrubicin and topotecan in sensitive SCLC patients. Amrubicin had a better response rate as well as a 4.5 week difference in progression-free survival [PFS]. In another randomized trial (#8042), this time in Japanese patients, amrubicin demonstrated superior activity over topotecan, with a 6 week difference in PFS. From Poniard’s perspective, these results make amrubicin a real threat, (assuming that picoplatin and topotecan have comparable efficacy), even though these trials involved primarily sensitive patients as opposed to the refractory/resistant population Poniard is targeting with picoplatin. It is also worth noting that Poniard targets a portion of the sensitive market as well with its ongoing phase III trial. On the safety front, picoplatin still looks advantageous, as amrubicin led to a high level of severe side effects, including 4 treatment-related deaths in the two studies. Nonetheless, it seems that unlike topotecan, amrubicin has the potential to lead to substantially better survival than picoplatin.

The third study (#8041) evaluated amrubicin in resistant/refractory SCLC patients in a single arm trial. Of the 69 patients that could be evaluated, 12 (17.4%) achieved an objective response and the median PFS was 13.8 weeks. Picoplatin had a response rate and a median PFS of 10% and 9.1 weeks, respectively, in a similar patient population, another reason to worry about picoplatin’s prospects.

In the meantime, amrubicin remains the biggest threat to Poniard’s picoplatin. While in the case of topotecan, competition will be based primarily on safety and feasibility issues, ambrubicin might show several weeks advantage in overall survival over picoplatin, and replace it already in 2011, only one year after picoplatin is expected to hit the market.

table-1-amru.PNG

table-2.PNG

If amrubicin is found to be more effective than picoplatin, Poniard will have several options. The first option will be abandoning the SCLC market and focus on larger markets. A second option is trying to combine picoplatin with amrubicin or topotecan given picoplatin’s promising safety profile. Topotecan, for example, was evaluated in combination with cisplatin in first line SCLC. The combination demonstrated similar efficacy and acceptable toxicity compared to standard therapy (etoposide with cisplatin), so it is reasonable to assume that it can also be combined with picoplatin. Combining amrubicin with cisplatin in a 2005 Japanese study resulted in promising clinical results, but again, the real value of this type of combination will have to be investigated in large, controlled trials. A third option might be targeting first line SCLC, by replacing the currently used platinum compounds.

In summary, picoplatin has a high probability of approval for the treatment of second line SCLC. The real challenges will come from potential competitors such as topotecan and amrubicin, if approved for overlapping indications. Amrubicin seems to be a more serious threat due its high activity in recent trials, but additional insight will be gained only when overall survival data from the amrubicin trials emerges later this year. On the safety front, picoplatin is superior, therefore, even a slightly worse efficacy profile relatively to topotecan or amrubicin should make it the standard of care.

As noted before, SCLC represents the shortest route to market for picoplatin but it is a relatively small market when compared to other indications for which platinum compounds are approved. The SCLC clinical program will hopefully provide the needed proof of concept for the activity of picoplatin and its superiority over available platinum compounds. This, coupled with positive results in other indications will help Poniard advance picoplatin in major indications such as prostate and colorectal cancer. However, In order to realize the full potential of picoplatin, Poniard will have strike a partnership deal with a large pharmaceutical company.

Disclosure: Author is long PARD and EXEL

Source: Poniard Pharmaceuticals: Platinum Rediscovered (Part II)