Pluristem is investigating PLX-PAD for the treatment of critical limb ischemia (CLI). CLI is the most severe form of PAD and is characterized by the blockage of major arteries in the lower extremities. The key diagnostic indicator for CLI is pain in the legs that occurs when at rest, due to lack of oxygen. CLI is a high-risk disease: in the US Medicare population, the rate of amputation in one year or less following diagnosis was 33.5% and the one-year mortality rate was 30.3%. The disease is caused by the build-up of atherosclerotic plaques in the vessels of the legs, typically secondary to poor peripheral circulation due to diabetes, obesity, or other vascular disorders. Additional risk factors for CLI are similar to other vascular disorders and include smoking, being of male sex, high cholesterol and high blood pressure. The working group for the Trans-Atlantic Inter-Society Consensus (TASC) on the Management of Peripheral Arterial Disease estimates the incidence of CLI in the US and Europe at between 500 and 1,000 new cases per year per one million in population.
The most common treatments for CLI are revascularization via a bypass or endovascular intervention (angioplasty, atherectomy, or stents). However, only half of all CLI patients are fit for these procedures. We expect the medical device technology to continue to advance and provide new options in the form of drug-coated balloons and other technology, especially in difficult-to-treat, below the knee occlusions. However, there will be a persistent need for non-invasive solutions for patients in poor health and with occlusion in smaller vessels. Cell-based therapies have emerged as potential treatments because the growth factors secreted by multipotent cells can encourage the formation of new blood vessels. There have been a large number of clinical studies of multipotent cells for the treatment of CLI going back to at least 2002. However, these studies have generally been small, and there has been little progress in the private sector (Exhibit 2), and no approvals. The most advanced trial was for Ixmyelocel-T from Vericel, which terminated early in 2013 following enrolment difficulties stemming from the trial design. The trial was terminated after a year when only 40 of the planned 594 patients had enrolled. Vericel terminated the trial after attempts to increase enrolment by increasing the number of trial sites (from 70 to over 100) and loosening the enrolment criteria (by removing the “no option” criterion) failed to accelerate the rate of new patients. The difficulties observed in this trial should serve as a precaution for the future clinical efforts to develop PLX-PAD. However, it is important to note that while the Vericel product required harvesting and then a return trip by the patient for infusion, PLX-PAD can be administered via a standard syringe in one visit. To our knowledge, currently the only other company technically with a Phase III development plan is Cesca Therapeutics. It initiated a Phase III for its SurgWerks-CLI platform in 2016, although it has not enrolled any patients, and this device appears to be deprioritized in favor of the company’s MXP system, which has not entered the clinic.
Exhibit 2: Cell-based therapies for PAD
Product |
Company |
Stage |
Auto/Allo |
Lineage |
Notes |
Ixmyelocel-T |
Vericel |
Phase III |
Autologous |
Mesenchymal stem cells |
Phase III terminated in 2013 due to poor enrolment |
SurgWerks-CLI and MXP |
Cesca |
Phase III |
Autologous |
Bone marrow derived mononuclear cells |
Stem cell isolation devices. Development stalled |
ERC-124 |
Intrexon |
Phase II |
Allogenic |
Endometrial regenerative cells |
Last public clinical development in 2013 |
ACP-01 |
Hemostemix |
Phase II |
Autologous |
Blood derived progenitor cells |
|
CLBS12 |
Caladrius Biosciences |
Phase II |
Autologous |
CD34+ cells |
|
Alecmestencel-T |
apceth |
Phase I/II |
Autologous |
Mesenchymal stem cells |
No progress since 2014 |
Biochymal |
Taiwan Bio |
Phase I/II |
Allogenic |
Mesenchymal stem cells |
|
Source: Evaluate Pharma, Pluristem Therapeutics documents
Pluristem reported results from two open-label Phase I studies (one in the US, n=12, one in Germany, n=15) of PLX-PAD in patients with CLI who lacked surgical options in 2011. The US study investigated the difference in safety and efficacy of a single administration of 280m cells, or the same injection given two weeks apart. The German trial investigated three different doses of cells: 200m, 300m and 600m. The primary efficacy endpoints of the trials were the fraction of patients with amputation-free survival (AFS, no amputations or death) at six months and one year.
Combined, the two studies showed 85% AFS, 100% for the US study and 73% for the German study (Exhibit 3). There is a high degree of variability for AFS reported in the literature, and the rate appears to have been increasing since the mid-1990s due to higher rates of revascularization procedures as well as better diabetes control, antiplatelet therapy, infection control and smoking cessation. The largest trial to date examining AFS in CLI patients (the TAMARIS gene therapy trial) showed an AFS of 67% in the control arm.
Exhibit 3: CLI amputation and survival studies
Author |
Trial |
Year |
No. |
Amp |
Death |
AFS |
Jivegård |
Spinal cord stimulation |
1995 |
26 |
50% |
31% |
N/A |
Lepäntalo |
Retrospective clinical review |
1996 |
105 |
46% |
54% |
28% |
Claeys |
Spinal cord stimulation |
1996 |
41 |
20% |
29% |
N/A |
Klomp |
Spinal cord stimulation |
1999 |
60 |
48% |
23% |
40% |
Spincemaille |
Spinal cord stimulation |
2000 |
18 |
50% |
28% |
N/A |
Amann |
Spinal cord stimulation |
2003 |
39 |
46% |
0% |
54% |
Marston |
Wound care only |
2006 |
86 |
38% |
0% |
62% |
Brass |
CIRCULASE (PGE1 analog) |
2006 |
190 |
11% |
10% |
81% |
Nikol |
TALISMAN (NV1FGF gene therapy) |
2008 |
56 |
34% |
23% |
48% |
Hiatt |
TAMARIS (NV1FGF gene therapy) |
2010 |
259 |
21% |
15% |
67% |
Powell |
Intramuscular hepatocyte GF |
2010 |
6 |
33% |
17% |
N/A |
Pluristem |
PLX-PAD US Study |
2010 |
12 |
N/A |
N/A |
100% |
Pluristem |
PLX-PAD German Study |
2011 |
15 |
N/A |
N/A |
73% |
Source: Pluristem Therapeutics, Benoit et al
It should be noted, however, that Pluristem studies were not powered for statistical significance and carry the inherent biases associated with open-label studies. Additionally, patients in the US study were relatively mild in terms of CLI: before the start of the trial, patients had transcutaneous partial oxygen (TcPO2) concentrations of 45.5mmHg, with is at the low end of the normal range (depending on location of measurement, the low end is 45-55 mmHg). Patients in the German study had TcPO2 concentrations of 12.6 at induction, by comparison. The company did not report any safety issues from the studies, and noted that there were no immune reactions or neoplasms as a result of the treatment.
Pluristem currently has an ongoing pivotal Phase III CLI trial in the US and EU. The trial is currently enrolling up to 246 patients who are otherwise unsuitable for revascularization, and will measure the time to amputation or death as the primary endpoint. The company has stated that it expects a single trial to be sufficient to support approval, and it has consulted with both the FDA and EMA regarding the pathway. In part, this is enabled by the large safety database that will be provided by the ongoing intermittent claudication clinical trial. The program has fast-track in the US and has an adaptive pathway designation in the EU, which may entitle it to early provisional approval (after 123 events). Additionally the program received fast-track status from the FDA in September 2017. All of these special programs ensure an increased level of interaction with the regulatory agencies and guidance. The company also has plans to initiate a 75-person study in Japan, through a subsidiary co-owned by Sosei. This is also expected to be the only trial needed for approval, as in Japan, regenerative products face a lower bar of statistical evidence for approval (statistical safety and a signal of efficacy). We should note that the decision to progress to a Phase III trial without a confirmatory Phase II study and without statistically demonstrating a treatment effect is exceptionally aggressive and the program is high risk.
The drug is also available in the US through the FDA’s Expanded Access (approved January 2018) program for CLI patients with severe disease that cannot participate in the Phase III. This program allows access to the treatment for patients outside of the clinical trials, and the potential for reimbursement to the company at cost. The FDA makes this determination on the basis that there is evidence of safety and effectiveness and a lack of other treatments. We believe that this designation is indicative of the innocuous safety profile of the treatment and the program may provide further support for the safety database.
Intermittent claudication
Pluristem is also developing PLX-PAD for the treatment of intermittent claudication (IC), a milder form of PAD than CLI. IC is characterized by pain in the legs that occurs with exertion, but goes away with rest, as opposed to CLI. IC can progress to CLI without treatment (although CLI can also occur de novo, without any prior history of claudication). The incidence of IC is substantially higher than CLI, with a prevalence of 1% to 5% of the US general population. Also, unlike CLI, the prognosis for patients with IC is generally positive, as the disease can resolve itself spontaneously, without the need for intervention. The first line of treatment recommended by TASC is encouraging increased activity, which can improve pain, and this is followed by medical treatment if the issue does not resolve itself. There are currently several approved medications for PAD that are used to treat IC: Pletal (cilostazol, Otsuka), Praxilene (naftidrofuryl, Merck Serono) and pentoxifylline. In addition, painkillers or drugs to treat the underlying atherosclerotic risk factors can be prescribed. All of these drugs are genericized and typically retail for less than $2 per day. Revascularization is rare for these patients, but is increasing in frequency.
The company is currently engaged in a 170-person, Phase II study of PLX-PAD for intermittent claudication (IC). The trial is a double-blind, randomized, placebo-controlled study measuring the maximum walking distance of IC sufferers on a treadmill a year after two injections of PLX-PAD. The trial was initiated in 2012 and had initial enrolment difficulties, although the company announced enrolment was complete in early 2017. We expect the trial to be complete and to provide top-line results in H118.