ARA-290

1. Introduction

The pursuit of therapeutic agents capable of arresting cellular injury and promoting tissue regeneration represents one of the most significant frontiers in modern biomedical research. For decades, the glycoprotein hormone erythropoietin (EPO) has been recognized primarily for its obligate role in hematopoiesis—the stimulation of red blood cell production in the bone marrow. However, a paradigm shift occurred with the discovery that EPO possesses potent cytoprotective properties independent of its hematopoietic functions. This “tissue-protective” activity is mediated through a distinct receptor complex, opening a new avenue for treating conditions characterized by chronic inflammation, ischemia, and neurodegeneration.

Despite the therapeutic promise of recombinant human EPO (rhEPO) in regenerative medicine, its clinical translation has been severely hindered by its primary erythropoietic activity. The high systemic doses of rhEPO required to achieve neuroprotection or cardioprotection inevitably lead to supraphysiological hematocrit levels, increasing blood viscosity and precipitating dangerous thrombotic events, hypertension, and stroke. This dichotomy—the need for tissue protection versus the risk of hematological toxicity—necessitated the engineering of non-hematopoietic EPO derivatives.

ARA-290, also known as Cibinetide, represents the lead candidate in this novel class of therapeutics. It is a synthetic 11-amino acid peptide modeled after the helix-B surface domain of the EPO molecule. Through precise structural engineering, ARA-290 has been designed to selectively activate the tissue-protective receptor—termed the Innate Repair Receptor (IRR)—while being sterically incapable of binding the homodimeric EPO receptor responsible for red blood cell production.

This report serves as an exhaustive analysis of ARA-290, synthesizing data from molecular biology, preclinical animal models, human clinical trials, and anecdotal evidence. It explores the peptide’s mechanism of action, its efficacy in treating small fiber neuropathy and metabolic disorders, its safety profile compared to native EPO, and its theoretical applications in neurodegenerative and autoimmune diseases.

2. Molecular Biology and Mechanism of Action

To understand the therapeutic potential of ARA-290, one must first dissect the complex receptor biology that governs the body’s response to stress and injury. The physiological response to tissue damage involves a delicate balance between pro-inflammatory clearance of debris and anti-inflammatory repair of structure. ARA-290 intervenes directly in this equilibrium.

2.1. The Innate Repair Receptor (IRR) Complex

The classical effects of EPO on red blood cells are mediated by the homodimeric EPO receptor. This receptor is constitutively expressed on erythroid progenitor cells in the bone marrow and binds EPO with high affinity, necessitating only low circulating levels of the hormone to maintain hematostasis.

In contrast, the tissue-protective effects are mediated by a heteromeric receptor complex known as the Innate Repair Receptor (IRR). The IRR is composed of one EPOR subunit and one beta-common receptor subunit (βc, also known as CD131). The βc subunit is shared with receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, and IL-5, highlighting its role in immune signaling.

2.1.1. Inducible Expression and Homeostasis

Unlike the homodimeric EPOR, the IRR is not constitutively expressed in most tissues. Under basal homeostatic conditions, the components of the IRR are undetectable or present at very low levels. However, upon cellular stress—induced by ischemia, hypoxia, mechanical trauma, or inflammation—the expression of both EPOR and βc is dramatically upregulated in the affected tissue. This upregulation sensitizes the injured tissue to circulating EPO (or exogenously administered ARA-290), creating a localized “repair window”.

ARA-290 was engineered to bind selectively to this EPOR-βc heteromer. Crucially, it does not interact with the homodimeric EPOR. This selectivity is the pharmacological basis for its safety profile; it allows for the activation of repair pathways without stimulating the bone marrow, thus avoiding erythropoiesis and the associated cardiovascular risks.

2.2. Intracellular Signaling Cascades

Upon binding to the IRR, ARA-290 triggers a conformational change that initiates a cascade of intracellular signaling events. These pathways are distinct from the JAK2/STAT5 pathway typically associated with erythropoiesis, focusing instead on anti-apoptosis, anti-inflammation, and cytoskeletal remodeling.

2.2.1. The JAK2/STAT3 Axis and Neuropathic Pain

The Janus Kinase 2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) pathway is a critical regulator of cell survival and inflammation. In the context of chronic pain and neuropathy, aberrant activation of JAK2/STAT3 in the dorsal root ganglia (DRG) and spinal dorsal horn is often pathological, contributing to central sensitization and the maintenance of pain states.

Research indicates that ARA-290 modulates this pathway to exert its analgesic and neuroprotective effects. While sustained, aberrant STAT3 phosphorylation (often driven by IL-6) is pro-nociceptive, the transient and specific activation of STAT3 via the IRR by ARA-290 promotes the transcription of neurotrophic factors and anti-apoptotic genes (such as Bcl-2 and Bcl-xL). This modulation effectively reprograms the sensory neurons, reducing their excitability and promoting structural repair.

2.2.2. Inhibition of Nuclear Factor-κB (NF-κB)

Perhaps the most significant anti-inflammatory action of ARA-290 is its suppression of Nuclear Factor-κB (NF-κB). NF-κB is a transcription factor that serves as a “master switch” for the inflammatory response. In response to stress signals (like TNF-α), NF-κB translocates to the cell nucleus, where it drives the expression of pro-inflammatory cytokines, chemokines, and adhesion molecules.

ARA-290 treatment has been shown to inhibit the nuclear translocation of NF-κB. By blocking this pathway, ARA-290 dampens the production of downstream inflammatory mediators such as TNF-α, IL-1β, and IL-6. This prevents the “cytokine storm” that often follows ischemic injury or autoimmune flares, thereby limiting secondary tissue damage and preserving cellular integrity.

2.2.3. TRPV1 Channel Antagonism

Beyond its transcriptional effects, ARA-290 exhibits direct neuromodulatory activity at the membrane level. Specifically, it has been identified as a novel antagonist of the Transient Receptor Potential Vanilloid 1 (TRPV1) channel.

The TRPV1 channel is a non-selective cation channel expressed on nociceptive neurons (pain receptors). It acts as a molecular integrator of painful stimuli, activated by heat, protons (acidosis), and chemicals like capsaicin. In chronic neuropathic pain, TRPV1 channels become sensitized and overactive, leading to thermal hyperalgesia (extreme sensitivity to heat) and spontaneous pain. ARA-290’s ability to inhibit TRPV1 activity provides a rapid mechanism for analgesia that complements its slower, long-term neuroregenerative effects.

2.3. Pharmacokinetics and Metabolism

Understanding the pharmacokinetic profile of ARA-290 is essential for interpreting its clinical dosing regimens and biological duration of action.

Plasma Half-Life: ARA-290 is a small peptide with a very short plasma half-life. Following intravenous (IV) administration, the terminal half-life is approximately 1.1 to 2.3 minutes. Following subcutaneous (SC) injection, the half-life extends to approximately 17 to 27 minutes.13
Bioavailability: The absolute bioavailability of subcutaneously administered ARA-290 ranges from 11% to 25% compared to intravenous dosing.
Metabolism: The peptide is rapidly degraded by plasma peptidases and metabolized in the liver, with renal elimination of metabolites.

There is a notable discrepancy between the short residence time of ARA-290 in the blood (~20 minutes) and its prolonged biological effects (lasting hours to days). This phenomenon is typical of “hit-and-run” agonists. The peptide needs only to bind the IRR briefly to initiate the phosphorylation cascades (JAK2, STAT3, PI3K/Akt). Once these pathways are activated, the signal is propagated and maintained intracellularly long after the ligand has been cleared from circulation. This allows for convenient once-daily dosing despite the rapid plasma clearance.

Table 1: Comparative Receptor Pharmacology

Receptor Complex	Subunits	Primary Ligand	Affinity (Kd)	Biological Function	Activated by ARA-290?
Erythropoietin Receptor	EPOR homodimer	EPO	High (pM)	Erythropoiesis (RBC production)	NO
Innate Repair Receptor	Heteromer (EPOR + βc)	EPO, ARA-290	Low (nM)	Tissue protection, anti-inflammation	YES

3. Preclinical Efficacy: Mammalian Models

Before entering human trials, ARA-290 was subjected to rigorous testing in a diverse array of animal models. These studies established its efficacy in treating conditions ranging from peripheral nerve injury to autoimmune disorders and cardiovascular disease.

3.1. Peripheral Neuropathy and Nerve Regeneration

Neuropathic pain represents a significant unmet medical need, often resistant to conventional analgesics like opioids or NSAIDs. ARA-290 has demonstrated profound effects in several rodent models of neuropathy.

3.1.1. Mechanical Injury Models

In models involving physical trauma to the nerves, such as sciatic nerve transection or chronic constriction injury (CCI), ARA-290 administration resulted in significant reductions in mechanical and cold allodynia (pain from non-painful stimuli).

Mechanism: In these models, ARA-290 was shown to suppress the activation of spinal microglia. Following nerve injury, microglia in the spinal cord typically transition to an activated, pro-inflammatory state, releasing cytokines that sensitize central pain pathways (central sensitization). ARA-290 treatment maintained microglia in a quiescent state, thereby interrupting the maintenance of chronic pain.
Dependence on βc: The specificity of ARA-290 was confirmed using knockout mice. In animals lacking the β-common receptor (CD131-/-), ARA-290 failed to produce any analgesic effect, confirming that the IRR is the obligatory mediator of its activity.

3.1.2. Experimental Autoimmune Neuritis (EAN)

EAN is the standard animal model for Guillain-Barré syndrome, an autoimmune demyelinating disease of the peripheral nervous system. In rats with EAN, ARA-290 treatment significantly improved clinical recovery scores, reduced nerve inflammation, and promoted remyelination.

Immune Modulation: The peptide altered the differentiation of T-helper cells. It increased the population of Foxp3+ regulatory T cells (Tregs) and IL-4+ Th2 cells (anti-inflammatory) while decreasing the population of IFN-γ+ Th1 cells (pro-inflammatory). This suggests that ARA-290 modulates the adaptive immune response, shifting the balance from autoimmunity to tolerance.16
Macrophage Phenotype: It also inhibited the activation of inflammatory macrophages and promoted their phagocytic activity, facilitating the clearance of myelin debris—a prerequisite for nerve regeneration.

3.2. Cardiovascular Protection and Aging

The tissue-protective domain of EPO has potent effects on the cardiovascular system.

Myocardial Infarction: In models of heart attack, ARA-290 reduces infarct size and preserves cardiac function. By inhibiting NF-κB and reducing the infiltration of inflammatory leukocytes, it limits the fibrotic scarring that typically leads to heart failure.
The Aging Heart: Chronic low-grade inflammation (“inflammaging”) drives age-related cardiovascular decline. In middle-aged rats, chronic ARA-290 administration mitigated age-related increases in blood pressure, preserved left ventricular ejection fraction, and improved cardiomyocyte autophagy. It also reduced the accumulation of lipofuscin (age pigment) in heart cells, suggesting a fundamental anti-aging effect at the cellular level.

3.3. Metabolic Dysregulation and Diabetes

Type 2 Diabetes (T2D) is characterized by insulin resistance and chronic systemic inflammation.

Glucose Control: In the Goto-Kakizaki rat model of non-obese T2D, ARA-290 improved insulin release and glucose tolerance. It appears to protect pancreatic beta-cells from glucose-induced toxicity and improves the signaling of insulin in peripheral tissues.
Adipose Tissue Inflammation: In diet-induced obesity models, ARA-290 reduced inflammation in white adipose tissue. Since inflamed fat tissue is a major source of systemic cytokines (like TNF-α) that drive insulin resistance, this provides a mechanistic link between IRR activation and improved metabolic health.

3.4. The Stroke Paradox: Interaction with rtPA

One of the most critical findings in preclinical research involves the interaction between tissue-protective agents and recombinant tissue plasminogen activator (rtPA), the standard “clot-busting” drug for acute ischemic stroke.

The EPO Problem: While EPO is neuroprotective alone, animal studies revealed that combining EPO with rtPA (particularly if delayed) exacerbated brain hemorrhage and increased mortality. This was linked to EPO-driven upregulation of Matrix Metalloproteinase-9 (MMP-9), an enzyme that degrades the blood-brain barrier, combined with rtPA’s fibrinolytic activity.
The ARA-290 Solution: Crucially, ARA-290 does not share this adverse interaction. In mouse models of cerebral ischemia, ARA-290 provided neuroprotection (reduced apoptosis, smaller infarct volume) without increasing the risk of hemorrhage when co-administered with rtPA. This suggests that the adverse vascular effects of EPO are mediated by the homodimeric receptor or other pathways not engaged by ARA-290, positioning Cibinetide as a safer adjunct therapy for stroke.

4. Clinical Efficacy: Human Trials

The transition from animal models to human clinical trials has focused on diseases where small fiber neuropathy (SFN) and chronic inflammation are central features. The most extensive data comes from Phase 2 trials in Sarcoidosis and Type 2 Diabetes.

4.1. Sarcoidosis-Associated Small Fiber Neuropathy

Sarcoidosis is a systemic inflammatory granulomatous disease. A significant proportion of patients develop a distinct neuropathy affecting the small, unmyelinated (C-fibers) and thinly myelinated (Aδ-fibers) nerves. This results in severe, burning pain, autonomic dysfunction, and profound fatigue. Current treatments (immunosuppressants) are often ineffective for this specific neuropathic component.

4.1.1. Corneal Confocal Microscopy (CCM) as a Biomarker

A major innovation in these trials was the use of Corneal Confocal Microscopy (CCM). The cornea is the most densely innervated tissue in the human body. CCM allows for the non-invasive visualization of these nerve fibers. Reduced Corneal Nerve Fiber Density (CNFD) correlates strongly with the severity of peripheral neuropathy and intra-epidermal nerve fiber density. Thus, CNFD serves as a surrogate marker for systemic nerve regeneration.

4.1.2. Phase 2b Trial Results (DOLOR Study)

In a double-blind, placebo-controlled trial, patients with sarcoidosis-associated SFN were randomized to receive ARA-290 (1 mg, 4 mg, or 8 mg) or placebo subcutaneously daily for 28 days.

Nerve Regeneration: The 4 mg dosing group demonstrated a statistically significant increase in Corneal Nerve Fiber Density (CNFD) compared to placebo. This effect represented an approximate 23% increase from baseline, providing objective evidence of nerve regrowth.
Symptom Improvement: Patients in the ARA-290 group reported significant improvements in the Small Fiber Neuropathy Screening List (SFNSL) scores. Specifically, improvements were seen in pain intensity and physical functioning.
Functional Capacity: Treatment was associated with an increased distance in the 6-minute walk test (6MWT), suggesting that pain relief translated into better functional mobility.

Interpretation: These results provided the first clinical evidence that activation of the IRR could modify the disease pathology (nerve loss) rather than simply masking symptoms.

4.2. Type 2 Diabetes and Neuropathy

ARA-290 was also evaluated in a Phase 2 trial involving patients with Type 2 Diabetes and painful neuropathy.

Protocol: Patients self-administered 4 mg of ARA-290 or placebo daily for 28 days, followed by a 28-day observation period.
Metabolic Outcomes: Subjects receiving ARA-290 showed improvements in Hemoglobin A1c (HbA1c) and lipid profiles that persisted through the 56-day observation period. This aligns with the preclinical finding that IRR activation improves insulin sensitivity.
Pain Reduction: Neuropathic symptoms, assessed via the PainDetect questionnaire, improved significantly. Specifically, patients reported reductions in “burning,” “tingling,” and “allodynia”.

4.3. Neuropsychiatric Effects: Depression and Cognition

Given the strong link between systemic inflammation and depression (the cytokine hypothesis of depression), researchers hypothesized that ARA-290 might possess antidepressant properties.

Human fMRI Study: A study was conducted in 36 healthy volunteers to assess neural processing of emotional stimuli. While ARA-290 did not produce subjective changes in mood (likely because the subjects were not depressed or inflamed), it did alter neural architecture. Functional MRI (fMRI) showed reduced neural responses to happy faces in the fusiform gyrus and faster categorization of positive words.
Rodent Models of Depression: In contrast to healthy humans, in mice subjected to chronic stress (a model of depression), ARA-290 was as effective as fluoxetine (Prozac) in reversing depressive behaviors (anhedonia, despair). This effect correlated with the suppression of microglial activation in the brain, reinforcing the concept that ARA-290’s psychotropic benefits are contingent on the presence of an underlying inflammatory pathology.

Table 2: Summary of Key Clinical Trial Outcomes

Indication	Trial Phase	Dosing Regimen	Key Findings	Reference
Sarcoidosis SFN	Phase 2b	4 mg SC / day (28 days)	Significant increase in CNFD (nerve regrowth); Reduced SFNSL scores; Improved 6MWT.	23
Type 2 Diabetes	Phase 2	4 mg SC / day (28 days)	Improved HbA1c and lipid profiles; Significant reduction in PainDetect scores.	10
Healthy Volunteers	Phase 1	Single/Multiple Ascending	Altered emotional processing (fMRI); No change in hematocrit; Excellent safety profile.	26

5. Safety Profile and Contraindications

A primary motivation for developing ARA-290 was to eliminate the adverse effects of EPO, and clinical data supports its success for this purpose.

5.1. Hematological Safety

Across all human trials, including those using doses up to 8 mg daily (substantially higher than the therapeutic 4 mg dose), there has been no evidence of erythropoiesis.

Hematocrit/Hemoglobin: No significant changes in red blood cell indices have been observed. This confirms the peptide’s inability to bind the homodimeric EPOR.
Thrombosis: No drug-related thrombotic events have been reported in trials, contrasting sharply with high-dose EPO therapy.

5.2. Adverse Events (AEs)

ARA-290 is generally well-tolerated. Reported AEs are typically mild and transient:

Injection Site Reactions: Mild pain, erythema (redness), or pruritus (itching) at the subcutaneous injection site.
Systemic Symptoms: Occasional reports of nausea, headache, or transient fatigue during the first week of treatment. These “flu-like” symptoms may be related to the modulation of the immune system and cytokine shifts.

5.3. Theoretical Malignancy Risk and Contraindications

While ARA-290 is safer than EPO regarding cardiovascular risk, the activation of cell survival pathways (JAK2/STAT3, Akt) raises theoretical concerns regarding cancer.

The Mechanism: Many tumors overexpress cytokine receptors to enhance their own survival and resist chemotherapy. If a tumor expresses the IRR, administration of ARA-290 could theoretically inhibit apoptosis in the cancer cells, promoting tumor growth or metastasis.
Strict Contraindication: Consequently, active malignancy is an absolute contraindication for ARA-290. Clinical trials rigorously excluded patients with a history of cancer within the past 5 years.

5.4. Immunogenicity

As a synthetic peptide, there is a risk that the body could recognize ARA-290 as foreign and develop neutralizing antibodies. However, clinical studies to date have screened for anti-ARA-290 antibodies and found no evidence of immunogenicity, likely due to its small size and similarity to the endogenous protein.

6. Anecdotal Evidence: The “Biohacking” and Grey Market Landscape

Due to the lack of FDA approval and the stalling of Phase 3 trials, a community of “biohackers” and patients with refractory chronic illnesses has turned to the “research chemical” market to access ARA-290. While this does not constitute clinical evidence, analyzing these reports provides insight into real-world usage patterns and subjective effects.

6.1. User Indications and Experiences

Analysis of user discussions (e.g., Reddit, Longecity) reveals several primary cohorts of unauthorized users:

Long COVID / PASC: A growing number of users are experimenting with ARA-290 for Post-Acute Sequelae of COVID-19. They theorize that Long COVID involves persistent neuroinflammation and small fiber neuropathy (manifesting as POTS or dysautonomia). Users often report subjective improvements in “brain fog,” energy levels, and orthostatic tolerance, aligning with the peptide’s anti-inflammatory mechanism.
Idiopathic SFN: Patients with confirmed small fiber neuropathy who do not respond to Gabapentin or IVIG often try ARA-290 as a “last resort.” Reports frequently cite reductions in burning pain and improvements in temperature sensitivity.
General “Anti-Aging”: Some biohackers use ARA-290 cyclically, aiming to reduce systemic “inflammaging” and improve biomarkers like HbA1c, even in the absence of diagnosed neuropathy.

6.2. Dosing Protocols and Logistics

The protocols primarily used are from the Phase 2b sarcoidosis trial:

Dosage: 4 mg (4000 mcg) per day is the standard anecdotal dose.
Route: Subcutaneous injection (typically into abdominal fat).
Cycle Length: Most users run “cycles” of 30 days, mirroring the 28-day trial period. Some report benefits tapering off after cessation, while others claim lasting remission.

6.3. Subjective Side Effects

Anecdotal reports often mention a “Herxheimer-like” reaction (worsening of symptoms) during the first few days of use, particularly increased fatigue or “flu-like” feelings. This is theoretically consistent with a shift in immune system activation status, though not formally characterized in trial literature.

7. Theoretical Applications and Future Directions

The versatility of the Innate Repair Receptor mechanism suggests that ARA-290 could have therapeutic utility across a wide range of pathologies beyond those currently studied.

7.1. Neurodegenerative Diseases

Alzheimer’s Disease (AD): Current AD research is shifting focus from amyloid plaques to neuroinflammation and microglial dysfunction. Since ARA-290 promotes the clearance of debris (like amyloid-beta) by modulating microglial phenotype and protecting neurons from inflammatory toxicity, it represents a promising disease-modifying candidate. Preclinical data showing slowed AD progression in mice supports this.
Parkinson’s Disease (PD): Similar to AD, PD involves neuroinflammation and mitochondrial dysfunction. ARA-290’s ability to improve mitochondrial quality control (mitophagy) and reduce oxidative stress could theoretically protect dopaminergic neurons in the substantia nigra.

7.2. Traumatic Brain Injury (TBI)

TBI involves an initial mechanical injury followed by a prolonged secondary injury phase driven by inflammation and edema. ARA-290’s ability to reduce edema and suppress NF-κB without the coagulation risks of EPO makes it an ideal candidate for acute administration by first responders or in emergency departments to limit secondary brain damage.

7.3. Transplant Medicine

Ischemia-reperfusion injury (IRI) is a major cause of graft failure in solid organ transplantation. The finding that ARA-290 protects pancreatic islets during transplantation suggests it could be used to pre-condition donor organs (kidney, liver, heart) or treat recipients immediately post-transplant to improve graft survival and reduce the incidence of acute rejection.

7.4. Regulatory Outlook and Development Status

As of late 2024 and heading into 2025, the development of ARA-290 (Cibinetide) has faced hurdles. While it holds Orphan Drug Designation and Fast Track status for Sarcoidosis, actively recruiting Phase 3 trials have been delayed. Development for indications like Depression and general Type 2 Diabetes appears to have been de-prioritized or discontinued in favor of orphan indications. The future of the drug likely depends on the successful execution of a large-scale Phase 3 trial to definitively prove its disease-modifying capabilities in SFN.

8. Conclusion

ARA-290 (Cibinetide) stands as a landmark achievement in the field of cytokine engineering. By isolating the tissue-protective pharmacophore of erythropoietin, scientists have created a molecule that harnesses the body’s innate repair mechanisms without the potentially lethal hematological side effects of the parent hormone.

The peptide’s mechanism is elegant and multifaceted: it acts locally at the site of injury to downregulate “master switches” of inflammation (NF-κB), modulate survival signaling (JAK2/STAT3), and provide immediate pain relief (TRPV1 antagonism).

Key Takeaways:

Efficacy: Clinical trials have demonstrated that ARA-290 can induce actual structural regrowth of nerve fibers in the cornea and reduce neuropathic pain in conditions (Sarcoidosis, Diabetes) that are notoriously difficult to treat.
Safety: The peptide exhibits an excellent safety profile in humans, with no evidence of erythropoiesis or thrombotic risk, validating the specificity of the Innate Repair Receptor concept.
Potential: Theoretical and preclinical evidence supports broad applications in neurodegenerative diseases, stroke, and autoimmune disorders.
Caution: Use is strictly contraindicated in active malignancy.

In summary, ARA-290 represents a prototype for “non-hematopoietic EPO derivatives”—a class of drugs that may one day transform the standard of care for chronic inflammatory and neuropathic diseases from mere symptom management to genuine tissue repair and disease modification.

Appendix: Comparison of EPO vs. ARA-290

Feature	Erythropoietin (rhEPO)	Cibinetide (ARA-290)
Primary Target	Bone Marrow (EPOR homodimer)	Injured Tissue (IRR Heteromer)
Half-Life	4-8 hours	~20 minutes (SC)
Effect on RBCs	Stimulates production (Increases Hematocrit)	None
Effect on Platelets	Pro-thrombotic (Increases reactivity)	Anti-inflammatory (Protects endothelium)
Stroke Safety	Contraindicated with rtPA (Hemorrhage risk)	Safe with rtPA (No hemorrhage risk)
Tumor Risk	Promotes tumor growth/angiogenesis	Contraindicated (Theoretical growth risk)
Main Clinical Use	Anemia (CKD, Chemo)	Investigational (Neuropathy, Sarcoidosis)