UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Amerigen Pharmaceuticals Limited and Argenan Pharmaceuticals LLC
`
`Petitioners
`
`v.
`
`Janssen Oncology, Inc.
`
`Patent Owner
`
`US. Patent No. 8,822,438 to Auerbach et al.
`Issue Date: September 2, 2014
`Title: Methods and Compositions for Treating Cancer
`
`Inter Panes Review No. 2016-00286'
`
`Declaration of Dr. Richard I. Doria
`
`I declare that all statements made herein on my own knowledge are true and that
`
`all statements made on information and belief are believed to be tme, and
`
`further, that these statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by fine or imprisonment, or
`
`both, under Section 1001 of Title [8 of the United States Code.
`
`Awe/QED HM?
`
`__—__.____
`
`Richard I. Doria, M.D.
`
`Dat
`
`' Case lPR2016-01317 has been joined with this proceeding.
`
`
`
`
`
`
`
`AMERIGEN 1093
`AMERIGEN 1093
`
`

`

`Table of Contents
`
`I.
`
`Introduction ................................................................................................. 1
`
`Education and Professional Background ...................................................... 1
`II.
`III. Legal Standards ........................................................................................... 3
`
`IV. Summary of Opinions .................................................................................. 4
`
`A. AA administered to humans inhibits BOTH 17-hydroxylase and 17,20-lyase
`activities. ............................................................................................................ 4
`
`B. Among the spectrum of P450c17 deficiency syndromes related to mutations
`in the P450c17 gene, the subtype designated as combined, partial 17-
`hydroxylase/17,20-lyase deficiency is the most relevant and appropriate for
`analogy in relation to men receiving long-term AA. ........................................... 5
`
`C. I disagree with Dr. Auchus’ conclusion (paragraph 58) that the relevant
`analogy between AA and P450c17 deficiency would be “isolated 17,20-lyase”
`deficiency (Auchus paragraph 58). ..................................................................... 9
`
`D. A POSA would conclude that there is a substantial risk for clinically relevant
`cortisol deficiency in men with mCRPC treated long term with AA. .................. 9
`
`E. POSA would conclude that there is a substantial risk for development of
`mineralocorticoid excess in men with mCRPC treated with long-term AA, and
`that “concomitant administration of replacement glucocorticoid” would be a
`reasonable, safe, and appropriate management strategy for prevention and
`treatment of mineralocorticoid excess. .............................................................. 13
`
`F. POSA would recognize the safety of “concomitant administration of
`replacement glucocorticoid” in the study population of men with mCRPC. ...... 17
`
`V. DEFINITIONS .......................................................................................... 22
`
`VI. DETAILED ANALYSIS OF OPINIONS .................................................. 23
`
`A. Background. ............................................................................................... 23
`B. Cortisol Levels and the Synacthen Test. ..................................................... 24
`
`1. Timing of cortisol collection in the standard ACTH1-24 stimulation
`test 24
`
`i
`
`

`

`2. Baseline, peak, and ∆-cortisol ............................................................ 25
`3. The standard, high-dose (250 m g) and low dose (1 m g) ACTH1-24
`stimulation tests ......................................................................................... 26
`4. Cut-scores used for the clinical diagnosis of adrenal insufficiency .... 27
`
`5. ACTH1-24-stimulated cortisol concentration is less influenced by time
`of day than ∆-cortisol ................................................................................. 27
`
`C. Study C in O’Donnell ................................................................................. 28
`
`1. ACTH1-24 stimulation testing before and after 11 days of once daily
`AA 28
`
`Post-AA mean ∆-cortisol values are markedly reduced compared to
`2.
`pre-AA ∆-cortisol values, and post-AA ∆-cortisol are markedly reduced
`compared to established reference ranges .................................................. 29
`
`3. ∆-cortisol is similarly decreased in AA-treated subjects and in patients
`with 17-hydroylase/17,20-lyase deficiency ................................................ 30
`
`4. Dr. Auchus’ dismissal of ∆-cortisol data in O’Donnell (Study C) is not
`justified ...................................................................................................... 31
`
`5. Dr. Auchus’ objection that O’Donnell presentation of cortisol data as
`mean without measure of variability is sustained, but this omission does not
`influence the POSA’s interpretation of Study C ......................................... 31
`6. Dr. Auchus’ concern that the dose of Synacthen (1 vs. 250 m g) used in
`Study C was not specified is invalid but, regardless, would not influence
`interpretation of ∆-cortisol data .................................................................. 33
`
`7. Dr. Auchus’ concern that time of day that the Synacthen test was
`performed was not specified is invalid but, regardless, would not influence
`interpretation of ∆-cortisol data .................................................................. 35
`
`8. Dr. Auchus argument (paragraph 28) that O’Donnell presentation of
`cortisol data in Study should have included peak cortisol instead of or in
`addition to ∆-cortisol is sustained, but the omission of peak cortisol
`concentration data does not invalidate or influence POSA’s interpretation of
`Study C ...................................................................................................... 36
`
`9.
`
`Summary of Study C analysis ............................................................ 39
`
`ii
`
`

`

`D. Endocrine data for single dose studies (Studies A and B) in O’Donnell would
`not dissuade a POSA from the conclusion that “adrenocortical suppression may
`necessitate concomitant administration of replacement glucocorticoid” in patients
`treated with long-term AA ................................................................................ 40
`
`E. The absence of overt manifestations of adrenal insufficiency during clinical
`event monitoring data reported in O’Donnell (“Overall Toxicity” section) would
`not dissuade a POSA from the conclusion that “adrenocortical suppression may
`necessitate concomitant administration of replacement glucocorticoid” in patients
`treated with long-term AA ................................................................................ 43
`
`F. The absence of overt manifestations of mineralocorticoid excess during
`clinical event monitoring data reported in O’Donnell (“Overall Toxicity” section)
`would not dissuade a POSA from the conclusion that concomitant administration
`of replacement glucocorticoid is indicated in patients treated with long-term AA
`
`46
`
`
`
`iii
`
`

`

`I, Richard I. Dorin, M.D., do hereby declare:
`
`I.
`
`Introduction
`
`1.
`
`At the request of Petitioners Amerigen Pharmaceuticals, Ltd. and
`
`Argentum Pharmaceuticals, LLC (“Petitioners”) in the matter of the inter partes
`
`review of U.S. Patent No. 8,822,438 (the “’438 Patent” (AMG 1001), requested by
`
`Petitioners and instituted by Patent Trial and Appeal Board of the United States Patent and
`
`Trademark Office in Case No. IPR2016-00286 and Case No. IPR2016-01317, I have been
`
`asked to provide my opinions regarding the expert declaration and deposition testimony of
`
`Richard Auchus, M.D., Ph.D., submitted on behalf of Patent Owner Janssen
`
`Oncology, Inc. (“Janssen”).
`
`2.
`
`I am being compensated for my work in this matter at the rate of
`
`$400.00 per hour. My compensation in no way depends on the outcome of this
`
`proceeding. The opinions I set forth herein are my own, and are based on the
`
`education, experience, training and skill that I have accumulated in the course of
`
`my career as a physician and researcher, as well as the materials I have reviewed in
`
`connection with this case.
`
`II. Education and Professional Background
`
`3.
`
`I currently practice medicine at the New Mexico Veterans
`
`Administration Healthcare System in Albuquerque, New Mexico. I am also a
`
`Professor of Medicine and Biochemistry & Molecular Biology at the University of
`
`1
`
`

`

`New Mexico School of Medicine. I have had clinical privileges and engaged in
`
`teaching and research at both New Mexico VA and University of New Mexico
`
`School of Medicine since 1988.
`
`4.
`
`I was board certified in Internal Medicine in 1982, and certified in
`
`Endocrinology and Metabolism in 1987.
`
`5.
`
`I received my bachelor of arts degree in Biology-Psychology magna
`
`cum laude from Wesleyan University in Middletown, Connecticut in 1975. I
`
`received my medical degree from University of California Los Angeles (UCLA)
`
`School of Medicine in 1979. I then completed three years of residency training in
`
`Internal Medicine at Santa Clara Valley Medical Center in San Jose, California. I
`
`did three years of endocrine fellowship training at Stanford University School of
`
`Medicine, and did a year of post-doctoral research at the University of Kyoto
`
`School of Medicine in the laboratories of H. Imura (Internal Medicine and
`
`Endocrinology, U. Kyoto) and S. Numa (Biochemistry and Molecular Biology, U.
`
`Kyoto).
`
`6.
`
`I am Professor of Medicine and Biochemistry & Molecular Biology at
`
`the University of New Mexico School of Medicine. I have authored approximately
`
`100 peer reviewed publications, presentations and abstracts in the fields of
`
`endocrinology and metabolism. I am a senior member of University of New
`
`Mexico and New Mexico VA Healthcare System Institutional Review Boards with
`
`2
`
`

`

`over 15 years of IRB experience.
`
`7.
`
`In preparing this declaration, I have relied on my knowledge, training
`
`and expertise, and the documents cited herein, including the documents listed in
`
`Exhibit A, as well as the materials discussed in the Auchus Declaration (JSN 2040)
`
`8.
`
`Attached as Exhibit B is my curriculum vitae providing the details of
`
`my education, experience and training in medicine, including in the field of
`
`endocrinology.
`
`III. Legal Standards
`
`9.
`
`I have been asked to adopt Dr. Serels’ definition of a person of
`
`ordinary skill in the art (“POSA”) at the effective filing date for purposes of this
`
`declaration. [AMG 1002, Serels Decl. ¶ 8.] I understand that the earliest possible
`
`effective filing date is August 25, 2006, and have used this date for my analysis
`
`10.
`
`I understand that Patent Owner’s experts (Drs. Rettig and Auchus)
`
`have proposed a different definition of the POSA. My opinions offered here would
`
`not change if I used Patent Owner’s experts’ definition of a POSA.
`
`11.
`
`I understand that the obviousness inquiry is a question of law based
`
`on four factual predicates: (1) "the scope and content of the prior art," (2) the
`
`"differences between the prior art and the claims at issue," (3) "the level of
`
`ordinary skill in the pertinent art," and (4) “secondary considerations” such as
`
`commercial success, long-felt but unsolved needs, failure of others, and
`
`3
`
`

`

`unexpected results. I also understand that the combination of familiar elements
`
`according to known methods is likely to be obvious when it does no more than
`
`yield predictable results. I understand that the motivation to combine may be
`
`found in many different places and forms. Thus, for example, a challenger is not
`
`limited to the same motivation that the patentee had.
`
`12.
`
`I have been informed that secondary considerations of non-
`
`obviousness include commercial success, satisfaction of a long-felt unmet need,
`
`unexpected results, prior failure of others, industry praise, licensing, and copying.
`
`I understand that evidence of such secondary considerations is only relevant to the
`
`obviousness analysis if the patentee can show a direct link, or nexus, between the
`
`secondary consideration and the claims of the patent, and that the evidence must be
`
`commensurate in scope with the asserted claims. I also understand that for results
`
`to be considered unexpected for these purposes, there must be a substantial
`
`difference from the prior art. In other words, a difference of kind, and not merely
`
`of degree.
`
`IV. Summary of Opinions
`
`A. AA administered to humans inhibits BOTH 17-hydroxylase and
`17,20-lyase activities.
`
`13. A POSA would recognize that both in vitro data (Barrie, AMG 1005)
`
`and in vivo data in human subjects (O’Donnell, AMG 1003) are clear and
`
`consistent. Collectively, they teach a POSA that abiraterone in vitro inhibits
`
`4
`
`

`

`BOTH 17-hydroxylase and 17,20-lyase activities and that administration of
`
`abiraterone acetate (AA) at physiologically relevant doses in humans similarly
`
`inhibits BOTH 17-hydroxylase and 17,20-lyase activities. The argument of Dr.
`
`Auchus that a POSA would conclude that AA does not affect 17-hydroxylase in
`
`humans, i.e. that its effects are limited to inhibition of 17,20-lyase activity, is
`
`incorrect.
`
`14. My opinions that a POSA would conclude that AA affects both 17-
`
`hydroxylase and 17,20-lyase activities are confirmed by publications that interpret
`
`the data of both Barrie and O’Donnell. In particular, Attard 2005 (AMG 1023)
`
`conducted an independent review of abiraterone, which interpreted the in vitro data
`
`(Barrie) and in vivo data (O’Donnell) as indicating that abiraterone in vitro and AA
`
`in vivo inhibits BOTH 17-hydroxylase and 17,20-lyase activities. That Attard
`
`2005 (AMG 1023) reached this same conclusion using the data (Barrie and
`
`O’Donnell) is proof of principle that a POSA in August 2006 would have reached
`
`a similar conclusion. In other words, a POSA would conclude that physiologically
`
`relevant doses of AA administered to humans would result in inhibition of BOTH
`
`17-hydroxylase and 17,20-lyase activities.
`
`B. Among the spectrum of P450c17 deficiency syndromes related to
`mutations in the P450c17 gene, the subtype designated as combined,
`partial 17-hydroxylase/17,20-lyase deficiency is the most relevant and
`appropriate for analogy in relation to men receiving long-term AA.
`
`15. The POSA would be aware of the extensive literature synthesizing the
`
`5
`
`

`

`clinical, biochemical, and molecular biology of patients with P450c17 gene
`
`mutations resulting in clinically recognized variations in 17-hydroxylase/17,20-
`
`lyase deficiency (1-3). (AMG 1153 (Attard 2012); AMG 1026 (Auchus 2001);
`
`AMG 1154 (Yanase 1991).) The single P450c17 gene encodes a single protein
`
`having two distinct enzymatic activities, i.e. 17-hydroxylase and 17,20-lyase
`
`activities. Since rational design and development of abiraterone was based on its
`
`ability to inhibit both 17-hydroxylase and 17,20-lyase activities in vitro, POSA
`
`would be aware that an analogy between patients with P450c17 gene mutations
`
`and men treated with AA could be usefully made. Moreover, POSA would
`
`appreciate that in lieu of data regarding the long term use of AA in men with
`
`mCRPC, experience garnered from studies of patients with relevant P450c17 gene
`
`mutations could provide useful insights into pathophysiology, clinical
`
`manifestations, and management options that would be anticipated for men with
`
`mCRPC receiving long-term AA treatment.
`
`16.
`
`In my opinion the form 17-hydroxylase/17,20-lyase deficiency most
`
`relevant to long-term AA in humans is combined, partial 17-hydroxylase/17,20-
`
`lyase deficiency (2-7). (AMG 1026 (Auchus 2001); AMG 1154 (Yanase 1991);
`
`AMG 1027 (Costa-Santos); AMG 1155 (Van Den Akker); AMG 1156 (Yanase).)
`
`There was an abundance of literature characterizing clinical and laboratory
`
`manifestations of patients having P450c17 gene mutations and the syndrome of
`
`6
`
`

`

`combined, partial 17-hydroxylase/17,20-lyase activity that was available to a
`
`POSA (2-7). (AMG 1026 (Auchus 2001); AMG 1154 (Yanase 1991); AMG 1027
`
`(Costa-Santos); AMG 1155 (Van Den Akker); AMG 1156 (Yanase).) In these
`
`patients, 17-hydroxylase activity is markedly reduced but not wholly absent, hence
`
`the term “partial” rather than “complete” deficiency is applicable. In general, the
`
`P450c17 mutations identified in patients with partial 17-hydroxylase/17,20-lyase
`
`activity are point mutations, e.g. single amino acid substitutions, that modify the
`
`structure of the protein and are associated with markedly reduced, but not complete
`
`elimination, of 17-hydroxylase and/or 17,20-lyase activities (2-7). (AMG 1026
`
`(Auchus 2001); AMG 1154 (Yanase 1991); AMG 1027 (Costa-Santos); AMG
`
`1155 (Van Den Akker); AMG 1156 (Yanase).) By contrast, mutations in the
`
`P450c17 gene associated with complete deficiency are often associated with
`
`frame-shift or truncation mutations that more radically alter the structure of the
`
`protein. These latter mutations therefore lead to complete elimination of 17-
`
`hydroxylase and/or 17,20-lyase activities (see for example Table 5 in Yanase et
`
`al.(3) AMG 1154 (Yanase 1991).)
`
`17.
`
`In reviewing the literature characterizing clinical and laboratory
`
`findings in patients with P450c17 mutations, a POSA would appreciate that
`
`cortisol concentrations observed in patients with P450c17 mutations associated
`
`with combined, partial 17-hydroxylase/17,20-lyase deficiency (3;5-7) (AMG 1154
`
`7
`
`

`

`(Yanase 1991); AMG 1027 (Costa-Santos); AMG 1155 (Van Den Akker); AMG
`
`1156 (Yanase)) are remarkably similar to comparable cortisol data reported in
`
`O’Donnell for men with mCRPC treated with AA, with baseline cortisol
`
`concentrations in the low normal range and markedly diminished ∆-cortisol in
`
`response to exogenous ACTH1-24 (8). (AMG 1003 (O’Donnell).)
`
`18.
`
`In view of the above clarification regarding combined 17-
`
`hydroxylase/17,20-lyase deficiency vs. isolated 17,20-lyase deficiency and
`
`complete vs. partial 17-hydroxylase deficiency, I disagree with Dr. Auchus’ choice
`
`of the term, “complete C17 deficiency” to represent “combined 17-
`
`hydroxylase/17,20-lyase deficiency” (JSN 2040 (Auchus declaration), ¶ 52). The
`
`use of the term “complete” is misleading, as it implies complete deficiency of 17-
`
`hydroxylase activity, even though he is using the term with a meaning synonymous
`
`to combined 17-hydroxylase/17,20-lyase deficiency. This terminology and train of
`
`thought is confusing, since it implies (incorrectly) that no cortisol production
`
`would be possible in patients with “complete c17 deficiency” (Auchus’ definition).
`
`Following this line of reasoning, Dr. Auchus incorrectly interprets the finding of
`
`baseline cortisol concentrations “within normal limits” in O’Donnell et al.(8)
`
`(AMG 1003) as evidence against the possibility that AA caused “complete c17
`
`deficiency”.
`
`8
`
`

`

`C.
`I disagree with Dr. Auchus’ conclusion (paragraph 58) that the
`relevant analogy between AA and P450c17 deficiency would be
`“isolated 17,20-lyase” deficiency (Auchus paragraph 58).
`
`19. Dr. Auchus has incorrectly concluded that a POSA would consider
`
`“isolated 17,20-lyase deficiency” as the P450c17 syndrome most analogous the
`
`AA. In fact, based on data of Barrie (AMG 1005) and O’Donnell (AMG 1003), a
`
`POSA would have correctly concluded that the P450c17 genetic syndrome of
`
`combined, partial 17-hydroxylase/17,20-lyase deficiency is most relevant and
`
`appropriate for analogy to AA treatment in humans. The erroneous analogy to
`
`isolated 17,20-hydoxylase deficiency proposed by Dr. Auchus is based upon his
`
`incorrect interpretation of cortisol data in O’Donnell et al. (Study C). (AMG
`
`1003.) This error propagates through his analysis. Accordingly, Dr. Auchus’
`
`reaches the incorrect conclusion that 17-hydroxlase activity is not affected by AA
`
`in humans. Similarly, Dr. Auchus’ reaches the incorrect conclusion that cortisol
`
`concentrations are not affected by AA in humans.
`
`D. A POSA would conclude that there is a substantial risk for
`clinically relevant cortisol deficiency in men with mCRPC treated long
`term with AA.
`
`20.
`
`In evaluating the risk for clinically relevant cortisol deficiency, a
`
`POSA would be aware that cortisol deficiency could manifest either as (i) overt
`
`adrenal insufficiency or (ii) failure to appropriately increase cortisol production
`
`during episodes of “concurrent stress” (9-11). (AMG 1160 (Dorin); AMG 1161
`
`9
`
`

`

`Grinspoon); AMG 1162 (Oelkers).)
`
`21. By way of background, a POSA would understand that requirements
`
`for cortisol production increase dramatically during acute episodes of “concurrent
`
`stress” (9;12;13) (AMG 1160 (Dorin); AMG 1163 (Melby 1958); AMG 1164
`
`(Melby (1960))) (see also Definitions). For example conditions such as surgery,
`
`urosepsis (severe urinary tract infection), or pneumonia are examples of
`
`“concurrent stress” that might be relevant in a population of men with mCRPC. In
`
`this context, a POSA would be aware of the literature indicating the normal
`
`response to concurrent stress is a dramatic increase in production of cortisol, and
`
`that failure to appropriately increase cortisol production is associated with
`
`unfavorable clinical outcomes (9;12-14). (AMG 1160 (Dorin); AMG 1163 (Melby
`
`1958); AMG 1164 (Melby (1960); AMG 1165 (Marik).) The requirement for
`
`increased cortisol during concurrent stress informs principles of “stress doses of
`
`cortisol” in critically ill patients that are cortisol deficient and also informs the
`
`standard “sick day” rules by which patients with an established diagnosis of
`
`adrenal insufficiency are instructed to increase cortisol replacement dose during
`
`periods of mild or moderate concurrent stress (9;11). (AMG 1160 (Dorin); AMG
`
`1162 (Oelkers).) Failure to increase cortisol in response to concurrent stress can
`
`lead to adrenal crisis, a life-threatening condition that requires intensive care
`
`hospitalization and, without appropriate cortisol replacement therapy, is commonly
`
`10
`
`

`

`a fatal condition (see also Definitions) (9;12-14). (AMG 1160 (Dorin); AMG 1163
`
`(Melby 1958); AMG 1164 (Melby (1960); AMG 1165 (Marik).)
`
`22. Moreover, a POSA would recognize from the teachings of O’Donnell
`
`et al. (8) (AMG 1003) that cortisol production rates are already at or near maximal
`
`in men treated with AA. Accordingly, the ability of mCRPC patients on long-term
`
`AA to increase cortisol production during episodes of “concurrent stress” would be
`
`severely compromised due to abiraterone-mediated inhibition of 17-hydroxylase
`
`activity. A POSA would also understand that adrenal crisis could occur in patients
`
`having no clinical or laboratory evidence of adrenal insufficiency prior to an acute
`
`episode of concurrent stress (11). (AMG 1162 (Oelkers).)
`
`23.
`
`In considering the risks of cortisol deficiency in men with mCRPC
`
`treated long-term with AA, a POSA would take into consideration the clinical
`
`issues specific to the treatment population, recognizing that the risk of concurrent
`
`stress and adrenal crisis would be far greater in a high-risk, elderly population.
`
`POSA would also recognize that the clinical manifestations of adrenal
`
`insufficiency and mCRPC overlap considerably, making the exclusion of overt
`
`adrenal insufficiency on clinical grounds challenging and perilous. And POSA
`
`would understand that for men with mCRPC, the interval between diagnosis of
`
`mCRPC and death is likely to be punctuated by episodes of “concurrent stress”, the
`
`occurrence of which is predictable but the timing of which is unpredictable.
`
`11
`
`

`

`Therefore POSA would recognize that risk of both (i) overt adrenal insufficiency
`
`and (ii) adrenal crisis during concurrent stress would be considerable in men with
`
`mCRPC treated for long term with AA. POSA would recognize the potential
`
`safety and efficacy of concomitant administration of replacement corticosteroid in
`
`decreasing the risk of both overt adrenal insufficiency and adrenal crisis in men
`
`with mCRPC treated with long-term AA. POSA would reach the same conclusion
`
`as O’Donnell et al. in recognizing that “adrenocortical suppression may necessitate
`
`concomitant administration of replacement glucocorticoid” (8) (AMG 1003) in
`
`patients receiving long-term AA therapy for treatment of mCRPC.
`
`24. For reasons outlined above, I disagree with Dr. Auchus’ interpretation
`
`of the clinical outcome data reported in O’Donnell and his conclusion that the
`
`absence of overt manifestations of adrenal insufficiency during and after 12 days
`
`of AA treatment reported in O’Donnell would provide sufficient justification for
`
`withholding concomitant administration of replacement glucocorticoid in men with
`
`mCRPC treated with long-term AA. POSA would recognize that 12 days of
`
`treatment was not a sufficient amount of time to assess the risk of long-term
`
`treatment with AA, especially in the absence of any episodes of concurrent stress.
`
`POSA would be aware that episodes of adrenal crisis had been reported in the
`
`setting of concurrent stress in patients with genetic forms of combined 17-
`
`hydroxylase/17,20-lyase deficiency (3;15;16). (AMG 1154 (Yanase (1991); AMG
`
`12
`
`

`

`1166 (Abad); AMG 1167 (Heremans).) POSA would also consider the risk of
`
`adrenal insufficiency or adrenal crisis during intercurrent stress in patients treated
`
`with AA in the relevant clinical context. For example, since men with mCRPC are
`
`generally elderly and the importance of co-morbid conditions in the clinical
`
`trajectory of patients with mCRPC is well established, the risk of clinically
`
`significant cortisol deficiency is far greater, for example, than an otherwise
`
`healthy, pediatric population.
`
`E.
`POSA would conclude that there is a substantial risk for
`development of mineralocorticoid excess in men with mCRPC treated
`with long-term AA, and that “concomitant administration of
`replacement glucocorticoid” would be a reasonable, safe, and
`appropriate management strategy for prevention and treatment of
`mineralocorticoid excess.
`
`25. On the basis of the known impact of abiraterone on biosynthetic
`
`pathways of adrenal steroidogenesis and an extensive literature characterizing
`
`clinical manifestations of with P450c17 mutations associated with combined,
`
`partial, 17-hydroxylase/17,20-lyase deficiency, a POSA would anticipate the
`
`development of clinically relevant mineralocorticoid excess in patients treated with
`
`AA for a long duration (3;17). (AMG 1154 (Yanase (1991); AMG 1168 (Auchus
`
`(2017).)
`
`26.
`
`In his declaration, Dr. Auchus acknowledges that concomitant
`
`administration of replacement glucocorticoid administration is a reasonable,
`
`customary, and appropriate option for management of mineralocorticoid excess in
`
`13
`
`

`

`patients with combined 17-hyroxylase/17,20-lyase deficiency, and by analogy
`
`would be a reasonable and appropriate option for management of
`
`mineralocorticoid excess in mCRPC patients treated with long-term AA.
`
`However, Dr. Auchus argues that that mineralocorticoid excess in this setting
`
`could be managed by alternative options that do not include concomitant
`
`administration of replacement glucocorticoid. In my opinion, a POSA would
`
`consider available management alternatives to replacement glucocorticoid to be
`
`quite limited. I disagree with Dr. Auchus’ conclusion that a POSA would prefer to
`
`use these alternative management options that do not include “concomitant
`
`administration of replacement glucocorticoid”. In my opinion, POSA would be
`
`aware that such an approach of managing mineralocorticoid excess associated with
`
`long-term AA use without concomitant administration of replacement
`
`glucocorticoid would be associated with significant risks, limited efficacy,
`
`increased costs, and decreased efficiency. For example, a POSA with endocrine
`
`consultation would be aware that the situation in 17-hydroxylase deficient patients
`
`and by analogy to AA-treated patients, in which glucocorticoid deficiency and
`
`mineralocorticoid excess syndromes coexist, is at variance with the more usual
`
`setting of primary adrenal insufficiency, in which glucocorticoid and
`
`mineralocorticoid deficiency syndromes obtain. Accordingly, in the usual situation
`
`of primary adrenal insufficiency, treatment of adrenal crisis with exogenous
`
`14
`
`

`

`corticosteroids corrects the glucocorticoid and mineralocorticoid deficiencies in
`
`concordant fashion, leading to improvement in hypotension and volume depletion.
`
`By contrast, because the mineralocorticoid excess syndrome is driven by elevated
`
`ACTH concentrations in 17-hydroxylase deficiency and by analogy in AA-treated
`
`patients, treatment of adrenal crisis with exogenous corticosteroids in that setting
`
`would be expected to correct glucocorticoid deficiency but decrease ACTH-
`
`dependent production of mineralocorticoid hormones. These considerations would
`
`raise concern for a POSA that in this setting (treatment of AA-associated
`
`mineralocorticoid excess with mineralocorticoid receptor antagonist without
`
`concomitant replacement glucocorticoids), usual and customary treatment of acute
`
`episodes adrenal insufficiency or adrenal crisis with corticosteroid replacement
`
`could potentially result in clinically significant mineralocorticoid deficiency (18).
`
`(AMG 1069 (New).) The clinical consequences of mineralocorticoid deficiency,
`
`such as hypotension and volume depletion, would be expected to be even more
`
`severe in a patient on high doses of mineralocorticoid receptor antagonist required
`
`in the management of mineralocorticoid excess without concomitant
`
`administration of replacement glucocorticoid. Accordingly, a POSA with
`
`endocrine consultation would consider the risk that for patients on AA whose
`
`mineralocorticoid excess was managed solely with mineralocorticoid antagonist
`
`(without concomitant administration of replacement glucocorticoid), initiation of
`
`15
`
`

`

`cortisol replacement for treatment of acute adrenal insufficiency (e.g. adrenal
`
`crisis) could actually lower blood pressure through a mechanism of decreased
`
`ACTH-dependent production of adrenal mineralocorticoids, such as
`
`deoxycorticosterone (DOC, see AMG 1026, Figure 1). Indeed, the development of
`
`hypotension following glucocorticoid replacement was a complication in
`
`subsequent phase 1 studies of AA in men with mCRPC (19). (AMG 1170 (Ryan
`
`2010).)
`
`27.
`
`I also note that at least one of the mineralocorticoid antagonists
`
`suggested by Dr. Auchus, potassium canrenoate, is not and never has been
`
`commercially available in the United States. In addition, potassium canrenoate
`
`was a known metabolite of spironolactone. It was known as of August 2006 that
`
`spironolactone could activate androgen receptor in patients with mCRPC (19;20)
`
`(AMG 1170 (Ryan 2010); AMG 1171 (Therasse)), and a POSA would have
`
`expected potassium canrenoate to have a similar risk of androgen receptor
`
`activation as spironolactone. See, e.g., Attard 2008 (JSN 2014) at 4656. In
`
`addition, eplerenone was a recently approved drug. Therefore, the efficacy of
`
`eplerenone in the management of mineralocorticoid excess would be understood to
`
`be exploratory. Cf. Auchus (JSN 2040) ¶¶ 61, 62. Eplerenone was known to be a
`
`far less potent mineralocorticoid antagonist than spironolactone (eplerenone having
`
`about 25% the potency as spironolactone), and efficacy at even maximum doses of
`
`16
`
`

`

`eplerenone would be uncertain. In addition, given the options to correct
`
`manifestations of mineralocorticoid excess, i.e. normalize deoxycorticosterone
`
`concentrations vs. blocking the effects of elevated deoxycorticosterone
`
`concentrations, the safety and logic of the former approach would be evident to a
`
`POSA.
`
`F.
`POSA would recognize the safety of “concomitant administration
`of replacement glucocorticoid” in the study population of men with
`mCRPC.
`
`28. A POSA would have been aware of an extensive literature, including
`
`clinical trials, that clearly established the risk profile of replacement glucocorticoid
`
`in the relevant treatment population of men with mCRPC (21-23). (AMG 1172
`
`(Osoba); AMG 1006 (Tannock (1996)); AMG 1022 (Tannock (2004)).) The
`
`known risks of concomitant administration of replacement glucocorticoid would be
`
`far more acceptable to a POSA in comparison to the unknown but predictable risks
`
`of AA without concomitant administration of replacement glucocorticoid. This
`
`would be esp