What drugs are in development for Chronic Limb-Threatening Ischemia?

Understanding Chronic Limb-Threatening Ischemia (CLTI)

Definition and Pathophysiology
Chronic Limb‐Threatening Ischemia (CLTI) represents the advanced stage of peripheral arterial disease (PAD) where chronic under‐perfusion has led to severe pain at rest, non‐healing ulcers, and even gangrene. The insufficient blood supply fails to meet the metabolic demands of limb tissues, initiating a cascade of cellular hypoxia, oxidative stress, inflammatory cytokine release, and impaired wound healing. Anatomically, the disease is characterized by the occlusion or severe stenosis of multiple arteries, frequently in patients with significant cardiovascular risk factors such as diabetes, smoking, and hyperlipidemia. The underlying processes include not only insufficient macrovascular response (e.g., blockage in major arteries) but also a failure in microvascular compensatory mechanisms. As native angiogenic and arteriogenic signals become exhausted, the limb’s capacity to regenerate the microvascular network dissipates.

Current Treatment Options
At present, the standard therapeutic approach for CLTI involves timely revascularization – whether surgically via bypass or endovascular techniques (e.g., angioplasty/stenting). Unfortunately, a significant subset of patients qualifies as “no‐option” because the vascular anatomy, extent of occlusion, or existing comorbidities preclude revascularization. In these cases, conventional management strategies are palliative. Pharmacologic therapies (such as antiplatelet agents), wound care, and pain management form the backbone of conservative treatment; however, these are generally unable to restore sufficient blood flow or improve long‐term limb salvage rates. As therapeutic revascularization limitations become apparent, especially in “no‐option” patients, there is a growing impetus to develop alternative therapies that stimulate angiogenesis and revascularization via endogenous or exogenous means.

Drugs in Development for CLTI

Overview of Drug Development Pipeline
The development pipeline for CLTI has evolved over the past decades with a range of advanced therapeutic modalities. These approaches aim to induce neovascularization, improve tissue perfusion, and promote limb salvage. A continuum of strategies is being actively explored that include:

• Gene therapy approaches designed to upregulate proangiogenic factors such as hepatocyte growth factor (HGF) by delivering plasmid DNA or genes that encode growth factors to targeted ischemic tissues.
• Cell‐based therapies, including autologous cell therapies (e.g., BioGenCell’s technology) using stem/progenitor cells that are “trained” to promote vascular regeneration, as evidenced by early phase clinical trials in no‐option CLTI patients.
• Small molecule therapies and biologics aimed at modulating vascular growth pathways. Although many agents in the pipeline are focused on broader “cardiovascular diseases,” some are being specifically repurposed for CLTI treatment owing to their proangiogenic effects – for example, investigational products that may fall under the category of mesenchymal stem cell therapies or small molecule modulators of receptors such as EP1/EP4 or soluble guanylate cyclase (sGC), which may later be adapted to CLTI.
• Translational research further indicates the possibility of combining drug products with novel biomaterial matrices, engineered biological scaffolds, or even physical interventions (such as mechanical stimulation therapies described in patents) to augment vascular regeneration.

Multiple drug development organizations worldwide are engaged in this space. Examples include Beijing Allife Medicine Technology Co., Ltd. (with several development dates noted in 2023 and 2024), Toulouse University Hospital (with drug development activity noted in November 2024), and MultiGene Vascular Systems Ltd., which first entered the development cycle as early as 2006. Additionally, strategic regulatory events—for instance, a fast track designation in the United States for a drug indicated for CLTI with an anticipated review approval date of December 2024—indicate that the pipeline is advancing steadily toward more rapid clinical validation. In combination with ongoing cell therapy trials in the United States, Europe, and Asia, the pipeline suggests a theme of “regenerative medicine” in which drugs are supplemented by advanced delivery platforms and synergistic biologic components.

Key Drugs and Their Mechanisms
Within this broad pipeline, the key investigational products can be grouped into two major categories:

1. Cell- and Gene-Based Therapies:
  a. Cell-Based Approaches:
   • BioGenCell and similar organizations are developing autologous cell therapies that extract a patient’s own blood components followed by ex vivo training procedures to enrich stem and progenitor cells with angiogenic potential. These cells are then reintroduced into the ischemic limb, where they act on endogenous pathways to promote collateral vessel formation. Early-phase clinical trials (e.g., BioGenCell’s Phase II studies) have shown promising improvements in limb perfusion, reduction in pain scores, and ultimately device a potential reduction in amputation rates.
  b. Gene-Based Approaches:
   • Gene therapy approaches leverage viral or plasmid delivery systems to introduce genes encoding for angiogenic factors such as HGF, vascular endothelial growth factor (VEGF), and bFGF directly into the ischemic tissues. For example, one translational study evaluated a double-blind, placebo-controlled HGF gene therapy approach (even though initially conducted in diabetic neuropathy, the underlying mechanism of inducing angiogenesis is similar to that desired in CLTI). Another preclinical study in a porcine model used naked DNA constructs to express HGF isoforms, thereby demonstrating improvements in myocardial perfusion—a concept that is being adapted to limb ischemia to stimulate localized vasculogenesis.
  c. Biomaterial-Enhanced Therapies:
   • Recent developments also focus on combining drug delivery with biodegradable scaffolds or biomaterials, which not only secure the therapeutic agent (whether gene vectors or cells) within the target tissue but also provide an extracellular matrix that supports sustained cell survival and function. These investigational strategies often attempt to recreate the natural niche for angiogenic cells to maximize vessel growth.

2. Small Molecule and Biologic Therapies:
  While many drugs in traditional cardiovascular development address coronary artery disease or heart failure, some investigational agents are being tailored for the CLTI setting.
  a. Growth Factor Mimetics and Receptor Modulators:
   • One notable investigational agent – identified with the drug name “FECS-Ad” – is a mesenchymal stem cell therapy developed by S. Biomedics Co., Ltd. Although primarily listed under cardiovascular diseases, the novel approach exemplifies how small molecules or biologics can modulate endothelial function and promote angiogenesis.
  b. Proangiogenic Receptor Modulators:
   • Other agents – for example, small molecules that inhibit EP1/EP4 receptors or modulate sGC – are designed to interfere with pathways that normally suppress angiogenesis. Their mechanism of action involves the dampening of vasoconstriction and promoting vasodilation, thus indirectly enhancing blood flow in ischemic tissues. Use of these small molecule modulators could also complement cell or gene therapy approaches, creating a combinatory therapeutic strategy.

3. Device–Drug Combinations and Patent-Claimed Methods:
  In addition to the conventional drug categories, several patents have been recently filed describing methods for treating chronic limb ischemia.
  a. Infusion-Based Therapies:
   • One patent describes a method for treating chronic critical ischemia through the infusion of ozonized saline solution following pharmacologic stimulation of collateral blood circulation. Although the primary focus is on physical/chemical stimulation, such methods are being developed in parallel with drug-based therapies to achieve synergistic outcomes.
  b. Mechanical and Stem Cell Activation Approaches:
   • Another patent describes a method that uses a dosed mechanical effect on the contents of bone marrow canals in the metatarsal bones along with clinical signs of improved blood supply. This approach is complementary to cell therapies and demonstrates the broad innovation spectrum that spans both device–drug combination products as well as purely pharmacological treatments.
  Overall, these patented methods highlight that drug development for CLTI is not limited to traditional orally active molecules or injectables but includes innovative platforms that aim to address the core pathophysiological deficits of local blood supply.

Clinical Trials and Research

Ongoing and Completed Trials
The clinical trial landscape for CLTI reflects a global, multi-phased effort to bring these novel drugs into clinical practice. Data extracted from clinical trial sources on Synapse showcase the following:

• Geographical Distribution and Phases:
Clinical trials addressing CLTI have been conducted in the United States, China, France, and the Netherlands, with trial phases ranging from Early Phase 1 and Phase 1/2 to Phase 2 and Phase 3 studies. For instance, the United States has contributed to a number of studies (e.g., BioGenCell’s cell therapy trial) while Asian markets are also active in early-phase cell therapy and gene therapy trials. There is one reported clinical trial site in China with a small trial design and several sites in Europe where advanced therapies (from organizations such as Toulouse University Hospital and Beijing Allife Medicine Technology Co., Ltd.) are under development.

• Study Designs and Endpoints:
The trial designs typically include double-blind, placebo-controlled studies for gene therapies and open-label, randomized studies for cell therapies. Primary endpoints focus on improvements in pain scores, functional limb recovery, and reduction in amputation rates. Many studies are designed with robust endpoints, using surrogate markers for revascularization (e.g., capillary density, improvement in ankle-brachial index) alongside patient-reported outcomes. Early safety data have generally revealed tolerability in the short term, with few significant adverse events reported, although long-term efficacy and durability require further evaluation.

• Recent Regulatory Developments:
A key indication of progress is the issuance of Fast Track designation for a product earmarked for CLTI treatment by regulatory agencies in the United States—its regulatory review approval date is set for December 2024. This designation typically reflects promising preclinical and early clinical efficacy data and a clear unmet need in the CLTI patient population.

Efficacy and Safety Data
The early-phase clinical trials provide multiple perspectives on the efficacy and safety of these novel therapies:

• Cell Therapy Data:
BioGenCell’s Phase II trial results, for example, have shown promising reductions in major adverse limb events and improvements in quality of life by stimulating endogenous angiogenesis via autologous cell therapy. Patients have experienced measurable improvements in ischemic pain and limb function without significant systemic adverse events. Moreover, the promising tolerability data from these early studies support further expansion in larger, multi-center studies.

• Gene Therapy Data:
Gene therapy approaches such as the HGF gene therapy have been previously validated in translational medicine studies involving diabetic neuropathy, demonstrating significant improvements in pain score reduction and demonstration of angiogenic effects over periods spanning from 3 to 9 months. Although these studies were not solely conducted in a CLTI population, the underlying mechanism (induction of angiogenesis) justifies their adaptation to CLTI. Safety profiles from these trials generally indicate a well-tolerated profile, with minimal severe adverse effects and a relatively rapid clearance of the gene products.

• Small Molecule and Receptor Modulator Data:
Small molecule drugs in early phase trials (such as agents similar to “GUR-602”) are still in the initial clinical stages (Phase 1 and Phase 1/2). While the primary data for these molecules come from cardiovascular studies, the receptor-modulating activity that targets multiple pathways (EP1 antagonism, EP4 antagonism, PGI2 receptor modulation, and sGC modulation) holds promise for CLTI given the shared pathophysiological processes of ischemia and impaired vasodilation. Early efficacy data have primarily been used to optimize dosing regimens and to ensure that target receptor modulation produces favorable hemodynamic effects.

• Integrated Approaches and Combination Strategies:
A number of recent studies are exploring combination strategies—for instance, pairing cell or gene therapies with biomaterial carriers or even mechanical stimulation (as described in patented methods) to maximize therapeutic outcomes. The rationale behind these strategies is that combination therapies maintain localized, sustained release of active growth factors while simultaneously providing a scaffold that supports tissue regeneration. Although still in preclinical or early clinical stages, these integrated approaches have yielded promising preliminary safety data and are anticipated to improve overall efficacy significantly.

Collectively, the emerging data underscore that many investigational products in the CLTI arena have demonstrated acceptable short-term safety and a signal for efficacy. Nonetheless, the durability of therapeutic benefits, particularly regarding long-term limb salvage and survival, remains an area of ongoing investigation.

Future Directions and Challenges

Potential Breakthroughs
Looking ahead, several breakthroughs could redefine the therapeutic landscape for CLTI:

• Regenerative Medicine and Personalized Approaches:
The use of autologous cell therapies in combination with gene therapy represents a new frontier in personalized medicine. By tailoring treatments based on patient-specific factors (e.g., regenerative capacity, baseline angiogenic potential), outcomes may be optimized. In the near future, the combination of these modalities with novel biomaterials or drug delivery systems is expected to yield more robust tissue regeneration, effectively reducing amputation rates and improving quality of life.

• Next-Generation Gene Vectors and Controlled Release Systems:
Advancements in vector design for gene therapy—achieving more precise, tissue-targeted delivery of angiogenic growth factors—along with controlled release mechanisms, hold the potential to produce sustained angiogenesis while minimizing off-target effects. These strategies could considerably enhance the long-term efficacy of gene-based therapies for CLTI.

• Digital and Imaging Biomarkers:
Emerging imaging technologies and digital biomarkers can provide more objective, quantifiable endpoints to assess revascularization. As these become integrated with clinical trial designs, it will be easier to monitor the effectiveness of new therapies, thus accelerating regulatory approval and clinical adoption.

Challenges in Drug Development for CLTI
Despite the promising pipeline, several hurdles remain:

• Heterogeneity of the Patient Population:
CLTI patients often have extensive comorbidities (e.g., diabetes, renal insufficiency) and diverse vascular pathologies. This heterogeneity makes it challenging to design clinical trials with highly standardized endpoints and comparable patient populations. Tailoring therapies to account for anatomical differences and systemic factors remains a significant challenge.

• Endpoint Standardization:
A recurring challenge in CLTI clinical studies is the selection of appropriate clinical endpoints. While surrogate markers (like the ankle-brachial index, capillary density, or pain score improvements) are valuable in early-phase trials, definitive endpoints such as limb salvage and amputation-free survival will be required in later stages. Standardizing these outcomes across trials is critical for meaningful comparison and regulatory success.

• Long-Term Safety and Durability:
Early-phase studies have focused on short- to medium-term safety and efficacy endpoints. However, given the chronic nature of CLTI, long-term data are crucial. The durability of the therapeutic effect, risks of late adverse events (particularly with gene or cell therapies), and the potential for immunogenicity need to be closely monitored over extended follow-up periods.

• Regulatory and Manufacturing Challenges:
Gene and cell therapies, in particular, face complex regulatory hurdles. Establishing robust manufacturing processes for autologous cells or gene vectors that maintain high quality and reproducibility is not trivial and can result in cost and scalability issues. Furthermore, the evolving regulatory landscape—with designations such as Fast Track status—requires that developers continuously adapt to new standards and evidence requirements.

• Integration with Existing Interventions:
For many CLTI patients, revascularization remains the standard of care. Therefore, many of the investigational drugs are likely to be used as adjuvants or adjuncts rather than stand-alone therapies. Integrating new therapies with conventional surgical or endovascular interventions is essential. This integration poses challenges in terms of procedural planning, optimal timing, and potential interactions between therapies.

• Economic and Accessibility Considerations:
The cost of advanced regenerative therapies (especially those based on autologous cells or gene vectors) may be prohibitive without demonstrable superiority over conventional treatments. Ensuring cost-effectiveness and broad accessibility will be essential to achieving widespread adoption in clinical practice.

Conclusion

In summary, the drug development pipeline for CLTI is multifaceted and reflects a paradigm shift from traditional revascularization techniques to advanced regenerative medicine. Current innovations include:

• Cell and gene therapies that aim to restore perfusion through the stimulation of angiogenesis. Autologous cell therapies (e.g., those developed by BioGenCell) have already reached Phase II clinical trials with promising safety and efficacy signals.
• Gene therapy approaches that deliver angiogenic growth factors such as HGF via plasmid or viral vectors, which have demonstrated potential in translational settings and are being adapted for CLTI.
• Small molecule and biologic agents that modulate vascular receptors to promote vasodilation and neovascularization are also under investigation. Although some of these agents were initially designed for other cardiovascular conditions, their mechanisms of action are being repurposed for CLTI.
• Innovative patent‐claimed methods – including mechanical stimulation and infusion-based therapies – further expand the therapeutic landscape, aiming to overcome the limitations of conventional approaches.

The clinical trial environment for CLTI is dynamic, with multiple ongoing studies internationally across a spectrum of phases. Early clinical data show encouraging improvements in pain, function, and perfusion with a tolerable safety profile, setting the stage for future, larger randomized trials to confirm limb salvage and overall survival benefits.

However, challenges such as patient heterogeneity, endpoint selection, long-term durability, regulatory approval, and cost remain to be addressed. Future breakthroughs are likely to come from integrated combination therapies that leverage the strengths of regenerative medicine, bioengineering, and precision drug design. If these hurdles can be overcome, the promise of transforming outcomes for no-option CLTI patients becomes increasingly tangible.

In conclusion, the drugs in development for CLTI are paving the way for a new era of treatment that transcends conventional revascularization. By targeting underlying pathophysiological pathways with cell- and gene-based strategies combined with novel small molecules and device-assisted therapy, researchers are aiming to deliver therapies that not only relieve symptoms but also promote lasting vascular regeneration. The future of CLTI treatment is likely to be defined by highly personalized, multimodal interventions that ultimately enhance limb salvage, improve quality of life, and offer hope to patients with severe, no-option disease.