OPAXIO (paclitaxel poliglumex, CT-2103; formerly known as Xyotax) is Cell Therapeutics‘ (CTIC) biologically enhanced paclitaxel. OPAXIO has had a rough life and in our opinion, stands on shaky ground. CTIC took OPAXIO quite far in clinical trials, but after not meeting its endpoints in various clinical trials, repositioned the drug as a woman-specific cancer therapy (women with NSCLC and ovarian cancer).

Post-study analyses of these late stage studies did show that OPAXIO prolonged survival among women, presumably due to increased estrogen levels. In fact, preclinical studies have shown that metabolism by some cancer cells is enhanced in the presence of estrogen, which leads to increased levels of paclitaxel in tumor tissue and greater anti-tumor effects.

Paclitaxel and Paclitaxel-Enhancing Agents

Paclitaxel is a microtubule inhibitor that binds the β subunit of tubulin, which in turn slows or arrests rapidly diving cancer cells. In the U.S, paclitaxel is approved for a number of cancers in various settings:

• First-line and subsequent therapy for the treatment of advanced ovarian cancer and in combination with cisplatin in the first-line setting;

• Adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy;

• Treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy;

• In combination with cisplatin for the first-line treatment of non- small cell lung cancer (NSCLC) in patients who are not candidates for potentially curative surgery and/or radiation therapy;

• Second-line treatment of AIDS-related Kaposi’s sarcoma.

Paclitaxel has been, and continues to be, researched in dozens of different cancers and settings. The problem with paclitaxel however, is that a significant number of side effects (difficulty breathing, hives, swollen eyes and lips, flushed face, and severe allergic reactions/hypersensitivity) are associated with the excipient used, Cremophor EL, a polyoxyethylated castor oil. Typically, steroids are given prior to beginning paclitaxel treatment to mitigate some of the side effects.

A few companies have attempted to develop alternative paclitaxel formualtions that are devoid of the Cremophor effects. They are listed in Table 1 below (Note: Oncogel is not designed to be administered intravenously, rather as a local gel for esophageal cancer).

OPAXIO links paclitaxel to a biodegradable amino acid carrier, a polyglutamate polymer. This results in a novel chemical entity which is rendered inactive in the bloodstream, thus suposedly sparing normal tissues from traditional paclitaxel side effects. OPAXIO is preferentially activated and released by the action of an enzyme called cathepsin B once inside tumor cells. Here’s a demonstration of how the compound works.

Now let’s review the clinical trials.

STELLAR 2

This trial compared OPAXIO to docetaxel (Taxotere) in the second-line treatment of patients with NSCLC. In a Phase 3 study of 849 patients, OPAXIO failed to meet its primary endpoint, demonstrating equal median overall survival (OS) of 6.9 months. Despite showing a lower incidence of infection, neutropenia, febrile neutropenia and fatigue relative to Taxotere, patients on OPAXIO demonstrated a significantly higher incidence of neuropathy (50% vs. 30% for Taxotere) with more grade 3/4 neuropathy (19%) vs. Taxotere (3%).

STELLAR 3

The STELLAR 3 was a Phase 3 trial designed to compare OPAXIO/carboplatin vs. paclitaxel/carboplatin in 400 patients with chemotherapy-naive advanced NSCLC and had poor performance status (PSS or PS2). This trial also missed its primary endpoints, demonstrating similar OS (7.8 months) to paclitaxel/carboplatin (7.9 months).

OPAXIO also demonstrated a significantly higher incidence of grade 3/4 neuropathy (17%) vs. the paclitaxel/carboplatin arm (10%), as well as a higher incidence of Grade 3/4 thrombocytopenia (23% vs. 8%) and Grade 3/4 neutropenia (27% vs. 16%).

STELLAR 4

This was also a Phase 3 trial in 381 patients with chemotherapy-naive advanced NSCLC and poor performance status (PSS or PS2) comparing OPAXIO to Gemzar (Gemcitabine) or Vinorelbine (Navelbine). Similar OS also resulted (7.2% OPAXIO vs. 6.5% G/V) as well as did Grade 3 neuropathies.

It should be noted, however, that patients on OPAXIO showed a 40% improvement in OS vs. patients on vinorelbine (N=32).

Additionally, in the STELLAR trials, OPAXIO was delivered over a shorter time period (12 min in STELLAR 4 and 19 min in STELLAR 2) without patients requiring steroids or other premedications.

PIONEER (PGT305)

The PIONEER trial was designed to enroll 600 PS2 chemotherapy-naive women with advanced stage NSCLC. The primary endpoint was overall survival and was measuring the efficacy of OPAXIO vs. paclitaxel in the first-line setting. The study, however, was terminated in December 2006 after a Data Safety Monitoring Board (DSMB) found an “aberrantly low rate of deaths in the control group.” A new protocol was then submitted to the FDA under an SPA, named PGT306, which was to analyze women with NSCLC and normal estrogen levels. An SPA was also filed for study PGT307, which is designed to evaluate OPAXIO in women with NSCLC with elevated estrogen levels.

EMEA

In April 2008, the EMEA accepted for review CTIC’s Marketing Authorization Application (MAA) for OPAXIO for first-line treatment of patients with NSCLC with ECOG (Eastern Cooperative Oncology Group) PS2. The EMEA’s review process generally takes 15 to 18 months. If the MAA is approved by the EMEA at the end of its review, CTIC will be authorized to begin selling OPAXIO in the EU. For a more detailed analysis of the process and the Novartis option, please see our past write up.

PGT201

This was a Phase 2 study of OPAXIO in combination with carboplatin for first-line induction and single-agent maintenance therapy in patients with advanced stage 3/4 ovarian cancer. At ASCO 2005, CTIC presented interim results from this study in an abstract titled:

“Phase II study of paclitaxel poliglumex (PPX) /carboplatin (C) for 1st line induction and maintenance therapy of stage III/IV ovarian or primary peritoneal carcinoma”

At the conclusion of the study, 80/82 patients achieved a major tumor response based on CA125 levels, including 85% with a CR and 12% with a PR. During the study, however, Grade 3 neuropathy occurred in 7/23 pts at the 210 mg/m2 dose level and resulted in withdrawal of 6 patients. As a result, the dose of OPAXIO was reduced to 175 mg/m2 for subsequent patients. Grade 4 neuropathy was not been reported, but there was a high rate neutropenia and Grade 3 thrombocytopenia.

Based on these results, OPAXIO is currently enrolling patients in the GOG212 study, a randomized Phase 3 maintenance trial in women with advanced ovarian or primary peritoneal cancer who achieve a complete clinical response to primary platinum/taxane therapy.

Discussion

OPAXIO has a checkered history with several failed trials. CTIC has mined the data of all the trials to reposition OPAXIO as an effective treatment for women with NSCLC, citing elevated estrogen levels as mechanism for increased effectiveness. CTIC is using the STELLAR results to support an MAA in the EU as first-line treatment of patients with NSCLC with ECOG PS2. The MAA was submitted to the EMEA in April of 2008 and a decision could come as early as July 2009. We highlight that the EMEA is historically more lax in its approval decision, but we still can not avoid the fact that the trials showed a significantly higher incidence of side effects, primarily neuropathy and thrombocytopenia. A clinical advantage from a safety perspective at this point to us seems questionable, despite the decrease need for pretreatment with steroids.

Given that OPAXIO has demonstrated non-inferiority to paclitaxel in the STELLAR trials, approval in the U.S. must be based off clear superiority in its patient subset (i.e. women), as well as demonstrate a favorable safety profile. The high grade and rate of neuropathy is concerning.

On the positive side, we note that in the U.S, CTIC does have an SPA from the FDA for women with NSCLC (PGT307), which is encouraging.

CTIC continues to enroll female patients in its PGT307 trial. OPAXIO has the potential to be the first gender-specific cancer treatment although we typically look negatively on data-mining and prospective studies based off subset analyses from failed trials. Ultimately, we remain neutral on the gender-based results (extracted from the STELLAR trials) simply because of the almost similar OS between treatment and control in STELLAR 3 (OPAXIO 7.8 months, Control 8.2 months). STELLAR 4 demonstrated an encouraging advantage of OPAXIO in women (OS 10.3 months) vs. control (OS 6.9 months).

Regarding the OPAXIO ovarian cancer trial (GOG0212), we also remain neutral given the high degree of side effects seen in PGT201, though the encouraging response rate seen in the trial makes us trend toward optimistic. CTIC expects to report interim PFS data YE09. Assuming we see positive data in PFS with acceptable safety (superior safety would be ideal), we would be more willing to add weight to OPAXIO’s potential in this indication and setting. For now, we remain on the sidelines.

We should also remember that there is only one other alternative formulation of paclitaxel approved in the US: Abraxane. Abraxane was approved in a 460 patient trial in the setting of metastatic breast cancer. Patients on Abraxane achieved a statistically significant higher reconciled target lesion response rate (the primary endpoint) of 21.5% vs. 11.1% for patients in the paclitaxel injection treatment arm, although there was no statistically significant difference in OS between the two study arms. Additionally, the overall response rate with Abraxane for study patients who failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapy was 15.5% vs. 8.4% with solvent-based paclitaxel.

Abraxane’s utilization of albumin allows for a higher dose to be administered, which effectively means more paclitaxel is made available to destroy cancer cells. This in turn allowed for Abraxane to gain approval based off efficacy. Additionally, because Abraxane lacks Cremophor, patients do not need pretreatment with steroids and antihistamines. Abraxane can also be administered over 30 minutes, vs. 3+ hours with Taxol/Paclitaxel. The 10-20 min infusion of OPAXIO would not be a serious marketable advantage.

Finally, we should note that Abraxane is currently the subject of over 400 clinical trials in various cancers and regimens, many of them for NSCLC and ovarian tumors. Approval in these areas would cause a serious competitive threat for OPAXIO given the established safety and efficacy profile of Abraxane.

In our opinion, OPAXIO has the potential be positive, but we remain cautious on a positive EMEA outcome. We also note the competitive landscape and the dominance of Abraxane. Approval based off a subset of patients (women) must be undoubtedly superior to control and safety issues (neuropathy, thrombocytopenia) must be limited to warrant further advancement in this setting. We also remain on the sidelines in the ovarian cancer maintenance indication until PFS data is released later this year.

It is too early for us to comment on OPAXIO’s potential in esophageal or brain cancer.

Therefore, we ask: Cell Therapeutics’ OPAXIO: Hype or Truth?

Answer: Hype, until proven otherwise.

Sources: pubmed, company reports, SEC filings

Positions: none

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