Antineoplaston Therapy and Sodium Phenylbutyrate

Number: 0240


Antineoplaston Therapy

Aetna considers antineoplaston therapy (auto-urine therapy) and associated medical services experimental and investigational because there is insufficient evidence published in the peer-reviewed medical literature validating the effectiveness of antineoplaston therapy for any indication.For additional information, see Experimental and Investigational and Backgrounds sections.

Sodium Phenylbutyrate (Buphenyl)

  1. Criteria for Initial Approval

    Aetna considers sodium phenylbutyrate (Buphenyl) medicallly necessary for chronic management of urea cycle disorder (UCD), including arginase deficiency, when both of the following criteria are met:

    1. The diagnosis is confirmed by enzymatic, biochemical, or genetic testing; and
    2. The member has elevated plasma ammonia levels at baseline.

    Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

  2. Continuation of Therapy

    Aetna considers continued sodium phenylbutyrate therapy medically necessary for members with chronic management of urea cycle disorder (UCD), including arginase deficiency, who are experiencing benefit from therapy as evidenced by a reduction in plasma ammonia levels from baseline.

Dosage and Administration

Buphenyl (sodium phenylbutyrate)

Buphenyl is supplied as tablets for oral use, and  is indicated for children weighing more than 20 kg and for adults.

The usual total daily dose of Buphenyl Tablets and Powder for persons with urea cycle disorders is 450– 600 mg/kg/day in persons weighing less than 20 kg, or 9.9–13.0 g/m2 /day in larger persons. The safety or efficacy of doses in excess of 20 grams (40 tablets) per day has not been established. 

Source: Horizon Pharma USA, 2020

Experimental and Investigational

  1. Antineoplaston Therapy 

    Aetna considers the following services associated with antineoplaston therapy experimental and investigational (not an all-inclusive list):

    1. Ancillary diagnostic laboratory, x-rays, MRI or CT scans done to monitor antineoplaston therapy
    2. Infusion pump and intravenous supplies for use with the infusion pump
    3. Placement of Hickman catheter.

    Aetna considers oral antineoplaston therapy or associated physician services for administering and monitoring oral antineoplaston treatment experimental and investigational because its effectiveness has not been established.

  2. Sodium Phenylbutyrate (Buphenyl)

    Aetna considers sodium phenylbutyrate experimental and investigational for the following (not an all-inclusive list) because its effectiveness for these indications has not been established:

    1. Alzheimer disease
    2. Amyotrophic lateral sclerosis
    3. Beta-thalassemia
    4. Breast cancer
    5. Duchenne muscular dystrophy
    6. Hepatic encephalopathy associated with cirrhosis
    7. Inclusion-body myositis
    8. Insulin resistance
    9. Beta-cell dysfunction
    10. Ischemic stroke
    11. Maple syrup urine disease
    12. Non-small cell lung cancer (NSCLC)
    13. Oral squamous cell carcinoma
    14. Prostate cancer or other cancers
    15. Sickle cell anemia
    16. Spinal muscular atrophy.


Antineoplaston Therapy

Antineoplastons are a group of naturally occurring peptides, which have been hypothesized to have anti-tumor activity.  Antineoplaston treatment is offered by the Burzynski Research Institute in Houston, Texas, and has long been a controversial treatment for various types of malignancy.

Antineoplaston therapy is not approved by the Food and Drug Administration (FDA) for any indication, and there are no controlled, peer-reviewed clinical trials to validate the effectiveness of antineoplaston therapy for any indication.

Primitive neuroectodermal tumors (PNETs) are often treated with cranio-spinal radiation and chemotherapy.  However, difficulties with conventional therapies can be encountered in very young children, in adult patients at high-risk of complication from standard treatment, as well as in patients with recurrent tumors.  In a phase II clinical trial, Burzynski et al (2005) studied the effect of antineoplaston (ANP) therapy in 13 children, either with recurrent disease or high-risk (median age of 5 years and 7 months, with a range of 1 to 11 years).  Medulloblastoma was diagnosed in 8 patients, pineoblastoma in 3 patients, and other PNET in 2 patients.  Prior therapies included surgery in 12 patients (1 had biopsy only, suboccipital craniotomy), chemotherapy in 6 patients, and radiation therapy in 6 patients.  Six patients had not received chemotherapy or radiation.  The treatment consisted of intravenous infusions of 2 formulations of ANP, A10 and AS2-1, and was administered for an average of 20 months.  The average dosage of A10 was 10.3 g/kg/day and of AS2-1 was 0.38 g/kg/day.  Complete response was accomplished in 23 %, partial response in 8 %, stable disease in 31 %, and progressive disease in 38 % of cases.  Six patients (46 %) survived more than 5 years from initiation of ANP; 5 were not treated earlier with radiation therapy or chemotherapy.  The serious side effects included single occurrences of fever, anemia, and granulocytopenia.  These investigators noted that the percentage of patients' response is lower than for standard treatment of favorable PNET, but long-term survival in poor-risk cases and reduced toxicity makes ANP therapy promising for very young children, patients at high-risk of complication of standard therapy, and patients with recurrent tumors.

In an open label, non- blinded, randomized, phase II clinical trial, Ogata and colleagues (2015) compared the effectiveness of hepatic arterial infusion (HAI) with 5-fluorouracil,with or without antineoplastons as a post-operative therapy for colorectal metastasis to the liver.  A total of 65 patients with histologically confirmed metastatic colon adenocarcinoma in liver, who had undergone hepatectomy, and/or thermal ablation for liver metastases were enrolled between 1998 to 2004.  Patients were randomly assigned to receive systemic antineoplastons (A10-I infusion followed by per-oral AS2-1) plus HAI (AN arm) or HAI alone (control arm) based on the number of metastases and presence/absence of extra-hepatic metastasis at the time of surgery.  Primary end-point was cancer-specific survival (CSS); secondary end-points were relapse-free survival (RFS), status and extent of recurrence, salvage surgery (rate) and toxicity.  Overall survival was not statistically improved (p = 0.105) in the AN arm (n = 32).  Relapse-free survival was not significant (p = 0.343).  Nevertheless, the CSS rate was significantly higher in the AN arm versus the control arm (n = 33) with a median survival time 67 months (95 % confidence interval [CI]: 43 to not calculated) versus 39 months (95 % CI: 28 to 47) (p = 0.037) and 5 year CSS rate 60 % versus 32 % respectively.  Cancer recurred more often in a single organ than in multiple organs in the AN arm versus the control arm.  The limited extent of recurrent tumors in the AN arm meant more patients remained eligible for salvage surgery.  Major adverse effects of antineoplastons were fullness of the stomach and phlebitis.  No serious toxicity, including bone marrow suppression, liver or renal dysfunction, were found in the AN arm.  The authors concluded that antineoplastons (A10 Injection and AS2-1) might be useful as adjunctive therapy in addition to HAI after hepatectomy in colorectal metastases to the liver.

Sodium Phenylbutyrate Therapy

U.S. Food and Drug Administration (FDA)-Approved Indications

  • Buphenyl (sodium phenylbutyrate) indicated as adjunctive therapy in the chronic management of patients with urea cycle disorders involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS). It is indicated in all patients with neonatal-onset deficiency (complete enzymatic deficiency, presenting within the first 28 days of life). It is also indicated in patients with late-onset disease (partial enzymatic deficiency, presenting after the first month of life) who have a history of hyperammonemic encephalopathy. It is important that the diagnosis be made early and treatment initiated immediately to improve survival. Any episode of acute hyperammonemia should be treated as a life-threatening emergency.

Compendial Use

  • Arginase deficiency

Sodium phenylbutyrate removes ammonia from the bloodstream, and has been approved by the FDA for use in patients with urea cycle disorders. The FDA has granted orphan drug designation of sodium phenylbutyrate for the following indications:

  • Treatment of amyotrophic lateral sclerosis (ALS) in combination with tauroursodeoxycholic acid dihydrate (designated July 2017)
  • Treatment for sickling disorders, which include S-S hemoglobinopathy, S-C hemoglobinopathy, and S-thalassemia hemoglobinopathy (designated July 1992)
  • For use as an adjuct to surgery, radiation therapy and chemotherapy for the treatment of patients with primary or recurrent malignant glioma (designated April 1998)
  • Treatment of spinal muscular atrophy (designated January and March 2007)
  • Treatment of urea cycle disorders (designated January 2010 and June 2013)
  • Treatment of maple syrup urine disease (designated August 2014)
  • Treatment of urea cycle disorders: carbamylphosphate synthetase deficiency, ornithine transcarbamylase deficiency, and arginiosuccinic acid synthetase deficiency (designated/approved November 1993)
  • Treatment of Wolfram syndrome in combination with tauroursodeoxycholic acid dihydrate (designated September 2020).

Since sodium phenylbutyrate has been approved by the FDA for treatment of other indications, physicians can prescribe it for patients without any danger of legal sanctions or need for compassionate use exemptions.  However, there is no adequate evidence in the peer-reviewed published medical literature demonstrating that the use of sodium phenylbutyrate improves the clinical outcomes of patients with other indications such as cancers of the prostate, breast, or cancers other than acute promyelocytic leukemia and malignant glioma.  Current evidence is limited to in-vitro and in-vivo studies and phase I studies.  Prospective phase III clinical outcome studies are necessary to determine the clinical effectiveness of sodium phenylbutyrate for cancer.

Sodium phenylbutyrate (Buphenyl) taken orally is metabolized in the liver into a combination of phenylacetylglutamine and phenylacetate, which then enter the bloodstream.  Those 2 chemicals are the prime ingredients of antineoplaston AS2-1.

Per the product information for Buphenyl, in female patients, the most common clinical adverse event reported was amenorrhea/menstrual dysfunction (irregular menstrual cycles), which occurred in 23% of the menstruating patients. Decreased appetite occurred in 4% of all patients. Body odor (probably caused by the metabolite, phenylacetate) and bad taste or taste aversion were each reported in 3% of patients. Other adverse events reported in 2% or fewer patients were: gastrointestinal: abdominal pain, gastritis, nausea and vomiting; constipation, rectal bleeding, peptic ulcer disease, and pancreatitis each occurred in one patient. Hematologic: aplastic anemia and ecchymoses each occurred in one patient. Cardiovascular: arrhythmia and edema each occurred in one patient. Renal: renal tubular acidosis Psychiatric: depression Skin: rash Miscellaneous: headache, syncope, and weight gain Neurotoxicity was reported in cancer patients receiving intravenous phenylacetate, 250–300 mg/kg/day for 14 days, repeated at 4-week intervals. Manifestations were predominately somnolence, fatigue, and lightheadedness; with less frequent headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of a pre-existing neuropathy. These adverse events were mainly mild in severity. The acute onset and reversibility when the phenylacetate infusion was discontinued suggest a drug effect.

Alzheimer Disease

Corbett et al (2013) noted that neurotrophins, such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are believed to be genuine molecular mediators of neuronal growth and homeostatic synapse activity.  However, levels of these neurotrophic factors decreases in different brain regions of patients with Alzheimer disease (AD).  Induction of astrocytic neurotrophin synthesis is a poorly understood phenomenon but represents a plausible therapeutic target because neuronal neurotrophin production is aberrant in AD and other neurodegenerative diseases.  These researchers delineated that NaPB, a FDA-approved oral medication for hyperammonemia, induces astrocytic BDNF and NT-3 expression via the protein kinase C (PKC)-cAMP-response element-binding protein (CREB) pathway.  Sodium phenylbutyrate treatment increased the direct association between PKC and CREB followed by phosphorylation of CREB (Ser(133)) and induction of DNA binding and transcriptional activation of CREB.  Up-regulation of markers for synaptic function and plasticity in cultured hippocampal neurons by NaPB-treated astroglial supernatants and its abrogation by anti-TrkB blocking antibody suggested that NaPB-induced astroglial neurotrophins are functionally active.  Moreover, oral administration of NaPB increased the levels of BDNF and NT-3 in the CNS and improved spatial learning and memory in a mouse model of AD.  The authors concluded that these findings highlighted a novel neurotrophic property of NaPB that may be used to augment neurotrophins in the CNS and improve synaptic function in disease states such as AD.  These findings from a mouse model of AD need to be examined in well-designed human studies.

Amyotrophic Lateral Sclerosis

In a phase II clinical trial, Cudkowicz and colleagues (2009) examined the safety and pharmacodynamics of escalating dosages of sodium phenylbutyrate (NaPB) in patients with amyotrphic lateral sclerosis (ALS).  A total of 40 research subjects at 8 sites enrolled in an open-label study.  Study medication was increased from 9 to 21 g/day.  The primary outcome measure was tolerability.  Secondary outcome measures included adverse events, blood histone acetylation levels, and NaPB blood levels at each dosage.  A total of 26 participants completed the 20-week treatment phase.  Sodium phenylbutyrate was safe and tolerable.  No study deaths or clinically relevant laboratory changes occurred with NaPB treatment.  Histone acetylation was decreased by approximately 50 % in blood buffy-coat specimens at screening and was significantly increased after NaPB administration.  Blood levels of NaPB and the primary metabolite, phenylacetate, increased with dosage.  While the majority of subjects tolerated higher dosages of NaPB, the lowest dose (9 g/day), was therapeutically efficient in improving histone acetylation levels.

Paganoni et al (2020) noted that sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models.  The safety and efficacy of a combination of the 2 compounds in persons with ALS are unknown.  In a randomized, double-blind, multi-center study, these researchers enrolled patients with definite ALS who had had an onset of symptoms within the previous 18 months.  Subjects were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once-daily for 3 weeks and then twice-daily) or placebo.  The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range of 0 to 48, with higher scores indicating better function) through 24 weeks.  Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time-to-death, tracheostomy, or permanent ventilation, or hospitalization.  A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 subjects) or placebo (48 subjects).  In a modified intention-to-treat (ITT) analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95 % confidence interval [CI]: 0.03 to 0.81; p = 0.03).  Secondary outcomes did not differ significantly between the 2 groups; AEs with the active drug were mainly gastro-intestinal (GI).  Subjects who received sodium phenylbutyrate-taurursodiol were more likely than those who received placebo to discontinue the trial regimen owing to AEs and to have early GI AEs. The authors concluded that sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks.  Secondary outcomes were not significantly different between the 2 groups.  Moreover, these researchers stated that longer and larger trials are needed to examine the safety and efficacy of sodium phenylbutyrate-taurursodiol in patients with ALS. 

Paganoni et al (2021) stated that an orally administered, fixed-dose co-formulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase-II clinical trial in ALS (CENTAUR).  These investigators reported results of a long-term survival analysis of participants in CENTAUR.  In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo.  Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension.  An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants.  Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis.  Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR.  Median overall survival (OS) was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio [HR], 0.56; 95 % CI: 0.34 to 0.92; p = 0.023).  Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo.  The authors concluded that combined with results from CENTAUR, these findings suggested that PB-TURSO has both functional and survival benefits in ALS. 

The authors stated that their analysis was limited by a relatively small sample size but was strengthened by inclusion of the entire randomized sample from CENTAUR and assessment of vital status up to 35 months after randomization.  Confirmation of vital status was facilitated by the use of a participant locating service, a novel approach that differentiated their survival analysis from those in other ALS studies.  Data on vital status that were incomplete because of discontinuation or loss to follow‐up may bias the results of survival analyses.  Participant tracing has been used in clinical trials to improve the accuracy of results by tracking long‐term outcomes for as many trial participants as possible.  This method may be particularly useful in trials with large drop-out rates, such as those in ALS, by accounting for potentially differing outcomes between participants who dropped out and those who continued on in the study.  The confirmation of vital status for all but 2 randomized participants, regardless of duration of follow‐up, provided the basis for statistically robust and comprehensive overall survival analyses.

An UpToDate overview of "Disease-modifying treatment of amyotrophic lateral sclerosis" (Galvez-Jimenez et al., 2021) lists “Tauroursodeoxycholic acid (TUDCA)” as an experimental therapy.  It states that “TUDCA has also been coformulated with sodium phenylbutyrate, a histone deacetylase inhibitor that reduces an adaptive stress response in the endoplasmic reticulum.  In a trial of 135 ALS patients, those treated with TUDCA with sodium phenylbutyrate showed a slower rate of functional decline (ALSFRS-R; 0.42 points per month, 95 % CI 0.03-0.81).  However, in a 24-week follow-up, change in vital capacity and decline in muscle strength showed only a trend in a favorable direction with treatment.  There was no change in serum biomarkers or time to death”.

Duchenne Muscular Dystrophy

Begam and colleagues (2016) performed a placebo-controlled pre-clinical study to determine if sodium 4-phenylbutyrate (4PB) can reduce contraction-induced myofiber damage in the mdx mouse model of Duchenne muscular dystrophy (DMD).  At 72 hours post-eccentric contractions, 4PB significantly increased contractile torque and reduced myofiber damage and macrophage infiltration.  The authors concluded that 4PB might modify disease severity in patients with DMD.

An UpToDate overview on "Duchenne and Becker muscular dystrophy: Management and prognosis" (Darras, 2020) does not provide a recommendation for treatment with sodium phenylbutyrate.

Hepatic Encephalopathy associated with Cirrhosis

Rahimi and Rockey (2016) noted that hepatic encephalopathy (HE) is a major complication in patients with decompensated cirrhosis, leading to higher re-admission rates causing a profound burden of disease and considerable health care costs.  Because ammonia is thought to play a crucial role in the pathogenesis of HE, therapies directed at reducing ammonia levels are now being aggressively developed.  Ammonia scavengers such as AST-120 (spherical carbon adsorbent), glycerol phenylbutyrate (GPB), sodium phenylacetate or sodium benzoate, and ornithine phenylacetate have been used to improve HE symptoms.  A new approach, bowel cleansing with polyethylene glycol 3350, appeared to be a promising therapy, with a recent study demonstrating a more rapid improvement in overt HE (at 24 hours after treatment) than lactulose.  Extracorporeal devices, although now used primarily in research settings, have also been utilized in patients with refractory HE, but are not approved for clinical management.  The authors stated that available evidence suggested that GPB decreased the likelihood of hospitalization for cirrhotic patients with recurrent HE when compared with placebo, by lowering ammonia levels.  Overall, GPB was considered to be safe among cirrhotic patients with recurrent HE; however, larger randomized controlled trials (RCTs) are needed to further establish the role of GPB in patients with HE.

Weiss and colleagues (2018) stated that HE influences short-term and long-term prognoses.  Recently, GPB has shown to be effective in preventing the occurrence of HE in a RCT.  In a preliminary study, these researchers examined the benefits of SPB in cirrhotic patients admitted to intensive care unit (ICU) for overt HE, in terms of ammonia levels decrease, neurological improvement, and survival.  Cirrhotic patients who presented with overt HE, ammonia levels greater than 100 μmol/L, and did not display any contra-indication were included; SPB was administered at 200 mg/kg/day.  Control group included historical controls treated by standard therapy, matched for age, sex, MELD score, and severity of HE.  A total of 18 patients were included and treated with SPB (age of 59 years [45 to 68], male gender: 15 [83 %], Child-Pugh B: 8 [44 %], Child-Pugh C: 10 [56 %], and MELD score of 16 [13 to 23]).  Ammonia levels significantly decreased in the SPB as compared to the control group from inclusion to 12 hours and from inclusion to 48 hours (p = 0.0201 and p = 0.0230, respectively).  The proportion of patients displaying neurological improvement was only higher in the SPB-treated group as compared to controls at ICU discharge (15 [83 %] versus 9 [50 %], p = 0.0339).  ICU discharge survival was significantly higher in patients treated with SPB (17 [94 %] versus 9 [50 %], p = 0.0017).  The authors concluded that in cirrhotic patients with overt HE, SPB could be effective in reducing ammonia levels and might be effective in improving neurological status and ICU discharge survival.  However, they stated that more extensive data, especially a RCT, are needed.

Inclusion-Body Myositis

Nogalska et al (2014) stated that sporadic inclusion-body myositis (s-IBM) is a severe, progressive muscle disease for which there is no enduring treatment.  Pathologically characteristic are vacuolated muscle fibers having: accumulations of multi-protein aggregates, including amyloid-β (Aβ)42 and its toxic oligomers; increased γ-secretase activity; and impaired autophagy.  Cultured human muscle fibers with experimentally-impaired autophagy recapitulate some of the s-IBM muscle abnormalities, including vacuolization and decreased activity of lysosomal enzymes, accompanied by increased Aβ42, Aβ42 oligomers, and increased γ-secretase activity.  Sodium phenylbutyrate is an orally bioavailable small molecule approved by the FDA for treatment of urea-cycle disorders.  These researchers described that NaPB treatment reverses lysosomal dysfunction in an in-vitro model of IBM, involving cultured human muscle fibers.  Treatment with NaPB improved lysosomal activity, decreased Aβ42 and its oligomers, decreased γ-secretase activity, and virtually prevented muscle-fiber vacuolization.  The authors concluded that NaPB might be considered a potential treatment of s-IBM patients.  These in-vitro findings need to be examined in well-designed human studies.

Insulin Resistance

Xiao et al (2011) noted that chronically elevated free fatty acids contribute to insulin resistance and pancreatic beta (β)-cell failure.  Among numerous potential factors, the involvement of endoplasmic reticulum (ER) stress has been postulated to play a mechanistic role.  These researchers examined the efficacy of NaPB, a drug with known capacity to reduce ER stress in animal models and in-vitro, on lipid-induced insulin resistance and β-cell dysfunction in humans.  A total of 8 over-weight or obese non-diabetic men underwent 4 studies each, in random order, 4 to 6 weeks apart.  Two studies were preceded by 2 weeks of oral NaPB (7.5 g/d), followed by a 48-hr i.v. infusion of intralipid/heparin or saline, and 2 studies were preceded by placebo treatment, followed by similar infusions.  Insulin secretion rates (ISR) and sensitivity (SI) were assessed after the 48-hr infusions by hyper-glycemic and hyper-insulinemic-euglycemic clamps, respectively.  Lipid infusion reduced SI, which was significantly ameliorated by pre-treatment with NaPB.  Absolute ISR was not affected by any treatment; however, NaPB partially ameliorated the lipid-induced reduction in the disposition index (DI = ISR × SI), indicating that NaPB prevented lipid-induced β-cell dysfunction.  The authors concluded that these findings suggest that NaPB may provide benefits in humans by ameliorating the insulin resistance and β-cell dysfunction induced by prolonged elevation of free fatty acids.  These results need to be validated by well-designed studies.

Ischemic Stroke

Yang and associates (2017) noted that oxidative stress and mitochondrial dysfunction play critical roles in ischemia/reperfusion (I/R) injury; DJ-1 is an endogenous anti-oxidant that attenuates oxidative stress and maintains mitochondrial function, likely acting as a protector of I/R injury.  These researchers examined the protective effect of a possible DJ-1 agonist, SPB, against I/R injury by protecting mitochondrial dysfunction via the up-regulation of DJ-1 protein.  Pre-treatment with SPB up-regulated the DJ-1 protein level and rescued the I/R injury-induced DJ-1 decrease about 50 % both i- vivo and in-vitro; SPB also improved cellular viability and mitochondrial function and alleviated neuronal apoptosis both in cell and animal models; these effects of SPB were abolished by DJ-1 knockdown with siRNA.  Furthermore, SPB improved the survival rate approximately 20 % and neurological functions, as well as reduced about 50 % of the infarct volume and brain edema, of middle cerebral artery occlusion mice 23 hours after re-perfusion.  The authors concluded that these findings demonstrated that pre-conditioning of SPB possessed a neuroprotective effect against cerebral I/R injury by protecting mitochondrial function dependent on the DJ-1 up-regulation, suggesting that DJ-1 is a potential therapeutic target for clinical ischemic stroke.

Maple Syrup Urine Disorder

Maple syrup urine disorder (MSUD) is a rare condition that occurs in approximately 1 in 86,800 to 185,000 live births. MSUD is a disorder affecting the aliphatic or branched-chain amino acids, and caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase complex (BCKDC), the second enzyme of the metabolic pathway of the three branched-chain amino acids, leucine, isoleucine, and valine. It is characterized by psychomotor delay, feeding problems, and a maple syrup odor of the urine (Bodamer, 2018).

Brunetti-Pierri et al (2010) stated that therapy with sodium phenylacetate/benzoate or NaPB in urea cycle disorder patients has been associated with a selective reduction in branched-chain amino acids (BCAA) in spite of adequate dietary protein intake.  Based on this clinical observation, these researchers examined the potential of phenylbutyrate treatment to lower BCAA and their corresponding α-keto acids (BCKA) in patients with classic and variant late-onset forms of maple syrup urine disease (MSUD).  They also performed in-vitro and in-vivo experiments to elucidate the mechanism for this effect.  These investigators found that BCAA and BCKA are both significantly reduced following phenylbutyrate therapy in control subjects and in patients with late-onset, intermediate MSUD.  In-vitro treatment with phenylbutyrate of control fibroblasts and lymphoblasts resulted in an increase in the residual enzyme activity, while treatment of MSUD cells resulted in the variable response that did not simply predict the biochemical response in the patients.  In-vivo phenylbutyrate increases the proportion of active hepatic enzyme and unphosphorylated form over the inactive phosphorylated form of the E1α subunit of the branched-chain α-keto acid dehydrogenase complex (BCKDC).  Using recombinant enzymes, these researchers showed that phenylbutyrate prevents phosphorylation of E1α by inhibition of the BCKDC kinase to activate BCKDC overall activity, providing a molecular explanation for the effect of phenylbutyrate in a subset of MSUD patients.  The authors concluded that phenylbutyrate treatment may be a valuable treatment for reducing the plasma levels of neurotoxic BCAA and their corresponding BCKA in a subset of MSUD patients and studies of its long-term efficacy are indicated.

Burrage et al (2014) stated that sodium phenylbutyrate (NaPBA) is a commonly used medication for the treatment of patients with urea cycle disorders (UCDs).  Previous reports involving small numbers of patients with UCDs have shown that NaPBA treatment can result in lower plasma levels of the branched-chain amino acids (BCAA) but this has not been studied systematically.  From a large cohort of patients (n = 553) with UCDs enrolled in the Longitudinal Study of Urea Cycle Disorders, a collaborative multi-center study of the Urea Cycle Disorders Consortium, these researchers examined if treatment with NaPBA leads to a decrease in plasma BCAA levels.  Their analysis showed that NaPBA use independently affected the plasma BCAA levels even after accounting for multiple confounding co-variates.  Moreover, NaPBA use increased the risk for BCAA deficiency.  This effect of NaPBA appeared specific to plasma BCAA levels, as levels of other essential amino acids are not altered by its use.  This study, in an unselected population of UCD subjects, is the largest to analyze the effects of NaPBA on BCAA metabolism and potentially has significant clinical implications.  These findings indicated that plasma BCAA levels should to be monitored in patients treated with NaPBA since patients taking the medication are at increased risk for BCAA deficiency.  On a broader scale, these findings could open avenues to explore NaPBA as a therapy in maple syrup urine disease and other common complex disorders with dysregulation of BCAA metabolism.

An UpToDate review on “Overview of maple syrup urine disease” (Bodamer, 2018) states that "treatment of urea cycle disorders with sodium phenylacetate/benzoate or sodium phenylbutyrate results in a reduction of branched-chain amino acids. Phenylbutyrate therapy reduced plasma levels of branched-chain amino acids in patients with intermediate MSUD, although additional studies are needed."

Non-Small-Cell Lung Cancer

Al-Keilani and colleagues (2018) stated that chemotherapy resistance is the main cause of the marginal clinical benefit of platinum-based chemotherapy and tyrosine kinase inhibitors in advanced non-small-cell lung cancer (NSCLC).  Thus, the identification of new therapeutic agents that can enhance the sensitivity of these drugs is of clinical importance.  Histone deacetylase inhibitors (HDACIs) are emerging as new promising agents with strong anti-proliferative effects against different types of cancers.  These investigators examined the synergistic potential of SPB added on top of standard chemotherapy used against NSCLC.  They evaluated the ability of SPB to overcome the resistance of NSCLC cell lines to cisplatin, gefitinib, and erlotinib.  MTT cell proliferation assay was used to measure the anti-cancer effects of cisplatin, erlotinib, or gefitinib alone or combined with various concentrations of SPB against A549, Calu1, and H1650 NSCLC cell lines.  Synergism was estimated by measuring synergy value (R), which is equal to the ratio of IC50 (the concentration of an inhibitor where the response (or binding) is reduced by half) of each primary drug alone divided by combination IC50s.  Student's t-test analysis was used to evaluate the potential differences between IC50 values.  ANOVA followed by Tukey's post-hoc was used to evaluate the potential differences among monotherapy and combination treatment groups.  Analyses were performed using R 3.3.2 software; p-value < 0.05 was considered to be statistically significant.  Sodium phenylbutyrate was shown to inhibit the growth of A549, Calu1, and H1650 cell lines in a dose-dependent manner (IC50 10, 8.53, and 4.53 mM, respectively).  Furthermore, the addition of SPB along with cisplatin, erlotinib, or gefitinib to A549, Calu1, and H1650 cell lines resulted in a synergistic anti-proliferative effect against the 3 NSCLC cell lines (R > 1.6, p-value < 0.05), thus suggesting that SPB could potentiate the effect of cisplatin, erlotinib, and gefitinib on A549, Calu1, and H1650 cell lines.  The authors concluded that current findings suggested a potential role of SPB as a sensitizing agent in NSCLC.

Oral Squamous Cell Carcinoma

Qian and colleagues (2018) noted that SPB as a salt of 4-phenylbutyric acid (4-PBA) has been reported to be an ammonia scavenger, histone deacetylase inhibitor, and an endoplasmic reticulum stress inhibitor in various diseases, including neurological diseases, inflammatory disorders, and carcinogenesis.  Although phenylbutyrate showed effective anti-tumor properties in many cancers, its role in oral squamous cell carcinoma (OSCC) remains further characterized.  In this study, the OSCC cell lines CAL27, HSC3, and SCC4 were treated with a series of doses of SPB for different times.  The IC50 of 3 cell lines for SPB was determined to be 4.0, 3.7, and 3.0 mM.  The CCK-8 assay indicated that the treatment of SPB induced continuous inhibition of cell vitality of 3 cell lines.  Apoptosis was assessed by Hoechst assay that showed that SPB could significantly promote cell apoptosis.  Moreover, the apoptosis-related pathway was analyzed, and the results showed that the expression of anti-apoptosis factor BCL-2 was down-regulated by SPB but the cleavage of caspase-3 was increased.  Meanwhile, it was found that SPB also impaired the migration and invasion of OSCC cells in-vitro.  Mechanistically, the transforming growth factor-β (TGFB) related epithelial-mesenchymal transition (EMT) was inhibited by SPB with decreased mesenchymal marker N-cadherin and increased epithelial marker E-cadherin.  Furthermore, the anti-tumor effect of SPB in-vivo was also demonstrated.  The administration of SPB induced remarkably tumor regression with decreased tumor volume, and the TGFB level and EMT phenotype in-vivo were also inhibited.  These data demonstrated that the treatment of SPB could function as anti-tumor therapeutics for OSCC.

Sickle Cell Anemia

Hines and colleagues (2008) stated that increasing hemoglobin F (HbF) appears to be beneficial for patients with sickle cell anemia.  These researchers previously reported that daily, oral sodium phenylbutyrate (OSPB) induces HbF synthesis in pediatric as well as adult patients with hemoglobin SS (HbSS).  The high doses and need for daily therapy, however, have limited its use.  In this study, these investigators reported a patient treated with pulsed-dosing of OSPB for over 3 years.  This patient developed a modest, but sustained elevation in HbF over the course of therapy without side effects.  Although larger studies are needed, this case demonstrates that pulsed-dosing with OSPB enhances HbF synthesis.  Perrine (2008) noted that arginine butyrate, erythropoietin, hydroxyurea, sodium phenylbutyrate, and 5-azacytidine/decitabine have shown efficacy in about 40 % to 70 % of sickle cell anemia and beta-thalassemia patients.  Many responses, although significant, were not completely ameliorating of symptoms or pathology, and trials of new agents with dual actions, or drug combinations, are needed.

Solid Tumors

In a phase I clinical trial, Lin and associates (2009) determined the minimal effective dose and optimal dose schedule for 5-azacytidine (5-AC) in combination with sodium phenylbutyrate in patients with refractory solid tumors.  The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied.  Three dosing regimens were studied in 27 patients with advanced solid tumors, and toxicity was recorded.  The pharmacokinetics of the combination of drugs was evaluated.  Repeat tumor biopsies and peripheral blood mononuclear cells (PBMC) were analyzed to evaluate epigenetic changes in response to therapy.  Epstein Barr virus titers were evaluated as a surrogate measure for gene re-expression of epigenetic modulation in PBMC.  The 3-dose regimens of 5-AC and phenylbutyrate were generally well-tolerated and safe.  A total of 48 cycles was administrated to 27 patients.  The most common toxicities were bone marrow suppression-related neutropenia and anemia, which were minor.  The clinical response rate was disappointing for the combination of agents.  One patient showed stable disease for 5 months whereas 26 patients showed progressive disease as the best tumor response.  The administration of sodium phenylbutyrate and 5-AC did not seem to alter the pharmacokinetics of either drug.  Although there were individual cases of targeted DNA methyltransferase activity and histone H3/4 acetylation changes from paired biopsy or PBMC, no conclusive statement can be made based on these limited correlative studies.  The authors concluded that the combination of 5-AC and sodium phenylbutyrate across 3-dose schedules was generally well-tolerated and safe, yet lacked any real evidence for clinical benefit.

Spinal Muscular Atrophy

Brahe et al (2005) stated that spinal muscular atrophy (SMA) is caused by insufficient levels of survival motor neuron (SMN) protein.  These researchers found that sodium 4-phenylbutyrate enhances SMN gene expression in-vitro, and that oral administration of sodium 4-phenylbutyrate significantly increases SMN expression in leukocytes of SMA patients.  They noted that this finding provides a rationale to further investigate the potential therapeutic effects of sodium 4-phenylbutyrate on patients with SMA.

Wirth et al (2006) stated that the molecular genetic basis of SMA is the loss of function of SMN1.  The SMN2 gene, a nearly identical copy of SMN1, has been detected as a promising target for SMA therapy.  Both genes encode identical proteins, but differ markedly in their splicing patterns with SMN1 produces full-length (FL)-SMN transcripts only, while the majority of SMN2 transcripts lacks exon 7.  Transcriptional SMN2 activation or modulation of its splicing pattern to increase FL-SMN levels is thought to benefit patients with SMA.  Drugs such as valproic acid, phenylbutyrate, sodium butyrate, M344 and SAHA can stimulate the SMN2 gene transcription and/or restore the splicing pattern, thereby raising the levels of FL-SMN2 protein.  Phase II clinical trials have shown promising results.  However, phase III double-blind placebo-controlled studies are needed to prove the effectiveness of these drugs.

An UpToDate overview on "Spinal muscular atrophy" (Bodamer, 2020) does not provide a recommendation for use of sodium phenlbutyrate for treatment of spinal muscular atrophy.

Urea Cycle Disorders

Haberle and colleagues (2012) stated that urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle (5 core enzymes, 1 activating enzyme and 1 mitochondrial ornithine/citrulline antiporter) with an estimated incidence of 1:8.000.  Patients present with hyper-ammonemia either shortly after birth (approximately 50 %) or, later at any age, leading to death or to severe neurological handicap in many survivors.  Despite the existence of effective therapy with alternative pathway therapy and liver transplantation, outcomes remain poor.  This may be related to under-recognition and delayed diagnosis due to the non-specific clinical presentation and insufficient awareness of health care professionals because of disease rarity.  These guidelines aimed at providing a trans-European consensus to: guide practitioners, set standards of care and help awareness campaigns.  To achieve these goals, the guidelines were developed using a Delphi methodology, by having professionals on UCDs across 7 European countries to gather all the existing evidence, scored it according to the SIGN evidence level system and drew a series of statements supported by an associated level of evidence.  The guidelines were revised by external specialist consultants, unrelated authorities in the field of UCDs and practicing pediatricians in training.  Although the evidence degree did hardly ever exceed level C (evidence from non-analytical studies like case reports and series), it was sufficient to guide practice on both acute and chronic presentations, addressed diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues.  Also, it identified knowledge voids that must be filled by future research.  The authors believed these guidelines will help to harmonize practice, set common standards and spread good practices with a positive impact on the outcomes of UCD patients.  These investigators stated that ammonia scavengers sodium benzoate, sodium phenylacetate or PBA are the mainstay drugs for bypassing the urea cycle, by conjugation of benzoate with glycine to generate hippurate, or of phenylacetate (phenylbutyrate is a precursor of phenylacetate) with glutamine to generate phenylacetylglutamine.  These conjugates are excreted in the urine.

According to the prescribing information, buphenyl (sodium phenylbutyrate) is indicated as adjunctive therapy in the chronic management of patients with UCDs involving deficiencies of carbamylphosphate synthetase, ornithine transcarbamylase, or argininosuccinic acid synthetase.  It is indicated in all patients with neonatal-onset deficiency (complete enzymatic deficiency, presenting within the first 28 days of life).  It is also indicated in patients with late-onset disease (partial enzymatic deficiency, presenting after the 1st month of life) who have a history of hyper-ammonemic encephalopathy.  It is important that the diagnosis be made early and treatment initiated immediately to improve survival.  Any episode of acute hyper-ammonemia should be treated as a life-threatening emergency.

Arginase deficiency is considered a urea cycle disorder (UCD). Lee (2020) states that UCDs, except for arginase deficiency, result in hyperammonemia and life-threatening illnesses, and that IV fluid administration, rather than hemodialysis, is often sufficient therapy in patients with arginase deficiency who present with milder hyperammonemia. However, if hyperammonemia is persistent, >200 micromol/L, or showing rapid increase, then pharmacologic therapy to remove ammonia should be instituted. "Pharmacologic therapy for hyperammonemia consists of initial IV administration of a combination preparation of sodium phenylacetate-sodium benzoate (Ammonul) followed by maintenance with oral sodium phenylbutyrate (Buphenyl) or glycerol phenylbutyrate (Ravicti) in all patients except those with NAGS deficiency without severe hyperammonemia. These drugs scavenge ammonia by creating an alternate pathway to excrete nitrogen precursors. Administration of arginine is also necessary for all UCDs except arginase deficiency (argininemia) because deficiencies of these enzymes prevent the formation of arginine, resulting in a catabolic state."

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Antineoplaston therapy - no specific code:

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C00.0 - D49.9 Neoplasms
G12.21 Amyotrophic lateral sclerosis
Z51.0 Encounter for antineoplastic radiation therapy
Z51.11 - Z51.12 Encounter for antineoplastic chemotherapy and immunotherapy

Sodium phenylbutyrate - no specific code:

Other CPT codes related to the CPB:

82140 Ammonia

ICD-10 codes covered if selection criteria are met:

E72.20 – E72.29 Disorders of urea cycle metabolism
E72.4 Disorders of ornithine metabolism

ICD-10 codes not covered for indications listed in the CPB:

C00.0 - C70.9
C73 - C92.32
C92.50 - C96.9
Malignant neoplasm [other than promyelocytic leukemia and malignant glioma]
D56.0 - D56.9 Thalassemias
D57.00 - D57.819 Sickle-cell disease
E71.0 Maple syrup urine disease
E88.81 Metabolic syndrome [insulin resistance]
G12.0 - G12.9 Spinal muscular atrophy
G30.0 - G30.9 Alzheimer's disease
G71.01 Duchenne or Becker muscular dystrophy
G72.41 Inclusion body myositis [IBM]
I63.00 - I63.9 Cerebral infarction [ischemic stroke]
K72.01, K72.11, K72.91 Hepatic encephalopathy

The above policy is based on the following references:

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