PSTI – Placenta Stem-Cells Brings Hope to PAD-Peripheral Artery Disease Patients
Intermittent Claudication or as called IC is a peripheral artery disease (PAD) caused by fatty deposits that accumulate in the arteries of the leg and reduce blood flow to exercising muscle and is generally a reliable indicator of occlusive arterial disease, which lead to a discomfort, weakness and a leg pain after any effort like exercise, run or even walk for a long distance.
In the U.S. approximately 3% of patients aged 40 years, and 6% of patients aged 60, have IC. It can progress to Critical Limb Ischemia (IC), a more severe form of peripheral artery disease which can lead to leg amputation and death.
PLURISTEM (PSTI) a cell therapy company, developer of placenta-based cell therapy product candidates for the treatment of multiple ischemic, inflammatory and hematologic conditions. Pluristem’s IC treatment using PLX-PAD a placental-derived adherent stromal cells, has the potential to address a big medical need in the US, EU and around the world, since the blockage of blood vessels in patients PAD have no approved drug in the market, The only current treatments are surgical to open blocked arteries that are risky for the patient or endovascular revascularization that come with very high costs to the healthcare system due to the need of second revascularization in many cases and the management of limb-threatening ischemia . Cell therapy is being explored as a better and non-surgical treatment. Pluristem could be the first to launch a commercial cell therapy for peripheral artery disease in the near future.
Two weeks ago, Pluristem reported positive top-line results from the IC Phase II trial which took place at 28 clinical sites in the U.S., Germany, South Korea and Israel. (Link to the PR) and most important outcome in my view was the validation of the study design in the ongoing Pivotal Phase III study in Critical Limb Ischemia (CLI), as the company is using the same dose of 300 million PLX-PAD cells as the optimal dose for treatment of PAD, also the two administrations of 300 million PLX-PAD cells demonstrated a statistically significant superior effect (p=0.0331) compared to a single administration of 300 million PLX-PAD cells in MWD- Maximum Walking Distance at week 52, suggesting that in chronic indications such as PAD a second treatment may be required to significantly improve the clinical outcome.
While the KOL’s and doctors specialize in PAD disease around the world were very excited from the clinical results, and from the option of treating PAD disease through intra muscular injections of stem cells, instead of surgical procedure which in many cases failed to keep the patients from coming back for revascularization within the next 12 months. In the study revascularization risk was reduced by 49% in the main efficacy group at week 65. Moreover; patients receiving 2 administrations of PLX-PAD cells originating from different placentas were 100% “revasc-free” (no revascularization events) at week 65.
To get more info about the study and what are the company plans with the IC and CLI, we approached Pluristem for an interview with Pluristem’s Co-CEO & President Yaky Yanay.
What was the target of the IC Ph2 study?
The clinical trial was a Phase 2, which has three objectives:
- Prove the efficacy of the IC treatment with PLX-PAD.
- Determine the optimal dose.
- Validation of the CLI Phase III clinical trial protocol, an advanced stage of the disease by determining the optimal treatment dose and the optimal dosing regimen.
What were the primary and secondary Outcome of the study?
The primary and the secondary endpoints were in fact with the same goal: evaluation of the improvement of patients’ walking distance with the dose of 300 million cells versus placebo.
This target was examined against two population groups: all patients receiving two treatments of 300 million PLX-PAD cells, and a group of those patients receiving two treatments of 300 million PLX-PAD cells originating from different placentas. The results of this subgroup are the most relevant, as this is the outline of the treatment provided by the Company in the CLI Phase III trial currently taking place in the US and Europe.
Another important goal of the study was to examine the rate of need for surgical procedure (vascularization or bypass surgery) with the intention of finding treatment as a reduction in the risk of surgical intervention.
What was the rational of using cells originating from different placentas?
The longtime experience and deeper research in placental-derived adherent stromal cells, has led Pluristem to understand that it is possible to maximize the efficiency of biological treatment by combining treatments from various sources. In the recent years, there has been many discussions in the field of biological products sold by companies such as Celgen or Amgen, which is trying to overcome the decline in the effectiveness of treatment over a long period of time in a significant proportion of these products, although in most cases clinical symptoms are not seen. Our deep understanding of the cells’ mechanisms of operation, and the unique technology we have developed, enables us to offer optimal treatment using cells originated from different placentas. This patented concept makes it possible to overcome potential obstacles in biological treatments and to stimulate an ideal body response to treatment.
From these insights, we chose to indicate the “results of improvement” in the group treated with PLX-PAD cells from two different placentas, as a key secondary endpoint, which was predefined by the regulators (FDA, EMA, etc.) prior to getting access to the IC study results.
There are many questions regarding the study results, what is your take?
It is important to understand that this is a Phase II trial aimed at learning as much as possible about the therapeutic abilities of the PLX-PAD cells, in order to change or validate the optimal protocol for the trial in the pivotal phase intended for marketing approval. Fortunately, the IC trial results confirmed the existing outline.
In the group treated with 2 doses of 300 million PLX-PAD cells originating from different placentas, showed statistically significant improvement at 52 weeks, and this is the most important news that fortunately has already been implemented in the CLI pivotal study protocol.
In the general population treated with 300 million PLX-PAD cells, there was a significant improvement in the population treated in the US, which we noted in the press release, because this is a significant number of the entire study patient population, as well as one of the most significant markets for us, the US market.
Another important significance of the results is a 50% reduction in the risk of surgical procedure in the main efficacy group, treated with 2 administrations of 300 million PLX-PAD cells, and 100% reduction in patients receiving 2 administrations of PLX-PAD cells originating from different placentas, they all were “revasc-free” (no revascularization events) at week 65, that is 13 weeks longer than the original 52 weeks target. This is a real positive news that PLX-PAD cells can be effective for the atrial atherosclerosis, which has aroused enthusiastic reactions among the doctors we talked to.
What is the benefit of Pluristem’s cells in atherosclerosis?
Atherosclerosis is a systemic and chronic disease, a highly complex disease. In order to lead to a treatment in such a complex disease, a very sophisticated drug that is capable of operating on many levels and capable of secreting an extensive cocktail of therapeutic proteins is needed, and this is exactly what our PLX-PAD cells know and intend to do. Pluristem aims to examine the field of peripheral artery disease (PAD). With the increasing incidence of diabetes, obesity, smoking and aging of the population, we see millions of PAD patients worldwide, a number that is only growing. Finding a medical solution, especially for patients who are not suitable for surgical procedures (about 40% of CLI patients, for example) is one of the major medical challenges of recent years. Since the publication of the IC results we have received many requests from both patients and doctors who are very encouraged by the results and wish to take part in the continuation of our clinical development in this field. It is important to remember that this is an unmet medical need that, beyond its severe impact on patients, also leads to high costs to the health systems around the world. Accordingly, the Pluristem PAD project received financial support, over tens of millions of dollars as grants, and the green light from many regulators enabling early marketing approval.
What’s the next step?
Regulators’ recognition of the severity of the disease and the need to find a suitable medical solution combined with the results of our early trials contributed to the regulatory approval of Phase III clinical trial of Critical-Limb-Ischemia (CLI), which is currently recruiting patients in the US and Europe under the accelerated pathways. We believe that if we can prove the efficacy of the treatment and reach the marketing stage, we will see extensive use of the product in other stages of the disease.
Following the positive results of the intermittent claudication trial (IC), we plan to meet with the various regulators and discuss our options for advancing the IC treatment to the next clinical trial.
It does sound like a good result that could be a real hope for the medical world. How do you explain the stock price reaction?
First, there may have been a misconception of the objectives of the trial. This is a phase II trial and the main objectives were to select the optimal dosing, treatment regimen and proof of the treatment effectiveness using cells from different placentas in the second dose. And these goals were successfully achieved. A much larger trial is now under way in CLI, recruiting 246 patients who will dosed twice with 300 million from different placentas as well. According to the results of the IC study, we are convinced that the trial is planned perfectly, including sample size, dose of treatment, and injection regimen. We do see a gap between the scientific-medical community’s and analysts’ reaction to the results, and the stock price reaction. Our role as management at the moment is to bridge the gaps and make the good results to be reflected in the company’s valuation.
The results from the US arm, with double treatment of 300 million cells were statistically significant. In addition, we saw that in the general population 2 treatments of 300 million cells were significant versus one treatment, which is a rigorous review, can you explain why? And will you study the use of PLX-PAD cells to prevent arteriosclerosis in blood vessels leading to and from the heart?
We are still conducting a more extensive analysis of the data and performing statistical analysis to get the full picture of the trial. We expect the full data to be published in a scientific publication in the coming months. We were able to demonstrate in the study that 2 treatments of 300 million cells were statistically significant effective versus one treatment. For the heart indication, our clinical focus right now is on our three pivotal studies. However, if there is a relevant partner interested in a particular indication that make sense in terms of the mechanism of action of the PLX-PAD cells and the disease, then we will consider it positively. We also have successful pre-clinical trials in this field.
Last week, Pluristem announced that it has entered into an additional collaboration agreement with the U.S. Department of Defense (DOD) and its United States Army Medical Research Institute of Chemical Defense (USAMRICD) to study the Company’s PLX-R18 cell therapy product in the treatment of long term lung injuries following exposure to mustard gas.
It is interesting because the DoD is currently in the late stages of the Acute-Radiation-Syndrome (ARS) trail, does this suggest they are seeing a positive results in the ARS?
We have no access to the DoD trial for the treatment of ARS, but our current project is to test the PLX-R18 cells, (same cells which are tested by the US government for ARS), to treat the long-term lung injuries following exposure to mustard gas, which will be funded by the U.S. National Institutes of Health (NIH) but the DoD will perform the study. We are glad that our cells are selected again for an important project like the mustard gas, and it is certainly worth mentioning the American government, which invests considerable resources in protecting and finding innovative medical solutions for the population and the US defense system.
Regarding the ARS trial, it is known that Amgen (AMGN) is going to lose its exclusivity if and when Pluristem’s ARS treatment is approved. Persistent rumors indicate that the company is approached by Amgen and / or other companies, is it true?
There is no doubt that the radiation project is of interest to many companies in the market, but I cannot comment at these rumors at the moment.
Disclosure: Author is Long PSTI