prior authorization review panel mco policy submission · 2020-07-23 · ancillary diagnostic...

Prior Authorization Review Panel MCO Policy Submission

A separate copy of this form must accompany each policy submitted for review. Policies submitted without this form will not be considered for review.

Plan: Aetna Better Health Submission Date:06/01/2020

Policy Number: 0240 Effective Date: Revision Date: 03/10/2020

Policy Name: Antineoplaston Therapy and Sodium Phenylbutyrate

Type of Submission – Check all that apply:

New Policy Revised Policy* Annual Review – No Revisions Statewide PDL

*All revisions to the policy must be highlighted using track changes throughout the document.

Please provide any clarifying information for the policy below:

CPB 0240 Antineoplaston Therapy and Sodium Phenylbutyrate

This CPB has been revised to modify the continuation of treatment criteria for sodium phenylbutyrate.

Name of Authorized Individual (Please type or print):

Benjamin Alouf, MD, MBA, FAAP

Signature of Authorized Individual:

Proprietary Revised July 22, 2019

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Antineoplaston Therapy and Sodium Phenylbutyrate - Medical Clinical Policy Bulletins | ... Page 1 of 32

(https://www.aetna.com/)

Antineoplaston Therapy andSodium Phenylbutyrate

Policy History

Last Review

03/10/2020

Effective: 04/07/1998

Next

Review: 01/28/2021

Review History

Definitions

Ad d i t ion al Information

Clinical Policy Bulletin

Notes

Number: 0240

Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.

I. 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.

II. Aetna considers services associated with antineoplaston

therapy experimental and investigational, including:

▪ Ancillary diagnostic laboratory, x-rays, MRI or CT

scans done to monitor antineoplaston therapy

▪ Infusion pump and intravenous supplies for use with

the infusion pump

▪ Placement of Hickman catheter.

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https://www.aetna.com/


III. 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.

IV. Aetna considers sodium phenylbutyrate medically

necessary for the treatment of urea cycle

disorders when the diagnosis is confirmed by

enzymatic, biochemical, or genetic testing.

V. Aetna considers continued treatment with sodium

phenylbutyrate medically necessary for members who

are experiencing benefit from therapy as evidenced by

a reduction in plasma ammonia levels from baseline.

VI. Aetna considers sodium phenylbutyrate experimental

and investigational for the treatment of breast cancer,

non-small-cell lung cancer, oral squamous cell

carcinoma, prostate cancer or other cancers because its

effectiveness for these indications has not been

established.

VII. Aetna considers sodium phenylbutyrate experimental

and investigational for the treatment of Alzheimer

disease, amyotrophic lateral sclerosis, beta-thalassemia,

Duchenne muscular dystrophy, hepatic encephalopathy

associated with cirrhosis, inclusion-body myositis,

insulin resistance and beta-cell dysfunction, ischemic

stroke, maple syrup urine disease, sickle cell anemia,

spinal muscular atrophy, and for all other indications

because its effectiveness for these indications has not

been established.

Dosing Recommendations

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The usual total daily dose of Buphenyl Tablets and Powder for

patients with urea cycle disorders is 450– 600 mg/kg/day in

patients weighing less than 20 kg, or 9.9–13.0 g/m 2 /day in

larger patients. The safety or efficacy of doses in excess of 20

grams (40 tablets) per day has not been established.

Source: Buphenyl prescribing information.

Background

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

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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.

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.

Sodium phenylbutyrate removes ammonia from the

bloodstream, and has been approved by the FDA for use in

patients with urea cycle disorders. It also has received an

orphan drug designation by the FDA for treatment of acute

promyelocytic leukemia. Sodium phenylbutyrate was given an

orphan drug designation by the FDA for use as an adjunct to

surgery, radiation therapy, and chemotherapy for treatment of

patients with primary or recurrent malignant glioma.

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 cancers of the

prostate, breast, or cancers other than acute promyelocytic

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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.

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.

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,

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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.

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

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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.

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.

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

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to elucidate the mechanism for this effect. These

investigators found that BCAA and BCKA are both significantly

reduced following phen ylbutyrate 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 t reatment 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.

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 i n 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,

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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 t hat 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 f atty acids. These

results need to be validated by well-designed studies.

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 thatNaPB, 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

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Antineoplaston Therapy and Sodium Phenylbutyrate - Medical ClinicalPolicy Bulletin... Page 10 of 32

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.

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 f ibers 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 t hat NaPB treatment

reverses lysosomal dysfunction in an in-vitro model of IBM,

involving cultured human m uscle f ibers. 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.

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

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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, 2014) and other reviews of MSUD

(Strauss, et al., 2013;McKusick, et al., 2013) do not mention

sodium phenylbutyrate as a therapeutic option.

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

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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 s urgery. 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 t o HAI after

hepatectomy in colorectal metastases to the liver.

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.

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.

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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

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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.

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.

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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 thatmustbe

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,

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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.

Sodium Phenylbutyrate for the Treatment of 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,

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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.

Sodium Phenylbutyrate for the Treatment of 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

Proprietary


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.

CPT Codes / HCPCS Codes / ICD-10 Codes

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

Code Code Description

Antineoplaston therapy - no specific code:

ICD-10 codes not covered for indications listed in the CPB ( no t all-inclusive):

C 00.0 -

D49.9

Neoplasms

G12.21 Amyotrophic lateral sclerosis

Z51.0 Encounter for antineoplastic radiation therapy

Proprietary



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

E 72.4 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

E 71.0 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]

Proprietary



I63.00 -

I 63.9

Cerebral infarction [ischemic stroke]

K72.01,

K72.11,

K72.91

Hepatic encephalopathy

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Proprietary

Antineoplaston Therapy and Sodium Phenylbutyrate - Medical Clinical Policy Bulletin... Page 21 of 32

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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan

benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care

services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors

in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely

responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is

subject to change.

Copyright © 2001-2020 Aetna Inc.

Proprietary

AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0240 Antineoplaston

Therapy and Sodium Phenylbutyrate For the Pennsylvania Medical Assistance plan sodium phenylbutyrate is also considered medically necessary for the treatment of urea cycle disorders.

For the Pennsylvania Medical Assistance Plan, effective 1/1/20 medication coverage requests

for medications on the statewide preferred drug list will be reviewed using the guidelines for

determination of medical necessity developed by the Pennsylvania Department of Human

Services.

www.aetnabetterhealth.com/pennsylvania revised 03/10/2020 Proprietary Proprietary

http://www.aetnabetterhealth.com/pennsylvania

prior authorization review panel mco policy submission · 2020-07-23 · ancillary diagnostic...

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