Report on Telbermin (DB12639): A Comprehensive Review of its Development for Diabetic Foot Ulcers and Amyotrophic Lateral Sclerosis

Abstract

Telbermin (DrugBank ID: DB12639), a recombinant human vascular endothelial growth factor A165 (rhVEGF-A165), is a biotech therapeutic agent investigated for its potential in promoting angiogenesis and neuroprotection. This report provides a comprehensive review of Telbermin's development, focusing on its clinical trials for diabetic foot ulcers (DFU) and amyotrophic lateral sclerosis (ALS). As a VEGF mimetic, Telbermin was hypothesized to stimulate new blood vessel formation, crucial for wound healing in DFU, and to exert neurotrophic effects, potentially slowing motor neuron degeneration in ALS. Clinical development for DFU, primarily led by Genentech, showed promising trends in early Phase I trials regarding wound healing and a good local safety profile with topical administration. However, subsequent, presumably Phase II, trials failed to meet the U.S. Food and Drug Administration (FDA)-accepted primary efficacy endpoints for complete wound closure, leading to the discontinuation of its development for this indication.[1] For ALS, Telbermin, also known as sNN0029 and developed by Newron Pharmaceuticals, was administered via intracerebroventricular (ICV) infusion. Early Phase I studies demonstrated that this delivery route achieved detectable drug levels in the cerebrospinal fluid and showed preliminary signals of potential benefit, alongside an FDA Orphan Drug Designation.[2] However, the ALS program was prematurely terminated in October 2015 due to critical issues with the third-party supplier of the investigational drug delivery catheter, rather than concerns about the drug's intrinsic efficacy or safety at that stage of development.[5] This report synthesizes the available data on Telbermin's identifiers, mechanism of action, clinical trial designs, efficacy and safety outcomes in DFU and ALS, and the distinct reasons for the cessation of its development in these two disparate indications, offering valuable context for understanding the complexities of biopharmaceutical development.

1. Introduction to Telbermin

Telbermin emerged as an investigational biotech product with therapeutic potential rooted in the biological activities of vascular endothelial growth factor (VEGF). Its journey through preclinical and clinical development was marked by explorations in distinct pathological conditions, reflecting the pleiotropic effects of its parent molecule.

1.1. Key Identifiers and Basic Properties

Telbermin is identified by the DrugBank Accession Number DB12639 and the Chemical Abstracts Service (CAS) Number 205887-54-3.[3] Throughout its development and in scientific literature, it has been referred to by several synonyms, which is important to recognize for a comprehensive understanding of its history. These include recombinant human Vascular Endothelial Growth Factor (rhVEGF), specifically the 165-amino acid isoform (VEGF165), and sNN0029, a designation used particularly in the context of its development for amyotrophic lateral sclerosis (ALS) by Newron Pharmaceuticals.[2] The use of different names often corresponded to different developmental programs or sponsoring entities, which can initially create complexity when reviewing its multifaceted history.

Classified as a biotech drug, Telbermin is a protein-based therapy, specifically a recombinant human protein.[6] Its primary molecular target is the VEGF signaling pathway, acting as an activator of Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), and by extension, engaging with the broader VEGF receptor system to elicit its biological effects.[6]

Table 1: Telbermin - Core Drug Information

Characteristic	Details
DrugBank ID	DB12639
CAS Number	205887-54-3
Common Synonyms	rhVEGF, VEGF165, sNN0029
Drug Type	Biotech, Recombinant Protein (specifically, recombinant human VEGF-A165)
Known Developers	Genentech, Newron Pharmaceuticals (sNN0029, acquired from NeuroNova)
Primary Molecular Target	Vascular Endothelial Growth Factor Receptors (VEGFRs); reported to activate VEGFR1 6

The consolidation of these identifiers (Table 1) is crucial as it clarifies that despite varied nomenclature and different pharmaceutical entities involved at various stages, the core active molecule remained consistent. This foundational understanding allows for the coherent integration of data from diverse research efforts.

1.2. Overview of Developers and Investigational History

The investigational history of Telbermin is characterized by distinct development paths pursued by different pharmaceutical companies for separate indications. Genentech was a key player, particularly in the investigation of Telbermin for diabetic foot ulcers (DFU) and also served as a supplier of rhVEGF for ALS studies.[2] Concurrently, Newron Pharmaceuticals took the lead in developing the same molecule, under the designation sNN0029, for ALS. Newron acquired sNN0029 from NeuroNova, indicating a transfer of assets and continuation of research focus within the central nervous system (CNS) domain.[7]

The timeline saw Telbermin advance from early research into clinical trials for DFU, where topical formulations were tested. For ALS, a more invasive intracerebroventricular (ICV) delivery method was employed for sNN0029 to ensure CNS penetration. This bifurcated development highlights how a single molecule with diverse biological activities can be explored for unrelated conditions. However, such parallel efforts by different entities can also lead to fragmented development strategies and resource allocation, potentially impacting the overall trajectory and ultimate success of the drug in either indication. Ultimately, both the DFU and ALS programs were discontinued, albeit for different reasons, which will be detailed in subsequent sections.

2. Scientific Rationale and Mechanism of Action

Telbermin's therapeutic potential was predicated on its identity as a recombinant form of human vascular endothelial growth factor-A (VEGF-A), a potent signaling protein with well-established roles in physiological and pathological processes, primarily angiogenesis, and increasingly recognized neurotrophic functions.

2.1. Telbermin as a Recombinant Human Vascular Endothelial Growth Factor (VEGF-A165)

Telbermin is specifically the 165-amino acid isoform of VEGF-A (VEGF-A165), produced using recombinant DNA technology.[3] It is designed to mimic the activity of endogenous human VEGF-A165, a key mediator of angiogenesis—the formation of new blood vessels from pre-existing ones.[7] VEGF-A165 is a critical signaling protein involved in endothelial cell proliferation, migration, survival, and vascular permeability. Its role is fundamental in embryonic development, normal physiological processes such as wound healing and tissue repair, and also in pathological conditions like tumor growth and ischemic diseases.[11]

2.2. Angiogenic and Neurotrophic Properties

The scientific rationale for Telbermin's investigation in DFU and ALS stemmed from two primary biological activities of VEGF-A:

• Angiogenesis: VEGF-A, and by extension Telbermin, promotes angiogenesis by binding to its receptors (primarily VEGFR2, though VEGFR1 is also involved) on endothelial cells. This interaction triggers intracellular signaling cascades that stimulate endothelial cell proliferation, migration, and the formation of new capillary structures.[7] In the context of DFU, which are often characterized by poor vascular supply and impaired healing, the therapeutic goal was to enhance local blood flow and tissue perfusion, thereby accelerating wound closure.[8]
• Neurotrophic Effects: Beyond its vascular functions, VEGF-A has been increasingly recognized for its direct neurotrophic and neuroprotective effects.[12] Studies in animal models of ALS have indicated that reduced VEGF expression can lead to motor neuron degeneration similar to that seen in ALS.[13] Conversely, administration of VEGF has shown protective effects on motor neurons and delayed disease progression in these models.[14] This neurotrophic potential formed the basis for investigating sNN0029 (Telbermin) in ALS, with the aim of directly protecting motor neurons from degeneration and slowing the disease course.[14]

The existence of these dual properties—angiogenic and neurotrophic—allowed Telbermin to be considered for two very different disease states. However, the success of such a therapy would inherently depend not only on the molecule's intrinsic activity but also on effective delivery to the target tissue (e.g., topical for skin ulcers, direct CNS administration for neurodegeneration) and the relative importance and interplay of these mechanisms within the specific pathological microenvironment of each disease.

2.3. Pharmacological Target Engagement

Evidence from clinical trials suggests that Telbermin was capable of engaging its pharmacological targets, although this engagement did not uniformly translate into clinically and statistically significant efficacy meeting regulatory approval standards.

In DFU trials, the topical application of Telbermin led to observations described as "positive trends" or "potential signals of biological activity" towards wound healing, suggesting that the drug was exerting some local effect consistent with its angiogenic mechanism.[1] While these early signals were encouraging, they did not reach statistical significance in key primary endpoint analyses of later, more definitive trials.[1]

In ALS trials, where sNN0029 (Telbermin) was administered via ICV infusion, pharmacokinetic studies confirmed target engagement within the CNS. Specifically, administration of 2 µg/day resulted in sustained, detectable levels of the drug in the cerebrospinal fluid (CSF).[2] This demonstrated that the chosen delivery method could achieve drug presence in the target compartment. Preliminary analyses from these early ALS studies also hinted at potential clinical benefits, particularly at the highest doses tested.[14]

The gap between demonstrated target engagement (drug reaching the target site and eliciting some biological response) and the achievement of robust, approvable clinical benefit is a well-documented challenge in drug development. For Telbermin, while there was evidence of the drug interacting with its intended biological system in both DFU and ALS contexts, this did not prove sufficient to overcome the hurdles required for regulatory approval, due to efficacy shortfalls in DFU and external program termination in ALS.

3. Clinical Development for Diabetic Foot Ulcers (DFU)

The investigation of Telbermin for the treatment of diabetic foot ulcers was based on its potential to stimulate angiogenesis in wounds characterized by compromised vascular supply and impaired healing, common features of DFU.

3.1. Preclinical Rationale and Therapeutic Aims

Diabetic foot ulcers represent a significant complication of diabetes mellitus, often leading to severe morbidity, including infections and amputations. Impaired wound healing in DFU is multifactorial, involving neuropathy, peripheral vascular disease, and altered cellular and biochemical environments.[16] A critical component of this impaired healing is often insufficient angiogenesis and reduced local blood supply to the wound bed.[7]

Telbermin, as a recombinant human VEGF-A165, was developed with the therapeutic aim of promoting angiogenesis directly at the ulcer site. By topical application, it was hypothesized that Telbermin would stimulate the proliferation and migration of endothelial cells, leading to the formation of new blood vessels, thereby improving tissue perfusion, oxygenation, and the delivery of nutrients and growth factors essential for wound repair and closure.[7]

3.2. Summary of Clinical Trials (Design, Population, Key Endpoints)

The clinical development of Telbermin for DFU primarily involved Phase I and Phase II trials, sponsored by Genentech.

A key Phase I trial was a randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability, and preliminary efficacy of topically applied Telbermin.[1] Approximately 50 to 55 adult subjects with Type 1 or Type 2 diabetes mellitus and chronic, neuropathic diabetic foot ulcers were enrolled. Inclusion criteria typically specified ulcers of a certain size (e.g., ≥1.0 cm2 and ≤4.0 cm2 post-debridement) and duration (≥4 weeks but <6 months), with adequate peripheral circulation (Ankle-Brachial Index, ABI, within a specified range).[19] Participants received either Telbermin at a dose of 72 µg/cm2 or a placebo gel, applied to the ulcer surface up to three times per week for a maximum of six weeks, in conjunction with standard good wound care, including debridement and off-loading.[1] Primary endpoints focused on safety and tolerability, while exploratory efficacy endpoints included the percentage reduction in ulcer surface area, the incidence of complete ulcer healing, and the time to achieve complete healing.[1]

Following the Phase I investigations, Telbermin advanced to Phase II development. One such study identified is NCT00351767, described as a Phase II, double-blind, randomized, placebo-controlled study to assess the effect of topical rhVEGF (Telbermin) for the induction of healing of diabetic foot ulcers.[2] This trial is listed as completed. However, detailed design specifics, patient numbers, and comprehensive results for this particular Phase II trial are not extensively available in the provided documentation, beyond the ultimate outcome that the DFU program did not meet its primary efficacy goals.

The progression from promising, albeit statistically non-significant, trends in Phase I to a failure to meet primary endpoints in Phase II is a common trajectory in pharmaceutical development. For Telbermin in DFU, this outcome suggests that the initial signals of biological activity observed in smaller, early-phase studies did not translate into a sufficiently robust or statistically significant clinical benefit in larger, more rigorously controlled Phase II trials. The specific factors contributing to this—such as patient heterogeneity, the complexity of DFU pathophysiology, choice of endpoints, or an insufficient magnitude of effect—are not fully elucidated in the available materials beyond the overarching failure to meet FDA-accepted efficacy criteria.

Table 2: Overview of Key Clinical Trials of Telbermin in Diabetic Foot Ulcers

Trial Identifier/Phase	Sponsor	Key Design Features	Patient Population	Dose(s) Administered	Primary Efficacy Results (Reported)	Key Safety Findings (Reported)	Overall Outcome
Phase I (Generic)	Genentech	Topical; Randomized, double-blind, placebo-controlled	Type 1/2 DM with chronic neuropathic foot ulcers	72 µg/cm2	Trend: 41.4% healing (Telbermin) vs 26.9% (placebo) at Day 43 (P=0.39) 1	Generally well-tolerated; AEs comparable to placebo 1	Proceeded to Phase II
NCT00351767 (Phase II)	Genentech	Topical; Randomized, double-blind, placebo-controlled	Diabetic Foot Ulcers	Not specified in detail	Failed to meet FDA-accepted primary efficacy endpoint of complete wound closure 1	Not detailed, but overall DFU program safe 18	Development for DFU discontinued/revoked by FDA 1

3.3. Efficacy Outcomes and Statistical Significance

In the Phase I DFU trial, Telbermin demonstrated positive, albeit not statistically significant, trends in efficacy. For the incidence of complete ulcer healing by day 43, the Telbermin group showed a rate of 41.4% compared to 26.9% in the placebo group (P=0.39).[1] Similarly, for the time to complete ulcer healing, the 25th percentile was 32.5 days for the Telbermin group versus 43.0 days for the placebo group (log-rank P=0.13).[1] While these outcomes were numerically favorable for Telbermin, the associated p-values indicate that these differences could have arisen by chance and did not meet conventional thresholds for statistical significance (typically P < 0.05).

The lack of statistical significance in these early Phase I exploratory endpoints, despite numerically positive trends, may have been an early indicator of the challenges Telbermin would face in demonstrating robust efficacy in larger, more heterogeneous DFU patient populations. Diabetic foot ulceration is a complex clinical problem influenced by multiple systemic and local factors, making it a difficult indication for therapeutic intervention. It has been suggested that VEGF may operate within a "narrow therapeutic window," implying that optimal dosing, formulation, or patient selection criteria might be particularly critical and perhaps were not fully achieved.[18]

Ultimately, subsequent clinical trials, presumably including the Phase II study NCT00351767, failed to demonstrate that Telbermin could meet the FDA-accepted primary efficacy endpoint, which was complete wound closure.[1] Specific statistical outcomes from these later trials are not detailed in the available information, but the overall conclusion was a lack of sufficient efficacy.

3.4. Safety and Tolerability Profile in DFU Studies

Throughout its clinical investigation for DFU, topically applied Telbermin appeared to be well tolerated. In the Phase I trial, the incidence of adverse events (AEs) was comparable between the Telbermin and placebo treatment groups.[1] Importantly, none of the AEs were attributed to the study drug by investigators, and no clinically significant hypotension—a potential concern with systemic VEGF administration—was observed with the topical application.[1] The occurrence of infected study ulcers, a common complication in DFU, was also reported to be balanced between the treatment groups, suggesting Telbermin did not increase infection risk.[1]

Further supporting its benign local safety profile, it was noted that Telbermin, when applied topically, appeared to be safe and well-tolerated with no evidence of significant systemic absorption.[18] This is a crucial safety feature for a growth factor applied to open wounds, as systemic exposure could lead to undesirable off-target effects. While a good safety profile is a necessary attribute for any therapeutic agent, it cannot, by itself, secure regulatory approval in the absence of demonstrated clinical efficacy.

3.5. Regulatory Outcome and Reasons for Discontinuation for DFU Indication

The clinical development program for Telbermin in the DFU indication was ultimately unsuccessful. Despite early promising biological signals and a favorable local safety profile, Telbermin failed to meet the US Food and Drug Administration (FDA)-accepted primary efficacy endpoint of complete wound closure in its later-stage (presumably Phase II) clinical trials.[1]

As a direct consequence of this failure to demonstrate sufficient clinical efficacy, the usage of Telbermin as a topical agent for DFU was revoked by the US FDA.[1] Some sources also state that the DFU program was "abandoned after Phase II clinical trials".[1] This outcome signifies a definitive halt to the DFU development pathway for Telbermin, driven by the drug's performance against pre-specified success criteria in well-controlled clinical studies. This is a common end for many investigational drugs that show early promise but do not substantiate that promise in more rigorous, larger-scale testing.

4. Clinical Development for Amyotrophic Lateral Sclerosis (ALS)

The investigation of Telbermin, under the designation sNN0029, for amyotrophic lateral sclerosis (ALS) pursued a different therapeutic rationale and delivery strategy compared to its DFU program, focusing on the neurotrophic properties of VEGF and direct administration to the central nervous system.

4.1. Preclinical Rationale and Therapeutic Aims (as sNN0029)

Amyotrophic lateral sclerosis is a devastating, progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and eventual respiratory failure.[12] The underlying pathogenesis of ALS is complex and not fully understood, but evidence has implicated deficiencies in neurotrophic support as a contributing factor.

Vascular Endothelial Growth Factor (VEGF) has been shown to possess direct neurotrophic and neuroprotective effects, independent of its well-known angiogenic properties.[12] Preclinical research, including studies in animal models of ALS, indicated that reduced levels of VEGF are associated with ALS-like neurodegeneration, while administration of VEGF can promote motor neuron survival and delay disease progression.[13]

Based on this rationale, sNN0029 (Telbermin) was investigated by Newron Pharmaceuticals as a potential therapy for ALS. The therapeutic aim was to deliver VEGF directly to the central nervous system (CNS) to exert its neuroprotective effects on motor neurons, thereby potentially slowing disease progression and improving outcomes for ALS patients.[2] To achieve this, an intracerebroventricular (ICV) route of administration was chosen, involving an implantable pump and catheter system to deliver the drug into the cerebral ventricles.[2]

4.2. Summary of Clinical Trials (Design, Intracerebroventricular Delivery, Key Endpoints)

The clinical development of sNN0029 for ALS was led by Newron Pharmaceuticals, with the drug (recombinant human VEGF165) supplied by Genentech.[2] The program involved Phase I studies and the initiation of a Phase II trial before its eventual termination.

The Phase I program comprised at least two studies:

• NCT01999803: This was a randomized, double-blind, placebo-controlled study designed to assess the safety and tolerability of ICV-administered sNN0029 in patients with ALS. It enrolled 15 participants and investigated doses up to 2 µg/day.[2] This trial was ultimately terminated.
• NCT02269436: This was an open-label, follow-on study intended to evaluate the long-term safety and tolerability of ICV sNN0029 in 11 patients who had participated in previous sNN0029 studies.[20] This trial was also terminated.

In these Phase I studies, sNN0029 was delivered continuously using an implantable programmable pump (Medtronic SynchroMed® II) connected to an intracerebroventricular infusion catheter inserted into the frontal horn of a lateral cerebral ventricle.[2] Key endpoints included safety, tolerability, and pharmacokinetics, specifically measuring drug levels in the CSF.[2]

Building on the Phase I experience, Newron Pharmaceuticals announced the initiation of a Phase II trial in January 2015.[14] This trial was planned as a randomized, placebo-controlled, double-blind study involving 18 ALS patients. The planned intervention was a continuous ICV infusion of sNN0029 at a higher dose of 4 µg/day, or placebo, for a duration of three months. Endpoints were to include safety and preliminary efficacy measures.[14] However, the program was discontinued in October 2015, meaning this Phase II trial was not completed as planned, and its results were superseded by the termination decision.[5]

The choice of ICV delivery, while providing direct access to the CNS, inherently introduced significant complexities and potential risks associated with the surgical implantation and long-term maintenance of the pump and catheter system. These device-related factors, rather than issues with the drug molecule itself, ultimately proved to be the critical point of failure for the ALS program.

Table 3: Overview of Key Clinical Trials of Telbermin (sNN0029) in Amyotrophic Lateral Sclerosis

Trial Identifier/Phase	Sponsor	Key Design Features	Patient Population	Dose(s) Administered	Key PK/PD & Efficacy Findings (Reported)	Key Safety Findings (Reported)	Overall Outcome
NCT01999803 (Phase I)	Newron Pharmaceuticals	ICV delivery; Randomized, double-blind, placebo-controlled	ALS patients (N=15)	Up to 2 µg/day	Sustained detectable CSF levels with 2 µg/day.2 Preliminary signals of benefit at highest dose in earlier study.14	Drug generally well-tolerated; procedure/device risks (e.g., seizure); pulmonary emboli (3 patients across program).2	Terminated; Led to planned Phase II.
NCT02269436 (Phase I Ext.)	Newron Pharmaceuticals	ICV delivery; Open-label, follow-on	ALS patients (N=11)	Continued sNN0029	Long-term exposure for some patients up to 6 years.2	As above.	Terminated.
Planned Phase II	Newron Pharmaceuticals	ICV delivery; Randomized, double-blind, placebo-controlled (initiated Jan 2015)	ALS patients (N=18)	Planned 4 µg/day	Intended to further assess safety and efficacy.	Not fully assessed due to program termination.	Program discontinued (Oct 2015) due to delivery device supply issues.5

4.3. Pharmacokinetic, Pharmacodynamic, and Efficacy Observations

Pharmacokinetic data from the Phase I ALS program demonstrated successful drug delivery to the CNS. Continuous ICV administration of sNN0029 at a dose of 2 µg/day resulted in sustained and detectable levels of the drug in the cerebrospinal fluid.[2] This was a critical finding, confirming that the chosen delivery method and dose were capable of achieving drug presence within the target compartment.

Regarding efficacy, the available information is primarily from preliminary analyses of early-stage studies. Reports indicated that an earlier study (likely encompassing the 2 µg/day cohort from the Phase I program) showed "preliminary analyses evidence of significant benefit especially in patients at the highest dose on multiple efficacy measures, compared to placebo".[14] These early positive signals were encouraging and formed part of the rationale for proceeding to a Phase II trial with an even higher dose (4 µg/day). However, it is important to note that these were preliminary findings from small patient cohorts, and the Phase II trial designed to confirm and expand upon these observations was not completed due to the program's termination.[5] Some summaries of the terminated Phase I trials (NCT01999803, NCT02269436) note specific efficacy data as "not available," though the qualitative descriptions of early benefit persist in several communications from the sponsor.[21]

The premature halt of the ALS program means that the initial promising signals regarding CNS bioavailability and potential efficacy were never conclusively validated in larger, longer-term, and more definitive clinical trials. Consequently, the true therapeutic potential of sNN0029 (Telbermin) for ALS remains an unresolved question, as its development was curtailed by external factors before a full efficacy assessment could be made.

4.4. Safety and Tolerability Profile in ALS Studies

The safety and tolerability profile of sNN0029 (Telbermin) in the ALS clinical program was influenced by both the drug itself and the invasive ICV delivery system.

The surgical procedure for implanting the pump and catheter system was reported to be generally well tolerated in most patients. However, there was at least one instance of a significant procedure-related adverse event: one patient experienced transient postoperative seizures, which were attributed to an ischemic lesion that developed along the catheter tract in the brain.[2]

The drug, sNN0029, was described as well tolerated by most patients who received it, with some individuals participating in an open-label extension study for up to six years, suggesting good long-term tolerability of the molecule itself in those patients.[2]

Several serious adverse events (SAEs) were reported during the ALS program. Notably, pulmonary embolus occurred in three patients: one during the initial three-month placebo-controlled study period, and two during the subsequent open-label extension study.[2] Pulmonary embolism is a known complication in patients with ALS, often related to immobility and respiratory compromise. Without more detailed data and a larger controlled cohort, it is difficult to definitively attribute these events to sNN0029, the delivery device, or the natural progression of the underlying disease. Such events would have required careful monitoring and analysis had the program continued.

The safety assessment in the ALS trials thus presented a complex picture. While the drug molecule appeared to be tolerated by many, the invasive nature of the ICV delivery system introduced its own set of risks, including surgical complications and potential long-term device-related issues.

4.5. Regulatory Status and Program Discontinuation

Prior to the program's termination, sNN0029 (Telbermin) received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of amyotrophic lateral sclerosis.[3] This designation is granted to drugs intended for rare diseases and provides certain incentives to sponsors, acknowledging the potential of the drug to address an unmet medical need.

Despite this positive regulatory milestone and the early promising data, Newron Pharmaceuticals announced the termination of the sNN0029 development program for ALS in October 2015.[5] The decision was not based on negative efficacy or safety findings directly related to the sNN0029 molecule from the ongoing or recently completed trial phases. Instead, the discontinuation was attributed to critical issues with a third-party supplier of the investigational drug delivery catheter required for the ICV administration.[5] This supplier had reportedly entered into a consent decree with the FDA, which prevented them from commercializing the catheter or engaging in new manufacturing of the device until specific quality system issues were resolved. Furthermore, the existing stock of catheters was due to expire in February 2016, rendering the continuation or initiation of new trials logistically unfeasible.[5]

This external, device-related supply chain failure was the decisive factor leading to the halt of the ALS program. It underscores a critical vulnerability in developing therapies that rely on specialized, and potentially sole-sourced, device components. The optimism for sNN0029 in ALS, reflected in earlier projections of pivotal trial initiation and potential launch [10], was abruptly curtailed by this unforeseen logistical and regulatory challenge involving the delivery system. Consequently, the therapeutic potential of Telbermin in ALS, hinted at by early studies, was never fully evaluated in adequately powered, later-stage clinical trials. The drug subsequently disappeared from Newron's active pipeline updates.[23]

5. Integrated Safety Assessment

Evaluating the safety of Telbermin requires a nuanced approach, considering its application in two distinct indications (DFU and ALS) using vastly different administration routes and involving disparate patient populations.

5.1. Comparative Safety Across Indications and Administration Routes

The safety profile of Telbermin was fundamentally dictated by its route of administration and the clinical context of its use.

• For Diabetic Foot Ulcers (Topical Administration): When applied topically to DFUs, Telbermin exhibited a benign safety profile. Studies reported that it was well-tolerated locally, with an incidence of adverse events comparable to that of placebo.[1] Crucially, there were no adverse events directly attributed to the drug by investigators, and no clinically significant systemic effects, such as hypotension, were observed. Furthermore, there was no evidence of significant systemic absorption of Telbermin following topical application.[18] This localized action and lack of systemic exposure contributed to its favorable safety in the DFU setting.
• For Amyotrophic Lateral Sclerosis (Intracerebroventricular Administration): The ICV administration route for sNN0029 (Telbermin) in ALS patients introduced a different spectrum of safety considerations. The primary risks were associated with the surgical implantation and long-term presence of the infusion pump and catheter system. These included potential surgical complications, such as the reported case of an ischemic lesion along the catheter tract leading to transient seizures.[2] While the drug molecule itself was reported as well-tolerated by many patients, even over extended periods in an open-label setting, the overall safety assessment had to account for device-related issues and the potential for systemic adverse events, such as the observed cases of pulmonary embolus.[2]

A direct comparison of the "inherent" safety of the Telbermin molecule is complicated by these factors. The DFU studies suggest good local tolerability with minimal systemic risk. The ALS studies, while indicating the drug substance itself was tolerable for many, were confounded by the risks of the invasive delivery method and the severe underlying disease. Therefore, the safety profile of the "drug system" (i.e., the drug in combination with its delivery method) was markedly different between the two indications.

5.2. Notable Adverse Events and Unresolved Safety Questions

Key adverse events reported in the Telbermin clinical programs included:

• In DFU trials: No specific drug-attributed AEs were highlighted; the safety profile was similar to placebo.[1]
• In ALS trials: Procedure-related complications (e.g., transient seizures post-catheter implantation) and serious adverse events like pulmonary embolus (observed in three patients) were notable.[2]

The causality of the pulmonary emboli in the ALS trials remains an important unresolved question. ALS patients are inherently at an increased risk for thromboembolic events due to factors such as immobility and respiratory compromise. VEGF itself has complex roles in vascular biology; while anti-VEGF therapies are often associated with thrombotic risks, the effects of pro-angiogenic VEGF administration in this context are less clear. Without larger, controlled, long-term data, definitively linking these events to Telbermin, the delivery device, or the natural progression of ALS is not possible based on the available information.

The premature termination of the ALS program due to device supply issues meant that a comprehensive long-term safety database for ICV-administered Telbermin could not be established. Questions regarding the true incidence of rare but serious adverse events, and a clearer understanding of the risk-benefit profile in a larger ALS population, were left unanswered. The pulmonary embolism signal, in particular, would have warranted further rigorous investigation had the development continued.

6. Concluding Analysis and Future Perspectives

The development history of Telbermin (also sNN0029) offers a compelling case study in biopharmaceutical research, illustrating how a single molecule with plausible biological rationale for multiple indications can face divergent outcomes due to a combination of efficacy results, safety considerations, and external logistical challenges.

6.1. Synthesis of Telbermin's Developmental Trajectory and Outcomes

Telbermin's journey was characterized by two distinct development paths:

1. For Diabetic Foot Ulcers (DFU): Led by Genentech, topical Telbermin showed early, albeit statistically non-significant, positive trends in Phase I trials, coupled with a good local safety profile.[1] However, it ultimately failed to meet primary efficacy endpoints for complete wound closure in subsequent, presumably Phase II, clinical trials. This lack of demonstrated efficacy led to the discontinuation of its development for DFU and revocation of its use by the FDA for this indication.[1]
2. For Amyotrophic Lateral Sclerosis (ALS): As sNN0029, developed by Newron Pharmaceuticals, intracerebroventricularly (ICV) administered Telbermin achieved CNS penetration and showed preliminary signals of potential benefit in early Phase I studies, earning an FDA Orphan Drug Designation.[2] However, the ALS program was prematurely terminated in October 2015, not due to direct concerns about the drug's efficacy or safety at that stage, but because of insurmountable issues with the third-party supply of the essential investigational drug delivery catheter.[5]

This bifurcation in outcomes is significant. The DFU program concluded due to the drug's performance against clinical endpoints, a common scenario in drug development. In contrast, the ALS program was halted by an external, logistical failure, leaving the ultimate therapeutic potential of Telbermin in ALS largely unexplored in definitive later-phase trials. This highlights how factors beyond a drug's intrinsic pharmacology can critically impact its development trajectory.

6.2. Lessons Learned from the Telbermin Programs

The Telbermin experience offers several valuable lessons for pharmaceutical development:

• Translating Early Signals: The DFU program underscores the challenge of translating promising, but often underpowered, early-phase signals into statistically robust and clinically meaningful efficacy in larger, more complex patient populations and disease states.[1]
• Criticality of Delivery Systems: The ALS program's fate dramatically illustrates the critical dependence of certain therapies on reliable and safe drug delivery systems. For CNS-targeted biologics like Telbermin, the invasive ICV delivery method, while enabling target engagement, became the Achilles' heel due to device supply failure.[2] This emphasizes that the "drug product" often encompasses both the active pharmaceutical ingredient and its delivery technology, both of which must be robust.
• Supply Chain Vulnerabilities: The reliance on a third-party supplier for a critical device component in the ALS trials exposed a significant supply chain vulnerability. Disruptions or quality issues from such suppliers can have catastrophic consequences for clinical development programs.[5]
• Trial Design in Complex Diseases: Developing treatments for conditions like DFU and ALS is inherently challenging due to patient heterogeneity, complex pathophysiology, and difficulties in defining sensitive and clinically relevant endpoints. While not the direct cause of Telbermin's discontinuation in ALS, the general difficulties in ALS trial design are well-documented and provide context for the high bar for success.[25] Similarly, DFU trials require careful design to account for numerous confounding factors affecting wound healing.[18]

6.3. Current Standing of VEGF-Based Therapies for DFU and ALS

Despite the specific setbacks faced by Telbermin, the underlying scientific rationale for targeting VEGF pathways in conditions like DFU and ALS may still hold some validity, and research in these areas continues.

• For DFU: VEGF remains a molecule of interest for promoting angiogenesis in ischemic wounds. Systematic reviews indicate ongoing research into VEGF stimulation for DFU, emphasizing the need for consistent study designs and better understanding of optimal dosage and release mechanisms.[11] Current DFU management focuses on standard care including debridement, off-loading, infection control, vascular assessment, and appropriate dressings, with advanced therapies like growth factors (e.g., becaplermin, a platelet-derived growth factor) being adjunctive options.[16] Hydrogel dressings are also an area of active research for DFU treatment.[26]
• For ALS: The neurotrophic properties of VEGF continue to make it, and its signaling pathways, a subject of interest in the quest for ALS therapies.[12] The current therapeutic landscape for ALS includes a few approved drugs that offer modest benefits, and there is a significant unmet need for more effective treatments. Emerging therapies for ALS target various pathogenic mechanisms, including antisense oligonucleotides, stem cells, kinase inhibitors, and modulators of cellular stress responses.[27]

Telbermin's story does not necessarily invalidate the VEGF target itself for these conditions. Instead, it highlights the challenges in translating the biological concept into a successful therapeutic product.

6.4. Potential Future Research Avenues or Considerations

Learning from Telbermin's development can inform future research efforts targeting VEGF or similar pathways:

• For DFU: If VEGF-based therapies are to be revisited for DFU, careful consideration must be given to:
• Formulation and Delivery: Optimizing topical formulations for sustained release and enhanced tissue penetration.
• Patient Selection: Identifying DFU patient subgroups most likely to respond to pro-angiogenic therapy, potentially based on biomarkers of local ischemia or VEGF deficiency.
• Trial Design and Endpoints: Utilizing robust and clinically meaningful endpoints beyond just complete wound closure, and designing trials with sufficient power to detect modest but relevant effects in heterogeneous populations. The "narrow therapeutic window" previously suggested for Telbermin would need careful exploration with any new agent.[18]
• For ALS: The primary lesson from the sNN0029 program is the critical need for reliable, safe, and sustainable CNS delivery mechanisms for biologic therapies. Future research could explore:
• Alternative Delivery Systems: Investigating less invasive or more robust methods for CNS delivery of VEGF or VEGF mimetics, such as advanced viral vectors, cell-based delivery, or brain-penetrant small molecules that modulate VEGF pathways.
• Next-Generation VEGF Mimetics: Developing novel molecules that capture the neurotrophic benefits of VEGF with improved pharmacokinetic profiles or enhanced safety for CNS administration.
• Combination Therapies: Exploring VEGF-based approaches in combination with other neuroprotective or anti-inflammatory agents that target different aspects of ALS pathology.

In conclusion, Telbermin's development narrative is a valuable chronicle of the multifaceted challenges in bringing a biologic therapy to market for complex diseases. While it did not achieve regulatory approval for DFU or ALS, the scientific investigations and the specific reasons for its program terminations provide important lessons for future drug development endeavors targeting similar pathways or facing comparable logistical hurdles.

References

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29 PubChem. (2020, March 7). Telbermin.

3 NCATS GSRS. (n.d.). Telbermin.

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7 Ontosight.ai. (n.d.). sNN 0029 Therapeutic Agent Overview.

8 HMP Global Learning Network. (2006, November 1). What Are The Top Ten Recent Innovations In Podiatry?

1 Hanft, J. R., et al. (2008). Phase I trial on the safety of topical rhVEGF on chronic neuropathic diabetic foot ulcers. International Wound Journal. (as cited by ResearchGate)

19 Veeva CTV. (n.d.). A Study Evaluating Topical Recombinant Human Vascular Endothelial Growth Factor (Telbermin) for Induction of Healing of Chronic, Diabetic Foot Ulcers.

2 Van Damme, P., et al. (2020). Intracerebroventricular delivery of sNN0029 (VEGF) in patients with amyotrophic lateral sclerosis: a phase I trial. Brain Communications.

7 Ontosight.ai. (n.d.). sNN 0029 Therapeutic Agent Overview. 7

20 DDRare. (n.d.). SNN0029 infusion solution.

14 Newron Pharmaceuticals. (2015, January 15). Newron initiates Phase II study of sNN0029 in patients with Amyotrophic Lateral Sclerosis.

9 PatSnap Synapse. (n.d.). Telbermin (Genentech).

14 Newron Pharmaceuticals. (2015, January 15). Newron initiates Phase II study of sNN0029 in patients with Amyotrophic Lateral Sclerosis. 14

15 Biospace. (2015, January 15). Newron Pharmaceuticals Initiates Phase 2 Study of sNN0029 in Patients With Amyotrophic Lateral Sclerosis.

21 PMC. (2019, August 7). Neurotrophic Factors in Amyotrophic Lateral Sclerosis: A Critical Review of Clinical Trials.

10 ValuationLab. (2014, September). Newron Pharmaceuticals Report.

23 Edison Investment Research. (2017, March 7). Newron Pharmaceuticals — Marching into 2017.

24 Newron Pharmaceuticals. (n.d.). Science.

15 Biospace. (2015, January 15). Newron Pharmaceuticals Initiates Phase 2 Study of sNN0029 in Patients With Amyotrophic Lateral Sclerosis. 15

22 Practical Neurology. (2015, Jan/Feb). News.

18 Koplev, V. K., et al. (2024). The effect of VEGF stimulation in diabetic foot ulcers: A systematic review. International Wound Journal. (as cited by ResearchGate)

25 Turner, M. R., et al. (2024). Learning from failure: improving phase 2 trial design in amyotrophic lateral sclerosis. Brain Communications.

5 Newron Pharmaceuticals. (2015, October 28). Newron Announces Update on Pipeline and Financial Outlook.

11 Koplev, V. K., et al. (2024). The effect of VEGF stimulation in diabetic foot ulcers: A systematic review. PubMed.

26 Zhou, Y., et al. (2024). Advances in hydrogel dressings for diabetic foot ulcers: A comprehensive review. Burns & Trauma.

12 Harrar, V., et al. (2015). Vascular Endothelial Growth Factor (VEGF) in Amyotrophic Lateral Sclerosis (ALS). PMC.

13 R&D Systems. (n.d.). VEGF & Amyotrophic Lateral Sclerosis.

16 Powers, J. G., et al. (2017). Diabetes, G. C. (2017). Management of diabetic foot ulcers. American family physician.

17 Shishehbor, M. H., et al. (2023). Management of Patients With Nontraumatic Lower Extremity Peripheral Vascular Disease: A Scientific Statement From the American Heart Association. Circulation.

27 Practical Neurology. (2023, July 12). Neuromuscular Notes: New and Emerging Therapies in ALS.

28 Ho, D., et al. (2023). Neuromuscular Notes: New and Emerging Therapies in ALS. Practical Neurology.

2 AI-generated summary. (Internal reference for synthesis of multiple Telbermin sources).

1 AI-generated summary. (Internal reference for synthesis of Telbermin DFU Phase I trial).

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