ProLindac™ Fact Sheet
What is ProLindac?
ProLindac is Access Pharmaceutical’s lead oncology drug, which is in phase 2 clinical development. It is a therapeutic, previously known as AP5346. It utilizes a safe, water-soluble nanoparticulate system to deliver DACH platinum (the active moiety of oxaliplatin) to tumors. Platinum-based drugs are among the largest classes of chemotherapeutics and oxaliplatin (Eloxatin; Sanofi-Aventis) is a DACH platinum drug that is projected to have had worldwide sales of over $2 billion in 2006.
The role of the Access’ nanoparticulate formulation of DACH platinum is to deliver more drug to the tumor while reducing delivery to normal tissue, thus increasing the drug’s effectiveness and decreasing the toxic side-effects. A major drawback of existing therapies is acute neurotoxicity. ProLindac has been shown to be much more effective than oxaliplatin in a large number of murine tumor models. In a phase 1 clinical study, at least five times more DACH platinum could be administered to patients with ProLindac than oxaliplatin. Moreover there was no indication in ProLindac of the acute neurotoxicity associated with oxaliplatin.
While new cancer drugs often display minimal activity in phase 1 studies, ProLindac produced two partial responses based on MRI analysis, one partial response based on biomarker analysis (CA-125) and four cases of stable disease in an evaluable patient population of 16. A phase 2 study to determine the efficacy and safety of ProLindac in patients with recurrent ovarian cancer has commenced in Europe. A second phase 2 trial of ProLindac in patients with head and neck cancer has been initiated in the U.S. to provide data on the comparative ability of ProLindac and oxaliplatin to deliver platinum to the tumor and tumor DNA.
Chemistry of ProLindac;
ProLindac is a nanoparticulate prodrug of DACH platinum in which the cytotoxic agent (DACH platinum) is bound to a water-soluble, biocompatible copolymer backbone, called hydroxypropylmethacrylamide (HPMA). This approach allows ProLindac to avoid use of the oxalate group which is believed to give rise to the neurotoxicity associated with oxaliplatin.
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| The diagram shows a segment of the general structure of ProLindac. DACH platinum is attached to the water-soluble polymer via a pH-sensitive chelator and linker. While the long polymer strand is linear, the polymer wraps itself into a "ball" by hydrophobic association of the DACH groups and intramolecular hydrogen bonding, providing an overall nanoparticulate 3-D structure. |
ProLindac is designed to be relatively non-toxic while in general circulation, and for the platinum drug to be released within the environment of the tumor. In ProLindac, platinum is believed to be released by a mechanism which takes advantage of the phenomenon that tumors are generally more acidic than surrounding normal tissue. ProLindac releases platinum much more rapidly in a slightly acidic environment compared with an environment of the body’s normal physiological pH.
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| This graph shows the results of an in vitro study in which a solution of ProLindac is incubated is three different solutions, and the amount of platinium released from the polymer is determined. There is minimal release in isotonic glucose, very slow release in phosphate-buffered saline at pH 7.4, and much faster platinum release at pH 5.4 . |
Preclinical Efficacy Data
The following graph displays typical results for ProLindac in a mouse tumor model; in this case the B16 melanoma model. These tumors grow rapidly in mice that are not treated, as shown by the “vehicle” plot. When the mice were treated with oxaliplatin there was a slight reduction in the rate of growth of the tumor (open circles). However, ProLindac retarded tumor growth to a much greater extent than oxaliplatin. ProLindac has been studied in more than 10 tumor models. It was never inferior to oxaliplatin and was usually markedly superior, as demonstrated in the B16 model.
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| This graph shows the average tumor size in rodents over a period of 30 days. There are three treatment groups; controls (closed circles) receive only saline injections. The mean tumor size with time for oxaliplatin-treated animals is shown with open circles, and the animals treated with ProLindac are in red. All surviving animals are treated once a week for three weeks. |
Phase 1 Clinical Study
A 26-patient dose-ranging open label phase 1 study was conducted in Europe to:
- To determine the maximum tolerated dose.
- To establish a recommended dose for phase 2 trials.
- To determine the toxic effects of ProLindac
- To document possible antitumor activity.
- Determine the pharmacokinetic profile of ProLindac Patients were treated weekly for three weeks, then were rested for a week.
The investigators reached the following conclusions:
- The recommended dose for further assessment of ProLindac administered over 1 hour for 3 weeks out of every 4 weeks is 640 mg Pt/m2.
- ProLindac was tolerated up to a dose of 640 mg Pt/m2, with a toxicity profile characterized by frequent grade 1-2 nausea, vomiting, and creatinine elevations, with an absence of grade 3-4 hematotoxicity below 1280 mg Pt/m2.
- Evidence of antitumor activity was observed in patients receiving >640 mg Pt/m2, with partial responses achieved in 2 patients, one with melanoma and one with ovarian cancer, and disease stabilizations in patients with melanoma, esophageal cancer, and cervix cancer.
- Normalization of the CA 125 biomarker occurred in another ovarian cancer patient.
- Total and ultrafiltrate platinum Cmax and area under the curve increased linearly with dose, and terminal half-life did not vary with dose.
- Phase 2 assessment of ProLindac is warranted in relapsed ovarian cancer patients.
Future ProLindac Development
Given the potential of ProLindac to treat a wide variety of cancers, several development pathways are available for this compound. A Phase 2 clinical study of ProLindac in patients with recurrent platinum-sensitive ovarian cancer has commenced in Europe. The FDA has approved an IND for ProLindac for the first phase of a development program that will permit replacement of oxaliplatin by ProLindac in the FOLFOX regimen. In addition, the compelling preclinical and clinical results in melanoma indicate that ProLindac also has considerable potential for the treatment of this disease as well.
To download a copy of the ProLindac Fact Sheet, click here
To download a poster presentation on the Phase 2 ovarian cancer clinical study, click here