All’s fair in Drugs and War

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GlaxoSmithKline
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$3 BILLION
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7/2/2012
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(4/1998 – 8/2003)
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United States alleges GSK participated in
preparing
publishing
distributing

misleading medical journal article that misreported that clinical trial of drug demonstrated efficacy in treatment when study failed to demonstrate efficacy
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At same time, United States alleges, GSK didn’t make available data from 2 other studies in which drug also failed to demonstrate efficacy
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(2001 – 2007)
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United States alleges GSK failed to include certain safety data about drug in reports to FDA meant to allow FDA to determine if drug continues to be safe for approved indications and to spot drug safety trends
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missing information included data regarding certain post-marketing studies
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data regarding 2 studies undertaken in response to European regulators’ concerns about safety of drug
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United States alleges GSK stated drug had positive cholesterol profile despite having no well-controlled studies to support that message
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Johnson & Johnson (J&J) and subsidiaries, Janssen Pharmaceuticals Inc. and Scios Inc.
Janssen Pharmaceutica Products, L.P.
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$2.2 BILLION +
——————————————————————
11/4/2013, Monday
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Johnson & Johnson (J&J) and Janssen
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complaint alleges J&J and Janssen were aware drug posed serious health risks, but companies downplayed these risks
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For example, when J&J study of drug showed significant risk of strokes and other adverse events in patients, complaint alleges Janssen combined study data with other studies to make it appear there was lower overall risk of adverse events
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year after J&J received results of 2nd study confirming increased safety risk for patients taking drug, but hadn’t published data, one physician who worked on study cautioned Janssen
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“[a]t this point, so long after [the study] has been completedwe must be concerned that this gives the strong appearance that Janssen is purposely withholding the findings.”
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complaint alleges Janssen knew patients taking drug had increased risk, but nonetheless promoted drug as “uncompromised by safety concerns
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When Janssen received initial results of studies indicating drug posed same risk as other antipsychotics, complaint alleges company retained outside consultants to re-analyze study results and ultimately published articles stating drug was actually associated with lower risk
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J&J and another of its subsidiaries, Scios Inc.
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8/2001 – FDA approved drug to treat patients with acutely decompensated congestive heart failure who have shortness of breath at rest or with minimal activity
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approval based on study involving hospitalized patients experiencing severe heart failure who received infusions of drug over average 36-hour period
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complaint alleged Scios had no sound scientific evidence supporting medical necessity of outpatient infusions and misleadingly used small pilot study to encourage serial outpatient use of drug
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Abbott Laboratories Inc.
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$1.5 BILLION
——————————————————————
5/7/2012, Monday
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(2001 – 2006)
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company marketed drug in combination with atypical antipsychotic drugs even after its clinical trials failed to demonstrate adding drug was any more effective than atypical antipsychotic alone for that use
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1999 – forced to discontinue clinical trial of drug due to increased incidence of adverse events, including
somnolence
dehydration
anorexia
experienced by study participants administered drug
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funded 2 studies of use of drug
both failed to meet main goals established for the study
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When 2nd study failed to show statistically significant treatment difference between antipsychotic drugs used in combination with drug and antipsychotic drugs alone, waited nearly 2 years to notify sales force about study results and another 2 years to publish results
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AstraZeneca LP / AstraZeneca Pharmaceuticals LP
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$520 MILLION
——————————————————————
4/27/2010, Tuesday
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engaged doctors to conduct studies on unapproved uses of drug
——————————————————————
recruited doctors to serve as authors of articles that were ghostwritten by medical literature companies and about studies doctors in question didn’t conduct
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then used
studies
articles

as basis for promotional messages about unapproved uses of drug
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REFERENCE:
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11/26/2013 – United States Department of Justice (DOJ) versus BIG Pharma: BIG Pharma fought the law, and the law won ?:
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https://stanislawrajmundburzynski.wordpress.com/2013/11/26/united-states-department-of-justice-versus-big-pharma-big-pharma-fought-the-law-and-the-law-won/
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Antineoplastons: Adverse Effects

National Cancer Institute (NCI) at the National Institutes of Health (NIH)
Antineoplastons
Adverse Effects:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page6
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http://www.burzynskiclinic.com/scientific-publications.html
Interim Reports on Clinial Trials:

1. 10/2003

NEURO-ONCOLOGY

Burzynski, S.R., Weaver, R.A., Bestak, M., Lewy, R.I., Janicki, T.J., Jurida, G.F., Paszkowiak, J.K., Szymkowski, B.G., Khan, M.I.

Phase II study of Antineoplastons A10 and AS2-1 (ANP) in children with recurrent and progressive MULTICENTRIC GLIOMA

A preliminary report
http://www.burzynskiclinic.com/images/stories/Publications/970.pdf
Neuro-Oncology. 2003; 5: 358
Volume 5 Issue 4 October 2003

12 patients

10 evaluable

1 – serious (grade 3) toxicity: reversible tinnitus
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Interim Reports on Clinial Trials:

16. 2003

DRUGS IN R&D
Drugs in R and D
(Drugs in Research and Development)

BT-11

BRAIN STEM GLIOMA

Phase II study of antineoplaston A10 and AS2-1 in patients with recurrent diffuse intrinsic BRAIN STEM GLIOMA:

a preliminary report.
http://www.ncbi.nlm.nih.gov/pubmed/12718563
Burzynski, S.R., Lewy, R.I., Weaver, R.A., Axler, M.L., Janicki, T.J., Jurida, G.F., Paszkowiak, J.K., Szymkowski, B.G., Khan, M.I., Bestak, M.
http://www.ncbi.nlm.nih.gov/m/pubmed/12718563
Drugs R D. 2003;4(2):91-101
Drugs in R&D 2003;4:91-101
http://www.burzynskiclinic.com/images/stories/Publications/960.pdf
12 patients

10 evaluable

Pg. 96

Only mild and moderate toxicities were observed, which included:
3 – skin allergy
2 – anaemia
2 – fever
2 – hypernatraemia
1 – agranulocytosis
1 – hypoglycaemia
1 – myalgia
1 – numbness
1 – tiredness
1 – vomiting
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Review Articles on Clinical Trials:

1. 3/2004

INTEGRATIVE CANCER THERAPIES

Burzynski, S.R.

The Present State of Antineoplaston Research
http://www.burzynskiclinic.com/images/stories/Publications/994.pdf
Integrative Cancer Therapies 2004;3:47-58
Volume 3, No. 1, March 2004
DOI: 10.1177/1534735-403261964

Pg. 56

Adverse Reactions

Serious adverse reactions:
1.4% – anemia
0.5% – hypernatremia and fever

Moderate adverse reactions:
0.76% – skin rash
0.9% – slurred speech

Most patients experience increased diuresis, which may lead to dehydration and thirst

Adverse reactions observed have usually been transient and mild

Noted in our studies and due to phenylacetate, which is the main ingredient of AS2-1:
confusion
Reversible grade 1 somnolence

It’s suspected other adverse reactions observed in our studies were due to A10.

They weren’t observed by Buckner et al since they used approximately 50 times lower dosages of A10 in their study.

On the other hand, A10 induces diuresis, which may result in rapid elimination of AS2-1 through kidneys, which will lower concentration of AS2-1 in plasma and reduce chances for higher grade toxicity observed by Buckner et al. [49]

49. Burzynski SR. Efficacy of antineoplastons A10 and AS2-1.
http://www.ncbi.nlm.nih.gov/pubmed/10377942/
Mayo Clin Proc. 1999;74:641-642.
http://www.ncbi.nlm.nih.gov/m/pubmed/10377942/
Mayo Clin Proc. 1999 Jun;74(6):641-2.
http://www.sciencedirect.com/science/article/pii/S0025619611641438
Mayo Clinic Proceedings
Volume 74, Issue 6 , Page 641, June 1999

Buckner et al described:
reversible grade 2 or 3 neurological toxicity, consisting of:
confusion
exacerbation of an underlying seizure disorder
transient somnolence
[48]

48. Buckner JD, Malkin MG, Reed E, et al. Phase II study of antineoplaston A10 (NSC 648539) and AS2-1 (NSC 620061) in patients with recurrent glioma. Mayo Clin Proc. 1999;74:137-145.
http://www.ncbi.nlm.nih.gov/pubmed/10069350/
Mayo Clin Proc. 1999 Feb;74(2):137-45.
http://www.ncbi.nlm.nih.gov/m/pubmed/10069350/
Mayo Clinic Proceedings
Volume 74, Issue 2, February 1999, Pages 137–145
http://www.sciencedirect.com/science/article/pii/S0025619611638354
Department of Oncology, Mayo Clinic Rochester, Minnesota, USA.
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Case Reports:

4. 9/2004

INTEGRATIVE CANCER THERAPIES

Special exception (SE) to BT-11

BRAIN STEM GLIOMA

Burzynski, S.R., Lewy, R.I., Weaver, R., Janicki, T., Jurida, G., Khan, M., Larisma, C.B., Paszkowiak, J., Szymkowski, B.

Long-term survival and complete response of a patient with recurrent diffuse intrinsic brain stem GLIOBLASTOMA MULTIFORME
http://www.burzynskiclinic.com/images/stories/Publications/1145.pdf
Integrative Cancer Therapies 2004;3:257-261
Volume 3, Number 3 September 2004
DOI: 10.1177/1534735404267748

Pg. 257

40 – age

Mild reversible side effects

Pg. 258

9/30/2009 – admitted for administration of treatment
Mild hypernatremia – On several occasions discontinued treatment from 1 to 3 days
Increased fatigue – off treatment 2 days
3/29/2000 – White blood cell (WBC) count decreased and discontinued treatment for 3 days

Pg. 259

7/10/2000 – White blood cell (WBC) count decreased and discontinued treatment until treatment restarted 7/13/2000
7/15/2000 – discontinued treatment elevation of transaminases (serum glutamic oxaloacetic transaminase; serum glutamic pyruvic transaminase) until restarted 7/28/2000
8/2001 – developed persistent diarrhea and was referred to a gastroenterologist, but there were no pathological findings except for changes related to obesity
8/21/2001 treatment discontinued due to resolution of tumor
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Interim Reports on Clinial Trials:

2. 10/2004

NEURO-ONCOLOGY

BT-20

Patients With GLIOBLASTOMA MULTIFORME (GBM)

Weaver, R.A., Burzynski, S.R., Bestak, M., Lewy, R.I., Janicki, T.J., Szymkowski, B., Jurida, G., Khan, M.I., Dolgopolov, V.

Phase II study of Antineoplastons A10 and AS2-1 (ANP) in recurrent GLIOBLASTOMA MULTIFORME
http://www.burzynskiclinic.com/images/stories/Publications/1218.pdf
Neuro-Oncology. 2004; 6: 384
Volume 6 Issue 4 October 2004
Abstracts from the Society for Neuro-Oncology Ninth Annual Meeting, Toronto, Ontario, Canada, November 18-21, 2004

22 evaluable patients
(6 men / 16 women / 27-63 /47 – median age)

Pg. 385

2 – grade toxicity: hypernatremia
2 – grade toxicity: somnolence
1 – grade 3 toxicity: anemia
1 – fatigue
1 – fever
1 – headache
1 – nausea
1 – tinnitus
1 – vomiting
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Interim Reports on Clinial Trials:

3. 10/2004 (DBSG)

NEURO-ONCOLOGY

Burzynski, S.R., Weaver, R. Bestak. M., Lewy, R.I., Janicki, T., Jurida, G., Szymkowski, B., Khan, M., Dolgopolov, V.

Long-term survivals in phase II studies of Antineoplastons A10 and AS2-1 (ANP) in patients with diffuse intrinsic BRAIN STEM GLIOMA
http://www.burzynskiclinic.com/images/stories/Publications/1219.pdf
Neuro-Oncology. 2004; 6: 386
Volume 6 Issue 4 October 2004

60 patients
(31 treated under Special Exception)

1 – reversible grade 3 toxicity: anemia
1 – reversible grade 3 toxicity: hypertension
1 – reversible grade 3 toxicity: hypokalemia
1 – reversible grade 3 toxicity: neutropenia
1 – reversible grade 3 toxicity: allergic skin rash
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Interim Reports on Clinial Trials:

4. 10/2004 (AT/RT of CNS)

NEURO-ONCOLOGY

Burzynski, S.R., Weaver, R. Bestak. M., Janicki, T., Jurida, G., Szymkowski, B., Khan, M., Dolgopolov, V.

Phase II studies of antineoplastons A10 and AS2-1 (ANP) in children with atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system

A preliminary report
http://www.burzynskiclinic.com/images/stories/Publications/1146.pdf
Neuro-Oncology. 2004; 6: 427
Volume 6 Issue 4 October 2004
Abstracts from the Eleventh International Symposium on Pediatric Neuro-Oncology, Boston, Massachusetts, June 13-16, 2004

11 children patients
(7 treated under Special Exception)

8 evaluable

1 – serious toxicity: reversible hypernatremia
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Interim Reports on Clinial Trials:

5. 10/2004

NEURO-ONCOLOGY

BT-12

CHILDREN WITH PRIMITIVE NEUROECTODERMAL TUMORS (PNET)

Burzynski, S.R., Weaver, R. Bestak. M., Janicki, T., Szymkowski, B., Jurida, G., Khan, M., Dolgopolov, V.

Treatment of PRIMITIVE NEUROECTODERMAL TUMORS (PNET) with antineoplastons A10 and AS2-1 (ANP)

Preliminary results of phase II studies
http://www.burzynskiclinic.com/images/stories/Publications/1147.pdf
Neuro-Oncology. 2004; 6: 428
Volume 6 Issue 4 October 2004
Abstracts from the Eleventh International Symposium on Pediatric Neuro-Oncology

17 patients
(12 months – 23 / 6 – median age)

15 evaluable

1 – serious side effect: anemia
1 – serious side effect: fever
1 – serious side effect: granulocytopenia
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Interim Reports on Clinial Trials:

18. 6/2005

INTEGRATIVE CANCER THERAPIES

BT-12

CHILDREN WITH PRIMITIVE NEUROECTODERMAL TUMORS (PNET)

CAN-01

CAN-1

PATIENTS WITH REFRACTORY MALIGNANCIES

Burzynski, S.R., Weaver, R.A., Janicki, T., Szymkowski, B., Jurida, G., Khan, M., Dolgopolov, V.

Long-term survival of high-risk pediatric patients with PRIMITIVE NEUROECTODERMALTUMORS treated with Antineoplastons A10 and AS2-1
http://www.ncbi.nlm.nih.gov/pubmed/15911929
Integrative Cancer Therapies 2005;4(2):168-177
http://www.ncbi.nlm.nih.gov/m/pubmed/15911929
Integr Cancer Ther. 2005 Jun;4(2):168-77
http://www.burzynskiclinic.com/images/stories/Publications/1220.pdf
DOI: 10.1177/1534735405276835
http://m.ict.sagepub.com/content/4/2/168.long?view=long&pmid=15911929
Pg. 168

13 children patients – recurrent disease or high risk

10 males / 3 females

(1 – 11 – age / 5 years, 7 months – median age)

3 – younger than 3

Pgs. 168 and 170

8 – Medulloblastoma
3 – pineoblastoma
2 – other PRIMITIVE NEUROECTODERMALTUMORS (PNET)

Pg. 168

10-BT-12 (7 males / 3 females)

3 – CAN-01 (3 males)

Pgs. 168 and 173

serious side effects:
1 – anemia
1 – fever
1 – granulocytopenia
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Interim Reports on Clinial Trials:

BT-11

BRAIN STEM GLIOMA

7. 7/2005

Burzynski, S.R., Weaver, R.A., Janicki, T.J., Burzynski, B., Jurida, G. Targeted therapy with ANP in children less than 4 years old with inoperable BRAIN STEM GLIOMAs. Neuro-Oncology. 2005; 7:300.
http://www.burzynskiclinic.com/images/stories/Publications/1224.pdf
Volume 7 Issue 3 July 2005
Abstracts from the World Federation of Neuro-Oncology Meeting

2 trials

Intrinsic diffuse brain stem glioma (BSG)

10 assessable patients

Less than 4 years old
(3 months – 3 years)

7 – no biopsy: dangerous tumor location
2 – anaplastic astrocytoma
1 – pilocytic astrocytoma

Serious toxicities:
Reversible anemia
Hypokalemia

No chronic toxicities
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Interim Reports on Clinial Trials:

BT-03


BT-11

BRAIN STEM GLIOMA (BSG)

BT-18

6. MIXED GLIOMA

ADULT PATIENTS WITH MIXED GLIOMA

“mixed glioma”, a type of PMBT

CAN-01

CAN-1

PATIENTS WITH REFRACTORY MALIGNANCIES

19. 3/2006

Burzynski, S.R., Janicki, T.J., Weaver, R.A., Burzynski, B. Targeted therapy with Antineoplastons A10 and AS2-1 of high grade, recurrent, and progressive BRAINSTEM GLIOMA. Integrative Cancer Therapies 2006;5(1):40-47
http://www.ncbi.nlm.nih.gov/pubmed/16484713
Integr Cancer Ther. 2006 Mar;5(1):40-7
http://www.ncbi.nlm.nih.gov/m/pubmed/16484713
DOI: 10.1177/1534735405285380
http://www.burzynskiclinic.com/images/stories/Publications/5825.pdf

http://m.ict.sagepub.com/content/5/1/40.long?view=long&pmid=16484713
Pg. 40

4 phase 2 trials

BRAINSTEM GLIOMA (BSG)

patients with inoperable tumor of high-grade pathology (HBSG)
glioblastoma

recurrent diffuse intrinsic glioblastomas and ANAPLASTIC ASTROCYTOMAs of brainstem

Pgs. 40 – 41 and 42

4 – glioblastomas (gliobastoma multiforme (GBM)) (GBM / BSG)

14 – anaplastic HBSG (patients with inoperable tumor of high-grade pathology (HBSG)) (Anaplastic astrocytoma / Anaplastic astrocytoma/mixed glioma)

14 – diffuse intrinsic tumors

12 – recurrence

18 patients

Pg. 42

(8 males / 10 females)

2 – 42 – age (10 – median age)

Pg. 43

BT-03 – 1 / female
BT-11 – 13 (8 males/5 females)
BT-18 – 1 / female
BT-22 – 2 / females
CAN-01 – 1 / female

Pg. 44

High-grade, recurrent, and progressive brainstem gliomas

Pgs. 40 and 45

Antineoplastons tolerated very well
1 – grade 4 toxicity (reversible anemia)

Pg. 45

2 – grade 3 toxicities: reversible anemia

Generally, the treatment was well tolerated and was free from chronic toxicities
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Interim Reports on Clinial Trials:

BT-11

BRAIN STEM GLIOMA

8. 10/2006

Burzynski, S.R., Janicki, T.J., Weaver, R.A., Szymkowski, B.G., Khan, M.I., Dolgopolov, V. Treatment of multicentric BRAINSTEM GLIOMAs with antineoplastons (ANP) A10 and AS2-1. Neuro-Oncology. 2006; 8:466.
http://www.burzynskiclinic.com/images/stories/Publications/2105.pdf
Volume 8 Issue 4 October 2006
Abstracts for the Eleventh Annual Meeting of the Society for Neuro-Oncology (SNO)

Brainstem gliomas and multicentric tumors (MBSG)

19 evaluable patients

3.9 – 40.8 (9.2 – median age)

(90% less than 18 years old)

95% diffuse intrinsic brain stem glioma
5% cervicomedullary tumor

The patients didn’t experience any serious toxicities (grades III – IV), and there were no chronic toxicities
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Interim Reports on Clinial Trials:

BT-11

BRAIN STEM GLIOMA

9. 4/2007 (NDBSG)

Burzynski, S.R., Weaver, R.A., Janicki, T.J., Jurida, G.F., Szymkowski, B.G., Kubove, E. Phase II studies of Antineoplastons A10 and AS 2-1 (ANP) in children with newly diagnosed diffuse, intrinsic BRAINSTEM GLIOMAs. Neuro-Oncology 2007; 9:206.
http://www.burzynskiclinic.com/images/stories/Publications/4021.pdf
Volume 9 Issue 2 April 2007
Abstracts from the Twelfth International Symposium on Pediatric Neuro-Oncology

20 assessable children

3 months – 20 – age

5 – high-grade gliomas

Serious toxicities included:
5 – anemia
1 – elevation of transaminases
1 – hypokalemia
1 – skin rash
There were no chronic toxicities
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Interim Reports on Clinical Trials:

10. 6/2008 (OPG)

BT-23 – CHILDREN WITH VISUAL PATHWAY GLIOMA

Phase II study of antineoplastons A10 and AS2-1 (ANP) in CHILDREN WITH optic PATHWAY GLIOMA:

A preliminary report
http://www.burzynskiclinic.com/images/stories/Publications/7287.pdf
Neuro-Oncology 2008; 10:450
Volume 10 Issue 3 June 2008

Burzynski, Stanislaw Rajmund
Janicki, Tomasz J.
Samuel, Shiney
Szymkowski, Barbara G.
Walczak, Marek
Weaver, Robert A.

16.5 months (1 year 4.5 months) – Median antineoplaston treatment

6/2008 – Protocol – CHILDREN WITH optic PATHWAY GLIOMA

12 Evaluable Children Patients
(7 months – 16 years / 6 years 3 months – Median age)
——————————————————————
0 – lost to follow-up
——————————————————————
No grade 3 or 4 toxicities
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Interim Reports on Clinical Trials:

11. 10/2008

(BT-8 – PATIENTS WITH ANAPLASTIC ASTROCYTOMA
9)

(BT-15 – ADULT PATIENTS WITH ANAPLASTIC ASTROCYTOMA
17)

Phase II study of antineoplastons A10 and AS2-1 (ANP) in PATIENTS WITH newly diagnosed ANAPLASTIC ASTROCYTOMA:

A preliminary report
http://www.burzynskiclinic.com/images/stories/Publications/7853.pdf
Volume 10 Issue 5 October 2008
Neuro-Oncology 2008; 10:821
Abstracts for the Thirteenth Annual Meeting of the Society for Neuro-Oncology, November 20-23, 2008

Burzynski, Gregory
Burzynski, Stanislaw Rajmund
Janicki, Tomasz J.
Samuel, Shiney
Szymkowski, Barbara G.
Weaver, Robert A.

FDA monitored study

5.7 months – Median Duration of Treatment

10/2008 – Protocol – Patients with Newly Diagnosed ANAPLASTIC ASTROCYTOMA (AA)

20 Evaluable Patients
(22 – 64 years / 40 – Median age)
——————————————————————
2 / 10% – grade 3 toxicity possibly related to antineoplastons (ANP)
(Shortness of breath / generalized weakness)

Interim Reports on Clinical Trials:

12. 12/2008

(BT-8 – PATIENTS WITH ANAPLASTIC ASTROCYTOMA: 9)

(BT-15 – ADULT PATIENTS WITH ANAPLASTIC ASTROCYTOMA: 17)

Phase II study of antineoplastons A10 and AS2-1 infusions (ANP) in PATIENTS WITH recurrent ANAPLASTIC ASTROCYTOMA
http://www.burzynskiclinic.com/images/stories/Publications/7898.pdf
Neuro-Oncology 2008; 10:1067
Volume 10 Issue 6 December 2008
Abstracts for the Eighth Congress of the European Association for Neuro-Oncology (EANO), Sept. 12-14, 2008, Barcelona, Spain

Burzynski, Gregory
Burzynski, Stanislaw Rajmund
Janicki, Tomasz J.
Szymkowski, Barbara G.
Walczak, Marek
Weaver, Robert A.

6.5 months – Median duration of treatment

FDA-monitored phase II clinical trial

12/2008 – Protocol – ADULTS WITH recurrent ANAPLASTIC ASTROCYTOMA (AA)

20 – Evaluable Assessable Adult Patients
(20 – 51 years / 41 – Median age)
——————————————————————
1 / 5% – serious toxicity of hypernatremia
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Case Reports:

BT-11 special exception (SE)

BRAIN STEM GLIOMA

1. 12/2009

Weaver, R.A., Szymkowski, B., Burzynski, S.R. Over a 10-year survival and complete response of a patient with diffuse intrinsic BRAINSTEM GLIOMA (DBSG) treated with antineoplastons (ANP). Neuro-Oncology 2009; 11:923.
http://www.burzynskiclinic.com/images/stories/Publications/8638.pdf
Volume 11 Issue 6 December 2009
Abstracts from the Third Quadrennial Meeting of the World Federation of Neuro-Oncology (WFNO) and the Sixth Meeting of the Asian Society for Neuro-Oncology (ASNO)
May 11-14, 2009
Yokohama, Japan

10.5 – age / female

1 episode of grade 3 vomiting which resolved within 3 days
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Interim Reports on Clinial Trials:

BT-11

BRAIN STEM GLIOMA

13. 12/2009 (DBSG)

Burzynski, S.R., Janicki, T.J., Weaver, R.A., Szymkowski, B., Burzynski, G.S. Phase II study of antineoplastons A10 and AS2-1 in patients with BRAINSTEM GLIOMA. Protocol BC-BT-11. Neuro-Oncology 2009, 11:951.
http://www.burzynskiclinic.com/images/stories/Publications/8639.pdf
Volume 11 Issue 6 December 2009
Abstracts from the Third Quadrennial Meeting of the World Federation of Neuro-Oncology (WFNO) and the Sixth Meeting of the Asian Society for Neuro-Oncology (ASNO)
May 11-14, 2009
Yokohama, Japan

40 patients

12 not evaluable

28 evaluable (ST) (23 children / 5 young adults)

12 – newly diagnosed / 16 previously treated)

Additional 52 evaluable (40 children / 12 young adults) treated under special exception (SE) (18 newly diagnosed)

ANP was well tolerated with serious toxicities occurring in less than 10% of patients in both groups:
anemia
dyspnea
elevated transaminases
fatigue
hypernatremia
hypokalemia
polyuria
skin rash
somnolence
subcutaneous extravasation
vomiting

No chronic toxicities
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Interim Reports on Clinical Trials:

14. 6/2010

BT-13 – CHILDREN WITH LOW GRADE ASTROCYTOMA

A Phase II Study of Antineoplaston A-10 and AS-1 Injections in CHILDREN WITH LOW-GRADE ASTROCYTOMAs.
http://www.burzynskiclinic.com/images/stories/Publications/8397.pdf
Neuro-Oncology 2010; 12, ii95.
Volume 12 Issue 6 June 2010

Acelar, Sheryll S.
Burzynski, Gregory S.
Burzynski, Stanislaw Rajmund
Janicki, Tomasz J.
Szymkowski, Barbara G.
Weaver, Robert A

17 / 100% – Evaluable for Safety

12 or more weeks or at least 4 weeks of Antineoplastons (ANP) but developed Progressive Disease (PD)
Patients Evaluable for Efficacy

83 weeks – Median Antineoplastons (ANP) (15 / 100% – Evaluable Patients)

6/2010 – Protocol – CHILDREN WITH Recurrent and / or Progressive LOW-GRADE ASTROCYTOMA (LGA)

17 Patients Accrued
(20 months {1 year 8 months} – 210 months {17 years 6 months} / 129 months {10 years 9 months} – Median age)
15 Evaluable Patients

Patients Showing Stable Disease (47 – 85 days / 60 – Median days of Antineoplastons (ANP))
Patients Showing Progressive Disease (47 – 85 days / 60 – Median days of Antineoplastons (ANP))
——————————————————————
Minimal toxicity
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Interim Reports on Clinical Trials:

15. 11/2010

BT-18 – ADULT PATIENTS WITH MIXED GLIOMA

Preliminary Results of a Phase II Study of Antineoplastons A10 and AS2-1 (ANP) in Adult Patients with Recurrent Mixed Gliomas.
http://www.burzynskiclinic.com/images/stories/Publications/8637.pdf
Neuro-Oncology 2010; 12:iv72.
Volume 12 Supplement 4 November 2010

Acelar, Sheryll S.
Burzynski, Gregory S.
Burzynski, Stanislaw Rajmund
Janicki, Tomasz J.
Szymkowski, Barbara G.
Weaver, Robert A

7 / 35% – not evaluated due to inadequate duration of treatment and lack of follow-up Magnetic Resonance Imaging (MRI) scans

4.4 months – median duration of treatment

11/2010 – Protocol – Adult Patients with Recurrent Mixed Gliomas

20 – Children Patients Accrued
13 – Evaluable Patients
(9 men / 4 women: 29 – 54 years / 38 – Median age)
——————————————————————
Antineoplastons (ANP) was well tolerated with the most common side effects being:
Dysgeusia
Hypernatremia
Hypersensitivity
Myalgias
Nausea
Urinary frequency

1 – Serious (grade 3) toxicity (urinary frequency)

No grade 4 toxicities

Antineoplastons: Phenylacetylglutaminate (PG or PAG), Phenylacetate (PN), and Phenylbutyrate (PB)

PHENYLACETYLGLUTAMINATE (PAG or PG) and PHENYLACETATE (PN) are metabolites of PHENYLBUTYRATE (PB) and are constituents of antineoplaston AS2-1
� � � � � � � � � � � � � � � �
Antineoplastons AS2-1 and AS2-5 are DERIVED FROM A10
� � � � � � � � � � � � � � � �
AS2-1 = 4:1 mixture of PHENYLACETIC ACID (PA) and PHENYLACETYLGLUTAMINE (PAG or PG)
� � � � � � � � � � � � � � � �
Antineoplaston AS2-5 = PHENYLACETYLGLUTAMINE (PAG or PG)
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National Cancer Institute (NCI) at the National Institutes of Health (NIH)
Antineoplastons
General Information: http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page2
� � � � � � � � � � � � � � � �
http://www.burzynskiclinic.com/scientific-publications.html
Review Articles on Clinical Trials:

1. 3/2004

Burzynski, S.R. The Present State of Antineoplaston Research. Integrative Cancer Therapies 2004;3:47-58.
http://www.burzynskiclinic.com/images/stories/Publications/994.pdf
Volume 3 Number 1 March 2004
DOI: 10.1177/1534735403261964

Pg. 48

Antineoplaston A2, which contributed to the highest number of complete responses in phase I clinical studies, was elected for final purification, isolation of active components, and structure determination.
Active ingredient identified as:
3-phenylacetylamino-2, 6-piperidinedione
and was named
antineoplaston A10. [27]

27. Burzynski SR, Hendry LB, Mohabbat MO, et al. Purification of structure determination, synthesis and animal toxicity studies of antineoplaston A10. In: Proceedings of the 13th International Congress of Chemotherapy. Vienna, Austria; 1983:17, PS. 12.4 11-4.

A10 has been reproduced by synthesis involving condensation of:
1-glutamine
with
phenylacetyl chloride
and subsequent cyclization of
phenylacetylglutamine (PG). [28]

28. Burzynski SR, Hai TT. Antineoplaston A10. Drugs of the Future. 1985;10:103-105.

Metabolism of A10 in human body yields:
phenylacetylglutamine (PG)
phenylacetylisoglutamine (isoPG)
phenylacetate (PN)
which were reproduced synthetically and formulated into:
antineoplaston
A10 injections (A10-I)
AS2-1
AS5
AS-25
[29-33]

29. Burzynski SR. Synthetic antineoplastons and analogs. Drugs of the Future. 1986;11:679-688.

30. Burzynski SR, Mohabbat MO, Lee SS. Preclinical studies of antineoplaston AS1-1 and antineoplaston AS2-5. Drugs Exptl Clin Res. 1986;12(suppl 1):11-16.
http://www.ncbi.nlm.nih.gov/pubmed/3743376/

http://www.ncbi.nlm.nih.gov/m/pubmed/3743376/
31. Burzynski SR, Khalid M. Antineoplaston A10 injections. Drugs of the Future. 1986;11:364-365.

32. Burzynski SR, Khalid M. Antineoplaston AS2-1. Drugs of the Future. 1986;11:361-363.

33. Burzynski SR. Antineoplaston AS2-5.. Annual Drug Data Report. 1986;8-319.

These formulations were submitted for basic research and phase I clinical studies. [34-44]

34. Burzynski SR, Mohabbat MO, Burzynski B. Animal toxicology studies on oral formulation of antineoplaston A10. Drug Exptl Clin Res. 1984;10:113-118.

35. Burzynski SR. Phase I clinical studies of antineoplaston AS2-5 injections. In: Ishigami J, ed. Recent Advances in Chemotherapy. Tokyo, Japan: University of Tokyo Press; 1985.

36. Burzynski SR, Burzynski B, Mohabbat MO. Toxicology studies of antineoplaston AS 2-1 injections in cancer patients. Drugs Exptl Clin Res. 1986;12(suppl 1):25-35.
http://www.ncbi.nlm.nih.gov/pubmed/3743378/

http://www.ncbi.nlm.nih.gov/m/pubmed/3743378/
37. Burzynski SR, Kubove E. Toxicology studies of antineoplaston A10 injections in cancer patients. Drugs Exptl Clin Res. 1986;12(suppl 1):47-55.
http://www.ncbi.nlm.nih.gov/pubmed/3743380/

http://www.ncbi.nlm.nih.gov/m/pubmed/3743380/
38. Lehner AF, Burzynski SR, Hendry LB. 3-phenylacetylamino-2,6-piperidinedione, a naturally-occurring peptide analog with apparent antineoplastic activity may bind to DNA. Drugs Exptl Clin Res. 1986;12(suppl 1):57-72.
http://www.ncbi.nlm.nih.gov/pubmed/3743381/

http://www.ncbi.nlm.nih.gov/m/pubmed/3743381/
39. Ashraf AQ, Liau MC, Mohabbat MO, et al. Preclinical studies of antineoplaston A10 injections. Drugs Exptl Clin Res. 1986;12(suppl 1):37-45.
http://www.ncbi.nlm.nih.gov/pubmed/3743379/

http://www.ncbi.nlm.nih.gov/m/pubmed/3743379/
40. Ashraf AQ, Liau MC, Kampalath BN, et al. Pharmacokinetic study of radioactive antineoplaston A10 following oral administration in rats. Drugs Exptl Clin Res. 1987;13(suppl 1):45-50.
http://www.ncbi.nlm.nih.gov/pubmed/3569015/

http://www.ncbi.nlm.nih.gov/m/pubmed/3569015/
41. Hendry LB, Muldoon TG, Burzynski SR et al. Stereochemical modeling studies of the interaction of Antineoplaston A10 with DNA. Drugs Exptl Clin Res. 1987;13(suppl 1):77-81.
http://www.ncbi.nlm.nih.gov/pubmed/3569020/

http://www.ncbi.nlm.nih.gov/m/pubmed/3569020/
42. Ashraf AQ, Burzynski SR. Comparative study of antineoplaston A10 levels in plasma of healthy people and cancer patients. Adv Exptl Clin Chemother. 1988;2:19-28.

43. Ashraf AQ, Kampalath BN, Burzynski SR. Pharmacokinetic analysis of antineoplaston A10 injections following intravenous administration in rats. Adv Exptl Clin Chemother. 1988;6:33-39.

44. Burzynski SR, Kubove E, Burzynski B. Phase I clinical studies of oral formulation of antineoplaston AS2-1. Adv Exptl Clin Chemother. 1988;2:29-36.

A10
A10-I
AS2-1
were selected for phase II studies.
2 initial phase II studies in
ASTROCYTOMA
and
HIGH-GRADE GLIOMA
began in
1988
and
1990
and were conducted outside investigational new drug (IND) process.

Since 1994 the FDA authorized 74 phase II studies with
A10
A10-I
AS2-1
under INDs
43,742
22,029
in advanced malignancies.

Pg. 49

Phenylacetate (PN)
is active ingredient of
antineoplaston AS2-1.

Phenylglutamine (PG)
is main ingredient of
A10-I.

Phenylglutamine (PG) exhibits antineoplastic activity across wide array of cancer cell lines.

Phenylglutamine (PG)
inhibits uptake of growth-critical amino acids, such as:
1-glutamine
and
1-leucine
in neoplastic cells.

Reduction in amino acid availability may contribute to drug’s antineoplastic activity.

Human glioma (U-87) cells rapidly take up Phenylglutamine (PG) by mechanism similar to facilitated diffusion.

Upon removal of Phenylglutamine (PG) from media, PG rapidly and completely effluxes from the cell.

Phenylglutamine (PG)
enters cells via stereospecific amino acid transporters for
1-glutamine.

Formulations of
Antineoplastons:

Antineoplastons
are a class of 12 antitumor agents.

Following synthetic antineoplaston formulations used in phase II studies.

Antineoplaston A10
capsules contain 500 mg of
3-phenylacetylamino-2, 6-piperidinedione.

Antineoplaston A10 injection
is mixture of sodium salts of
Phenylglutamine (PG)
and
Phenylacetylisoglutamine (isoPG)
in 4:1 ratio.

Available in 500 mL and 1000 mL (300 mg/mL) plastic bags.

Antineoplaston AS2-1
capsules containing 500 mg of 4:1
Phenylacetate (PN)
and
Phenylglutamine (PG).

Antineoplaston AS2-1 injection
is mixture of
Phenylacetate (PN)
and
Phenylglutamine (PG)
in 4:1 ratio.

Available in 250 mL (80 mg/mL) plastic bags.
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Interim Reports on Clinial Trials:

18. 6/2005

INTEGRATIVE CANCER THERAPIES

BT-12

CHILDREN WITH PRIMITIVE NEUROECTODERMAL TUMORS (PNET)

CAN-01

CAN-1

PATIENTS WITH REFRACTORY MALIGNANCIES

Burzynski, S.R., Weaver, R.A., Janicki, T., Szymkowski, B., Jurida, G., Khan, M., Dolgopolov, V.

Long-term survival of high-risk pediatric patients with PRIMITIVE NEUROECTODERMALTUMORS treated with Antineoplastons A10 and AS2-1
http://www.ncbi.nlm.nih.gov/pubmed/15911929
Integrative Cancer Therapies 2005;4(2):168-177
http://www.ncbi.nlm.nih.gov/m/pubmed/15911929
Integr Cancer Ther. 2005 Jun;4(2):168-77
http://www.burzynskiclinic.com/images/stories/Publications/1220.pdf
DOI: 10.1177/1534735405276835
http://m.ict.sagepub.com/content/4/2/168.long?view=long&pmid=15911929
Antineoplastons (ANP) A10 and AS2-1, which are synthetic analogs of naturally occurring derivatives of glutamine, isoglutamine, and phenylacetic acid, have shown an increasing spectrum of activity in primary brain tumors. [1]

Review Articles on Clinical Trials:

1. 3/2004

Burzynski, S.R. The Present State of Antineoplaston Research. Integrative Cancer Therapies 2004;3:47-58.
http://www.burzynskiclinic.com/images/stories/Publications/994.pdf
Volume 3 Number 1 March 2004
DOI: 10.1177/1534735403261964
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IV. Aetna considers SODIUM PHENYLBUTYRATE medically necessary for the treatment of acute promyelocytic leukemia and malignant glioma
http://www.aetna.com/cpb/medical/data/200_299/0240.html
� � � � � � � � � � � � � � � �
The FDA has approved SODIUM PHENYLBUTYRATE as a treatment to remove ammonia from the bloodstream in individuals with urea cycle disorders
� � � � � � � � � � � � � � � �
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 individuals with primary or recurrent malignant glioma
http://www.anthem.com/medicalpolicies/policies/mp_pw_a050524.htm
� � � � � � � � � � � � � � � �
Cumulative List of all Products that have received Orphan Designation: Total active designations: 2002 Effecive: (sic – Effective:) 5/5/2009
http://www.fda.gov/downloads/forindustry/developingproductsforrarediseasesconditions/howtoapplyfororphanproductdesignation/ucm162066.xls
PHENYLBUTYRATE (PB) and SODIUM PHENYLBUTYRATE are listed alphabetically in the lower 1/4th of this document
� � � � � � � � � � � � � � � �
Sodium Phenylbutyrate (PB)
Year – Pubmed (110 entries)
1958 1st entry
1995 1st clinical trial
2001 Phase 1
2009 Phase 2
2012 Phase 3
� � � � � � � � � � � � � � � �
Phenylacetate (PN)
Year – Pubmed (29,686 entries)
1883 1st entry
1994 Phase 1
1999 Phase 2
2013 latest
� � � � � � � � � � � � � � � �
Antineoplaston(s)
Year – Pubmed (88 entries)
1976 1st entry
1986 Phase 1
1999 Phase 2
2003 Phase 2 preliminary
2004 Phase 2 preliminary
2012 latest
� � � � � � � � � � � � � � � �
National Cancer Institute (NCI) at the National Institutes of Health (NIH)
Antineoplastons (PDQ®) Overview:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page1

http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/patient
General Information:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page2
History:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page3
Laboratory/Animal/Preclinical Studies:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page4
Human/Clinical Studies:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page5
Adverse Effects:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page6
Summary of the Evidence for Antineoplastons:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page7
Changes to This Summary:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page8
About This PDQ Summary:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page9
Questions and Answers About Antineoplastons:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/patient/page2
Current Clinical Trials:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/patient/page3
Changes to This Summary:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/patient/page4