ALKERMES EXHIBIT 2016
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`Page 1 of 9
`
`

`

`alcohol dependence” as part of an appropriate plan of management for addictions.
`Naltrexone has not been widely used for this indication due to the general belief that its
`efficacy is limited, and that poor compliance is one of the more significant factors
`contributing to this limited efficacy. The sponsor has proposed that an extended—release
`depot preparation may improve compliance and, therefore, effectiveness. They have also
`proposed that the absence of a first-pass effect in the liver may decrease the hepatic
`toxicity noted in the original naltrexone application resulting in the inclusion of a boxed
`warning in the package insert.
`’
`
`Review of the CMC portion of this application was completed by Jila H. Boal, Ph.D.
`Review of the pharmacology and toxicology data presented in this application was
`completed by Mamata De, Ph.D. A supervisory review was provided by Daniel Mellon,
`Ph.D., Supervisory Pharmacologist in this division. Review of the clinical pharmacology
`and biopharmaceutics data in the application was completed by Srikanth C. Nallani,
`Ph.D. A clinical review of the safety and efficacy data submitted was completed by
`Mwango Kashoki, M.D., M.P.H. A statistical review and evaluation was completed by
`Dionne Price, Ph.D. Celia Winchell, M.D. provided a supervisory review of the
`application. Consultation on this application was also obtained from the Division of
`Pulmonary and Allergy Products (DPAP), the Division of Drug Marketing, Advertising
`and Communications (DDMAC), and the Office of Drug Safety (ODS).
`
`As the clinical and statistical reviews have thoroughly detailed and analyzed the data
`submitted in this application, I will only briefly summarize their findings in this memo.
`
`Eflicacy:
`
`A single adequate and well-controlled study was submitted in support of efficacy. Study
`21-003 (003) was a multicenter, randomized, placebo-controlled, double—blind, parallel-
`group study comparing VivitrolTM (190 mg or 380 mg) and placebo for six months.
`Adults meeting the DSM IV diagnostic criteria for alcohol dependence, and who had at
`least two episodes of heavy drinking (4 drinks per day for women and 5 drinks per day for
`men) per week were admitted to the study. Complete abstinence at baseline was not
`required. Subjects received monthly intramuscular injection of drug or placebo in the
`gluteal muscle.
`
`Alcohol consumption was collected using the Time Line Follow-back Method and the
`quantity then converted into a number of standard drinks using a protocol-specified
`definition/formula. Psychosocial treatment was provided using the BRENDA
`(Biopsychosocial, Report, Empathy, Needs, Direct advice and Assessment of
`responsiveness) model. 'The protocol-specified primary outcome analysis was a
`comparison of the event rate of heavy drinking with heavy drinking defined as at least
`four drinks per day for women and five drinks a day for men.
`
`NDA 21-897 Division Director’s Approvable Memo
`VivitrolTM
`
`2
`
`December 23, 2005
`
`Page 2 of 9
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`Page 2 of 9
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`

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`Recent analyses conducted by the NIAAA documented an apparent link between various
`patterns of drinking and the likelihood of drinking-related psychosocial consequences.
`The results of these analyses suggest that the strongest predictor of avoiding significant
`consequences is the absence of a_ny heavy drinking days (employing observation periods
`of 3 to 12 months), with heavy drinking days defined as more than four drinks for males
`and more than three drinks for females. Therefore, at the request of the Division, a
`responder analysis was performed to add perspective on the clinical relevance of the
`results of the primary analysis. The agreed upon responder categories included:
`
`no heavy drinking days per month
`0 and S 1 heavy drinking day per month
`1 and S 2 heavy drinking days per month
`
`2 and S 3 heavy drinking days per month
`3 and S 4 heavy drinking days per month
`4 heavy drinking days per month
`
`The results of the primary outcome analysis demonstrated a statistically significant
`treatment effect for the 380-mg dose only. Dr. Price’s Table 5 summarizing this data is
`reproduced below:
`
`Comparison of Median Event rate of Heavy Drinking: Non-Parametric Analyses
`
`Any missing data day is defined as a heavy drinking day
`
`Treatment Group
`
`Placebo
`
`N
`
`204
`
`Median Event Rate of
`Heavy Drinking
`0.35
`
`Percent
`Difference
`
`p-value‘
`Wilcoxon test
`unstratified
`
`'
`
`0.69
`13%
`0.30
`206'
`190 mg
`0.05
`41%
`0.20
`201
`380 m
`
`p-value compared to placebo
`
`The sponsor also analyzed the data based on abstinence at baseline (defined as abstinent
`for 7 days prior to treatment) and based on subjects’ treatment goal at baseline (total
`abstinence or several other options). While the subjects’ treatment goal did not appear to
`influence the outcome, whether or not a subject was abstinent at baseline had a profound
`effect on the subject’s response to treatment. The data supporting this conclusion is
`summarized in Dr. Winchell’s table from page 12 of her review, reproduced below:
`
`_ NUMBER OF SUBJECTS
`PLACEBO 190 MG 380 MG
`.
`
`
`
`
`
`
`HAZARD RATIO (P-VALUE)
`190 MG vs.
`380 MG vs.
`
`PLACEBO
`PLACEBO
`FACTOR
`
`0.925 (0.4803)
`0.790 (0.0532)
`188
`193
`190
`Yes
`Lead-in
`0.049 (<0.0001)
`0.202 (0.0053)
`17
`17
`19
`No
`Drinkin
`0.879 (0.4994)
`0.718 (0.1119)
`90
`90
`90
`Yes
`Treatment Goal
`0.912 (0.4841)
`0.785 (0.0991)
`115
`120
`119
`No
`of Abstinence
`
`
`NDA 21-897 Division Director’s Approvable Memo
`VivitrolTM
`
`3
`
`December 23, 2005
`
`Page 3 of 9
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`Page 3 of 9
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`

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`The results of the responder analysis showed a small effect of treatment and only at
`greater than 1 heavy drinking day per month. However, when the effect of abstinence at
`baseline was included in the analysis, a much larger effect was seen for all strata,
`including 0 heavy drinking days per month. The data supporting these conclusions are
`summarized in Dr. Winchell’s tables from pages 13 and 14 of her review, reproduced
`below:
`
`Responder analysis using 5/4 definition of responders
`and 2-month grace period.
`HDD per
`Placebo
`190 mg
`380 mg
`
`month
`(n=204)
`(n=206)
`(n=201)
`0
`22 (11%)
`25 (12%)
`26 (13%)
`0-1
`36 (18%)
`37 (18%)
`39 (19%)
`0—2
`47 (23%)
`51 (25%)
`61 (30%)
`0—3
`52 (26%)
`59 (29%)
`70 (35%)
`
`0-4
`56 (28%)
`65 (32%)
`79 (39%)
`
`Responder analysis using 5/4 definition of responders and 2-month grace period.
`Placebo -
`190 mg
`380 mg
`
`HDD per
`Non-
`Abstinent
`Non—
`Abstinent
`Non-
`Abstinent
`month
`abstinent
`abstinent
`abstinent
`
`(n = 186)
`(n=l8)
`(n = 189!
`(n=l7)
`(n = 184)
`(n=l7)
`20 (11%)
`2(ll%)
`15(8%)
`10(59%)
`19 (10%)
`7(4l%)
`0
`31 (17%)
`5 (28%)
`27 (14%)
`10 (59%)
`30 (16%)
`9 (53%)
`0-1
`40 (22%)
`7 (39%)
`41 (22%)
`10 (59%)
`49 (27%)
`12 (71%)
`0-2
`44 (24%)
`8 (44%)
`49 (26%)
`10 (59%)
`58 (32%)
`12 (71%)
`0-3
`
`0-4 14(82%) 48 (26%) 8(44%) 55 (29%) 10(59%) 65 (35%)
`
`
`
`
`
`
`Clinical Safety:
`
`Exposure
`
`Over one thousand subjects were exposed to VivitrolTM. Dr. Winchell’s summary table
`of exposure by number of injections (page 16 of her review) is reproduced below:
`
`
`
`At least 1 injection
`At least 3 in'ections
`
`
`At least 24 in'ections
`
`At-least 12 in'ections
`At least 18 in'ections
`
`98
`
`NDA 21-897 Division Director’s Approvable Memo
`VivitrolTM
`
`4
`
`December 23, 2005
`
`Page 4 of 9
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`Page 4 of 9
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`

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`Deaths
`
`Five deaths occurred in the VivitrolTM database. Based on Drs. Kashoki and Winchell’s
`reviews, only two of those deaths were possibly related to study drug exposure. These
`two deaths were both suicides in subjects treated with study drug for extended periods of
`time. One occurred after five months of treatment, but not until two months after, the last
`dose. The other occurred after the subject had received 33 doses.
`
`Discontinuations Due to Adverse Events (AE5)
`
`,
`
`There was a slightly higher rate of dropout due to adverse events for the study drug—
`treated subjects compared to the placebo-treated subjects. However, there was no clear
`dose effect. The most common reasons for discontinuation were:
`injection site reactions,
`alcoholism (i.e., lack of efficacy), nausea, pregnancy, abnormal LFTs, and suicide-related
`AEs. There was a slightly higher incidence of dropout due to suicidal behavior for the
`drug—treated vs. the placebo—treated subjects, 0.9% vs. 0%, respectively). There was also
`a slightly higher incidence of dropout for depression, 0.3% vs. 0% for the drug vs.
`placebo-treated subjects, respectively. Neither of these events appeared to be dose-
`related, and the percentage of subjects dropping out for depression was highest in subjects
`treated with oral naltrexone.
`
`Serious Adverse Events
`
`Suicide-related serious AEs were reported more frequently in the drug-treated subjects
`compared to the placebo—treated subjects (1.4% vs. 0%, respectively). One subject in the
`380-mg treatment group developed a severe injection site reaction described as necrosis
`requiring fairly extensive tissue excision. Histopathological evaluation of the excised
`tissue documented a “hypersensitivity reaction.” One subject treated with 380-mg
`VivitrolTM developed apparent eosinophilic pneumonia not responsive to antibiotics, but
`responsive to steroid treatment.
`
`Common Adverse Events
`
`The following gastrointestinal adverse events occurred more frequently in the VivitrolTM—
`treated subjects: nausea, vomiting, diarrhea, abdominal pain, dry mouth,
`flatulence/bloating, decreased appetite and decreased weight. Additional adverse events
`that occurred with greater frequency in VivitrolTM-treated subjects were: asthenia,
`injection site reactions, headache, dizziness, somnolence/sedation, muscle cramps,
`arthralgia, back pain, rash, angioedema/urticaria, anxiety, and depression and/or suicidal
`ideation.
`
`While abnormal LFTs occurred with slightly greater frequency in the drug-treated
`subjects, the rates were comparable for the VivitrolTM-treated subjects and the oral
`naltrexone-treated subjects. Injection site reactions in the placebo-treated subjects were
`
`NDA 21-897 Division Director’s Approvable Memo
`VivitrolTM
`
`5
`
`December 23, 2005
`
`Page 5 of 9
`
`Page 5 of 9
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`

`

`generally innocuous tenderness, while induration and pruritis were seen commonly in the
`VivitrolTM-treated subjects. Injection site pain was seen most often in the higher dose
`group, suggesting that naltrexone itself is serving as an irritant. Depression also appeared
`to occur about twice as frequently in the drug-treated subjects compared to the placebo-
`treated subjects.
`
`Of note, elevated eosinophil counts occurred with greater frequency in VivitrolTM-treated
`subjects and with the extent of elevation occurring in an apparently dose-related pattern.
`Additionally, all twelve cases of urticaria and angioedema occurred in VivitrolTM-treated
`subjects.
`
`Medication Errors:
`
`The Division of Medication Errors and Technical Support (DMETS) in the Office of
`Drug Safety has recommended that the VivitrolTM Kit not contain the proposed three
`syringe needles (i.e., two 20-gauge 1 ‘/2 inch and one 20-gauge 1/2 inch), as “This may
`cause confusion and error as healthcare practitioners may inadvertently use the 1 V2 inch
`needle for reconstitution and then switch to the shorter 1/2 inch needle for the
`
`intramuscular (TM) injection. Additionally, some practitioners may not switch the
`needles prior to administration.”
`
`I do not agree with this speculative scenario. Physicians, nurses and other health-care
`practitioners are quite familiar with the need to use a longer needle for a gluteal IM
`injection. The longer needle would also make transfer of the diluent more difficult.
`
`Nonclinical Safety:
`
`Dr. De has recommended that this application should not be approved at this time due to
`the absence of adequate evidence that the exposure (toxicokinetic data) in the referenced
`naltrexone preclinical studies provides support for the higher exposures found in the
`clinical pharmacokinetic studies for VivitrolTM compared to the oral formulation, and the
`consequent need for the sponsor to perform Segments I, II and III reproductive toxicity
`studies and carcinogenicity studies in two species. However, Dr. Mellon has
`recommended that the application is approvable. While he concurs with Dr. De that there
`is currently inadequate preclinical support for the naltrexone exposure levels found with
`VivitrolTM, he has concluded that the sponsor may be able to' perform a bridging study
`that will allow interpretation of the relative exposure to naltrexone between the existing
`animal and human studies, thereby obviating the need for additional toxicology studies.
`If the sponsor is unable to document adequate preclinical support for the higher exposure
`levels based on this bridging study, he recommends that the reproductive toxicology
`studies and the carcinogenicity studies would then be required.
`
`NDA 21-897 Division Director’s Approvable Memo
`VivitrolTM
`
`6
`
`'December 23, 2005
`
`Page 6 of 9
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`Page 6 of 9
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`

`

`Dr. Mellon has also determined that the references to products other than Revia cited in
`this application are not necessary for a determination of the preclinical safety of
`VivitrolTM and, therefore, the absence of patent certification and relative bioavailability
`studies for these references is moot.
`
`Biopharmaceutics:
`
`Dr. Nallani has concluded that the application is approvable if the sponsor agrees to
`provide revisions to the drug release specifications to include the addition of appropriate
`Day 14 and Day 28 drug-release information.
`In addition, he recommends that the
`sponsor should be required to agree to the following Phase 4 commitments:
`
`o
`
`-
`
`conduct in vitro CYP inhibition studies using conventional substrates, as the data
`submitted in the application were drawn from studies employing fluorescent
`substrates which tend to introduce non—specificity in detection, and;
`
`in vitro studies in human hepatocytes to evaluate the potential of
`conduct
`naltrexone to induce CYP3A4 and CYP1A2.
`
`is important to note that Dr. Nallani has also determined that VivitrolTM has, on
`It
`average, a 4-fold greater AUC than the oral formulation of naltrexone.
`
`Chemistry, Manufacturing and Controls:
`
`Dr. Boal has concluded that the application is approvable based on the CMC data
`submitted, but that the 'sponsor should agree to the following Phase 4 commitment:
`
`0 Assess the in vitro drug release data and percent crystallinity for the first five
`commercial batches in order to tighten the ranges for the in vitro drug release
`specifications and - the percent crystallinity of
`naltrexone in the microspheres.
`
`Discussion:
`
`The sponsor has provided evidence that VivitrolTM is effective for the treatment of
`alcohol dependence, but only in patients who are abstinent for seven days at the initiation
`of treatment. While there was a numerical trend supportive of non-abstinent subjects
`being responsive to treatment with VivitrolTM, the overwhelming source of the
`statistically significant treatment effect found in the primary outcome analysis came from
`the abstinent-at-baseline subjects. This finding was also supported by the responder
`analyses.
`
`NDA 21-897 Division Director’s Approvable Memo
`VivitrolTM
`
`i
`
`7
`
`December 23, 2005
`
`Page 7of 9
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`Page 7 of 9
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`

`

`VivitrolTM appears to have a significantly more concerning adverse event profile
`compared to the approved oral formulation of naltrexone. The most concerning set of
`adverse events that appear to be unique to this formulation are those related to the
`immune system: a notably high frequency of peripheral eosinophilia and frequent skin
`reactions (one quite serious, requiring extensive tissue excision) in VivitrolTM-treated
`subjects; twelve cases of urticaria and angioedema occurring only'in VivitrolTM-treated
`subjects; and one case of apparent eosinophilic pneumonia in a subject treated with
`VivitrolTM.
`I concur with our own expert consultants from DPAP that these findings do
`not represent clear evidence of a specific immunologic effect. However, the presence of
`all of these abnormalities, especially the presence of the notable case of probable
`eosinophilic pneumonia, an extremely rare and life-threatening disorder when not treated
`quickly and appropriately, has raised a high level of concern regarding the safety of this
`product.
`
`In light of these safety concerns, we must consider the riskzbenefit ratio for the to-be-
`treated patient population. As noted above, the likelihood of achieving effective
`treatment with VivitrolTM appears to be differentially related to drinking status at the
`initiation of treatment. Abstinent patients have a relatively high degree of success and,
`thus, the benefits associated with treatment would likely outweigh the risks associated
`with untreated alcoholism. However, it is unclear whether VivitrolTM is truly effective in
`
`non-abstinent patients
`
`/
`
`/‘ /“ /
`
`In addition to the clinical safety concerns noted above, the sponsor has not provided
`adequate preclinical support for thenaltrexone exposure levels found with VivitrolTM.
`Due to the fact that VivitrolTM results in a 4—fold higher exposure to naltrexone compared
`to the approved oral formulation, it will be necessary for the sponsor to provide data from
`a bridging toxicokinetic study that will allow interpretation of the relative exposure to
`naltrexone based on the currently existing animal and human studies, thereby obviating
`the need for additional toxicology studies. If, however, the sponsor is unable to document
`adequate preclinical support for the higher exposure levels based on this bridging study,
`reproductive toxicology studies and carcinogenicity studies would then be required.
`
`Action:
`
`Approvable
`
`Bob A. Rappaport, MD.
`Director
`
`Division of Anesthesia, Analgesia and Rheumatology Products
`~ Office of Drug Evaluation II, CDER, FDA
`
`NDA 21-897 Division Director’s Approvable Memo
`’
`VivitrolTM
`
`8
`
`December 23, 2005
`
`Page 8 of 9
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`Page 8 of 9
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`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Bob Rappaport
`12/23/2005 04:06:31 PM
`MEDICAL OFFICER
`
`Page 9 of 9
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`Page 9 of 9
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