The power of the placenta rings truer than ever in an upcoming therapeutic indication planned by Pluristem Therapeutics, Inc. (PSTI) using PLX cell therapy for treating pregnant women with preeclampsia, a leading cause of maternal and infant illness and death costing the global healthcare system $3 billion per year. Its third FDA Orphan Drug application has been submitted, on the tails of approval of two others, one for aplastic anemia implicated in blood disorders and the other for Buerger's disease that affects circulation in the hands and feet. When official, this would mark an important point in the company's history and speaks well of their relationship with regulatory authorities. Orphan Drug status carries clear benefits - seven years of market exclusivity, tax credits for clinical trial expenses, and special attention within the FDA to help clear the way to eventual commercialization.
The acute need for a cure that has been generally left under-treated in generations of women drives the effort. Moving quickly to bring PLX cells into human testing for preeclampsia, Pluristem recently announced that they have brought together a body of scientific thought leaders to help guide them in study design. Of particular note is the inclusion of James M. Roberts, M.D. of the University of Pittsburgh and senior scientist at Magee-Women's Research Institute, a leader in women's health issues, and Baha M. Sibai, M.D of the University of Texas Medical School. Both serve on the Medical Advisory Board of the Preeclampsia Foundation.
Preeclampsia, formerly termed toxemia, occurs in 6% to 8% of pregnant women in the US alone, characterized by high blood pressure, swelling of the arms and legs, and proteinurea, or protein in urine - an indication of malfunctioning kidneys. It strikes in the second trimester and ecumenical in its reach. A history of hypertension increases risk although women deficient in vitamins E and C, as well as magnesium, those carrying multiple fetuses, mothers over 40 years old and diabetics are just as likely to be prone. Left undiagnosed the condition may lead to eclampsia, or full-blown seizures that could be fatal.
Improperly functioning placentas are considered preeclampsia's root cause and managing the disease, when recognized, leaves much to be desired in medical ingenuity. Primary prevention does not exist. Anti-hypertensives might be prescribed, but the only 'cure' is either abortion or delivery, and premature birth can cause a flood of downstream problems, accelerating costs to our already overburdened healthcare system.
Researchers have long been baffled by preeclampsia's source, but recent work in studies of the placenta may provide insight into pathophysiology, particularly why the disease has a specific onset and can still present post-partum. More studies are underway and Pluristem's preclinical work, potentially moving into humans, could prove invaluable to the scientific effort.
Attention to preeclampsia has been building, and Pluristem's timing to explore treatment options could not be better. Recently, the American Heart Association and the American Stroke Association set down first-ever guidelines for preventing stroke in women, based on the fact that more than 50% of the 795,000 strokes each year in the US happen to women, often leading to brain injury. Also recognized is the strong correlation between preeclampsia and the risk for stroke or hypertension, which doubles and quadruples, respectively, as preeclamptic women age. Going beyond obstetric care, both organizations intend the guidelines, which include regular screening and treatment of mothers with a history of preeclampsia, to reach out to all providers of these patients. This is a landmark move, acknowledging the need for procedures geared specifically to women and possibly ushering in a new era of women's healthcare.
In another positive move, May has been declared Preeclampsia Awareness Month, to raise knowledge of better medical outcomes for mothers and their babies, also giving the condition the status of breast cancer, whose national recognition month is October.
Pluristem began its investigation into using PLX cells for preeclampsia with a study headed by Brett Mitchell of Texas A&M College of Medicine, where efficacy was shown in specifically-designed preeclamptic animal models. Dr. Mitchell leads in his field with theories about the source of preeclampsia, targeting a dysfunctional immune system and placental inflammation that contributes to its danger. His hypothesis of the anti-inflammatory properties of PLX cells, and their potential for increasing blood flow worked well in these preclinical trials where animals showed an early normalization of systolic blood pressure and proteinurea, with less disruption to the endothelium, or blood vessel lining.
Another preclinical trial, conducted by the reputable contract research organization Charles River Laboratories International, Inc. (CRL) showed no signs of toxicity when pregnant animals and their fetuses were injected with PLX cells intramuscularly, based on a statistically-significant decrease in systolic blood pressure in mice induced with hypertension, with a likewise reduction of proteinurea, suggesting normal blood pressure and kidney function - all mothers and babies remained well. Importantly, PLX cells had no effect on control mice, contributing greatly to the safety conclusion. Plans to move forward in human testing are being shaped with the help of the company's newly formed steering committee.
It is likely that PLX Cells perform many unknown functions that have yet to be fully discovered or understood. Last summer, University of Pittsburgh Schools of the Health Sciences published an interesting study showing placental cells to have an ability to halt viruses crossing from women to their babies in-utero, pointing toward an approach to fight viral infection during pregnancy and increase the likelihood of a healthy birth. Human placental cells are proving to divulge biochemical mechanisms evolved to prevent viral infection of other cells and tissue, leading researchers to hope for the development of future novel therapies - possibly an antibiotic based on cell therapy.
Pluristem faces a number of clear risks in this latest addition to its pipeline; along with standard regulatory hurdles and the expense of clinical trials, the cause of this maternal disease remains elusive and that may complicate study procedures and cloud the issue at the FDA, where unknown mechanisms of action do not always sit well when results are finally reviewed. On a positive note, I feel the agency would be motivated to look kindly on Pluristem's applications to begin human studies as there is no cure available for preeclampsia, and its backlash for the women who have suffered it is harsh.
Preeclampsia is a pervasive, worldwide medical condition, dangerous to pregnant women where standardized treatment criteria is problematic and management of the disease is flawed. Pluristem's PLX cells may represent a way to streamline care while improving its quality, without subjecting women to a battery of pills for hypertension or convulsion whose effect might be deleterious on a growing fetus. If approved to start clinical trials, this would be Pluristem's ninth indication, proving its technology to be a true platform and driving more value to its underappreciated stock.