- - - - - - 1 Pipeline Report Fourth quarter 2013 To help keep prescribers informed about medications in development, the Walgreens Pipeline Report provides a summary of the specialty medications that may be approved by the FDA within the next few years. While not all-inclusive, this report focuses on medications in phase III studies that may impact treatment for certain specialty disease states or conditions. It also highlights select, recently approved or soon-to-be-approved specialty medications of interest to the marketplace. This report is not intended to be used by patients. Medications to watch Here is a closer look at a few recently approved or soon-to-be approved medications that may have a significant impact on therapeutic classes and treatment for specific disease states and conditions. Obinutuzumab Genentech has developed obinutuzumab for the treatment of chronic lymphocytic leukemia (CLL). Obinutuzumab targets the CD20 protein on malignant B-cells and is administered by intravenous (IV) infusion. In a randomized, open-label, three-arm phase III trial, the efficacy of obinutuzumab in combination with chlorambucil, as compared to Rituxan (rituximab) plus chlorambucil or chlorambucil alone in patients with previously untreated CLL was examined. The primary endpoint was progression-free survival (PFS). In stage I of the trial, 589 patients were randomized in a 2:2:1 fashion to receive a maximum of six 28-day cycles of either obinutuzumab (1000 mg IV infusion, on days one, eight and 15 of cycle one and day one of cycles two through six) plus chlorambucil (0.5 mg/kg orally, days one and 15 of cycles one through six) or Rituxan (IV infusion day one, 375 mg/m 2 cycle one, 500 mg/m 2 cycles two through six) plus chlorambucil, or chlorambucil alone. Patients treated with obinutuzumab plus chlorambucil or Rituxan plus chlorambucil experienced a significantly longer median PFS (23 months and 15.7 months, respectively) than those treated with chlorambucil alone (approximately 11 months). The most common serious adverse events reported in the obinutuzumab group were infusion-related reactions and neutropenia. In stage II of the trial, an additional 192 patients were enrolled to allow for a direct comparison of obinutuzumab plus chlorambucil to Rituxan plus chlorambucil. At a preplanned interim analysis, an independent data monitoring committee determined that the trial met its primary endpoint of a longer PFS for patients in the obinutuzumab group compared to the Rituxan group. Genentech filed a biologics license application (BLA) for obinutuzumab in April 2013. The FDA granted breakthrough therapy designation to obinutuzumab in May 2013 and granted priority review status to the BLA in July 2013. A response to the BLA is expected in December 2013. Information on recently approved, soon to be approved and phase III trial specialty medications. Information on recently approved, soon to be approved and phase III trial specialty medications.
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Pipeline Report
Fourth quarter 2013
To help keep prescribers informed about medications in development, the Walgreens Pipeline Report provides a summary of the specialty medications that may be approved by the FDA within the next few years. While not all-inclusive, this report focuses on medications in phase III studies that may impact treatment for certain specialty disease states or conditions. It also highlights select, recently approved or soon-to-be-approved specialty medications of interest to the marketplace. This report is not intended to be used by patients.
Medications to watch Here is a closer look at a few recently approved or soon-to-be approved medications that may have a significant impact on therapeutic classes and treatment for specific disease states and conditions.
Obinutuzumab Genentech has developed obinutuzumab for the treatment of chronic lymphocytic leukemia (CLL). Obinutuzumab targets the CD20 protein on malignant B-cells and is administered by intravenous (IV) infusion.
In a randomized, open-label, three-arm phase III trial, the efficacy of obinutuzumab in combination with chlorambucil, as compared to Rituxan (rituximab) plus chlorambucil or chlorambucil alone in patients with previously untreated CLL was examined. The primary endpoint was progression-free survival (PFS).
In stage I of the trial, 589 patients were randomized in a 2:2:1 fashion to receive a maximum of six 28-day cycles of either obinutuzumab (1000 mg IV infusion, on days one, eight and 15 of cycle one and day one of cycles two through six) plus chlorambucil (0.5 mg/kg orally, days one and 15 of cycles one through six) or Rituxan (IV infusion day one, 375 mg/m2 cycle one, 500 mg/m2 cycles two through six) plus chlorambucil, or chlorambucil alone. Patients treated with obinutuzumab plus chlorambucil or Rituxan plus chlorambucil experienced a significantly longer median PFS (23 months and 15.7 months, respectively) than those treated with chlorambucil alone (approximately 11 months). The most common serious adverse events reported in the obinutuzumab group were infusion-related reactions and neutropenia.
In stage II of the trial, an additional 192 patients were enrolled to allow for a direct comparison of obinutuzumab plus chlorambucil to Rituxan plus chlorambucil. At a preplanned interim analysis, an independent data monitoring committee determined that the trial met its primary endpoint of a longer PFS for patients in the obinutuzumab group compared to the Rituxan group.
Genentech filed a biologics license application (BLA) for obinutuzumab in April 2013. The FDA granted breakthrough therapy designation to obinutuzumab in May 2013 and granted priority review status to the BLA in July 2013. A response to the BLA is expected in December 2013.
Information on recently approved, soon to be approved and phase III trialspecialty medications.Information on recently approved, soon to be approved and phase III trial specialty medications.
Ibrutinib Pharmacyclics has filed a new drug application (NDA) for ibrutinib for the treatment of previously treated patients with CLL/small lymphocytic lymphoma (SLL) and for the treatment of previously treated patients with mantle cell lymphoma (MCL). Ibrutinib is an orally administered Bruton’s tyrosine kinase (BTK) inhibitor that prevents cell growth and survival.
In an open-label, phase 1b/2 trial, patients with relapsed or refractory CLL or SLL were enrolled and randomized to ibrutinib 420 mg once daily (51 patients) or ibrutinib 840 mg once daily (34 patients). The primary endpoint of the trial was safety and secondary endpoints included overall response rate and PFS. Adverse effects were predominantly grade 1 or 2 and included diarrhea, fatigue and upper respiratory tract infection. The overall response rate in both groups was 71 percent and, at 26 months, the estimated PFS was 75 percent.
In a separate open-label, phase II trial, 111 patients with relapsed or refractory MCL were enrolled in two groups: patients who had received at least two cycles of Velcade (bortezomib) therapy and patients who had received less than two cycles of Velcade or had not received prior Velcade. The primary endpoint of this trial was overall response rate. After a median follow-up time of 15.3 months, the overall response rate was 68 percent, with a complete response rate of 21 percent and a partial response rate of 47 percent. Prior treatment with Velcade did not affect the response rate. The most common treatment-related adverse events were diarrhea, fatigue and nausea.
The FDA has designated ibrutinib as an orphan drug and granted it breakthrough therapy designation. The NDA was filed in July 2013 and accepted by the FDA for priority review.
Eteplirsen Eteplirsen is an investigational medication for the treatment of Duchenne muscular dystrophy (DMD). DMD is a rare disease linked to the X-chromosome that affects one in every 3,600-6,000 boys worldwide. It is characterized by progressive muscle weakness and premature death. DMD is caused by mutations in the gene that codes for dystrophin, a protein that helps keep muscle cells intact. Prednisone is currently the main treatment of choice for DMD, as it has been shown to increase muscular strength. Eteplirsen is a ribonucleic acid modulator (RNA) that restores protein translation and dystrophin production.
In a randomized, double-blind, placebo-controlled, phase IIb trial (Study 201), 12 boys ages 7 years to 13 years with a confirmed DMD genotype expected to be responsive to treatment with eteplirsen were enrolled. The boys were randomized in a 1:1:1 fashion to treatment with eteplirsen 30 mg/kg IV once weekly, eteplirsen 50 mg/kg IV once weekly or placebo. Upon completing Study 201, all patients were enrolled in an open-label extension trial (Study 202). In this trial, the placebo-treated patients were transitioned to eteplirsen 30 mg/kg or eteplirsen 50 mg/kg once weekly. The primary endpoint of the trials was the change from baseline in the percent of dystrophin-positive fibers present in muscle biopsies.
Both trials met their primary endpoints. After 48 weeks of treatment, eteplirsen administered at either 30 mg/kg or 50 mg/kg resulted in a statistically significant increase in dystrophin-positive fibers to 47 percent of normal. The placebo/delayed-treatment group, which had received 24 weeks of eteplirsen at either 30 mg/kg or 50 mg/kg following 24 weeks of placebo, also showed a statistically significant increase in dystrophin-positive fibers to 38.3 percent of normal.
Eteplirsen has been designated as an orphan drug with fast-track status. Sarepta Therapeutics plans to file an NDA in the first half of 2014.
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Medications recently approved Manufacturer/ Drug name
Indication Mechanism of action/Drug class
Route of administration
Approval date
Comments
Human immunodeficiency virus ViiV Healthcare/ Tivicay (dolutegravir)
In combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and children ages 12 and older and weighing at least 40 kg
Prevents virus replication/ Integrase inhibitor
Oral 8/12/13 • Tivicay can be used in treatment-naïve and treatment-experienced patients
For the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test
Inhibits cell growth and survival/ Tyrosine kinase inhibitor (TKI)
Oral 7/12/13 • Deletions in exon 19 and L858R mutations account for approximately 90 percent of all EGFR mutations
In combination with Kalydeco (ivacaftor) in patients with cystic fibrosis (CF) who have two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
Increases the movement of CFTR to the cell surface/CFTR corrector
Oral • FDA granted breakthrough therapy designation
• Data from two phase III trials expected in 2014, followed by NDA submission
SC injection • FDA accepted NDA for standard review September 2013
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Pipeline medications in phase III trials (continued)
Manufacturer/ Drug name
Indication Mechanism of action/Drug class
Route of administration
Comments
Hepatitis Gilead Sciences/ Sofosbuvir
In combination with ribavirin as an all-oral therapy for patients with genotypes 2 and 3 hepatitis C virus (HCV) infection and in combination with ribavirin and peginterferon alfa for treatment-naive patients with genotypes 1, 4, 5 and 6 HCV infection
Oral • FDA granted fast-track status • NDA filed April 2013 • FDA granted priority review
status • A response to the NDA is
expected December 2013
Janssen and Medivir AB/ Simeprevir (TMC435)
In combination with peginterferon alfa and ribavirin for the treatment of chronic HCV infection in treatment-naive and treatment-failure genotype 1 patients
For the treatment of relapsing-remitting multiple sclerosis (MS)
Unknown mechanism of action in MS/Interferon
SC injection • Dosed once every two or four weeks
• FDA granted fast-track status • BLA filed May 2013
Teva Pharmaceuticals/ Laquinimod
For the treatment of relapsing-remitting MS
Inhibits autoimmune and inflammatory disease activity/ Immunomodulatory agent
Oral • First patient enrolled in third phase III trial March 2013
• This trial is being conducted under a special protocol assessment
Neurogenic disorders Chelsea Therapeutics/ Northera (droxidopa)
For the treatment of symptomatic neurogenic orthostatic hypotension in patients with primary autonomic failure, dopamine beta-hydroxylase deficiency and nondiabetic autonomic neuropathy
Increases norepinephrine levels in the nervous system/Synthetic catecholamine
Oral • Designated as an orphan drug with fast-track status
• Received a complete response letter March 2012
• FDA accepted resubmission of NDA
• A response to the NDA is expected February 2014
Neutropenia Teva Pharmaceuticals/ Lipegfilgrastim
To reduce the duration of severe neutropenia in cancer patients undergoing chemotherapy
Inhibits the binding of immunoglobulin E (IgE)/IgE-directed antibody
SC injection • Regulatory submissions planned for the second half of 2013
UCB Pharma/ Cimzia (certolizumab pegol)
For the treatment of Crohn’s disease and RA
For the treatment of PsA and axial spondyloarthritis
Targets TNF alpha, which is involved in the inflammatory process/TNF inhibitor
SC injection • sBLA filed and under FDA review February 2013
Multiple sclerosis Biogen Idec and Elan/Tysabri (natalizumab)
For the treatment of relapsing forms of MS (generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate MS therapy) and for the treatment of Crohn’s disease
For the first-line treatment of relapsing forms of MS in patients who have tested negative for antibodies to the JC virus
Binds and inhibits alpha-4 integrins from adhering to their counter-receptors/ Selective adhesion molecule inhibitors
Binds to the CD52 antigen on B-cells and T-cells/ Therapeutic antibody
IV infusion • FDA granted fast track status
• sBLA filed June 2012 • A response to the sBLA
was expected in the second half of 2013; however, the FDA has extended the review period
• A response is now expected in late 2013
• Marketed as Campath for CLL indication
Oncology Bayer HealthCare and Onyx Pharmaceuticals/ Nexavar (sorafenib)
For the treatment of hepatocellular carcinoma (HCC) and RCC
For the treatment of locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer
Inhibits cell growth and survival /TKI
Oral • sNDA filed June 2013 • FDA granted priority
review status • A response to the sNDA
is expected December 2013
Celgene/ Revlimid (lenalidomide)
For the treatment of previously treated MM, MDS and relapsed of refractory MCL
For the treatment of newly diagnosed MM
Possesses immuno-modulatory, anti-inflammatory and antiangiogenic properties/ Thalidomide analogue
Oral • Primary endpoint achieved in phase III trial July 2013
GlaxoSmithKline/ Mekinist (trametinib)
For the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations
In combination with Tafinlar for the treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation
Inhibits cell growth and survival/ Mitogen-activated extracellular signal regulated kinase (MEK) inhibitor
Oral • sNDA filed July 2013 • FDA granted priority
review • A response to the sNDA
is expected January 2014
New indications in the pipeline (continued)
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Manufacturer/ Drug name
Current indication
Investigational indication
Mechanism of action/Drug class
Route of administration
Comments
Oncology GlaxoSmithKline/ Tafinlar (dabrafenib)
For the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation
In combination with Mekinist for the treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation
Inhibits cell growth and survival/BRAF kinase inhibitor
Oral • sNDA filed July 2013 • FDA granted priority
review • A response to the sNDA
is expected January 2014
GlaxoSmithKline/ Votrient (pazopanib)
For the treatment of RCC and soft tissue sarcoma
For the treatment of advanced epithelial ovarian cancer
Inhibits cell growth and survival/TKI
Oral • Designated as an orphan drug
• Primary endpoint achieved in phase III trial June 2013
• Regulatory filings planned for 2013
Incyte Corporation/ Jakafi (ruxolitinib)
For the treatment of patients with intermediate or high-risk MF, including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF
For the treatment of polycythemia vera
Inhibits the formation and development of blood cells/JAK inhibitor
Oral • FDA granted fast track status
• Phase III results expected in early 2014
• sNDA filing planned for the first half of 2014
Novartis/Tasigna (nilotinib)
For the treatment of chronic and accelerated phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in patients resistant or intolerant to prior therapy that included Gleevec, and for the first-line treatment of Ph+ CML
For the treatment of c-Kit-positive melanoma
Inhibits cell growth and survival/TKI
Oral • sNDA planned for 2014
Roche/Perjeta (pertuzumab)
In combination with Herceptin (trastuzumab) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease
For neoadjuvant treatment (before surgery) in people with HER2-positive early-stage breast cancer
Prevents the HER2 receptor from pairing with other HER receptors/HER2 receptor antagonist
IV infusion • sBLA filed in 2013 • FDA granted priority
• Primary endpoint achieved in two phase III trials August 2013
• sBLA filing planned for 2013
Peyronie’s disease Auxilium Pharmaceuticals/ Xiaflex (collagenase clostridium histolyticum)
For the treatment of Dupuytren’s contracture with a palpable cord
For the treatment of Peyronie’s disease
Breaks down collagen deposits/ Purified collagenase
Injection • Designated as an orphan drug
• sBLA filed November 2012
• A response to the sBLA is expected September 2013
New indications in the pipeline (continued)
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Glossary of terms Antibody-drug conjugate—consists of a monoclonal antibody linked to a cytotoxic drug.
BLA—stands for “biologics license application,” similar to an NDA but used for investigational medications that are considered to be biologic agents.
Breakthrough therapy designation—intended to expedite the development and review of a potential new drug for serious or life-threatening diseases.
Complete response letter—issued to let the applicant know that the review period for an investigational agent is complete, and that the NDA or BLA is not yet ready for approval.
Double-blind trial—a type of study in which the participants and the investigators are blinded to treatment. This type of study has less bias than nonblinded studies.
Fast track—designation granted by the FDA to an investigational agent indicating an expedited review of the NDA or BLA; usually applies to medications that treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs.
NDA—stands for “new drug application,” the process by which a manufacturer submits information to the FDA to gain approval for the agent; conducted after phase III development is completed.
Orphan drug—a medication that treats a rare disease that affects fewer than 200,000 Americans. A medication granted orphan drug status is entitled to seven years of marketing exclusivity.
Phase III—last phase of medication development; involves safety and efficacy trials of the new medication. This phase of development can take years to complete.
Priority review—designation granted by the FDA to an investigational agent after it has been submitted to the FDA for approval. A priority designation means that the FDA will review and take action on the application (approve or not approve) within six months instead of the standard 10 months for all other medication filings.
Refusal to file letter—a letter the FDA issues to the applicant if it determines the application is not sufficiently complete.
Rolling submission—usually applies to fast-track medications; indicates that the review process can be started even before the FDA receives all the information. However, the FDA requires all the information before a final decision about approval can be made.
sBLA—stands for “supplemental biologics license application,” similar to sNDA but used for already approved investigational medications that are considered to be biologic agents.
sNDA—stands for “supplemental new drug application,” the process by which a pharmaceutical company submits information to the FDA to gain approval for a new indication for an agent that has already been approved by the FDA.
SPA—stands for “special protocol assessment,” an agreement with the FDA that the manufacturer’s clinical protocol for a phase III trial is acceptable to support an NDA or BLA.
Treatment-naive—patients who have never been treated before for a particular condition.
References Journals: Beytía M, Vry J, Kirschner J. Drug treatment of Duchenne muscular dystrophy: available evidence and perspectives. Acta Myol. 2012;31:4-8.
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:34-42.
Fairclough RJ, Bareja A, Davies KE. Progress in therapy for Duchenne muscular dystrophy. Exp Physiol. 2011;96:1101-13.
Goede V, Fischer K, Humphrey K, et al. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): final stage 1 results of the CLL11 (BO21004) phase III trial. J Clin Oncol. 2013;31 (suppl; abstract 7004).
Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369: 507-16.
Yoshida K, Yatabe Y, Park JY, et al. Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer. J Thorac Oncl. 2007:2:22-8.
Websites: Adis Insight—bi.adisinsight.com
ClinicalTrials.gov—clinicaltrials.gov
Manufacturers’ websites
Muscular Dystrophy Association—mda.org
U.S. Food and Drug Administration—fda.gov
Information in the report is current as of September 2013, and was accessed on September 16, 2013. This report is for educational purposes only and is not deemed as an endorsement by Walgreen Co., its subsidiaries or affiliates. Claims made in this report about the efficacy of medications or the results of studies have been made by the medication manufacturer, the FDA or another third party.