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Update on clinical trials evaluating the effect of biologic therapy in patients with critical limb ischemia

2012; Elsevier BV; Volume: 56; Issue: 1 Linguagem: Inglês

10.1016/j.jvs.2012.03.255

1097-6809

Richard J. Powell,

Lymphatic System and Diseases

Critical limb ischemia (CLI) represents the most severe degree of peripheral arterial disease and is associated with significant morbidity and mortality. In patients with CLI who do not have revascularization options, major amputation is required within 1 year in as many as 40% of patients. Biologic therapies, which include gene therapy and cellular therapy, offer the potential to promote wound healing and prevent amputation in patients who otherwise have poor options for revascularization. Several recent phase 2 trials have shown acceptable safety and suggest that these biological therapies have the potential to improve outcomes in patients with "no-option" CLI. Phase 3 trials are now in progress. This report summarizes the recent results of, and future plans for, gene and cellular therapy clinical trials in patients with CLI. Critical limb ischemia (CLI) represents the most severe degree of peripheral arterial disease and is associated with significant morbidity and mortality. In patients with CLI who do not have revascularization options, major amputation is required within 1 year in as many as 40% of patients. Biologic therapies, which include gene therapy and cellular therapy, offer the potential to promote wound healing and prevent amputation in patients who otherwise have poor options for revascularization. Several recent phase 2 trials have shown acceptable safety and suggest that these biological therapies have the potential to improve outcomes in patients with "no-option" CLI. Phase 3 trials are now in progress. This report summarizes the recent results of, and future plans for, gene and cellular therapy clinical trials in patients with CLI. Critical limb ischemia (CLI) represents the most severe degree of peripheral arterial disease and is associated with significant morbidity and mortality. In patients with CLI who do not have revascularization options, major amputation is required within 1 year in as many as 40% of patients and mortality is as high as 20%. Biological therapies which include gene therapy and cellular therapy offer the potential to promote wound healing and prevent amputation in patients who otherwise have poor options for revascularization. This report summarizes the results of recent gene and cellular therapy clinical trials in patients with CLI. Fibroblast growth factor (FGF) has been extensively studied in the context of CLI. The Efficacy and Safety Study of NV1FGF in Patients With Severe Peripheral Artery Occlusive Disease (TALISMAN) phase 2 trial (http://Clinicaltrials.gov NCT00798005) of 125 patients reported a significant improvement in amputation-free survival (AFS) from 52% in placebo-treated patients with no options for revascularization compared with 73% in patients treated with FGF plasmid (P = .009).1Nikol S. Baumgartner I. Van Belle E. Diehm C. Visona A. Capogrossi M. et al.TALISMAN 201 investigatorsTherapeutic angiogenesis with intramuscular NV1FGF improved amputation-free survival in patients with critical limb ischemia.Mol Ther. 2008; 16: 972-978Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar In this trial, which was conducted entirely in Europe, there was a decrease in major amputation at 1 year from 34% in placebo-treated patients to 16% in NV1FGF-treated patients (P = .015). In addition, mortality was 12% in the treated patients compared with 23% in placebo-treated patients. The 34% major amputation rate was unusually high compared with previous no-option CLI trials. It is also unclear why a limb-sparing therapy would have such a dramatic effect on mortality. In a separate study, these investigators proved proof of concept of gene therapy when they identified the FGF plasmid, mRNA, and protein in the amputation specimens in patients with CLI who received FGF plasmid injections prior to amputation.2Baumgartner I. Chronos N. Comerota A. Henry T. Pasquet J.P. Finiels F. et al.Local gene transfer and expression following intramuscular administration of FGF-1 plasmid DNA in patients with critical limb ischemia.Mol Ther. 2009; 17: 914-921Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar These findings led Sanofi-Aventis to complete a phase 3 pivotal trial; the Efficacy and Safety of XRP0038/NV1FGF in Critical Limb Ischemia Patients With Skin Lesions (TAMARIS) trial (NCT00566657). Unlike the earlier phase 2 trial, the TAMARIS trial failed to show a difference in AFS when compared to placebo in patients with CLI.3Belch J. Hiatt W.R. Baumgartner I. Driver I.V. Nikol S. Norgren L. et al.Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia.Lancet. 2011; 377: 1929-1937Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar This trial enrolled 525 patients at 170 sites in over 30 countries with hemodynamically confirmed ischemic ulcers or minor gangrene. Major amputation or death at 1 year occurred in 33% of placebo-treated patients and 36% of FGF-treated patients. The amputation-free survival for both groups was similar to the FGF-treated patients in the phase 2 TALISMAN trial. The likely explanation for the different results observed in the phase 2 TALISMAN and phase 3 TAMARIS trials is likely a type II error. The only remaining gene therapy under late-phase clinical evaluation is hepatocyte growth factor (HGF) plasmid. Early phase 2 trials (NCT00189540, NCT00060892) have shown that HGF plasmid gene therapy can improve TcPO2 and pain scores in patients with CLI compared with placebo.4Powell R.J. Goodney P. Mendelsohn F.O. Moen E.K. Annex B.H. HGF-0205 Trial InvestigatorsSafety and efficacy of patient specific intramuscular injection of HGF plasmid gene therapy on limb perfusion and wound healing in patients with ischemic lower extremity ulceration: results of the HGF-0205 Trial.J Vasc Surg. 2010; 52: 1525-1530Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 5Powell R.J. Simons M. Mendelsohn F.O. Daniel G. Henry T.D. Koga M. et al.Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia.Circulation. 2008; 118: 58-65Crossref PubMed Scopus (233) Google Scholar A simultaneous trial in Japan was stopped early by the data safety monitoring board due to an improvement in ulcer size in 100% of the HGF plasmid-treated patients compared with an improvement in 40% of the placebo-treated patients (P = .014).6Shigematsu H. Yasuda K. Iwai T. Sasajima T. Ishimaru S. Ohashi Y. et al.Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia.Gene Ther. 2010; 17: 1152-1161Crossref PubMed Scopus (155) Google Scholar Based on these data, the sponsoring company (AnGes) plans to begin a pivotal phase 3 trial (Table). This trial plans to enroll 560 poor-option patients with CLI manifested as either tissue loss or rest pain. Poor option is defined as patients who are not endovascular candidates and are suboptimal candidates for surgical bypass. This would include patients who have significant comorbid risk, the need for synthetic below-the-knee bypass, or vein bypass with either nongreat saphenous vein or a great saphenous vein <3 mm in diameter. Patients will undergo multiple intramuscular injections of HGF plasmid over a 6-month period. The primary end point is AFS at 18 months. This trial, though currently not registered with http://clinicaltrials.gov, will be registered prior to an expected start date in 2012.TableOngoing biological therapy trials for CLISponsorTherapyPhasePatient populationNo. to be enrolledStart date (expected)Expected date of completionhttp://clinicaltrials.govAastromIxmyelocel-T3No-option CLI:tissue loss594February 2012Mid-2015NCT01483898AnGesHGF plasmid3Poor option CLI: rest pain or tissue loss∼5602012PendingBiometConcentrated bone marrow aspirate3No-option CLI: rest pain or tissue loss152June 2010May 2014NCT01049919HarvestConcentrated bone marrow aspirate3No-option CLI: tissue loss210May 2011June 2014NCT01245335PluristemAllogeneic placental-derived stem cells1No-option CLI: rest pain or tissue loss15June 2009May 2012NCT00919958ViroMedHGF plasmid isoforms: HGF 728 and 7232No-option CLI: rest pain or tissue loss50March 2010May 2013NCT01064440CLI, Critical limb ischemia; HGF, hepatocyte growth factor.All phase 3 trials utilize amputation-free survival as primary end point. Open table in a new tab CLI, Critical limb ischemia; HGF, hepatocyte growth factor. All phase 3 trials utilize amputation-free survival as primary end point. A second HGF plasmid phase 2 trial in no-option CLI patients, using a plasmid that codes for two separate HGF isoforms, sponsored by ViroMed, is currently enrolling and is expected to be completed by March 2013 (NCT01064440). Cellular therapies can be divided into autologous and allogeneic. Several phase 1/2 trials have been recently completed, including Harvest Technologies (NCT00498069) and Biomet, both of which have reported promising early results of phase 2 trials using bone marrow mononuclear cells in the treatment of CLI.7Iafrati M.D. Hallett J.W. Geils G. Pearl G. Lumsden A. Peden E. et al.Early results and lessons learned from a multicenter, randomized, double-blind trial of bone marrow aspirate concentrate in critical limb ischemia.J Vasc Surg. 2011; 54: 1650-1658Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 8Murphy M.P. Lawson J.H. Rapp B.M. Dalsing M.C. Klein J. Wilson M.G. et al.Autologous bone marrow mononuclear cell therapy is safe and promotes amputation-free survival in patients with critical limb ischemia.J Vasc Surg. 2011; 53 (Epub;2011, April 22): 1565-1574.e1Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Both companies have developed point-of-care cell preparation systems that, following bone marrow harvest of 240 to 300 mL, allow separation of the cells and extraction of the bone marrow mononuclear cells component for direct intramuscular injection into the ischemic limb. Based on promising early results, both companies have begun phase 3 trials and are performing these trials through Investigator Device Exemptions from the Center for Device and Radiologic Health of the Food and Drug Administration (FDA). Based on their phase 2 trial in which major amputations occurred in 18% of treated patients compared with 29% in placebo-treated patients, Harvest Technologies has initiated a phase 3 trial (NCT01245335) that plans to enroll 210 no-option CLI patients with only tissue loss and is expected to be completed by June 2014. Murphy and coworkers have shown amputation-free survival of 86% in an open-label trial using autologous bone marrow cells in patients with rest pain or ischemic ulcers.8Murphy M.P. Lawson J.H. Rapp B.M. Dalsing M.C. Klein J. Wilson M.G. et al.Autologous bone marrow mononuclear cell therapy is safe and promotes amputation-free survival in patients with critical limb ischemia.J Vasc Surg. 2011; 53 (Epub;2011, April 22): 1565-1574.e1Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Biomet plans to enroll 152 no-option CLI patients with either minor tissue loss or rest pain and is expecting completion of the study by May 2014 (NCT01049919). Aastrom recently published the analysis of their phase 2 trial utilizing expanded autologous stem cells, ixmyelocel-T, in the treatment of no-option CLI patients.9Powell R.J. Comerota A.J. Berceli S.A. Guzman R. Henry T.D. Tzeng E. et al.Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia.J Vasc Surg. 2011; 54: 1032-1041Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar In the A Randomized, Double-Blind Multicenter Phase II Trial Comparing Expanded Autologous Bone Marrow-Derived Tissue Repair Cells and Placebo in Patients with Critical Limb Ischemia (RESTORE-CLI) trial, 50 mL of bone marrow aspirate from the patient was sent to the sponsor, and the cells were cultured in a bioreactor and expanded over a 2-week period. The cell population, which when expanded is enriched with mesenchymal precursors and alternatively activated macrophages, is then returned to the trial site for intramuscular injection into the ischemic limb of the patient. This trial enrolled 72 patients with either ischemic rest pain or tissue loss. Those treated with cellular therapy, ixmyelocel-T, experienced overall treatment failure defined as death, major amputation, doubling of wound size from baseline, or new-onset gangrene in 40% of patients compared with 67% of placebo-treated patients at 12 months (log rank P = .003).10Powell RJ, Marston WA, Berceli SA, Guzman R, Henry TD, Longcore AT, et al. Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: the randomized, double-blind, placebo-controlled RESTORE-CLI trial [published online ahead of print March 27, 2012]. Mol Ther doi:10.1038/mt.2012.52.Google Scholar These differences were especially pronounced in patients who presented with tissue loss at baseline. In the subgroup of patients presenting with wounds, 45% of ixmyelocel-T-treated patients compared with 88% of control patients experienced a treatment failure event (P = .01). For AFS, 21% of ixmyelocel-T-treated patients with baseline wounds and 44% of control patients with baseline wounds experienced a major amputation of the injected leg or death (P = .169). Currently, Aastrom has begun a phase 3 trial, An Efficacy and Safety Study of Ixmyelocel-T in Patients with Critical Limb Ischemia (REVIVE) (NCT01483898), through the Center of Biologic Evaluation and Research of the FDA to assess the efficacy of this therapy on AFS in no-option CLI patients with tissue loss. Completion of this trial is expected in mid-2015. When comparing the two different stem cell techniques currently in phase 3 trials, the advantage of the Harvest Technologies system includes point-of-care therapy, whereby patients can be treated at one setting; a major disadvantage is the amount of bone marrow that is removed, which is not trivial. Potential advantages of the Aastrom technique include a significantly smaller bone marrow aspirate and the potential to expand cell lines important in the anti-inflammatory/angiogenic/healing process prior to injection. The main disadvantage is the 2-week delay between bone marrow harvest and cell therapy injection. The recently completed phase 1 allogeneic cell therapy trial sponsored by Pluristem (NCT00951210) has shown promising safety and potential efficacy. This open-label trial of allogeneic placental stem cells (PLX-PAD cells) will be entering phase 2 placebo-controlled trials. PLX-PAD cells are mesenchymal-like stromal cells derived from the full-term placenta and are expanded in the sponsor's proprietary bioreactor. The cells are reportedly immune-privileged and would offer a potentially "off-the-shelf" treatment option. CLI trials face multiple hurdles that have resulted in delays in completion. Early concerns over off-target angiogenesis and the potential for progression of diabetic proliferative retinopathy or occult tumor growth had resulted in significant restrictions in the inclusion and exclusion criteria for entry into the study. As early studies demonstrated an acceptable safety record for this therapy and potential concerns over off-target angiogenic complications have lessened, these restrictions have decreased. The overall comorbid burden of the CLI patient population results in a high incidence of adverse events throughout the conduct of the study. The heterogenous nature of CLI results in highly variable natural history. Patients with ischemic tissue loss have a major amputation rate of up to 35% at 1 year compared with <10% in patients with rest pain. In addition, the FDA suggests that AFS should be the primary efficacy end point in a phase 3 CLI trial. This has resulted in studies with an expectant enrollment of at least 500 patients. The reason for this is that biological treatment of CLI is a limb-sparing procedure and is not expected to significantly influence mortality. Because of the nonspecific nature of this end point, the selective inclusion/exclusion criteria, and the heterogenous and frail nature of the CLI patient population, large numbers of patients are needed to complete a clinical trial to detect any potential efficacy on amputation at 1 year. This requires a dedicated group of site investigators willing to deal with these issues to complete such trials within a reasonable time frame. In summary, there have been promising early safety and efficacy trial data for both gene and cellular therapies in patients with CLI. Despite these early promising results, there have been no phase 3 trials that have shown this therapy to be effective. Current trial design has improved, and there are currently many phase 3 clinical trials that are either actively enrolling or are in early stages of development. These are potentially disruptive technologies that, if proven effective, could dramatically alter how we care for patients with CLI in the future.