(12) United States Patent
`Marks et al.
`
`(10) Patent No.2
`(45) Date of Patent:
`
`US 9,006,224 B2
`Apr. 14, 2015
`
`US009006224B2
`
`(54) NEUROENDOCRINE TUMOR TREATMENT
`
`(75)
`
`Inventors: Peter Wayne Marks, Woodbridge, CT
`(US);DaV1d Lebwohl, Mad1s0n,NJ
`(US)
`
`(73) Assignee: Novartis AG, Basel (CH)
`s
`otice:
`u ect to an
`1SC aimer, t e term 0 t
`*
`N '
`s bj
`yd’
`1
`'
`h
`f iii
`patent is extended or adjusted under 35
`Uisici 154(1)) by 589 days.
`
`(21) Appl. No.:
`.
`(22) PCT F11ed3
`
`12/094,173
`
`N0V- 20: 2006
`
`(86) PCT No;
`
`PCT/EP2006/068656
`
`§ 371 (C)(1),
`(2), (4) Date: May 19, 2008
`
`(87)
`
`pCT pub. N0‘; W02007/057457
`
`PCT Pub. Date: May 24, 2007
`
`(65)
`
`Prior Publication Data
`US 2008/0255029 Al
`Oct. 16, 2008
`
`Foreign Application Priority Data
`(30)
`NOV 21 2005
`(GB)
`0523658 3
`"""""""""""""""""" "
`'
`’
`'
`Jan. 19, 2006
`(GB) ................................. .. 0601082.1
`Feb. 10,
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
`Apr. 21, 2006
`(GB) ................................. .. 0607942.0
`May 10, 2006
`(GB) ................................. .. 0609272.0
`
`May 18’ 2006
`(GB)
`06099121
`Sep. 14, 2006
`(EP) ................................... .. 06120660
`
`(51)
`
`(2006.01)
`(200601)
`(2006.01)
`
`Int- 0-
`A6IK 31/436
`A61K 38/31
`A61K 45/06
`(52) U'S' Cl‘
`CPC ~~~~~~~~~~~~~ ~~ A61K 38/31 (2013-01); A61K 31/436
`(2013.01);A6IK45/06 (2013.01)
`(58) Field of Classification Search
`CPC .................................................... A61K 31/436
`See application file for Complete Search history‘
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,538,739 A
`2002/0183239 A1
`
`7/1996 Bodmer et al.
`12/2002 Gibbons, Jr. et al.
`
`2002/0183240 A1
`2003/0008923 A1
`2004/0175339 A1
`2005/0187184 A1
`
`12/2002 Gibbons
`1/2003 Dukart et al.
`9/2004 sherman
`8/2005 Gibbons, Jr. et al.
`
`EP
`RU
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`0 462 071
`i2/i991
`2264405 C2
`11/2005
`97/05167
`2/1997
`97/47317
`12/1997
`
`W0
`W0
`
`W0
`W0
`W0
`
`W0
`
`W002/055019
`02/080975
`
`3/2002
`10/2002
`
`WO2004/004644 A2
`2004/078133
`2005/082411
`
`2006/071966
`
`A2
`
`1/2004
`9/2004
`9/2005
`
`7/2006
`
`OTHER PUBLICATIONS
`Merck Manuals, Pancreatic endocrine tumors, 2009, pp. 1-4.*
`Novartis Data Sheet. Novartis, GEP NE tumors, published online on
`Apr. 2005, pp. i_2.*
`Arnold et al. Chapter 15 of “Gastrointestinal and Liver Tumors” by
`Wolfgang Scheppack, 2004, Chapter 15, pp. 195-233.*
`Asano Takayuki, et al: “The rapamycin analog CCI-779 is a potent
`inhibitor of pancreatic cancer cell proliferation”, Biochemical and
`Biophysical Research Communications, 331, May 27, 2005, pp.
`295-302.
`Boulay Anne, et al: “Antitumor efficacy of intermittent treatment
`sshedules With the rapamycin derivative RAD001 correlates With
`prolonged inactivation ofribosonial protein S6 kinase 1 in peripheral
`blood mononuclear cells”, Cancer Research, 64, Jan. 1, 2004, pp.
`252-261.
`Boulay Anne, et al: “Prolonged effect of the rapamycin derivative
`lI){1ADd0i)1 or111p7§0tS6(i<ir1_ase(:i:ictivity in tumors, slt<in and iateriplllircilral
`oo
`ymp oc
`es
`erive
`rom a syngeneic ra pancrea ic
`or
`model: correlation With efficacy of intermittent dosing schedules”,
`Proceedings of the American Association for Cancer Research
`gnnuaii/If"’tt_1nga 43tsP~ 602~_
`_ d
`d
`d th 1_
`1
`H d th
`urns
`ris iane, e
`:
`pamycin-in uce en 0
`e ia ce
`ea
`and tumor vessel thrombosis potentiate cytotoxic therapy against
`pancreatic cancer”Clinical Cancer Research, vol. 10, Mar. 15, 2004,
`pp. 21094199.
`an orally active
`Terence, et al: “In Vivo activity
`rapamycin derivative in experimental tumor models”, Proceedings of
`t11\ieAr2r:)<e0ricanz;1ssoc1at10n for Cancer ReseanehAnnna1Meenng,43.
`ar.
`, p.
`.
`Stephan Susann, et al: “Effect ofrapamycin alone and in combination
`with antiangiogenesis therapy in an Ofihotopic model Ofhuman pan_
`creatic cancer”, Clinical Cancer Research, vol. 10, 200-10-15, pp.
`6993-7000, 2004.
`Townsley Carol A., et al: “Evaluation of adverse events experienced
`by older patients participating in studies of molecularly targeted
`ia\gen7ts glonei o£6combi2n1aAtii1ori 1,4(9Zancer Therapy: Clinical, vol. 12,
`0~
`5
`PL 5
`5 PR
`'
`~
`Database Medline: Canobbio L. et
`al:
`“Use of long-acting
`soniatostatin analog, lanreotide, in neuro-endocrine tumors.” Oncol-
`ogy reports, vol. 1, No. 1 Jan. 1994 p. 129-131.
`Hofsli, Eva et al., “Expression of Chiriomogranin A and Somatostatin
`fr‘fI°1:I1’(§°rS ‘V“0I1’*‘i‘;jf*1“°f§5“_21J7;3‘°i1(1)j)2aM°1e°“1‘““dCe““1‘“E“d°'
`Dorlanrillllustrated Ila/Ifedical Dictionary, “Dorlands Illustrated Medi-
`cal Dictionary”, Elsevier Saunders, 2012, Ed. 32nd 955.
`The Merck Index; 15111 edition; 2013; p. 718.
`Hanin et al., “Effect of Interferon-a Treatment .
`Nuclear Medicine, No. 52, 2011; pp. 580-585.
`
`. 7’; The Journal of
`
`* Cited by examiner
`
`. 7 Samira Jean_LOuiS
`E
`P .
`’””‘”y ’‘‘””’”e’
`.
`(74) Attorney, Agent, or Firm — Gregory Ferraro
`
`ABSTRACT
`(57)
`A method for treating endocrine tumors by administration of
`an mTOR inhibitor, optionally in combination With another
`drug
`
`3 Claims, N0 Drawings
`
`Par Pharm., Inc.
`Exhibit 1001
`Page 001
`
`Par Pharm., Inc.
`Exhibit 1001
`Page 001
`
`

`
`US 9,006,224 B2
`
`1
`NEUROENDOCRINE TUMOR TREATMENT
`
`The present invention relates to organic compounds, more
`specifically to the use of mTOR inhibitors in neuroendocrine
`tumor treatment.
`
`5
`
`An mTOR inhibitor as used herein is a compound which
`targets intracellular mTOR (“mammalian Target of rapamy-
`cin”). mTOR is a family member of phosphatidylinositol
`3-kinase (P13-kinase) related kinase. The compound rapa-
`mycin and other mTOR inhibitors inhibit mTOR activity via
`a complex with its intracellular receptor FKBP12 (FK506-
`binding protein 12). mTOR modulates translation of specific
`mRNAs via the regulation of the phosphorylation state of
`several different
`translation proteins, mainly 4E-PB1,
`P70S6K (p70S6 kinase 1) and eEF2.
`Rapamycin is a known macrolide antibiotic produced by
`Slreplomyces hygroscopicus of formula
`
`
`
`Other mTOR inhibitors include rapamycin derivatives, for
`example including rapamycin substituted in position 40 and/
`or 16 and/or 32.
`
`Examples of other mTOR inhibitors include 40-O-alkyl-
`raparnycin derivatives, e.g. 40-O-hydroxyalkyl-rapamycin
`derivatives, for example 40-O-(2-hydroxy)-ethyl-rapamycin
`(everolimus),
`rapamycin derivatives which are substituted in 40 position by
`heterocyclyl, e.g. 40-epi-(tetrazolyl)-rapamycin (also known
`as ABT578),
`32-deoxo-raparnycin derivatives and 32-hydroxy-rapamycin
`derivatives, such as 32-deoxorapamycin,
`16-O-substituted rapamycin derivatives such as 16-pent-2-
`ynyloxy-32-deoxoraparnycin,
`16-pent-2-ynyloxy-32(S or
`R)-dihydro-rapamycin, or 16-pent-2-ynyloxy-32(S or R)-di-
`hydro-40-O-(2-hydroxyethyl)-raparnycin,
`rapamycin derivatives which are acylated at the oxygen in
`position 40, e.g. 40- [3 -hydroxy-2-(hydroxy-methyl)-2-meth-
`ylpropanoate]-rapamycin (also known as CCI779 or tem-
`sirolimus),
`rapamycin derivatives (also sometimes designated as rapal-
`ogs) as disclosed in WO9802441 orWO0l 14387, e.g. includ-
`ing AP23573, such as 40-O-dimethylphosphinyl-raparnycin,
`compounds disclosed under the name biolimus (biolimus
`A9), including 40-O-(2-ethoxy)ethyl-raparnycin, and com-
`pounds disclosed under the name TAFA-93, AP23464,
`AP23675 orAP23841; or
`
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`mTOR inhibitors as e.g. disclosed in WO2004101583,
`WO9205179, WO9402136, WO9402385 and WO9613273.
`Preferred mTOR inhibitors include
`
`rapamycin, and/or
`40-O-(2-hydroxyethyl)-raparnycin, and/or
`32-deoxorapamycin, and/or
`16-pent-2-ynyloxy-32-deoxoraparnycin, and/or
`16-pent-2-ynyloxy-32 (S or R)-dihydro-rapamycin, and/or
`16-pent-2-ynyloxy-32 (S or R)-dihydro-40-O-(2-hydroxy-
`ethyl)-rapamycin, and/or
`40- [3 -hydroxy-2 - (hydroxy-methyl)-2-methylpropanoate] -
`rapamycin (also known as CCI779) and/or
`40-epi-(tetrazolyl)-rapamycin (also known as ABT578), and/
`or
`
`the so-called rapalogs, e.g. as disclosed in WO9802441,
`WO0114387
`and WO0364383, AP23573, AP23464,
`AP23675 or AP23841, e.g. AP23573, and/or
`compounds disclosed under the name TAFA-93, and/or
`compounds disclosed under the name biolimus.
`More preferably an mTOR inhibitor is selected from the
`group consisting of rapamycin, and/or
`40-O-(2-hydroxyethyl)-raparnycin, and/or
`32-deoxorapamycin, and/or
`16-pent-2-ynyloxy-32-deoxoraparnycin, and/or
`16-pent-2-ynyloxy-32 (S or R)-dihydro-rapamycin, and/or
`16-pent-2-ynyloxy-32 (S or R)-dihydro-40-O-(2-hydroxy-
`ethyl)-rapamycin, and/or
`40- [3 -hydroxy-2 - (hydroxy-methyl)-2-methylpropanoate] -
`rapamycin (also known as CCI779) and/or
`40-epi-(tetrazolyl)-rapamycin (also known as ABT578), and/
`or
`
`AP23573,
`such as 40-O-(2-hydroxyethyl)-rapamycin.
`mTOR inhibitors, on the basis of observed activity, have
`been found to be useful e.g. as immunosuppressant, e.g. in the
`treatment of acute allograft rejection and have additionally
`potent antiproliferative properties which make them useful
`for cancer chemotherapy, particularly for the treatment of
`solid tumors, especially of advanced solid tumors.
`Endocrine, e.g. neuroendocrine tumors (NETs), are found
`in the endocrine system. Carcinoid tumors, are a special type
`of tun1or, generally classified as endocrine tumors. Carcinoid
`tumors belong to the family of neuroendocrine tumors which
`derive from the neuroendocrine cell system. In the intestinal
`tract, these tumors develop deep in the mucosa, growing
`slowly and extending into the underlying submucosa and
`mucosal surface. This results in the formation of small firm
`
`nodules, which bulge into the intestinal lumen. Pancreatic
`neuroendocrine tumors (islet cell tumors), which were for-
`merly classified as APUDomas (tumors of the amine precur-
`sor uptake and decarboxylation system), comprise less than
`half of all neuroendicrine tumors and only 1-2% of all pan-
`creatic tumors. Pancreatic NETs can arise either in the pan-
`creas (insulinomas, glucagonomas, nonfunctioning pancre-
`atic NETs, pancreatic NETs causing hypercalcemia) or at
`both pancreatic and extrapancreatic sites (gastrinomas, VlPo-
`mas, somatostatinomas, GRFomas). The hormones secreted
`by pancreatic NETs depend upon the cell of origin and are
`physiologically involved in a network of autocrine, paracrine,
`endocrine and neurotransmitter communication. While hor-
`
`mone secretion is not observed in all cases ofpancreatic NET,
`the apparently “nonfunctioning” (i.e., non-secreting) pancre-
`atic NETs tend to be more aggressive and present with symp-
`toms of tumor bulk (see e.g. Barakat et al, Endocrine-related
`cancer 2004; 1121-18 and Tomassetti et al, Ann Oncol 2001;
`12(Suppl 2): S95-S99).
`
`Par Pharm., Inc.
`Exhibit 1001
`Page 002
`
`Par Pharm., Inc.
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`

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`US 9,006,224 B2
`
`3
`All pancreatic NETs, with the exception of 90% of insuli-
`nomas, have long-term metastatic potential. Most are overtly
`malignant at the time of diagnosis, and 60% or more present
`with liver metastases. The most common cause of death from
`
`pancreatic NET is hepatic failure (Warner R R P, Gastroen-
`terology 2005; 128: 1 668-16842005).
`In a recent review, the 5-year survival rate in a series of 83
`consecutive patients with pancreatic NETs has been reported
`to be 55.3% which points to an unmet medical need for
`continued treatment in patients with pancreatic NETs whose
`disease has progressed following 1 or more courses of che-
`motherapy.
`Carcinoid tumors have historically been classified, accord-
`ing to their point of origin in embryonic development, as
`arising from the foregut (e.g., bronchial, pulmonary or gastric
`carcinoid), midgut (e.g., small intestine or appendiceal carci-
`noid), or hindgut (e.g., rectal carcinoid), see e.g. Kulke M.,
`Cancer Treatment Reviews 2003; 29:363-370.
`Primary foregut tumors are confined to the thymus, lung,
`stomach, and duodenum. Midgut carcinoids are located in the
`distal ileum, cecum, and proximal colon. One interesting
`subset ofthis group is appendiceal carcinoids, which are often
`benign and rarely give rise to metastatic disease. The midgut
`carcinoids dominate the malignant carcinoid tumors, particu-
`larly when the carcinoid syndrome is present.
`The hindgut tumors are primarily located in the distal colon
`and rectum.
`
`Data suggest that the incidence of pulmonary and gastric
`carcinoid has increased in the past two decades.
`According to histopathologic criteria, carcinoids can be
`divided into typical (TC) and atypical (AC) carcinoids. Car-
`cinoids can be placed in a spectrum of neuroendocrine
`tumors, ranging from low-grade malignant TC to intermedi-
`ate AC to high-grade large-cell neuroendocrine carcinoma
`and small-cell lung carcinoma.
`Carcinoid lung tumors e.g. include neuroendocrine carci-
`noma, Kulchitsky cell carcinoma (KCC), bronchial carcinoid
`tumors, bronchial adenomas, typical carcinoids, atypical car-
`cinoids, carcinoid syndrome, small-cell carcinomas, Kul-
`chitsky cells, argentaffin cells, pulmonary carcinoids, neu-
`roendocrine lung tumors, (primary) pulmonary neoplasms,
`bronchopulmonary carcinoid tumors, lung neoplasms, lung
`cancers, pulmonary cancers, intrabronchial mass.
`Bronchial carcinoid tumors may originate from the neuro-
`secretory cells ofbronchial mucosa and were previously clas-
`sified as bronchial adenomas. Bronchial carcinoids are now
`
`classed as low-grade malignant neoplasms because of their
`potential to cause local invasion, their tendency for local
`recurrence, and their occasional metastases to extrathoracic
`sites.
`
`Bronchial carcinoids belong to a group of neuroendocrine
`tumors, which cover a range of tumors ranging from bron-
`chial carcinoid at one of the spectrum, with a small cell
`carcinoma, or possibly large cell neuroendocrine tumors at
`the other end. They demonstrate a wide range of clinical and
`biologic behaviors, including the potential to synthesize and
`secrete peptide hormones and neuroamines, particularly
`adrenocorticotropic hormone (ACTH), serotonin, somatosta-
`tin, and bradykinin.
`Bronchial carcinoid tumors may arise from Kulchitsky
`cells (argentafiin cells) within the bronchial mucosa. The
`predominant distribution of cells are believed to occur at the
`bifurcation of the lobar bronchi. These cells are neurosecre-
`
`tory cells, which belong to the amine precursor uptake and
`decarboxylation (APUD) system. They have the capacity to
`synthesize serotonin (5-hydroxytryptamine), 5-hydroxytryp-
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`tophan, ACTH, norepinephrine, bombesin, calcitonin, antidi-
`uretic hormone (ADH), and bradykinin.
`Large-cell neuroendocrine carcinoma of the lung is a
`newly recognized climcopathologic entity, which is distinct
`from small-cell carcinoma and has a poor prognosis.
`Typical carcinoid tumors of the lung represent the most
`well differentiated and least biologically aggressive type of
`pulmonary neuroendocrine tumor. These tumors characteris-
`tically grow slowly and tend to metastasize infrequently.
`Atypical carcinoid tumors have a more aggressive histologic
`and clinical picture. They metastasize at a considerably
`higher rate than do typical carcinoid tumors. Carcinoid syn-
`drome has been reported in association with very large bron-
`chopulmonary carcinoid tumors or in the presence of meta-
`static disease. It is noted much less frequently in association
`with carcinoids of pulmonary origin than those originating
`within the gastrointestinal tract. Endocrine syndromes found
`in association with small cell carcinoma ofthe lung are found
`less commonly with carcinoid tumors of the lung; however,
`some endocrine abnormalities have been attributed to both
`
`typical and atypical pulmonary carcinoid tumors.
`Carcinoid tumors of the GI tract may display an aggressive
`biology similar to that ofadenocarcinomas, particularly when
`they are located in the colon, stomach, and small intestine, see
`e.g. Modlin I M et al, Gastroenterology 2005; 128: 1717-
`1751. For small-intestinal carcinoids, which are the most
`frequent cause of carcinoid syndrome due to metastatic dis-
`ease in the liver, the incidence ofmetastasis increases propor-
`tionally with the size of the primary tumor (Tomassetti et al
`2001, ibidem).
`The incidence and survival data available suggest that
`clinical trials ofnew anticancer agents inpatients with midgut
`carcinoid tumors may provide the opportunity to address an
`unmet medical need in a growing segment of the population
`of patients with carcinoids.
`Carcinoid syndrome is caused by hypersecretion ofnumer-
`ous hormone products by the tumor cells, including kinins,
`prostaglandins, substance P, gastrin, corticotrophin and chro-
`mogranin A (see e.g. Davis et al, Gynecology & Obstetrics
`1973; 137:637-644). Various endocrine or neuroendocrine
`syndromes can be initial clinical manifestations of either
`typical or atypical pulmonary carcinoid tumors. Carcinoid
`syndrome, hypercortisolism and Cushing syndrome, inap-
`propriate secretion ofADH, increased pigmentation second-
`ary to excess MSH, and ectopic insulin production resulting
`in hypoglycemia are some ofthe endocrinopathies that can be
`produced by a pulmonary carcinoid tumor in a patient who is
`otherwise asymptomatic.
`The most common symptoms are hemoptysis, cough,
`recurrent pulmonary infection, fever, chest discomfort and
`chest pain, unilateral wheezing, and shortness of breath,
`flushing and diarrhea. Paraneoplastic syndromes are rare and
`include carcinoid syndrome, Cushing’s
`syndrome, and
`ectopic growth hormone-releasing hormone secretion.
`Other less frequent symptoms include cardiac manifesta-
`tions secondary to fibrosis ofthe endocardium (Jacobsen M B
`et al, Eur Heart J 1995; 16:263-268) which may result in
`valvular regurgitation (valvular heart disease), with varying
`degrees of heart failure in patients with cardiac manifesta-
`tions. Wheezing or asthma-like symptoms, pellagra-like skin
`lesions with hyperkeratosis, abdominal pain, telangiectasias
`and paroxysmal hypotension are also seen in a number of
`patients. Patients with pulmonary carcinoid often show
`symptoms like recurrent pneumonia, cough, hemoptysis or
`chest pain. The majority ofpulmonary carcinoid tumors are in
`the perihilar area. Ectopic secretion of corticotropin from
`pulmonary carcinoid tumors may also account for Cushing’s
`
`Par Pharm., Inc.
`Exhibit 1001
`Page 003
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`US 9,006,224 B2
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`5
`syndrome. Early in the course, symptoms are usually episodic
`and may be provoked by stress, catecholamines, and inges-
`tion of food or alcohol. During acute paroxysms, systolic
`blood pressure typically falls 20 to 30 mmHg. Endocardial
`fibrosis can cause Valvular heart disease, usually affecting the
`proximal side of the tricuspid and pulmonary Valves and
`leading to tricuspid insufiiciency and secondary right-sided
`heart failure.
`
`A recent review of chemotherapeutic treatment of carcino-
`ids reports that the sensitivity of these tumors to various
`cytotoxic drugs is low, and combination does not increase
`their effectiveness. Based on their review of various combi-
`
`including dacarbazine/fluorouracil or
`nation therapies,
`5-fluorouracil/epirubicin, the authors conclude that that they
`are unable to recommend a specific chemotherapeutic regi-
`men for patients with well-differentiated neuroendocrine
`malignancies ofthe GI tract (Arnold R, RinkeA et al, Clinical
`Gastroenterology 2005; l9(4):649-656). The apparent refrac-
`toriness of such tumors to currently available therapies points
`to an unmet medical need for treatment in this patient popu-
`lation.
`
`As part of the endocrine system that regulates hormones,
`the pituitary gland controls many of the other glands through
`secretion. Our “master gland,” the pituitary makes some hor-
`mones, but also acts as an intermediary between the brain and
`other endocrine glands. Our hormones and the pituitary gland
`accomplish many homeostatic and specialized functions, like
`bone growth and uterine contractions.
`Neurons carry messages regarding the production of hor-
`mones between the pituitary gland and the hypothalamus.
`Both are located at the base of the brain, nestled in a rounded
`part of bone, carefully protected. They are connected by a
`bunch of neurons called the infundibulum. Together, they
`work to regulate all the hormones that circulate in the blood-
`stream, controlling things like growth and hair pigmentation.
`Hormones are the long-distance messangers that can inform
`cells when to become active or stay dormant. The pituitary
`gland controls the thyroid, adrenal glands, ovaries and testes,
`even though it’s only the size of a pea.
`There are different parts of the pituitary gland that have
`selective functions. The posterior lobe, called the neurohypo-
`physis, releases the hormones vasopressin and oxytocin, but
`doesn’t produce them. Vasopressin is an anti-diuretic that
`controls how the kidneys absorb water. Oxytocin is a special
`hormone only present during childbirth to speed contractions.
`The anterior lobe of the pituitary gland is called the adeno-
`hypophysis. It produces a variety of hormones, such as pro-
`lactin that stimulates lactation in women. Melanocyte spurs
`the body to produce melanin for skin and hair pigmentation.
`Follicle-stimulating hormone indicates where and when hair
`should grow during development. The very important growth
`hormone controls bone growth to determine height, espe-
`cially active during adolescence. Hormones control glands as
`well. The thyroid reacts to thyrotropin, the adrenal glands are
`stimulated by adrenocorticotropin, and the sex glands are
`affected by luteinizing hormone. The pituitary gland is
`responsible for many stages and aspects of our maturation.
`Pituitary tumors are in general noncancerous (benign),
`comprising only 10 percent of brain tumors. However,
`because ofthe location ofthe pituitary gland, at the base ofthe
`skull, a pituitary tumor grows upward. And, eventually, many
`pituitary tumors press against the optic nerves, causing vision
`problems. Symptoms vary depending upon what type of
`tumor is growing and what area of the pituitary gland is
`affected. Pituitary tumors can cause symptoms that are
`caused by excess production ofpituitary hormones and symp-
`toms caused by reduced production of pituitary hormones.
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`Other symptoms may be due to the proximity ofthese tumors
`to local brain structures, such as the optic nerves leading to
`loss of vision. Each individual also experiences symptoms
`differently, and the symptoms many resemble other condi-
`tions or medical problems
`The most common type of pituitary tumor is called a clini-
`cally nonfunctioning tumor, because patients do not have the
`classic pituitary syndromes from excess hormones, such as in
`acromegaly. These types oftun1ors may be detected during an
`evaluation of an incidental problem. A clinically nonfunc-
`tioning tumor may cause hypopituitarism, or an underactive
`pituitary gland, which may lead to failure of sexual function,
`reduced sperm production, and cessation of a woman’ s men-
`strual period, along with fatigue.
`Another common pituitary tumor is called a prolactinoma,
`a benign tumor that produces the prolactin hormone. Prolac-
`tin stimulates breast milk production after childbirth. Women
`with a prolactinoma may have reduced or absent menstrual
`cycles along with breast milk production.
`An uncommon pituitary tumor causes excess growth hor-
`mone production (a hormone necessary for normal childhood
`growth) resulting in acromegaly. In adults, such tumors lead
`to excessive somatic growth and multiple systemic, medical
`consequences. Another uncommon pituitary tumor results in
`Cushing’s disease, a disorder of excess steroid production.
`Multiple endocrine neoplasia type 1 (MEN 1) is a relatively
`uncommon inherited disease. Individuals who inherit the
`
`gene for MEN 1 have an increased chance of developing
`overactivity and enlargement of certain endocrine glands.
`The endocrine glands most commonly affected by MEN 1 are
`the parathyroid, pancreas, and pituitary glands. Almost every-
`one who inherits MEN 1 develops overactivity ofthe parathy-
`roid glands (hyperparathyroidism) at some stage in their life.
`The other endocrine glands become overactive less fre-
`quently, however, people who inherit MEN 1 will usually
`develop overactivity in more than one endocrine gland. Over-
`activity in different endocrine glands may occur simulta-
`neously or at separate times during a persons life. MEN 1 can
`lead to overactivity and enlargement of the three endocrine
`glands listed above (the endocrine glands which start with the
`letter “P”). People who inherit the gene for MEN 1 are pre-
`disposed to developing an overactivity in hormone produc-
`tion from the parathyroid glands, pituitary gland and pancreas
`(that is why physicians will measure hormones in the blood to
`check for overproduction of each specific hormone).
`Increased hormone production is usually associated with
`enlargement of these glands. Endocrine gland enlargement
`and hormone overproduction does not usually occur in all
`areas of an endocrine gland at the same point in time. Some
`parts of overactive endocrine glands grow more rapidly than
`others, and produce more hormone than other parts of the
`same gland. The parts ofan endocrine gland which grow most
`rapidly become “lumpy”. These lumps are usually benign.
`Benign lumps in endocrine glands are known as adenomas.
`Adenomas are benign (not cancerous), and do not spread to
`other parts of the body. Pituitary adenomas (pituitary tumors,
`nervous system tumor) can lead to nerve damage, growth
`disturbances, and changes in hormonal balance. Symptoms of
`pituitary adenomas can vary considerably, largely depending
`on whether or not the tumor is secreting one or more of a
`variety of hormones. Even if the tumor is not producing any
`hormones,
`its location at the base of the brain can cause
`significant symptoms. Symptoms may e.g. include double or
`blurred vision, loss of peripheral vision, sudden blindness,
`headache, dizziness, loss of consciousness, nausea, weak-
`ness, unexplained weight changes, amenorrhea, erectile dys-
`function in men, decreased sexual desire, especially in men,
`
`Par Pharm., Inc.
`Exhibit 1001
`Page 004
`
`Par Pharm., Inc.
`Exhibit 1001
`Page 004
`
`

`
`US 9,006,224 B2
`
`7
`growth of skull, hands, and feet, deepening of voice, changes
`in facial appearance (due to changes in facial bones), wider
`spacing ofteeth, joint pain, increased sweating, purple stretch
`marks on the abdomen, increased hair growth, fat deposits
`where the neck meets the spine, moodiness or depression,
`easy bruising, palpitations (rapid or irregular heartbeat),
`tremor, increased appetite, feeling warm or hot, difficulty
`falling asleep, anxiousness, frequent bowel movements, lump
`in the front of the neck (enlarged thyroid).
`It was found that mTOR inhibitors may be used for the
`treatment of such special type of tumors
`In accordance with the particular findings the present
`invention provides in several aspects:
`1.1 A method for treating endocrine tumors, comprising
`administering to a subject in need thereof a therapeutically
`effective amount of an mTOR inhibitor.
`
`1.2 A method for inhibiting growth of endocrine tumors,
`comprising administering to a subject in need thereof a
`therapeutical effective amount of an mTOR inhibitor.
`1.3 A method for inhibiting or controlling endocrine tumors,
`comprising administering to a subject in need thereof a
`therapeutically effective amount of an mTOR inhibitor.
`1.4 A method for inducing endocrine tumor regression, e.g.
`tumor mass reduction, comprising administering to a sub-
`ject in need thereof a therapeutical effective amount of an
`mTOR inhibitor.
`
`1.5 A method for treating endocrine tumor invasiveness or
`symptoms associated with such tumor growth, comprising
`administering to a subject in need thereof a therapeutically
`effective amount of an mTOR inhibitor.
`
`1.6 A method for preventing metastatic spread of endocrine
`tumors or for preventing or inhibiting growth of microme-
`tastasis, comprising administering to a subject in need
`thereof a therapeutically effective amount of an mTOR
`inhibitor.
`1.7 A method for the treatment of a disorder associated with
`endocrine tumors, comprising administering to a subject in
`need thereof a therapeutically effective amount of an
`mTOR inhibitor.
`1.8 The use of an mTOR inhibitor for the manufacture of a
`medicament for use in any method of 1.1 to 1.7 above.
`1.9 A pharmaceutical composition comprising an mTOR
`inhibitor in association with at least one pharmaceutically
`acceptable excipient, e.g. appropriate carrier and/or dilu-
`ent, e.g. including fillers, binders, disintegrants, flow con-
`ditioners, lubricants, sugars or sweeteners, fragrances, pre-
`servatives, stabilizers, wetting agents and/or emulsifiers,
`solubilizers, salts for regulating osmotic pressure and/or
`buffers; for use in any method or use of 1.1 to 1.7 above.
`Endocrine tumors as indicated herein e. g. include neuroen-
`docrine tumors, e.g. including carcinoid tumors, pancreatic
`neuroendocrine tumors and tumors in parathyroid, pancreas,
`and pituitary glands.
`Carcinoid tumors as indicated herein e.g. include typical
`and atypical carcinoids, ranging from low-grade malignant
`typical to intermediate atypical to high-grade large-cell neu-
`roendocrine carcinoma and small-cell lung carcinoma; e.g.
`including carcinoids arising from the
`foregut e.g., bronchial, pulmonary or gastric carcinoids,
`e.g. including primary foregut tumors confined to the
`thymus, lung, stomach, and duodenum; e.g. carcinoid
`tumors of the GI tract, e.g. located in the colon, stomach
`or small intestine, e.g. small-intestinal carcinoids, e.g.
`including
`midgut, e.g., small intestine or appendiceal carcinoids, e.g.
`located in the distal ileum, cecum, and proximal colon,
`or
`
`hindgut, e.g., rectal carcinoids.
`
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`15
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`20
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`25
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`35
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`8
`Carcinoid lung tumors as indicated herein e.g. include
`neuroendocrine
`carcinoma, Kulchitsky cell
`carcinoma
`(KCC) (Kulchitsky cells, argentaffin cells), bronchial carci-
`noid tumors, bronchial adenomas, e.g. including bronchial
`adenomas such as a small cell carcinoma and large cell neu-
`roendocrine tumors, typical carcinoids or atypical carcinoids
`associated with large bronchopulmonary carcinoid tumors or
`small-cell carcinomas, pulmonary carcinoids, neuroendo-
`crine lung tumors, large-cell neuroendocrine carcinoma of
`the lung, (primary) pulmonary neoplasms, bronchopulmo-
`nary carcinoid tumors, lung neoplasms, lung cancers, pulmo-
`nary cancers, intrabronchial mass.
`Pancreatic neuroendocrine tumors as indicated herein e.g.
`include islet cell
`tumors, APUDomas,
`insulinomas, glu-
`cagonomas, nonfunctioning pancreatic NETs, pancreatic
`NETs associated with hypercalcemia, gastrinomas, VlPo-
`mas, somatostatinomas, GRFomas.
`Endocrine or neuroendocrine tumor symptoms as indi-
`cated herein e.g. include hemoptysis, cough, recurrent pul-
`monary infection, fever, chest discomfort and chest pain,
`unilateral wheezing, shortness of breath, flushing and diar-
`rhea, endocrine or neuroendocrine syndromes carcinoid syn-
`drome, e.g.
`including manifestations of either typical or
`atypical pulmonary carcinoid tumors, Cushing’s syndrome,
`inappropriate secretion ofADH, increased pigmentation sec-
`ondary to excess MSH, and ectopic insulin production result-
`ing in hypoglycemia, ectopic growth hormone-releasing hor-
`mone secretion, ectopic secretion of corticotropin, cardiac
`manifestations secondary to fibrosis of the endocardium (en-
`docardial fibrosis), valvular regurgitation (valvular heart dis-
`ease),
`tricuspid insufficiency, secondary right-sided heart
`failure, wheezing or asthma-like symptoms, pellagra-like
`skin lesions with hyperkeratosis, abdominal pain, telang-
`iectasias and paroxysmal hypotension, recurrent pneumonia,
`cough, chest pain.
`Tumors in parathyroid, pancreas and pituitary glands as
`indicated herein, e.g. include pituitary tumors, nervous sys-
`tem tumor, such as adenomas, multiple endocrine neoplasia
`type 1 (MEN 1).
`Pituitary tumor symptoms as indicated herein include
`symptoms that are associated with excess production of pitu-
`itary hormones and symptoms caused by reduced production
`of pituitary hormones, loss of vision, clinically nonfunction-
`ing tumor, e.g. associated with hypopituitarism underactive
`pituitary gland, e.g. associated with failure of sexual function,
`reduced sperm production, and cessation of a woman’ s men-
`strual period, along with fatigue, prolactinoma, a benign
`tumor that produces the prolactin hormone, acromegaly, e.g.
`associated with excessive somatic growth and multiple sys-
`temic, medical consequences, Cushing’s disease, nerve dam-
`age, growth disturbances, changes in hormonal balance,
`double or blurred vision, loss of peripheral vision, sudden
`blindness, headache, dizziness, loss of consciousness, nau-
`sea, weakness, unexplained weight changes, amenorrhea,
`erectile dysfunction in men, decreased sexual desire, espe-
`cially in men, growth of skull, hands, and feet, deepening of
`voic