® (lbrutinib, PCI-32765)
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`lmbruvica
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`Chronic Graft Vs. Host Disease
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`Module 1.2
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`Overall Reviewer's Guide
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`Pharmacyclics LLC
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`IMBRUVICA@ (Ibrutinib, PCI-32765, JNJ-54179060)
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`Overall Reviewer's Guide
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`Confidentiality Statement
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`The information in this document contains trade secrets and commercial information that are privileged or confidential and may
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`In any event, persons to whom the
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`not be disclosed unless such disclosure is required by applicable law or regulations.
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`infonnation is disclosed must be infom1ed that the infonnation is privileged or confidential and may not be further disclosed by
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`them. These restrictions on disclosure will apply equally to all future information supplied to you which is indicated as
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`privileged or confidential.
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`

`

`® (lbrutinib, PCI-32765)
`
`lmbruvica
`
`Chronic Graft Vs. Host Disease
`
`Module 1.2
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`Overall Reviewer's Guide
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`TABLE OF CONTENTS
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`l. GENERAL INFORMATION .................... ............ ........................ ............ ............ ............................ 3
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`1.1. Applicant Name and Address ............................................................................................................... 3
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`1.2. Application Number.. .......................................................................................................................... 3
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`.................................................................. 3 ............ ............ ..........1.3. Trade Name ...................................
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`.................................................................. 3 ............ ............ ..........1.4. Name of the Active Substance .........
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`............ ..... 3 ............ ............ ............ ........................ ............ ............ ...........2. OVERVIEvV .....................
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`................ 3 3. REGULATORYIJISTORY ...................... ............ ........................ ............ ............ ............
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`................ 5 4. GENERAL FORMAT OF THE SUPPLEMENTAL NDA ............. ............ ............ ............
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`5. REQUEST FOR PRIORITY REVIEW ................. ........................ ............ ............ ............................ 6
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`................ 8 ..................... ............ ........................ ............ ............ ............6. l\i()DULE IN}'ORMATION
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`6.1. Module 1 -Administratjve Information and Prescribing Information ...................................................... 8
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`6.2. Module 2 -Summaries ....................................................................................................................... 9
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`6.3. Module 5 -Clinical Study Reports ....................................................................................................... 9
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`............ .. 10 ............ ............SUBMISSION 7. TECHNICAL IN}'ORMATION ON THE ELECTRONIC
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`.... 10 ...................................................................................7.1. Naming Conventions .................................
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`............. 10 ..............................................................7.2. Summary of eCTD Validation ................................
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`7.3. Technical Point of Contact ................................................................................................................ 10
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`2
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`

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`® (lbrutinib, PCI-32765)
`
`lmbruvica
`
`Chronic Graft Vs. Host Disease
`
`1. GENERAL INFOAAIA TION
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`Module 1.2
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`Overall Reviewer's Guide
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`The present Supplemental New Drug Application (sNDA) to NDA No. 205552
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`concerns ibrutinib (IMBRUVICA, PCI-32765, JNJ 54179060) 140 mg hard gelatin
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`capsules as a single-agent oral therapy to treat patients with chronic graft-versus-host
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`disease (cGVHD) after failure of one or more lines of systemic therapy.
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`The recommended dose for the treatment of cGVHD is 420 mg (3 x 140 mg capsules)
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`of ibrutinib administered orally, once daily, at approximately the same time each day.
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`The capsules should be swallowed whole with a glass of water.
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`1.1. Applicant Name and Address
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`Pharmacyclics LLC (Pharmacyclics)
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`995 East Argues Ave.
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`Sunnyvale, CA 94085-4521, USA.
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`In December 2011, Pharmacyclics entered into a joint development agreement with
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`Janssen Research & Development, LLC (JRD), located at 920 US Highway 202,
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`Raritan, NJ 08869, USA. As part of this agreement, Pharmacyclics delegated conduct
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`of some of the studies included in this application to JRD. JRD also completed some of
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`the documents included herein.
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`1.2. Application Number
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`NDA No. 205552
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`1.3. Trade Name
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`IMBRUVICA®
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`1.4. Name of the Active Substance
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`ibrutinib
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`2. OVERVIEW
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`This Overall Reviewer's Guide presents a brief description of the format and content of
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`each module of this sNDA to facilitate locating and understanding each of the
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`documents contained therein. Details of each major module and its respective content
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`are further described below.
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`This application has been prepared in accordance with the FDA' s input.
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`3. REGULATORY HISTORY
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`Pharmacyclics received approvals for IMBRUVICA for the following indications;
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`3
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`® (lbrutinib, PCI-32765)
`lmbruvica
`
`Chronic Graft Vs. Host Disease
`
`Module 1.2
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`
`Overall Reviewer's Guide
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`• Accelerated approval for the treatment of patients with Mantle Cell Lymphoma
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`(MCL)who have received at least one prior therapy on 13 November 2013
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`• Accelerated approval for the treatment of patients with Chronic Lymphocytic
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`Leukemia (CLL) who have received at least one prior therapy on 12 February 2014
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`• Full approval for the treatment of patients with CLL who have received at least one
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`prior therapy, and approval for the treamtment of patients with CLL with l 7p
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`deletion on 28 July 2014
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`• Full approval for the treatment of patients with Waldenstrom' s Macroglobulinemia
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`(WM) on 29 January 2015
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`• Full approval for the treatment of patients with CLL on 04 March 2016
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`• Full approval for the treatment of patients with CLL/SLL, and dosing of
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`IMBRUVICA ® (ibrutinib) with bendamustine and rituximab in patients with
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`CLL/SLL; full approval for the treatment of patients with CLL/SLL with l 7p
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`deletion on 06 May 2016
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`• Accelerated approval for the treatment of patients with Marginal Zone Lymphoma
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`(MZL) who require systemic therapy and have received at least one prior
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`anti-CD20-based therapy on 18 January 2017
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`A list of the key FDA correspondences regarding this application is located in
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`Module 1.6.3 Correspondences Regarding Meetings.
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`Pharmacyclics was granted the following designations in support of this sNDA
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`submission:
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`Approval
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`For the treatment of cGVHD 22 Jun 2016 Module 1.7.l
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`Breakthrough
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`of cGVHD 23 Jun 2016 Module 1.2
`Orp han Drug For the treatment
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`4
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`

`

`® (lbrutinib, PCI-32765)
`
`lmbruvica
`
`Chronic Graft Vs. Host Disease
`
`Module 1.2
`
`
`Overall Reviewer's Guide
`
`
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`4. GENERAL FO�fAT OF THE SUPPLEMENTAL NDA
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`The pivotal Phase l b/2 clinical study PCYC-1129-CA in support of this application for
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`the treatment of patients with cGVHD after failure of one or more lines of systemic
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`therapy is outlined below:
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`Study No.
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`Study Title
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`A Multicenter Open-label Phase lb/2 Study of Ibrutinib in
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`PCYC-1129-CA
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`Steroid Dependant or Refractory Chronic Graft versus Host
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`The module 2 summary documents and Study 1129 Clinical Study Report (CSR) do not
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`describe MZL as an approved indication as it has been only recently approved
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`(18 January 2017).
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`Patent Information
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`The US patents 7514444; 8008309; 869771 l; 8735403; 8754091; 8957079; 9181257
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`and 9296753 have been submitted previously with an sNDA (SN 0164; MZL Efficacy
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`Supplement) and are currently listed under NDA 205552. These patents continue to
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`claim the drug or method of using the drug for which approval is sought in the current
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`NDA Supplement.
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`Efficacy narratives
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`Efficacy narratives for all 42 patients in the all-treated population from pivotal study
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`PCYC-1129-CA are provided in Attachment 5 of the PCYC-1129-CA CSR.
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`Safety narratives
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`Safety narratives have been written for the below categories of adverse events and are
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`provided in Attachment 4 to the Study 1129 Clinical Study Report (CSR):
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`• Subjects who discontinued study treatment due to an adverse event
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`• Subjects who experienced a treatment emergent (TE) major hemorrhage
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`• Subjects who developed a new malignancy (for non-melanoma skin cancer,
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`only serious adverse events have a written narrative)
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`• Subjects who died within 30 days of last dose of study treatment
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`event as defined in the protocol
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`fibrillation
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`• Subjects who experienced a TE Serious Adverse Event (SAE) of atrial
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`5
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`

`

`® (lbrutinib, PCI-32765)
`
`lmbruvica
`
`Chronic Graft Vs. Host Disease
`
`Module 1.2
`
`
`Overall Reviewer's Guide
`
`
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`• Any event of Tumor Lysis Syndrome (TLS) or Progressive Multifocal
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`Leukoencephalopathy (PML)
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`• Any embryo-fatal toxicity
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`• All TE SAEs
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`Clinical Pharmacology Outline
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`Reference is made to the FDA Additional Clinical Pharmacology Comments detailed in
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`the Meeting Minutes of the Type B (pre-sNDA) meeting held on 31 August 2016.
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`Pharmacyclics' responses to these comments are located in 2.7.2 Summary of Clinical
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`Phannacology and 5.3.5.2 PCYC-1129-CA CSR (including Appendix 9.2
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`Pharmacokinetics Report). The requested PK datasets (pc.xpt and pp.xpt) are included
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`as part of the SDTM datasets generated for the PCYC-1129-CA CSR Additional
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`exploratory PK/PD analyses outputs developed to support Section 2.7.2, as detailed in
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`the PCYC-1129-CA PK/PD Analysis Reviewers's Guide, are provided in
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`Module 5.3.5.4.
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`Pharmacyclics is also submitting two model files, in .cmp format, and a table of
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`contents file ('readme') for the PBPK report 16-031-Hu-PO-PBPK (FK12024) being
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`submitted under Module 5.3.5.4. The table of contents file ('readme') and the archival
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`.txt files are being submitted in Module 5.3.5.4 per CDER ESUB recommendation.
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`The model files in .cmp and .txt format and table of contents file ('readme') are being
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`submitted via CD-ROM under separate cover, as .cmp format is not supported by the
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`electronic Common Technical Document (eCTD).
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`The sNDA is being submitted electronically in Tnternational Conference on
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`Harmonisation (ICH) Common Technical Document format (CTD) in accordance with
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`the Final Guidance for Industry, "Providing Regulatory Submissions in Electronic
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`Format -Human Pharmaceutical Product Applications and Related Submissions Using
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`the eCTD Specifications" (May 2015) and is organized in accordance with the Common
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`Technical Document format.
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`5. REQUEST FOR PRIORITY REVIEW
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`Submitted under Breakthrough Therapy Designation, Pharmacyclics is requesting
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`priority review for this sNDA based on the efficacy and safety data from pivotal
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`Study PCYC-1129-CA indicating that treatment with ibrutinib 420 mg/day results in a
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`positive benefit-risk profile for subjects with cGVHD after failure of I or more lines of
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`systemic therapy. This is a sign ificant
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`outcome considering that there are no approved
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`6
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`

`

`® (lbrutinib, PCI-32765)
`
`lmbruvica
`
`Chronic Graft Vs. Host Disease
`
`Module 1.2
`
`
`Overall Reviewer's Guide
`
`therapies or established standard of care for patients after failure of 1 or more lines of
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`systemic therapy.
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`The efficacy data from Study 1129 indicate that treatment with ibrutinib at a dose of
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`420 mg/day provides robust and clinically meaningful sustained responses in the setting
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`of overall reduction in use of steroids in subjects with cGVHD after failure of 1 or more
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`lines of systemic therapy. Efficacy data for 42 subjects with a median time on study of
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`13.9 months showed the following:
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`• The best overall response rate (BORR) using the widely accepted 2005 National
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`Institute of Health Consensus Panel Response Criteria with modifications was
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`66.7% (95% confidence interval [CI]: 50.5, 80.4) in the All-treated Population.
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`• The responses were sustained. The rate of sustained response for� 20 weeks
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`was 71.4% (95% CI: 51. 3, 86.8) for responders (20 of 28 subjects).
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`• The observed median corticosteroid doses were reduced over time in the
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`All-Treated Population. Of note, 5 of 28 responders (17.9%) discontinued
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`corticosteroid therapy while in response.
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`• The improvement rate in Lee cGVHD Symptom Scale summary score was
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`60.7% for the responders (17 of 28 subjects) and was 7.1 % for the
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`non-responders (1 of 14 subjects) over the duration of the study.
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`The safety profile of ibrutinib in subjects with cGVHD after failure or l or more lines of
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`systemic therapy is acceptable. No additional warnings or precautions are suggested over
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`what is currently outlined in the prescribing information.
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`Treatment with ibrutinib also provides an added advantage of convenient oral dosing in an
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`outpatient setting. These efficacy and safety findings collectively show that ibrutinib fulfills
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`a clear, unmet medical need.
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`7
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`

`

`® (lbrutinib, PCI-32765)
`
`lmbruvica
`
`Chronic Graft Vs. Host Disease
`
`Module 1.2
`
`
`Overall Reviewer's Guide
`
`6. _MODULE INFORMATION
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`In this submission, Pharmacyclics is including the following documents:
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`6.1. Module 1 -Administrative
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`Information and Prescribing Information
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`Location
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`Description
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`Module 1.1
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`F orms
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`Module l.1.2 Form FDA 356h
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`Module l.1.3 Form FDA 3397
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`Module 1.2
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`Cover Letters
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`Module 1.2
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`Cover Letter
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`• Reviewer's Guide: Overall reviewer's guide summarizes the content of this
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`sNDA and provides hyperlinks to main or nonstandard documents in the eCTD
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`• FDA Form 3674
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`• Orphan Drug Designation for cGVHD
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`Module 1.3
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`Administrative Information
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`Module 1.3.3 Debarment Certification
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`List of Investigators for Study PCYC-1129-CA
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`Module 1.3 .4
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`Financial Certification and Disclosure
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`FDA Form 3454 (Certification)
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`• Attachments to Form 3454
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`FDA Form 3455 (Certification)
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`• FDA Form 3455 (Disclosure) - Jason Dubovsky
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`Module 1.6
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`Meetings
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`Module 1.6.3 Correspondence Regarding Meetings
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`Module 1.7
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`Fast Track
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`Module 1.9
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`Pediatric Administrative Information
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`Breakthrough Therapy Designation for cGVHD
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`Module 1.7. I
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`Module 1. 9. 6
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`Other Correspondence Regarding Pediatric Exclusivity or Study
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`Module 1.12
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`Other Correspondence
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`Module 1.12.14 Environmental Analysis
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`Module 1.14
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`Labeling
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`Module l .14.1.2 Annotated Draft Labeling
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`Module 1.14 .1.3 Draft Labeling Text
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`• USPI ( clean, redline)
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`• Patient Inforamtion ( clean, redline)
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`SPL
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`Module 1.16
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`Risk Management Plans
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`Module 1.16 .1
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`Phannacovigilance Plan
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`8
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`

`

`® (lbrutinib, PCI-32765)
`
`lmbruvica
`
`Chronic Graft Vs. Host Disease
`
`6.2. 1\!Iodule 2 -Summaries
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`Module 1.2
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`Overall Reviewer's Guide
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`Location
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`Description
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`Module2
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`Summaries
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`Module 2.5
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`Clinical Overview for cGVHD
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`Module 2.7
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`Clinical Summary
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`Module 2.7.2 Summary of Clinical Pharmacology Studies
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`Module 2.7.3 Summary of Clinical Efficacy for cGVHD
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`Module 2.7.4 Summary of Clinical Safety for cGVHD
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`Module 2.7.6 Synopses of Individual Studies
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`PCYC-1129-CA
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`PCI-32765LYM1003
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`6.3. 1\!Iodule 5 -Clinical Study Reports
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`Location
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`Description
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`Modules
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`Clinical Study Reports
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`Module 5.2
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`Tabular Listing of Clinical Studies
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`(PK) Studies Module 5.3.3 Reports of Human Pharmacokinetic
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`with the Moderate Interaction Study oflbrutinib Module 5.3.3.2 PCI-32765L YM1003 : A Drug-Drug
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`and Strong CY3A Inhibitors in Patients with B-cell Malignancy
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`PCI-32765LYM1003 Case Report Forms
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`PCI-32765LYM1003 DataSets/Outputs
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`Module 5.3.5.2 Study Reports and Related Information on Uncontrolled Clinical Studies
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`PCYC-1129-CA: A Multicenter Open-Label Phase l b/2 Study oflbrutinib in Steroid
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`Dependant or Refractory Chronic Graft Versus Host Disease
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`PCYC-1129-CA Case Report Forms
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`PCYC-1129-CA Datasets
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`Module 5.3.5.3 Reports of Analysis of Data from More than One Study
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`Int.egrated Summary of Safety (ISS)
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`ISS cGVHD TFLs
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`ISS Datasets
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`Module 5.3.5.4 Other Study Reports
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`16-031-Hu-PO-PBPK (FK12024): Physiologically Based Phannacokinetic Drug-Drug
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`Interaction Simulations of JNJ-54179060 (PCI-32765 or lbrutinib) and the Strong
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`CYP3A4 Inhibitor Posaconazole in Non-Fasted Healthy Subjects.
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`• Table of contents file ('readme ') for the PBPK report 16-031-Hu-PO-PBPK
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`(FK12024)
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`• Model files in .txt format to support the PBPK report .
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`OSI Request (Study PCYC-1129-CA):
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`• Study Related Information
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`• Site Listings (Appendix 1)
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`Clinical Phannacolot:,>y Analyses
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`subjects with renal or hepatic impairment)
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`• (FDA requested exposure-response table, exposure-safety table, and listing of
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`Module 5.4 Literature References
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`• PK/PD Analysis Reviewer's Guide
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`9
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`

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`® (lbrutinib, PCI-32765)
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`lmbruvica
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`Chronic Graft Vs. Host Disease
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`Module 1.2
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`Overall Reviewer's Guide
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`7. TECHNICAL INFORMATION
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`ON THE ELECTRONIC SUBMISSION
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`7.1. Naming Conventions
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`The following terms are used interchangeably to describe the drug substance throughout
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`the sNDA: IMBRUVICA, ibrutinib, PCI-32765, JNJ-54179060.
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`7.2. Summary of eCTD Validation
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`This sNDA in eCTD format has been validated using Lorenz eValidator Version 5.8.1.
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`7.3. Technical Point of Contact
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`If you need any further technical help with regard to the use of the eCTD presentation of
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`this sNDA, please contact:
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`Linette Hickson
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`Director, Regulatory Operations
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`Pharmacyclics LLC
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`Telephone: 408.215.3185
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`Email: lhickson@pcyc.com
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`