ProLindac

Fact Sheet

What is ProLindac?

ProLindac is Access Pharmaceuticals’  lead oncology drug, which has completed a phase 2 monotherapy study in ovarian cancer patients. 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 European phase 2 study to determine the efficacy and safety of ProLindac in patients with recurrent ovarian cancer has recently been completed.

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.
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.
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.
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.

Phase 2 Clinical Study:

Given the promising data seen in ovarian cancer patients in the Phase 1 study, Access opted to further explore dosing and scheduling optimization in a phase 2 setting in this patient population using more convenient q2w and q3w schedules with dose escalation guided by dose intensity. The study, which has now been completed, enrolled late stage and multiply pretreated ovarian cancer patients that were potentially platinum sensitive. The protocol design called for dose escalation following treatment of patients at lower dose levels when there was no evidence of toxicity.

Despite the heavily pretreated nature and marginal platininum sensitivity of the study population, sustained levels of activity were seen in several patients at higher dose levels. Furthermore, the level of activity observed in the patients treated at the highest dose levels on both schedules benchmarks favorably with previous published reports of single agent oxaliplatin in a similar but less pretreated population. Of the 26 patients enrolled into the study, 22 were considered evaluable according to the RECIST criteria. Of these patient 42% demonstrated a clinically significant stabilization of disease. For patients in the dosed at the highest dose intensity, disease stabilization was achieved in 66% of cases

Although the maximum tolerated dose / recommended dose (RD), based on acute or sub acute phenomena according to the standard phase I study design, were not reached, it was determined that doses of 1680 mg/m2 q3w or 1100 mg/m2 q2w) would be the RD for further studies because of the high level of meaningful stabilizations reported at these doses. Also, sustained and significant reductions in Ca-125, the established specific serum marker for ovarian cancer, were also observed in many patients.

No evidence of acute neurotoxicity was observed in any patient in the trial, which is in marked contrast to Eloxatin, the approved DACH platinum drug, which is associated with significant and debilitating acute neurotoxicity in many patients receiving this drug. Chronic nuerotoxicity was observed in a number of patients that received multiple courses of ProLindac, but all cases resolved when patients came off the study. Overall, ProLindac was well tolerated by the patients in the study.

Future ProLindac Development:

Given the very promising monotherapy data generated by the Phase 2 study, future studies of ProLindac will concentrate on the use of this agent in combination with other chemotherapeutic agents such as paclitaxel, gemcitabine, 5FU/leucovorin and flouropyrimidines in various clinical settings.

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


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