Gamida Cell Phase 3 Study Design Outline Approved by FDA and EMA


Gamida Cell, a cell therapy company based in Jerusalem, Israel, has reached agreements with the US Food and Drug Administration (USFDA) and the European Medicines Agency (EMA) with regards to a Phase III study design outline for testing their NiCord product. NiCord is a blood cancer treatment derived from a single umbilical cord blood until expanded in culture and enriched with stem cells by means of the company’s proprietary NAM technology.

Gamida Cell is moving forward now with plans to commence an international, multi-center, Phase III study of NiCord in 2016. Phase I/II data of 15 patients are expected in the fourth quarter of 2015. NiCord is in development as an experimental treatment for various types of blood cancers including Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Myelodysplastic Syndrome (MDS), and Chronic Myelogenous Leukemia (CML).

NiCord® is derived from a single cord blood unit which has been expanded in culture and enriched with stem cells using Gamida Cell’s proprietary NAM technology. NAM technology proceeds from the observation that nicotinamide, a form of vitamin B3, inhibits the loss of functionality that usually occurs during the culture process of umbilical cord blood stem cells, when added to the culture medium. Pre-clinical studies have also shown that the expanded cell grafts manufactured using NAM technology demonstrate improved functionality following infusion in a living animal. These stem cells show improved movement, home to the bone marrow, and show higher rates of engraftment, or durable retention in the bone marrow. Based on these results, Gamida Cell is currently testing in clinical trials (in patients) cells expanded in culture with the NAM platform to determine their safety and effectiveness as a treatment for blood cancers, sickle-cell anemia and thalassemia. NiCord is intended to fill the crucial clinical need for a treatment for the vast majority of blood cancer patients indicated for bone marrow transplantation, with insufficient treatment options. This segment has a multi-billion dollar market potential.

“The FDA and EMA feedback is a major regulatory milestone for NiCord. NiCord is a life-saving therapy intended to provide a successful treatment for the large number of blood cancer patients who do not have a family related matched donor. Gamida Cell is dedicated to changing the paradigm in transplantation by bringing this therapy to market as soon as possible,” said Dr. Yael Margolin, president and CEO of Gamida Cell.

“The positive regulatory feedback confirms that Gamida Cell’s NiCord program is on a clear path to approval both in the U.S. and EU. We look forward to continuing the development of this very important product in cooperation with sites of excellence in cord blood transplantation worldwide,” said Dr. David Snyder, V.P. of Clinical Development and Regulatory Affairs at Gamida Cell.

The Phase III study will be a randomized, controlled study of approximately 120 patients. It will compare the outcomes of patients transplanted with NiCord to those of patients transplanted with un-manipulated umbilical cord blood.

 

CAR Immune Cells to Treat Childhood Cancers


In clinical trials, cancer treatments that use genetically modified versions of a patient’s own cells to specifically target the disease have remarkable results. The next step for these companies that spent enormous amounts of time, capital, and intellectual energy inventing and designing these treatments is to get them into hospitals despite their enormous price tags.

Novartic CAR T-Cell therapy

In two separate clinical trials, one sponsored by the Swiss company Novalis AG and another by the Seattle-based biotech company Juno Therapeutics Inc., close to 90% of all patients saw their leukemia completely disappear after being given experimental “CAR” or “chimeric antigen receptor” T-cell therapies.

Both trials examined small numbers of patients (22 children in the Novartis trial and 16 adults in the Juno trial). These patients had acute lymphoblastic leukemia, which is the most common childhood cancer. All of them had also not responded to the available standard treatments. Consequently, both companies are now conducting larger trials.

“CAR T cells are probably one of the most exciting concepts and fields to come out in cancer in a very, very long time,” says Dr. Daniel DeAngelo, a Boston-based hematologist and associate professor of medicine at Harvard Medical School, who wasn’t involved in either study.

Usman Azam, head of cell and gene therapies at Novartis, calls the therapies “critically important” for Novartis. “I think that a cure for cancers such as leukemia and lymphoma through a CAR technology is plausible,” said Dr. Azam in an interview with The Wall Street Journal. “Our job is to get this into patients as soon as we feasibly can.”

Novatis created a new research unit headed by Dr. Azam. Novartis’ rationale is to accelerate the advent of CAR T-Cell Therapy to medical markets. The U.S. Food and Drug Administration (US FDA) granted Novartis’ leading CAR therapy “breakthrough” designation in July of 2014. Presently Novartis wants to file it with regulators in 2016.

CAR therapies use the patient’s own immune system to fight the cancer, but with a genetic-engineering twist. “Immunotherapies,” culture immune cells from the patient and manipulate them in culture to sensitize them to the cancer. CAR therapies extract T-cells, which are disease-fighting white blood cells, from a patient’s blood. These T-cells are then genetically engineered and grown in a laboratory for around 10 days and reintroduced into the patient.

The T-cells are usually infected with a hamstrung virus that can introduce genes into cells but cannot productively infect them. These recombinant viruses endows the T-cells with genes that encode chimeric antigen receptors, or CARs. CARS bind specifically to proteins on the surface of malignant cancer cells. Once attached to the cancer cells, the T-cells can kill them very effectively.

Both Novartis and Juno are tapping academic scientists to develop their treatments. For example, Novartis has teamed with the University of Pennsylvania and Juno has formed a formal relationships with scientists at Memorial Sloan-Kettering Cancer Center in New York, Seattle Children’s Hospital and the Fred Hutchinson Cancer Research Center, which is also in Seattle.

Even though Novartis and Juno will probably be the first to bring their immunotherapies to the market, other companies are also in the hunt to bring similar therapies to medical markets. Pfizer Inc., Kite Pharma Inc., and Celgene Corp., which is working in collaboration with Bluebird Bio Inc. all are developing competing strategies.

“Competition will keep all of the companies involved on their toes,” said Hans Bishop, Juno’s chief executive.

Unfortunately, CAR therapies still have a few unanswered questions surrounding them. For example: “How long do they last?” Given the small numbers of patients who have been treated with these treatments to date, it is very hard to tell with the available data. Another confounding factor is that those patients in the previous clinical trials whose cancer went into remission after the CAR therapies then became eligible for stem-cell transplants, which can also prolong survival.

Secondly, a potentially dangerous side effect called “cytokine-release syndrome,” shows the therapy is working, but can cause a sharp drop in blood pressure and a surge in the heart rate. The deaths of two patients in a Juno-backed Sloan-Kettering trial in March caused a temporary halt in the study because of worries over these particular adverse reactions.  “Patients need to be healthy enough to combat that side effect,” says Mr. Bishop, who thinks it is now manageable. Patients are once again being recruited for this trial, and patients with a risk of heart failure are excluded, and the modified cell dose for patients with very advanced leukemia also has been lowered.

But largest hurdle of all will probably be the cost of these therapies. Since they are a genetically engineered product, CAR T-cells are very complex to manufacture; each batch is composed of unique, personalized T-cells that were made from a patient’s own blood cells. The inability to mass-produce CAR T-cells will definitely increase the price companies charge for them.

“What we’re talking about here is a single, very expensive therapy that’s used once for a specific patient and is not generalizable,” says Dr. Malcolm Brenner, director of the Center for Cell and Gene Therapy at the Texas Children’s Hospital in Houston, who, in MArch, signed an agreement to commercialize his own CAR research with Celgene.

Novartis and Juno both insist that it is too early to speculate on the price of the treatment, but Dr. Usman agrees the challenge is getting the manufacturing process to “a viable level where it’s both affordable and attractive.”

Citigroup believes CAR therapies could cost in excess of $500,000 per patient, which it notes is roughly in line with the cost of a stem cell transplant, even though most analysts think it is too early to estimate potential revenue or price.

“This technology needs to be widely developed and accessible to patients,” says Dr. DeAngelo. “If the cost is going to be a hindrance, it’s going to be a really sad day.”

Scalability and cost are one reason Pfizer is taking a different approach to this field. “We would like to take it to the next level, where CAR therapies become a more standardized, highly controlled treatment,” said Mikael Dolsten, Pfizer’s head of global research and development.

Working with French biotech Cellectis SA, Pfizer wants to develop a generic CAR therapy for use in any patient. While this will certainly lower the cost of the treatment, since it is the result of a mass-produced, off-the-shelf-product, this work is still at the preclinical stages and may not work in humans.

Global head of health-care research at Société Générale, Stephen McGarry, thinks that the revolutionary treatments being developed by Novartis and Juno could justify “astronomical” prices, he believes health-care payers and patients will probably protest such high prices. “When you look at the initial data with the Novartis therapy, you’re getting cures in some kids—what do you charge for that?” he asks.

Amgen’s New Drug Blinatumomab Shows Success in ALL Patients


Amgen Corporation announced updated results from its Phase 2 study with blinatumomab. Blinatumomab is a specially produced antibody that targets a protein called “CD19.” This antibody is made by an engineered cell line that produces one and only one kind of antibody. Such an antibody is called a “monoclonal antibody.” Monoclonal antibodies are made by antibody-making cells (B-lymphocytes) that are fused to tumor cells. The tumor cell immortalizes the B lymphocyte and this immortal cell now makes one type of antibody for its entire existence. Such a cell line that results from the fusion of a tumor cell with a B lymphocyte is called a “hybridoma” cell line.

CD19 is a cell surface protein that is made on the surfaces of B lymphocytes. Because B lymphocytes can over-grow and form blood-based tumors, an antibody that binds tightly to CD19 can specifically target B lymphocyte-based tumors. The binding of such antibodies also alerts other immune cells (T cells) to home to those cells and destroy them.

Blinatumomab, however, is an even more special molecule, because it binds CD19 at one end of the protein and a T cell-specific protein called CD3. Blinatumomab, therefore, acts as a bridge between tumor cells and T cells. It helps the T cells recognize the tumors as foreign. It is therefore an unusual type of chemotherapeutic agent called a bi-specific T-cell engager or BiTE. Another BiTE is MT110:, which is used to treat gastrointestinal and lung cancers, and is directed against the EpCAM antigen and the T cell surface protein B3.

Treatment with blinatumomab helped achieve a high-rate of complete response (CR) in 72% of all adult patients who were diagnosed with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL), and were treated in the study.

Full results of the study will be presented at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 4, 2012.

For more information on this Phase 2 single-arm dose-ranging clinical trial, 26 of the 36 patients treated with blinatumomab (across all of tested doses and schedules) achieved a complete response with partial recovery of their blood cell counts. All but two patients achieved a “molecular response..” Molecular response means that the presence of leukemic cells were not detectable with polymerase chain reaction (PCR) assays. There were also not treatment-related deaths or serious adverse events reported in this study.

Median survival was 9.0 (8.2, 15.8) months with a median follow-up period of 10.7 months at the time of the analysis. In the group of patients who received the selected dose of blinatumomab, the median survival time was 8.5 months, and the median duration of response in the 26 patients who responded to treatment was 8.9 months.

Max Topp, department of internal medicine II, University of Wuerzburg and chair of the study, said: “For these patients with limited treatment options, the remission rate observed in the trial is a vast improvement over the current standard of care. These results also represent significant progress in our research of immunotherapies; a new approach to fighting cancer that we believe could make a real difference for patients.”

Patients who received the selected dose and schedule, the most common adverse events were mild and included fever, (70%), headache (39%), shaking (30%) and fatigue (30%). Reversible central nervous system events led to treatment interruptions in six patients with two patients permanently discontinuing treatment.