Blinatumomab will change the future of relapsed/refractory Acute Lymphoblastic Leukemia patients?

During the ASCO 2014, Amgen had shown the latest data of a novel ALL treatment, Blinatumomab.

Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. Blinatumomab is currently investigated for acute lymphoblastic leukemia (ALL), specially in persistence or relapse/ refractory after chemotherapy indicates resistance to chemotherapy. As the current ALL treatment were knowing for the high toxicity and low medical response, Blinatumomab can offer a real medical alternative.  Blinatumomab, was designed as orphan drug by the FDA for ALL in 2008. Blinatumomab binds to CD19, a protein which is expressed solely by B cells and is overexpressed in ALL tumor cells. Blinatumomab also binds to cytotoxic T cells through an interaction with the protein CD3, redirecting T cells to lyse CD19-expressing B-precursor ALL cells. The Phase II study of blinatumomab, reflect the potential of this molecule as an first-in-class bispecific T cell antibody.

The results showed that 43% of the 189 blinatumomab-treated patients achieved complete remission (CR) or CR with partial hematological recovery (CRh) within the first two cycles of therapy, with 80% of responses occurring within the first cycle. The median relapse-free survival was 5.9 months, and OS was 6.1 months. In total, patients were treated with more than five cycles of blinatumomab.

In cycle 1, patients underwent a run-in phase of 9μg blinatumomab per day for the first week, with 28μg per day for the remaining three weeks.

In cycle 2, patients were treated with 28μg blinatumomab per day.

The primary endpoint assessment of CR/CRh was performed at the end of the second cycle, and patients who responded to blinatumomab therapy were eligible to receive three additional cycles of therapy.

Current acute lymphoblastic leukemia chemotherapies were mainly composed by four-drug combination of vincristine, prednisone, anthracycline, and cyclophosphamide or L-asparaginase, or a five-drug combination including vincristine, prednisone, anthracycline, cyclophosphamide, and L-asparaginase. Although, the treatment related high mortality rate around 20 to 30%. Otherwise, there is an important unmet need for innovative therapies, more safe and efficient for the patient.

If Blinatumomab will demonstrate efficacy and safety in ALL treatment, the new compound will have the chance to reach a high pricing regarding the FDA orphan drug accreditation. Blinatumomab is currently investigated in the Phase III TOWER trial versus the investigator’s choice of standard of care chemotherapy in adult subjects with R/R precursor B-cell ALL.

Regarding the blinatumomab’s result shown in ASCO convincing results in adult patients with R/R ALL, and the important medical need, blinatumomab seems to be a possible multi-indication revolution for ALL, and non-Hodgkin’s lymphoma patients.

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Roche provides update on phase III study of onartuzumab in people with specific type of lung cancer

Roche  announced  that an independent data monitoring committee has recommended that the phase III METLung study be stopped due to a lack of clinically meaningful efficacy.

The study evaluated if onartuzumab (MetMab) in combination with Tarceva (erlotinib) helped patients with previously treated, advanced non-small cell lung cancer (NSCLC) whose tumours were identified as MET-positive live longer compared to Tarceva alone. Overall adverse event rates were generally similar between the two groups. Data will be submitted for presentation at a forthcoming medical meeting.

« These results are disappointing because new options are needed for patients with lung cancer, the most common and deadly cancer worldwide,” said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. « We remain committed to helping patients with lung cancer and are studying several investigational medicines in this disease.”

Roche is evaluating the implications of the METLung study results across the ongoing onartuzumab clinical programme.

About the METLung Study (NCT01456325)

  • METLung is a Phase III, randomised, double-blind study evaluating the efficacy and safety profile of onartuzumab in combination with Tarceva in patients with previously treated (second- or third-line) advanced NSCLC identified to be MET-positive. The METLung study included a companion diagnostic immunohistochemistry (IHC) test that was co-developed with Ventana Medical Systems, Inc., a member of the Roche Group.
  • Four hundred and ninety-nine patients were randomized to receive 150 mg of Tarceva taken daily plus either:
    • Intravenous 15 mg/kg of onartuzumab every three weeks
    • Intravenous placebo every three weeks
  • The primary endpoint is overall survival. Secondary endpoints include progression-free survival, objective response rate and safety profile.
  • The results announced today are from a pre-specified interim analysis.

About Lung Cancer

According to the World Health Organization, it is estimated that nearly 1.6 million people worldwide died of lung cancer in 2012; NSCLC accounts for 85 percent of all lung cancers.

About the MET Pathway

MET is a protein found on the surface of cells and acts as a receptor that binds to another protein called Hepatocyte Growth Factor (HGF), also known as « Scatter Factor ». When HGF binds to MET, it causes MET proteins to form pairs (dimerise), which triggers a signalling cascade that tells cells to grow, divide, and spread to other parts of the body. Activation of the MET pathway has been proposed as a mechanism of tumour growth and spread (metastasis).

About Onartuzumab

Onartuzumab, an investigational monovalent (one-armed) monoclonal antibody designed to specifically target the MET receptor, is being studied in various cancers.


Source: Roche

Breast cancer reimbursement – state of the art across AJE ( America – Japan- Europe)


Healthcare authorities across the G7markets (France, Germany, Italy, Spain, UK, USA and the Japan) have been busy implementing oncology regulatory, pricing, and reimbursement reforms from 2008.

Driven by their high budget deficits post-recession, governments through their austerity packages want a significant drug price cuts to reduce overall oncology expenditures. Pharmaceutical companies need to be mindful of the new market access and reimbursement requirements. New drugs and indications in oncology need to prove their cost effectiveness against marketed comparators in Germany and France. However, several countries are working on improving breast cancer patient access to certain innovative and expensive drugs.

The most widely used drugs for breast cancer are hormonal therapies and chemotherapies – two types of therapies with long-established histories in breast cancer treatments. Hoffmann Krueger reports the countries oncology reimbursement particularities.


Drugs treatments for breast cancer are generally covered by private insurance and/or Medicare in US. Under private insurance, reimbursement varies according to the index plan as well as formulary tier placement within the index plan. In some cases, expensive treatment may not be reimbursed, such as trastuzumab and bevacizumab.

Office-based oncologists still receive a fee-for-service for administering intravenous therapies. In contrast, prescription of oral chemotherapy garners no specific fee-for-service. Medicare reimbursement policies are shaped by the United States Pharmacopeia’s (USP) Guidelines. These guidelines indicate that health plans must cover “all or substantially all” drugs in six classes, including antineoplastics.


Cancer patients in France do not have to worry about payments for essential drugs. In general, oncology drugs are fully reimbursed because they treat life-threatening diseases. Initiatives taken by the French government including the creation of the Institut National du Cancer (INCa; National Cancer Institute) and the Plan Hôpital (Hospital Plan) have improved care to cancer patients.

To control spending on drugs that qualify for supplementary reimbursement, ceiling prices are determined either through negotiations between the manufacturers and the Comité Economique des Produits de Santé (CEPS; Economic Committee for Health Care Products)

Manufacturers are also subject to price/volume constraints, they have to reduce their prices if sales volume is judged to have grown excessively. High-priced new drugs can be added to this list as soon as they receive marketing authorization in France.

After 12 months on the market, a drug is either approved to remain on this list, in which case it becomes subject to a ceiling price, or it is removed from the supplementary reimbursement list and covered by the relevant disease-associated tariff payable to the hospital.

To encourage hospital pharmacies to negotiate manufacturer discounts on these medicines, hospitals are permitted to keep a proportion of any price difference they secure between the ceiling price and their actual purchase price. When evaluating agents for reimbursement, France’s Transparency Commission considers the Service Medical Rendu (SMR; therapeutic benefit) and melioration du Service Medical Rendu (ASMR; improvement in therapeutic benefit) of the agents and target population characteristics. Because the SMR and ASMR ratings are considered important for drugs as bevacizumab, docetaxel, paclitaxel, and capecitabine and because breast cancer is a serious disorder, the treatments are fully reimbursed.


Unlike in many other European markets, cancer patients in Germany are frequently treated by office based physicians. Office-based physicians are currently subject to Richtgrößen—indicative prescribing amounts those determine the maximum expenditure on medicines per patient per quarter. Clinicians who exceed these amounts by more than 25% face the prospect of heavy fines. Some expensive therapies are excluded from indicative prescribing amounts.

In Germany, cancer patients frequently have out-of-pocket costs that are high by European standards. In line with the German Social Security Code’s goal of maintaining cost-effectiveness in medical treatments, German law dissuades off-label prescribing of any medications, levying a fine on the prescribing physician

United Kingdom

In UK all citizens are eligible for prescription drug reimbursement from the National Health Service (NHS) for licensed therapies. Patients pay a low, flat prescribing fee per prescription; seniors and cancer patients are exempt from copayments.

The NICE (National Institute for Health and Clinical Excellence – NICE) have an important role in evaluation of the cost-benefit balance for new drugs and indications treatments. If NICE issues a negative opinion, most Primary Care Trusts (PCTs) exclude the drug from their formularies, obligating patients to either pay out-of-pocket treatment

Many NICE decisions regarding expensive treatments have been reimbursement controversies (e.g., trastuzumab in early-stage HER2-positive; trastuzumab beyond progression; lapatinib in combination with capecitabine as a second-line treatment).

British oncology experts notice that NICE recommendations do not result in automatic reimbursement of expensive treatments. For this reason, variation among PCTs in formulary coverage, yields an inequitable environment in which certain patients, depending on geographic location, can afford vital medications while others cannot. Thought leaders interviewed also indicate that because cost is such a concern, oncologists often choose the least-expensive drug within a desired class (e.g., generic paclitaxel over branded docetaxel (Taxotere)).


Oncologists in Italy indicate that any drug may be prescribed forbreast cancer if it is approved by the Agenzia Italiana del Farmaco (AIFA; Italian Medicines Agency); however, cost-containment measures have created some regional differences in prescribing. Some oncologists believe strongly that cost is a big problem, some others say they do not feel particularly constrained by the guidelines within which they are required to prescribe.

The Prontuario Farmaceutico Nazionale (PFN: National Pharmaceutical Formulary) classifies the reimbursement status of available therapies. Current metastatic breast cancer therapies are awarded class status H, indicating that full reimbursement is provided only in the hospital setting. The administration of class H requires specialist supervision.


In Spain the Sistema Nacional de Salud (SNS; National Health System) covers the full cost of medications or requires a nonrefundable patient copayment for part of the cost. oncologist note that no significant reimbursement obstacles hinder the prescribing of most breast cancer therapies. However, labeling and treatment location may affect whether a particular drug will be used because it may not be completely reimbursed.

The exception in breast cancer is trastuzumab, which was being prescribed for early-stage prior to the European Medicines Agency’s approval for that indication. Additionally, it is unlikely that expensive agents such as bevacizumab will be prescribed by hospital-based physicians because hospitals closely watch their annual pharmacy budgets.


Although lack of access to international gold-standard cancer therapies has long been one of the main deficiencies of the Japanese oncology system for many tumor types, several of the key chemotherapeutics used to treat breast cancer have been available in Japan within one to three years of their launch in other major countries. Biologics (such as trastuzumab) generally reach the market in Japan two to three years after their launch in other major pharmaceutical markets.

In an effort to accelerate the launch of important new drugs in Japan, in January 2005, the Ministry of Health, Labor, and Welfare (MHLW) established an expert panel called the Mishoninyaku Shiyo Mondai Kentokaigi (Study Council on the Use of Unapproved Drugs). Once a drug is considered to have significant potential and is recommended by the study council to the MHLW, the drug manufacturer is asked by the MHLW either to begin clinical trials or to conduct supplementary trials that would allow wider access to the agent before it is formally approved. Off-label prescribing is reportedly uncommon because it presents reimbursement problems, and the patient is forced to pay the whole cost of treatment.

The Japanese KOL reports  that regulatory approval is the most critical variable in prescribing drugs in Japan, followed by efficacy; cost is generally not considered a defining variable. Once approved, drugs in Japan must undergo a rigorous pricing process and then possibly face the prospect of biennial price cuts. Although it is not the case with all chemotherapeutics, the Japanese prices of some breast cancer therapies (e.g., docetaxel) are the lowest of any of the major markets we cover— the result of several mandatory government price cuts. However, the prices of generic therapies are much higher in Japan than they are in the other major markets.

The emergence of novel targeted agents such as lapatinib and bevacizumab has resulted in growing disparity in access to expensive treatments in the G7 markets. As previously mentioned, MAbs are usually subject to intense scrutiny by payers. Even when they receive regulatory approval, not all MAbs are placed on drug formularies and reimbursement lists.

Reimbursement can be a particular problem for patients with late-stage breast cancer because premium-priced agents must show clinically relevant and cost-effective benefit in these patients.

Compared with physicians in the UK and the rest of Europe, physicians in the United States experience significantly fewer reimbursement restrictions. As we discussed, bevacizumab was conditionally approved in 2008 under the FDA’s fast-track development program to treat metastatic HER2-negative breast cancer. Most oncologists in the United States disagree with ODAC’s recommendation and tell us that they will continue to prescribe bevacizumab to their patients for as long as it continues to be reimbursed.

Elena Kienesberger

Hoffmann Krueger Oncology Excellence

Oncology Market Forecast, what are the key challenges ?

Oncology will remain by far the largest segment until 2018, with strong growth from both inline products and new products, off-setting a number of major patent expiries over the period. 


The great commercial success experienced by cancer therapies leaders(Roche, Sanofi, Novartis, AstraZeneca, and Eli Lilly) makes the market extremely attractive for the drug developers. The treatment of cancer has shifted away from mass market blockbuster drugs toward a more focused attack on the disease with targeted therapies. However, the crisis, and the austerity packages imposed by healthcare authorities could see slower commercial growth and larger generic erosion of key brands princeps.

The Hoffmann – Kruger analysis is shows that Roche is by far the dominant player in the world wide oncology market, 2012 with 35% market share in 2012. Roche is expected to remain the oncology leader until 2018. Although the low growth rate of Roche portfolio is due to the potential entry of biosimilar Herceptin and Rituxan between 2012 and 2018.

Roche has consolidated its position as the global leader in this sector via acquisitions (e.g. Genentech) or licensing agreements. Roche’s R&D strategy rests on developing well-differentiated personalized medicines built on an understanding of disease biology. Novartis’ oncology strategy is moving away from a blockbuster-driven structure and has diversified its portfolio to include novel targeted agents that address numerous pathways and cancer types, as well to a lesser degree as the older hormonal and supportive care agents. Amgen is looking to strengthen its presence in oncology. Recent acquisitions have been geared toward this goal and added a diverse array of technologies. The BioVex deal added the cytolytic, live-virus vaccine T-VEC (OncoVex) which is in Phase III for melanoma, while the Abgenix acquisition added earlier-stage small molecules and MAb. Sanofi has actively sought oncology-focused late-stage licensing deals, but many of these programs have ended quickly. Small acquisitions, such as BiPar and TargeGen, have also been used to supplement the portfolio, while the acquisition of Genzyme provided a presence both in hematological malignancies.

AstraZeneca had shunned biologics, as well as in-licensing, preferring to concentrate on internal/acquired R&D of small molecules. The 2003 research alliance with Abgenix (now part of Amgen) to develop human oncology monoclonal antibodies against oncology indications was the company’s first foray into biologics. The subsequent acquisitions of KuDos (2005), CAT (2006) and MedImmune (2007) have strengthened the oncology biologics pipeline To improve its future in oncology, J&J established Ortho Biotech Oncology Research & Development to unite the efforts of several J&J companies in the development of oncology and hematology small molecules and biologics. The company aims to bolster its hematological malignancy pipeline and in December 2011, in-licensed worldwide rights to Pharmacyclics novel BTK-inhibitor, PCI-32765. This candidate is in development for B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma and diffuse B-cell lymphoma.

In September 2009, Eli Lilly established two therapeutic business units, one of which focuses on Oncology, demonstrating the high strategic importance of this field. The acquisition of ImClone for $6.5b in November 2008, was driven by the company’s ambitions to expand in oncology. This brought royalties and milestone payments from BMS and Merck KGaA for Erbitux, and rights to its late-stage pipeline, including ramucirumab. In December 2011, Lilly signed an antibody drug conjugate deal with Immunogen to use their maytasanoid Targeted Antibody Payload (TAP) technology with existing Lilly monoclonal antibodies, to develop novel antibody-drug conjugate cancer treatments.

Pfizer has built an oncology portfolio via acquisitions (e.g. Pharmacia and Wyeth, and smaller transactions such as Serenex, CovX and Coley). It established an oncology business unit in 2008; its R&D is focused on Biologics & Targeted Agents and its diverse pipeline addresses numerous targets but so far has failed to progress any biologics to market after a number of high-profile, late-stage failures (e.g. figitumumab, remelimumab and ProMune). The development of Xalkori established Pfizer as one of the forerunners in personalized medicine for lung cancer; it is advancing molecular testing in the disease and is exploring further opportunities in both lung cancer and into oncology genomics more generally. BMS has actively sought to develop a strong and broad oncology franchise, establishing a powerful network of contacts within the oncology community from early-stage research with universities and research institutes, through to commercialization and marketing. The company is focused on immuno-oncology; it launched Yervoy in 2011 and has several candidates in clinical trials with potential utility across a range of tumor types.


Regarding this element, the statistical analysis, and the KOL interviews we can be sure about the market results,  but as Winston Churchill said: 

« The most essential qualification for a politician is the ability to foretell what
will happen tomorrow, next month, and next year, and to explain afterwards
why it did not happen« 


Elena Kienesberger