Peregrine Pharmaceuticals, Inc. (PPHM) was formed more than 30 years ago and has never been profitable. Their lead asset, bavituximab, has been in development since 2005; 735 patients have been treated in 16 trials and there is currently no visible path to registration. Despite the doom and gloom, Peregrine's top five executives feel justified in rewarding themselves with nearly $3MM/year in compensation; so much for pay for performance.
Bavituximab, a first-in-class phosphatidylserine-targeting chimeric antibody (having mouse and human components), is the centerpiece of Peregrine's pipeline. Phosphatidylserine (PS) is a phospholipid that is expressed on the surface of many cancer cells and cells undergoing apoptosis making it a logical target for cancer therapy.
Clinical development of bavituximab for the treatment of cancer began in 2008. Since that time, Peregrine has conducted twelve Phase-I/-II studies and treated 613 cancer patients but has yet to observe a statistically significant improvement over a contemporary standard-of-care (SOC).
Peregrine initiated a randomized Phase-II study of docetaxel ± bavituximab in 2nd-line NSCLC patients (N=121) in 2010. The results of the study were the subject of a recent press release in which the company reported that the "results from this Phase-II trial indicate a meaningful improvement in median overall survival of 11.7 months in the 3mg/kg bavituximab plus docetaxel arm compared to 7.3 months in the control arm (HR=0.73; p value=0.217)." To add to the hype, the company went on to say that "these compelling results strongly support advancing the 3mg/kg bavituximab plus docetaxel combination into Phase-III development in second-line NSCLC." To be clear, this was a failed trial (P = 0.217), the results were not compelling and the "improvement" in median overall survival was orders of magnitude away from achieving statistical significance. This was, in part, due to the inclusion of a 1 mg/kg dose arm which reduced the size of each arm to 40 patients. Given that there was a significant volume of data available for docetaxel in combination with 3mg/kg of bavituximab at the time this study was initiated, there was no apparent reason to include the 1mg/kg arm.
Based on the results of a Phase-II study (NCT00687817) with bavituximab in combination with paclitaxel and carboplatin in previously untreated NSCLC patients (N=49), the company initiated a randomized Phase-II study with carboplatin/paclitaxel ± bavituximab (NCT01160601) in the same patient population (N=86). It is disappointing that the company chose to limit this study to 86 patients as it will be difficult to "tease out" differences between the arms of the study. Clinical development is more than simply conducting clinical trials, it's about asking hard questions and designing and conducting clinical trials to secure definitive answers. Regrettably, this study, which should read out shortly, is underpowered and not designed to provide definitive answers.
Another Peregrine study in NSCLC that will not likely advance the development of bavituximab is study NCT01323062, in which the safety and efficacy of bavituximab in combination with pemetrexed (Alimta®) and carboplatin in previously untreated patients (N=25) is being evaluated. It is not clear what the company had in mind when designing this trial as pemetrexed is only approved for use in combination with cisplatin.
The story is the same with bavituximab in pancreatic cancer. Peregrine has just completed study NCT01272791 in patients with previously untreated, stage IV pancreatic cancer. Patients (N=70) were randomized to receive gemcitabine ± bavituximab. The company reported a more than doubling of overall response rates (ORR) and an improvement in overall survival (OS) when compared with gemcitabine alone (control arm). Patients treated with the combination had a 28% tumor response rate as compared to 13% in the control arm. Median OS, the primary endpoint of the trial, was 5.6 months for the bavituximab plus gemcitabine arm and 5.2 months for the control arm (hazard ratio = 0.75) but this difference was not statistically significant. As with the previously mentioned studies, this study was also underpowered and not designed to show differences between the treatment arms.
Peregrine also has ongoing open-label studies in liver, rectal, castrate-resistant prostate, and breast cancer. In regards to the latter, the company has completed two open-label studies in metastatic breast cancer and has a third ongoing in Her-2 negative breast cancer patients (N=14) who are being treated with paclitaxel. It is not at all clear why the company is conducting this trial as ~ 70 (~75% of 92 patients treated) Her-2 negative patients were treated in previously completed studies.
The efficacy and safety of bavituximab was evaluated in three open-label and one randomized trial in patients with hepatitis C (HCV). The randomized trial showed bavituximab plus Ribavirin to be inferior to PEG-IFN/Ribavirin. As a consequence of these results and a shift to all oral treatments, it is assumed that there will be no further development of bavituximab in hepatitis C.
Peregrine is also developing an iodine-131-labeled antibody targeting a DNA/histone-H1 complex (Cotara program) for the treatment of glioblastoma. According to the company, Cotara's targeting mechanism enables it to bind to the dying tumor cells and deliver its radioactive payload to the adjacent living tumor cells with minimal radiation exposure to healthy tissue. Cotara is delivered in a single-dose using convection-enhanced delivery (CED), a method developed by the NIH that enables targeting of specific tumor sites in the brain. The company has treated 75 patients with Cotara in three open-label Phase-I/-II studies. Without any supporting randomized Phase-II data, the company is planning to initiate a registrational Phase-III study trial based on input received from the FDA.
History Structure and Partnerships
Peregrine was founded in 1981 and is based in Tustin, California. It has license and R&D agreements with the University of Texas Southwestern Medical Center at Dallas, Affitech A/S, and Merck KGaA. As of December 2012, the company had $24.4 MM available and an annual burn rate of $25-$35 MM. Initiation of Phase-III trials in NSCLC and glioblastoma would push the burn rate to the higher end of the range.
Peregrine, through its wholly-owned subsidiary, Avid Bioservices, Inc., offers integrated current good manufacturing practice (cGMP) commercial and clinical manufacturing services in the United States, including contract manufacturing of antibodies, recombinant proteins, and enzymes; cell culture development; process development; and testing of biologics for biopharmaceutical and biotechnology companies under cGMP. Avid Bioservices is not yet cash-flow-positive.
In reviewing the development history of bavituximab it is difficult to understand the rationale for much of what Peregrine has done; specifically, the large number of open-label studies, the small number of randomized studies and the fact that the randomized trials were underpowered. Moreover, the company has not provided statistical information (e.g., power to detect differences of a stated magnitude) for any of its randomized trials leading one to wonder if the trials were so underpowered that the company was uncomfortable sharing this information. Then there are the results from the failed randomized trials in 2nd-line NSCLC and 1st-line pancreatic cancer which have seemingly been ignored by the company. Finally, the development history of bavituximab suggests reluctance on Peregrine's part to test the drug in a well-powered study. The party is over for Peregrine, investors are losing patience and it's time to move on.