This Changes Everything: Approval of Imbruvica (ibrutinib) for Frontline Use in CLL (chronic lymphocytic leukemia)

This is big news in stark contrast to the preliminary NICE recommendation to note approve ibrutininb  for relapsed and refractory patients in the UK despite approval in almost 50 other countries.

Here is one of the many links on this story. Here's another.

On the other side of the ocean in the USA, in stark contrast,  there was good news of FDA frontline approval of ibrutinib. This changes everything. I will comment more on this later.

Here is the official press release from Abbvie for your review and appraisal:

PRESS RELEASE

IMBRUVICA® (ibrutinib) Approved by U.S. FDA for the First-line Treatment of Chronic Lymphocytic Leukemia

         ·  Approval based on data from the Phase 3 RESONATETM-2 trial showing an 84% reduction in the risk of progression or death with IMBRUVICA compared to chlorambucil 


         ·  First FDA-approved chemotherapy-free treatment option for first-line CLL patients 


         ·  This is the 5th treatment indication for IMBRUVICA 
NORTH CHICAGO, Ill., Mar. 4, 2016 – AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) approved IMBRUVICA® (ibrutinib) as a first-line treatment for patients with chronic lymphocytic leukemia (CLL).1 The approval is based on data from the randomized, multi-center, open-label Phase 3 RESONATETM-2 (PCYC-1115) trial, which evaluated the use of IMBRUVICA versus chlorambucil in 269 treatment-naïve patients with CLL or small lymphocytic lymphoma (SLL) aged 65 years or older. The RESONATE-2 data were previously presented at the American Society of Hematology (ASH) Annual Meeting in December 2015 and also simultaneously published in The New England Journal of Medicine. IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company and Janssen Biotech, Inc. 
“This approval represents a significant leap forward for patients diagnosed with CLL who may want to consider an alternative first-line treatment to traditional chemotherapy,” said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. “AbbVie is committed to making significant improvements in the lives of patients with hematologic malignancies and will continue to explore ways to improve treatment options for patients.” 
The prevalence of CLL is approximately 115,000 patients in the U.S.2 with approximately 15,000 newly diagnosed patients every year.3 CLL is a disease of elderly patients, with an average diagnosis age of 71.3 
The National Comprehensive Cancer Network (NCCN) recently published an update to its clinical practice guidelines for non-Hodgkin’s lymphomas, granting IMBRUVICA a category 1 recommendation for certain CLL patients, the highest recommendation assigned by the organization. Specifically, NCCN recommends IMBRUVICA as a first-line treatment option for frail CLL patients with significant comorbidities, as well as for CLL patients with or without del 17p or the genetic mutation TP53 who are 70 years or older, or younger patients with significant comorbidities. The NCCN guidelines inform prescribing and reimbursement practices in many institutions in the U.S. and internationally. 
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“The progression-free survival data seen in these previously untreated CLL patients are strong and encouraging,” said Dr. Jan Burger, M.D., Ph.D., Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX and the RESONATE-2 lead study investigator.* “This is especially important for first-line CLL patients, when considering the safety profile. This treatment represents another option for these patients.”

IMBRUVICA is now approved to treat CLL patients regardless of their treatment history (treatment-naïve and previously-treated patients). In addition, IMBRUVICA is approved to treat high-risk CLL patients with del 17p,1 a genetic aberration that occurs when part of chromosome 17, the location of the tumor suppressor gene `

IMBRUVICA significantly prolonged progression-free survival (PFS; primary endpoint) as determined by an Independent Review Committee (IRC), reducing the risk of progression or death by 84% versus chlorambucil (hazard ratio [HR], 0.161 [95% confidence interval: 0.091, 0.283]; median PFS: not reached for IMBRUVICA vs. 18.9 months [95% confidence interval: 14.1, 22.0] for chlorambucil).1 IMBRUVICA was also associated with a significantly higher IRC-assessed overall response rate (ORR: a composite of complete and partial responses; 82.4% vs. 35.3%; P<0 .0001="" chlorambucil.="" span="" versus="">1 Five patients (3.7 percent) in the IMBRUVICA arm achieved a complete response, compared to two patients (1.5 percent) in the chlorambucil arm.1

The safety of IMBRUVICA in this patient population was consistent with previously reported studies. The adverse reactions (AR) reported in the U.S. Prescribing Information reflect exposure to IMBRUVICA with a median duration of 17.4 months versus a median exposure to chlorambucil of 7.1 months: nearly 2.5 times longer exposure for IMBRUVICA. Warnings and Precautions include hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, second primary malignancies, embryo-fetal toxicity and tumor lysis syndrome. The most commonly occurring adverse reactions of all Grades in CLL patients treated with IMBRUVICA in the RESONATE-2 trial (>20%) were diarrhea, musculoskeletal pain, cough and rash.

Please see the Important Safety Information section below.

About the RESONATE-2 Study

RESONATE-2 is a Pharmacyclics-sponsored study which enrolled 269 treatment-naïve patients with CLL or SLL aged 65 years or older in the U.S., EU and other regions. Patients were randomized to receive either IMBRUVICA 420 mg orally, once daily until progression or unacceptable toxicity, or chlorambucil on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in Cycle 1 was 0.5 mg/kg and was increased based on tolerability in Cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg. The primary endpoint of the study was PFS as assessed by an IRC according to the International Workshop on

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Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis. Key secondary endpoints included ORR (based on the same iWCLL criteria), overall survival (OS) and safety.

Patient Access to IMBRUVICA

AbbVie and Janssen strive to make access to IMBRUVICA easy by helping patients understand their insurance benefits for IMBRUVICA. The YOU&iTM Support Program is a personalized program that includes information on access and affordability, nurse call support and resources for patients being treated with IMBRUVICA. This includes the YOU&iTM Instant Savings program, which provides co-pay support to eligible commercially insured IMBRUVICA patients. Patients can access the program by contacting 1-877-877-3536, option 1 or by visiting http://www.IMBRUVICA.com.

The YOU&iTM Instant Savings program is not available for patients enrolled in Medicare or Medicaid. For a list of patient support organizations that may be able to provide financial support please visit: http://www.cancer.net/navigating-cancer-care/financial-considerations/financial-resources.

About IMBRUVICA

IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton's tyrosine kinase (BTK).1 BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.1,4 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.1

IMBRUVICA is approved to treat patients with CLL, patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia. Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.1

IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers. More than 6,000 patients have been treated with IMBRUVICA in clinical trials. Currently, 14 Phase 3 trials have been initiated with IMBRUVICA and more than 90 trials are registered on www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS

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Hemorrhage - Fatal bleeding events have occurred in patients treated with IMBRUVICAÒ. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICAÒ.

The mechanism for the bleeding events is not well understood. IMBRUVICAÒ may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICAÒ for at least 3 to 7 days pre- and postsurgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and nonfatal infections have occurred with IMBRUVICAÒ therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICAÒ. Evaluate patients for fever and infections and treat appropriately.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) occurred in patients treated with IMBRUVICAÒ. Monitor complete blood counts monthly.

Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICAÒ, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICAÒ treatment and dose modification.

Hypertension - Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA® with a median time to onset of 4.5 months (range, 0.03 to 18.40 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA®. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.

Second Primary Malignancies - Other malignancies (range, 5% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICAÒ. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4% to 13%).

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Tumor Lysis Syndrome - Tumor lysis syndrome has been infrequently reported with IMBRUVICAÒ therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICAÒ can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICAÒ and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia* (57%, 53%, 43%), diarrhea (51%, 48%, 37%), anemia* (41%, 37%, 13%), neutropenia* (47%, 46%, 44%), musculoskeletal pain (37%, 32%†, NA‡), fatigue (41%, 29%, 21%), bruising (30%, 25%†, 16%†), nausea (31%, 24%, 21%), rash (25%, 23%†, 22%†), and upper respiratory tract infection (34%, 19%, 19%).

*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased). †Includes multiple ADR terms.
‡Not applicable; no associated ADRs.

The most common Grade 3 or 4 non-hematologic adverse reactions (≥5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%). Approximately 4% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.

Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, subdural hematomas, and atrial fibrillation (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS
CYP3A Inhibitors - Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A

inhibitor must be used, reduce the IMBRUVICAÒ dose.
CYP3A Inducers - Avoid coadministration with strong CYP3A inducers.

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SPECIFIC POPULATIONS
Hepatic Impairment - Avoid use in patients with moderate or severe baseline hepatic impairment. In patients

with mild impairment, reduce IMBRUVICAÒ dose.
Please see Full Prescribing Information: http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

About AbbVie

AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company’s mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world’s most complex and serious diseases. Together with its wholly-owned subsidiary, Pharmacyclics, AbbVie employs more than 28,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking Statements

Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, the likelihood that the transaction is consummated, the expected benefits of the transaction, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2014 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

*Disclaimer: Dr. Jan Burger served as the primary investigator of this Pharmacyclics-sponsored clinical study. He has served as an unpaid advisor to both Pharmacyclics and Janssen in developing the compound ibrutinib. Dr. Burger does not have a financial interest in either company.

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North Chicago, IL 60064

Contacts:

Media

Erica Jefferson

Investors

Liz Shea

Physicians

U.S. Medical Information

Phone: 408-990-7313

IMBRUVICA is a registered trademark of Pharmacyclics LLC SOURCE AbbVie Inc.

Phone: 847-935-2211

American Cancer Society. What are the key statistics for chronic lymphocytic leukemia? Available

from: http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics. Accessed March 2016.

4 Genetics Home Reference. Isolated growth hormone deficiency. Available from: http://ghr.nlm.nih.gov/condition/isolated- growth-hormone-deficiency. Accessed March 2016.

Phone: 877-877-3536

1 IMBRUVICA US Prescribing Information, March 2016.

2 IMS Database [Data on File] 3

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North Chicago, IL 60064

CLL (chronic lymphocytic leukemia) Treatment Internationally: We Can't Always Get What We Want

Below is an article from the Brampton Guardian.

This unfortunate CLL patient can't even get bendamustine and rituximab in Ontario, Canada, let alone ibrutinib or idelalisib or ABT-199 or obinutizumab. OHIP, the provincial insurance won't pay for any of it.

Here in the USA, she would automatically qualify for ibrutinib as as second line therapy or she could get her BR or enter a trial or a host of other choices. Not so in Canada.

I am so lucky to be able to have received ibrutinib in a clinical trial long before it was approved.

Others, mostly those wanting a non-chemo first line therapy, have been less fortunate. Still on clinical trials.gov, a quick look found eight open trials for untreated CLL patients with either ABT-199 or ibrutinib or idelalisib or obinutuzumab. And there are many more options using other very promising TKIs and mAbs in development. It's true that you can't be assured that you can get ibrutinib by prescription for frontline treatment, but at least most American untreated patients have many fine options with or without chemo.

When I advocate for more research on the the multi-drug non -chemo treatments for those of us such as myself not in CR after two years of ibrutinib, it is not meant at the expense of those needing other therapies or better access.

I want to see improved access for all of us. One way that might be possible is by following a path such a Professor Hallek outlined at ASH 2013 to limit the duration of therapy and thus control cost. I would just leave out or at least severely restrict the chemo piece of his protocol. His full article is available and well worth reading. It is a thoughtful discussion and one vision of the possible future of CLL treatment.

This is all new territory and we need the trials on untreated patients and we need the trials on relapsed patients and we need the trials on patients not in CR.

Truth is we are barely at the break of dawn of this new era of treatment and we need so many studies to help guide us. We are making this up as we go along.

What we also need to remember is that we are are all in this together and none of us, myself included, should wish for an option that limits another's choices. At least in the USA, we are not at that point.

Canada may be a different story. There is a petition at the end of the attached article. Her denial of care seems cruel, unjust, unscientific, and just plain dumb to me.

I understand that nearly all cancer treatment is expensive. I understand society must make tough choices about how to allocate limited resources. But making choices based solely on arbitrary protocols and short term dollars signs is not good policy, especially when it clearly stands against both the best evidence based medicine and the specific clinical circumstances of the patient.

Truth is that ibrutinib might be a smarter choice than BR for this patient after relapsing only four years post FR. Truth is we learn nothing in this article about the state of her marrow. Can it handle more chemo? We don't even know her FISH. If she is 17p deleted, BR could be a dangerous waste of time and resources, and might leave her worse off than before the therapy.

In the end with CLL, one has to chose which battles to fight. Anne and her oncologist have made their choice and are pushing for BR, so I am assuming they are on their game and have done their due diligence.

Yesterday, I heard from patients in Turkey and China looking in vain for novel therapies. I quote from the latter email discussing ibrutinib: Indeed the medicine cost is too high, and even if it's approved to be imported to China, the market price in China would be still higher (with extremely high custom rate), and yet any imported medicine is out of the range of medical insurance in China.

It's tough for my friends in Europe too. NICE that regulates new drugs in the EU can be very price sensitive and there seems to be be fewer non-chemo trials.

I know how spoiled I am living in the USA. I know how lucky I am to have nabbed a spot in my trial.

I wish everyone everywhere had access to what they needed to be well.

After all, we are all in this together. 

But there is only one of me and I am spread pretty thin already, so I narrow my focus, and try to make sure that at least those of us in North America get the best possible and smartest treatments out there.

The LLS is doing important work on improving access through its patient advocacy and other efforts. They deserves our support. See the photo below.

Brampton woman denied OHIP coverage for life-saving cancer drugs

Brampton Guardian

BRAMPTON — 

Anne Mitchell is fighting an uphill battle.
After four years in remission, the 67-year-old mother of two is gearing up for her second battle with Chronic Lymphocytic Leukemia.
But dealing with cancer isn’t the only obstacle the Brampton woman must overcome. The real challenge now — apart from fighting the illness — is coming up with the money to pay for life-saving drugs.
“My mother can’t receive chemotherapy drugs, purely for bureaucratic reasons,” said Mitchell’s daughter Eleanor Elliott, who has launched on an online petition in a bid to pressure the provincial government to dole out the $52,000 her mother needs for the chemotherapy drugs Bendamustine and Rituximab.

The drugs are covered by OHIP.

Mitchell is being denied coverage based on what family members say is a technicality. Bendamustine is covered for first-time chemotherapy treatments.
But, since Mitchell has undergone chemo before, the drug isn’t covered by OHIP. The other drug, Rituximab, is approved for second line use, but only in tandem with Fludarabine — a drug that Mitchell can’t take because she suffered an extreme, adverse reaction to it during her first bout with chemotherapy.
“The drugs that my mother’s oncologist prescribed are funded by the government. However, in my mother’s case, they have denied her funding,” Elliott said. “If a drug is approved for funding, how can you deny a Canadian citizen access to that drug? How is this possible in our great country that prides itself on universal healthcare?”
In October 2010, doctors treated Mitchell’s cancer with Fludarabine and Rituximab, two very powerful chemotherapy drugs.
Mitchell, who has lived in Bramalea for nearly 40 years, received got through two treatments before the regime was abruptly stopped because of her negative reaction to Fludarabine.
Mitchell was hospitalized for weeks with a severe lung infection that nearly killed her.
Despite that setback, her cancer went into remission and Mitchell and husband John, 68, were looking forward to better days.
But the cancer has returned and doctors believe Mitchell’s fighting chances are good if treated with a combination of Bendamustine and Rituximab.
However, the hefty price tag on those drugs now stands in Mitchell’s way.
Mitchell’s latest chemo treatment was to start April 7. Shortly after arriving in the oncology department at Brampton Civic Hospital, she received news that the $8,700 for the Bendamustine and Rituximab would have to come out of her own pocket.
“I felt complete and utter shock,” said an emotional Mitchell, describing her reaction when told OHIP denied her payment.
Mitchell used a credit card to cover the $4,500 cost for the first round of Bendamustine. She needs six treatments in total and can’t afford the cost.
Elliott said the hospital administered the Rituximab at no charge and has put through an appeal to Ontario’s health ministry for the $4,200.
“I sat in shock as my mother had to pull out a credit card to pay for her treatment,” said Elliott, who is concerned that her parents will be forced to spend their retirement savings on cancer treatments.
With her mother facing an uphill fight, Elliott has taken to social media for support. Her online petition has so far garnered more than 600 signatures, She plans to present the petition to provincial health officials.
Bramalea MPP Jagmeet Singh has offered his support in the form of a letter sent to Ontario Health Minister Deborah Matthews appealing for help

Meanwhile, Elliott has also reached out to the manufacturer of Bendamustine.
According to Elliott, Lundbeck Canada has agreed to cover 20 per cent of the cost of the Bendamustine, but the family will have to pay the cost up front and then apply for a rebate.
But, as Elliott noted, that works out to be just about 10 per cent of the total cost of her mother’s required treatment.
Elliott argues that her mother wasn’t able to complete her first round of chemotherapy and therefore should still be considered a first-time patient.
Falling under the category of first-time chemotherapy patient would make her eligible for the Bendamustine. Elliott also wants Ontario to waive the requirement that OHIP will only cover Rituximab if taken with Fludarabine.
She argues that approved chemotherapy drugs be approved “without discrimination and without bureaucratic intervention that could cost Canadians, like her mother, their lives.”
To view the online petition click here .