When examining the success rate of drug candidates for the treatment of cancer, numbers are not encouraging. Historical figures show that once such a candidate reaches clinical trials, it has a 5% chance to be approved compared to more than 10% for the overall pharma industry. One of the things that makes cancer so difficult to treat is the fact that cancer cells share so many characteristics and functions with normal cells. This makes developing treatments that specifically affect cancer cells but spare normal cells, very challenging. Throughout the years, there has been a positive trend from non-specific, highly toxic treatments such as chemotherapy and radiotherapy towards compounds which specifically target cancer cells. Drug industry has come a long way from the early mustard gas derivatives, which were the first chemotherapy treatments, towards targeted therapies such as small molecule inhibitors and monoclonal antibodies.
Antibodies are playing an increasing role in cancer therapy due to their unique ability to recognize and target cancer cells in a specific manner. Antibodies do not target cancer cells as a whole, but certain structural elements presented on these cells called Tumor associated antigens [TAA]. Such elements must be selectively present on cancer cells, and absent from normal cells. Dozens of TAAs have been recognized so far, serving as targets for many treatments. Such targets, which usually play a critical role in the disease onset and progression, include agents that facilitate growth, enable cell migration and stimulate formation of new blood vessels. Recognizing such targets is a crucial primary step in the long way of developing an antibody-based treatment for cancer, but success is far from granted, even after such a target is found and validated as a TAA. In fact, there are validated TAAs that have been well known for many years, but there is still no approved antibody targeting them.
The first dilemma in choosing a TAA is whether to go after the “traditional” TAAs, which have been known and examined for years by many research teams, or to investigate poorly studied targets, perhaps even totally new, unfamiliar targets. Both routes have their advantages and disadvantages. One of the biggest advantages in targeting a well-known TAA is reducing chance of failure, as the target has already been validated. The downside of such a strategy is a potentially crowded, competitive market. Just like any other field, competition is excellent for customers (patients) but very bad for vendors (drug companies). A good example for that might be Amgen’s (AMGN) Vectibix, an approved monoclonal antibody that targets the same TAA Imclone’s (IMCL) Erbitux, does. Both antibodies are approved for the treatment of colorectal cancer and compete in the same market segment. Targeting a less common TAA, bears higher levels of risk, but makes success much sweeter, since there is a long period of market dominance until competition catches up.
Peregrine Pharmaceuticals (PPHM) is a very good example of a company that focuses on new, non-validated targets. The company is developing a monoclonal antibody by the name of bavituximab, which targets phosphatidylserine molecules [PS] presented on the outer side of cancer blood vessel cells. PS is quite a unique target. While most TAAs are used by tumors in order to survive, grow and metastasize, PS is only a side-effect, a characteristic of cancerous tissues from which cancer does not benefit. In normal, healthy vascular cells, PS is tightly segregated to the internal side of the cell. This segregation appears to be impaired in many kinds of tumor blood vessels, where PS becomes present on the external side of the cells, likely in response to certain conditions in the tumor microenvironment. This phenomenon was observed in lung, breast, prostate and pancreatic cancer, among others. If peregrine’s claims are proven right, PS is a great example of a very specific TAA, since it only presented by cancer blood vessel cells. Since monoclonal antibodies that are injected into the blood stream can recognize only targets that are presented on the external side of cells, healthy cells that have PS exclusively on their inner side will be unaffected, while cancer blood vessels would be targeted by the antibody exclusively.
Targeting tumor blood vessels is a promising strategy for fighting solid tumors. Once a tumor reaches a certain size, it cannot rely on existing blood vessels for the supply of nutrients and oxygen, and therefore builds or manipulates its microenvironment to build additional blood vessels. One approach for targeting cancer vascular tissues is using treatments that inhibit the growth of such cells. A good example of such an agent (generally referred to as “antiangiogenic”) is Genentech’s (DNA) Avastin, a monoclonal antibody that targets a molecule that induces formation of new blood vessels. However, antiangiogenic drugs are designed to inhibit the formation of new vessels but have limited effect on the existing tumor vasculature. Vascular targeting agents such as bavituximab may be superior to antiangiogenic agents in many cases since they target existing tumor blood vessels.
Recognizing the importance of PS as a target is just the first step. The next one is trying to target PS with a monoclonal antibody and evaluate whether the antibody actually binds tumor blood vessels in a specific manner, without binding normal cells. Several experiments in mice were conducted using a mouse version of bavituximab, which was evaluated for its ability to bind tumor vessels. The experiments showed a clear localization of the antibody to tumor blood vessels, with virtually no binding to healthy blood vessel tissues.
Specific binding is still not a guarantee for actual clinical activity, as a clear anti-tumor effect should be demonstrated as a result of binding. There are several mechanisms by which antibodies can inhibit tumor growth. One such mechanism is the recruitment of the immune system against cells the antibody binds. When researchers examined tissues bound by bavituximab, there was a clear presence of white blood cells that infiltrated into the tissue. Strong tissue destruction in the core of tumors, with survival of a peripheral rim was observed, which was another validation of the antibody’s anti-tumor effect in mice. This pattern, where the inner core of the tumor is affected while the external parts of the tumor remain unaffected, seems to be typical of anti-vascular agents such as bavituximab. Blood vessels in the interior of the tumor are presumed to be more sensitive to such treatments due to their distance from the body’s normal blood system. In contrast, compounds that target the tumor cells directly tend to be more effective against the periphery, where cells multiply at a faster pace. Hence, combining vascular targeting with direct tumor targeting may result in an additive effect.
To date, numerous pre-clinical experiments that evaluated the synergistic effect of bavituximab and conventional therapies, in various different types of cancers, demonstrated a clear synergy with conventional therapies such as chemotherapy and radiotherapy. These experiments involved growth of human cancer cells inside mice, and the treatment with the antibody, traditional therapy or a combination of the two.
A recent publication evaluated the combination of radiation therapy and the mouse version of bavituximab for the treatment of lung cancer in mice. The combination of bavituximab with radiation seems promising since recent studies show that vascular cells may expose PS after irradiation, making them more sensitive to the antibody. Mice bearing lung cancer tumors that were considered resistant to radiation, were treated with radiation, the antibody or the combination of the two treatments. While radiation therapy alone had no effect on tumor growth, the combination regimen led to a relative reduction of 80% in tumor growth. Mice treated with the combination grew by only 1.8-fold over the course of the experiment, as oppose to 5-fold growth in mice treated with radiation. Furthermore, combination therapy reduced blood vessel density and enhanced white blood cells infiltration into the tumor mass beyond the reduction observedwith radiation therapy.
Another example might be an article published on 2005 evaluating the effect of combining the antibody with the chemotherapy agent gemcitabine for the treatment of mice bearing pancreatic cancer tumors. The antibody significantly enhanced the therapeutic efficacy of gemcitabine, leading to increased infiltration of white blood cells in the tumor and to decrease metastasis rate, especially in the liver.
The inevitable conclusion from numerous pre-clinical studies is that in mice, targeting PS can improve the efficacy of conventional therapy without additional side effects. The enhanced therapeutic effect seem to be due to the ability of these conventional therapies to increase exposure of PS on tumor blood vessels, amplifying the target, as well as the high sensitivity the tumor core has towards bavituximab.Clinical trials
Peregrine has initiated 2 phase I trials, primarily aimed at evaluating safety of bavituximab for the treatment of several types of cancers, including breast, lung and pancreatic cancer. Although generally, phase I studies are not aimed at evaluating efficacy, in cancer, they commonly involve efficacy assessment in addition to safety and dosing issues.
The first clinical trial evaluating bavituximab for the treatment of cancer was initiated in late 2005, and was designed to accommodate up to 28 patients with advanced solid tumors who stopped responding to standard treatments. This trial is still ongoing. Patients receive bavituximab as their only treatment, which makes expectations from this trial modest, since it is clear that monoclonal antibodies are more effective as part of a combination of treatments. Since it is quite clear now that bavituximab has an excellent safety profile, we can only hope that a subtle anti-tumor response is observed in some of the patients. Even if bavituximab achieves a single digit response rate among these patients, it would be a positive indication for this unique antibody’s abilities. This trial might be the last trial in which bavituximab is evaluated as a single agent, as it seems very likely that follow-on clinical trials will involve regimens that combine bavituximab with other conventional treatments.
Last year, the company initiated an additional phase Ib study that was conducted in India. Due to the synergistic effect bavituximab demonstrated in pre-clinical trials, and since the majority of cancer monoclonal antibodies are administered in combination with other compounds, it was clear that bavituximab had to be evaluated in combination with other treatments. In this trial the two goals were proving the combination does not lead to increased toxicity and side effects, and the evaluation clinical response. For that purpose, the company recruited 12 patients with various solid malignancies (such as breast, lung, ovary and pancreatic) who received a combination of bavituximab and standard chemotherapy. In addition to evaluating the safety of bavituximab, the treatment’s clinical effect was also evaluated.
The company has published top line results from this small study, which were quite positive, relatively to a phase I study. Analyzing such a trial should be done very carefully, especially due to the small size, the lack of control group and the fact each patient knew what he/she was getting. These factors make the results very preliminary and unreliable, however, some insight can still be gained.
First and foremost, the combination of bavituximab with chemotherapy agents was verified as safe, as no substantial increase in side effects was observed. When patients were evaluated for efficacy, response rate was 50%, hence, 50% of patients demonstrated some sort of measurable clinical response. This trial was not a comparative trial, which means that we don’t have any idea what was bavituximab’s contribution to these responses. Basically, the clinical effect may be the outcome of the chemotherapy treatments alone. A final answer to this question may come only several years from now, after a large comparative phase III trial is conducted. For now, all we can do is look at historical performance of the chemotherapy agents, and compare the response rates they have achieved in order to get a vague impression about the performance of bavituximab in this trial. Since the company has yet to publish final analysis from the trial, we’ll have to do some speculating.
The combination of bavituximab and gemcitabine seemed to be very effective with a response rate of 75%. From this figure we can assume that there were 4 or 8 patients receiving gemcitabine and bavituximab. Gemcitabine is common for the treatment of NSCLC (Non-small cell lung cancer) and pancreatic cancer, so we can assume that this subgroup of patients had either of the two. An article published in July 2007, which evaluated results from 2 large clinical trials with 503 pancreatic cancer patients, revealed that overall response rate for patients treated with gemcitabine as their only therapy was 14%. Historical response rate for gemcitabine among advanced NSCLC patients was is in the range of 20%-26%. Either way we look at it, a response rate of 75% compares very favorably to historical results, and can be viewed as an indication for this kind of regimen. However, just to make things clear, it certainly does not mean that bavituximab combined with gemcitabine will have a 75% response rate among a larger patient population.
In addition, 50% of Patients receiving combination of bavituximab and carboplatin+paclitaxel achieved objective tumor response, which means that these patients saw their tumors shrink at least 30% (partial response). Carboplatin +paclitaxel are used for the treatment breast, ovarian and NSCLC. During the call, company management revealed that both metastatic breast cancer patients who received bavituximab and carboplatin+paclitaxel had a partial response. In other words, among breast cancer patients, the objective response rate was 100%. Carboplatin+paclitaxel was assessed both as salvage as well as first-line treatment of advanced breast cancer patients in phase II studies which disclosed 40-60% response rates. This figure is an encouraging sign, but it also demonstrates why results of early, small clinical trials must be taken with a pinch of salt, as even the most optimistic observer understands a 100% objective response rate is unrealistic in advanced breast cancer. The great success rate among breast cancer patients also implies that patients with other types of cancers did not achieve partial response in this trial. There was an even number of patients who received carboplatin+paclitaxel, probably 4 or 6, and we know only half of them had a partial response, 2 of which were breast cancer patients. It means that 2-3 patients with either ovarian or NSCLC did not respond very well to the treatment. This compared with historical figures for carboplatin+paclitaxel of 25%-30% objective tumor response among NSCLC patients and more than 60% among ovarian cancer patients.
Encouraged by results from the phase Ib trial, Peregrine decided to launch several phase II clinical trials in order to focus on certain kinds of cancers specifically. In July, the company announced that it has submitted a clinical protocol with the Drug Controller General of India (DCGI) for a Phase II trial of bavituximab in combination with chemotherapy in patients with non-small cell lung cancer (NSCLC). Last week, the company announced another protocol submitted with the DCGI, for the evaluation of bavituximab in combination with paclitaxel/carboplatin in patients with metastatic breast cancer. The company expects to file at least two more protocols for evaluation of bavituximab for additional conditions. It is likely that advanced pancreatic cancer will be one of these conditions, due to the promising effect bavituximab had in combination with gemcitabine in a pre-clinical and the phase Ib clinical trial.
Apart from bavituximab for the treatment of cancer, Peregrine is pursuing 2 other clinical programs. The first is bavituximab as an anti-viral therapy, currently evaluated in a phase I trial. The second clinical program is evaluation of Cotara, a monoclonal antibody conjugated to a radioisotope for the treatment of brain tumors, currently in phase II. Each one of these programs seems attractive by itself, however, bavituximab for cancer treatment has the biggest potential, in our opinion.
In assessing the risk/reward ratio of Peregrine, investors should take several factors under consideration. The fact that bavituximab still hasn’t demonstrated efficacy in a phase II trial combined with the exploratory nature of PS as a target makes it very speculative. On the other hand, the impressive pre-clinical activity and synergies with other therapies, as well as the preliminary results from the phase Ib trial are encouraging. Another thing we really like about peregrine is the aggressive clinical program it is pursuing. Since antibodies for cancer have an annoying tendency to be effective only for a portion, and not for the majority of cancer types they are evaluated for, launching 4 phase II trials in one year means that chances for success (as well as expenses…) are greater. Bottom line, we wouldn’t bet the farm on Peregrine, but we can’t help thinking that the little company from Tustin may be on to something.
Disclosure: Author has a long position in PPHM