Blinatumomab Breakthrough drug emerges for B-cell ALL

After decades of research, scientists have discovered a drug that engages the immune system to fight B-precursor acute lymphoblastic leukemia, a rare and aggressive type of cancer. Blinatumomab, which has been approved by the FDA in the United States, is now awaiting the green light for its release in Europe.

how would you like to have a soldier at your disposal, programmed to attack specific enemies in your defense? Even more amazing, these soldiers can detect hostile elements masquerading as friends, and eliminate these threats to keep you safe.

Now imagine these soldiers inside your body.

This is what researchers found out more than 30 years ago—that the cure to some cancers can be found in the human body, and that antibodies can
be engineered to attack and kill tumour cells. Their knowledge, however, did not translate to a clinically approved, commercially available treatment for cancer until December 2014, when linatumomab entered the United States.

Blinatumomab is the first and only bispecific CD19-directed CD3 T-cell engager (BiTE®) immunotherapy to be approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia (B-cell ALL), a rare and aggressive type of blood cancer. Blinatumomab is
manufactured by Amgen and marketed in the United States under the brand name BLINCYTO.

B-cell ALL is a condition in which the bone marrow generates too many B-cell lymphoblasts, an immature type of white blood cell. It is estimated that approximately 6020 new ALL cases are diagnosed in the United States each year. Of these, roughly 2400 occur among adults. In the European Union,
There are more than 7200 new diagnoses of ALL annually with approximately 40% or 3000 diagnoses occurring among adults.

With the FDA’s approval for the commercial release of BLINCYTO in December 2014, there is hope that the mortality rate among B-cell ALL patients will drop. The availability of such a drug to treat a rare blood cancer is groundbreaking for B-cell ALL patients.

Dr. Christian Stein of Ascenion (left) and Dr. Peter Kufer of Amgen (right).

Christian Stein, Chief Executive Officer of Ascenion, the technology transfer partner in this discovery, said ‘this is the first time the patients will receive proper treatment because before, chemotherapy was basically the option with all its terrible side effects and lack of specificity.’

Ending deception

Blinatumomab is an investigational BiTE antibody construct that helps the body’s immune system to detect and kill cancer cells, which have long been able to trick the immune system into thinking that they are normal healthy cells. Because the immune system is deceived, it has been unable to eliminate tumours.

With Blinatumomab, the T cells—a type of white blood cells known to be the immune system’s most potent killer of cells perceived as threats—are able to recognize malignant B cells and work against CD19, a protein found on the surface of B cells that cause leukaemias and lymphomas. The drug connects these two cell types and stimulates the T cell to apply cytotoxic activity on the target cell. ‘The development of Blinatumomab was quite an exciting journey,’ says Dr. Peter Kufer, Executive Director of BiTE technology at Amgen Research Munich (formerly Micromet) and one of the pioneers that discovered the drug. ‘I am really grateful to have had the opportunity over such a long period of time to substantially contribute to the development of a drug that made it to approval and now prolongs or even saves patient’s lives.’

Various formats of T cell-recruiting bispecific antibody constructs have been in existence since the 1980s, but nobody knew how to best combine the antitumour cell with the anti-T cell binding arm. Hence, for more than two decades, there was no major progress in this approach. Meanwhile, Kufer’s group at the Institute of Immunology at Ludwig-Maximilian-Universität in Munich had developed Blinatumomab, which as a single agent efficiently induces T cells to kill CD19 positive tumour cells. Kufer collaborated with the research group of Dr. Ralf Bargou from the Molecular Medicine in the Helmholtz Association (MDC) in Berlin, who provided the CD19 binding arm.

Small partner, big partner

In 1998, Micromet, a small pharmaceutical outfit founded in Munich, Germany acquired the intellectual property rights to Blinatumomab from the academic partners owning the IP. Micromet brought the biotechnology company MedImmune on board in 2003, granting the latter a licence to co-develop its lead drug candidate Blinatumomab, then labeled MT103. The partnership, however, was discontinued, and Micromet reacquired the complete rights to develop and market Blinatumomab.

The year 2004 was an important turning point for the clinical development of MT103. ‘We started to treat patients continuously in our clinical trials to provide T cells with the help they required long enough for them to recognize and kill tumour cells,’ says Kufer. A year later, developers of the drug observed the first objective clinical response in a patient with non-
Hodgkin’s lymphoma, a cancer that originates in the lymphatic system.

In 2008, an article was published in the peerreviewed journal, SCIENCE, on MT103’s high clinical response rate in non-Hodgkin’s lymphoma patients. ‘In the same year, we started to see molecular responses in adult ALL patients with minimal residual disease,’ Kufer recalls. ‘In 2010 we observed the first objective clinical responses in adult patients with relapsed/refractory ALL, which paved the way to the pivotal 211 study.”

The Phase II study of Blinatumomab at Micromet caught the attention of pharmaceutical firm Amgen, which was headquartered in the United States. Amgen forged a US$1.2-billion deal to acquire
Micromet in 2012. Following the acquisition, the pivotal ‘211 study’ was conducted: 189 adults with B-cell ALL were enrolled and treated with Blinatumomab via infusion for at least four weeks. Of the patients assessed in the study, 81 achieved complete remission or complete remission with partial haematologic recovery within two cycles of Blinatumomab treatment.

The majority of the responses—in 64 out of the 81 patients—occurred within the first cycle of treatment. Among the patients who achieved complete remission with partial haematologic
recovery, 32 proceeded to haematopoietic stem cell transplantation and 60 achieved minimal residual disease response, which was an important parameter in predicting relapse.

Armed with substantial clinical proof, Amgen announced on 22 September 2014 its submission of a Biologics License Application to the US FDA for Blinatumomab (trade name: BLINCYTO). On
3 December 2014, the FDA granted BLINCYTO breakthrough therapy designation, priority review and orphan product designation, five months ahead of its supposed application review completion. The orphan product designation of BLINCYTO highlights it as a drug that may offer a significant improvement in treatment over existing options.

‘Blinatumomab is the first clinical and regulatory validation of the BiTE® platform, a new and innovative approach that helps the body’s own immune system fight cancer. Where approved, LINCYTO is a new option to help manage this serious disease,’ Amgen says.

Price tag

Even if the drug was a niche indication with a relatively small patient population, BLINCYTO racked up US$15M in sales for the first quarter of 2015. The U.S. Wholesale Acquisition Cost price at which Amgen sells BLINCYTO to wholesalers, without taking into account discounts, rebates, and other price concessions, is $89000 per cycle. The median duration of treatment for patients who responded in clinical studies was two cycles.

Amgen says the price of BLINCYTO reflects the significant clinical, economic and humanistic value of the product to patients and the healthcare system, as well as the complexity ofeveloping, manufacturing, and reliably supplying innovative biologic medicines.

In the United States, BLINCYTO is a breakthrough therapy for an ultra-orphan patient population. Approximately 900 patients have Philadelphia chromosome-negative relapsed/refractory ALL.
‘These patients have a median overall survival of just three to five months and BLINCYTO is the first major treatment advance for these patients in more than two decades,’ Amgen says.

Efforts are also underway to make the drug available in Europe in the near future. On 25 September 2015, Amgen announced that the Committee for Medicinal Products for Human Use (CHMP), the
scientific committee of the European Medicines Agency adopted a positive opinion recommending a conditional marketing authorization for BLINCYTO for the treatment of adults with Philadelphia
chromosome-negative relapsed or refractory B-precursor ALL. Conditional licence requires for it to be renewed every year and it will be converted to full standard licence once post-licensing commitments have been fulfilled. Amgen expects a decision on the conditional marketing authorization application from the European Commission in the coming months.

Looking back, Kufer says the determination to proceed with a completely new mode of action to obtain clinical proof would have been hardly possible under a big pharmaceutical company setting. He says the acquisition of Micromet by Amgen happened at the appropriate stage of the drug development. ‘It was critical that the development chain from university via small biotechnology company to big pharmacy worked, and that the transitions from one phase to the next came at the right time points,’ Kufer says.

In the spotlight: Bloody war

Blood cancers are keeping the field of biomedical research busy.
Leukaemia alone has four main types: acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), acute lymphocytic leukaemia (ALL), and chronic lymphocytic leukaemia. The keydistinctions between these types of blood cancers are related to how fast they progress and where the tumour cells grow. Because of this, treatment is often complex; it is not limited to one kind of therapy. Thus, it is imperative that investigative and clinical studies on new forms of therapies are intensified to offer patients a cure. Worldwide, leukaemia is the 11th most common cancer, with roughly 352000 new cases diagnosed in 2012, according to Cancer Research UK. It is estimated that there are only close to 600 adults with Phrelapsed or refractory B-precursor ALL in France, Germany, Italy, Spain, and the U.K.