Posts

tubes filled with pink liquid

Manufacturing technologies lag behind breakthroughs in CAR-T cancer treatment

tubes filled with pink liquid

Drug companies around the country are banking on the cutting-edge cancer treatments known as CAR-T, but many manufacturing processes are holding back the treatment from reaching the market. With the success of CAR-T, which essentially re-trains T Cells to identify and target the cancer-causing cells, many manufacturers still need to catch up in the development process.

Currently, there are nearly 700 CAR-T studies in the database ClinicalTrials.gov, including 152 industry-sponsored trials that are active, recruiting or enrolling by invitation. According to market research firm, Coherent Market Insights, they predict the CAR-T market will grow to $8 billion worldwide by 2028 from $168 million in 2018.

Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research at Children’s National Health System, was featured in a recent Bloomberg Law article stating that academics, industry participants and medical product regulators are trying to catch up with the technology and determine the best standards for developing these products. Although this is an exciting and positive time in the field of oncology, it also presents a big learning curve.

Making these cells requires extracting patients T cells. They are then genetically engineered in a laboratory to produce proteins that allow them to identify cancer-causing cells. The new cells are then multiplied and then reintroduced into the body to kill off the cancer cells. The entire process can take a few weeks to complete.

“This is not a drug,” Bollard said. “This is a living biologic, and it comes from the patient and individuals. There’s so much variability.”

Along with manufacturing challenges, the outlook on creating more therapies is looking good. The FDA predicts that it will be approving 10 to 20 gene therapy products a year by 2025. Other companies are working to develop a manufacturing platform that can help reduce the complexity of the current system and ultimately make CAR-T manufacturing easier to scale.

Kwitkin-family-photo

A rare diet: Could you survive on six grams of protein a day?

Clara Barton

Clara Rose Kwitkin was born at a healthy 7 pounds, 14 ounces on Nov. 12, 2018.

Children’s National Health System introduces clinic to help adults with phenylketonuria, a rare inherited disorder, experiment with Palynziq, an FDA-approved drug that helps the body process phenylalanine.

“What can you eat?” is a common question for picky eaters, particularly individuals with phenylketonuria (PKU), a rare inherited metabolic condition that prevents an enzyme in the body from processing the amino acid phenylalanine (Phe), a building block of protein.

About one in 10,000 or 15,000 people in the U.S. with PKU, approximately 50,000 people worldwide, understand this line of questioning. 

“It’s emotional,” says 27-year-old Ashley Kwitkin, a Northern Va. resident and new mom, about the complexities of following a low-Phe diet.

When Kwitkin previously went “off diet,” meaning eating more than six grams of protein a day, the equivalent of a handful of almonds, she felt the consequences: irritability, moodiness and poor concentration. Her body couldn’t process Phe.

The National Institutes of Health mentions excessive levels of Phe can lead to toxic levels in the blood and tissues, and even cause brain damage.

Kwitkin’s motivation during pregnancy quickly changed. “It’s not just me anymore,” notes Kwitkin, who gave birth to Clara Rose Kwitkin on Nov. 12. “It’s me and my child. The moment we met her, our lives changed forever.”  

If Kwitkin went off her PKU-approved diet while pregnant, she may have increased the chance that her baby would have been born with intellectual disabilities, heart problems, delayed growth, microcephaly or behavioral problems.

Fortunately, Kwitkin received medical clearance from her doctors to move forward with a safe and healthy pregnancy. While she is a carrier for PKU, her husband is not – which meant their child had less than a 1 percent change of being born with this rare disease.

Like many adults with PKU, Kwitkin is grateful for advancements with early disease detection and treatment. If she had been born six decades earlier, she may have been hospitalized for neurological impairments, before PKU was recognized, screened for and treated with a low-Phe diet to support cognitive development.

Kwitkin is grateful for the popularity of gluten-free, PKU-friendly products and specialty food stores – compared to when she was growing up and had to order medical bread, which cost $13 a loaf and came out of a can. This trend makes it easy to find PKU-friendly meals to eat.

Expanding her palate is one of the reasons Kwitkin is following the results of a new clinic at Children’s National to help people with PKU experiment with Palynziq, an enzyme substitution therapy that helps people with PKU digest Phe.

Palynziq was approved by the Food and Drug administration on May 24, 2018 and a team of metabolic dietitians and geneticists at Children’s National have been helping a handful of adult PKU patients test out the treatment, slowly, over a preliminary period.

To prescribe the drug in a medically-supervised setting, the doctors introduced the injectable enzyme treatment to participants in small .25-mg doses, which started on Aug. 20, 2018, and monitored their progress as they worked up to the standard 20-mg treatment, a milestone many in the group reached in November 2018.

If the treatment continues to go well, based on the results of the FDA’s recommended titration schedule, the medical team will enroll additional participants in its clinic and share the results with other medical centers.

The timing of the new Palynziq clinic is also perfect for Kwitkin. If the drug works for her in the future, she won’t have to make three dinners: one for her, one for her husband and one for Clara Rose. While Kwitkin is currently off the low-Phe diet, she looks forward to resuming a PKU-friendly diet in the future – especially as she and her husband consider having a second child.

Kwitkin’s PKU-friendly diet consists of “safe” foods, such as unlimited amounts of peaches, apples, cabbage and green beans, which contain zero traces of Phe, and portioned amounts of low-Phe foods: pasta, bread, baked potatoes and specialty-ordered, low-protein items.

While planning for pregnancy, Kwitkin adjusted her protein intake to eight grams of protein a day. During pregnancy, she ate up to 19 grams of daily protein – to satiate her body’s needs and the needs of her baby – and regularly checked in with Erin MacLeod, Ph.D., a metabolic dietitian at Children’s National who is guiding the Palynziq clinic.

Kwitkin-family-photo

Ashley Kwitkin and her husband look forward to expanding their family in the future.

While the new Palynziq therapy carries potential benefits, such as the ability to join a family potluck without counting grams of protein, have second servings of broccoli, a carefully-portioned vegetable on the PKU diet, or thinking clearly while eating a low-Phe diet, a motivating factor for many of MacLeod’s patients, the treatment also carries risks. 

Potential side effects of Palynziq include severe allergic reactions – swelling of the face, lips, eyes and tongue – as well as shortness of breath, a faster heart rate, rashes, confusion, lightheadedness, nausea and vomiting.

So far, minor side effects, such as rashes and injection-site soreness, are noted among participants in the Palynziq trial at Children’s National. The full 20-mg prescription could be increased or decreased, based on how a person’s immune system responds to the foreign agent. If all continues to go well for the participants, they will take the recommended dose, equivalent to about 20 injections a week, and check in with the medical team every three months during the first year. Based on their benefit-risk assessment of the new drug, they can then segue into bi-annual visits if they want to continue with the treatment.  

“Our goal is to help participants decide if this therapy is a good fit for them, based on their lifestyle and health preferences,” notes MacLeod. For some people, MacLeod explains, such as those entering college or who form strong social connections around food, and who may experience the impact of going ‘off diet,’ this treatment could change their lives. Others, such as those who are in the process of moving to a new city or are in a busy period of their lives, may prefer following a strict low-protein diet compared to taking daily enzyme injections.

Another factor Kwitkin and MacLeod will keep in mind as the Palynziq clinics advance is the treatment’s variability. For example, Kuvan, the first drug of its kind is an enzyme therapy developed to help the body break down Phe. The drug was approved by the FDA in 2007, but only works in a small portion of the PKU population – about 10 percent of patients with a mild form of the condition. Instead of eating high-Phe foods, Kuvan users follow a mild-protein diet.

MacLeod views this type of individualized meal planning and how her patients react to food as a science, which drew her to the field. She works with 70 to 100 PKU patients each year from infancy to adulthood, including patients in their 60s, to help them meet their unique metabolic needs.

MacLeod is also tracking the use of gene therapy in metabolic disorders in addition to how the gut flora, or gut bacteria, helps PKU patients modulate and break down Phe.

“A lot of research is happening right now,” adds MacLeod about accelerations with PKU therapy. “I’ve seen how patients respond to new treatments, including a carefully-measured, low-Phe diet, and how their lives start to change once they can think clearly and feel better, which is a motivating factor and goal for many of our patients. I’ve also seen others pursue their dreams, which in Kwitkin’s case was to become a parent and history teacher.”

Like Kwitkin and others impacted by PKU, MacLeod looks forward to ongoing developments and research for this rare disease.

 

Doctors-working-with-Digital-Tablet

New network will advance treatments for children

Doctors-working-with-Digital-Tablet

Three leaders from Children’s National Health System are among the investigators of a new FDA-funded program created to launch a global clinical trials network. The initial $1 million grant from the Food and Drug Administration (FDA) establishes a network among the Institute for Advanced Clinical Trials for Children (I-ACT for Children), the National Capital Consortium for Pediatric Device Innovation (NCC-PDI) (affiliated with Children’s National), PEDSnet, the James M. Anderson Center for Health Systems Excellence and the Critical Path Institute, to address the unmet medical needs of children by improving quality and efficiency in developing innovative pediatric drugs and devices.

Along with the fiscal 2017 funds, there is a potential for $1 million in funding each year for an additional four years to I-ACT for Children, contingent on annual appropriations and the availability of funding. I-ACT for Children is a new independent, nonprofit organization that works to improve the planning and completion of pediatric clinical trials. PEDSnet and the Anderson Center will serve as the network’s data and learning core, while the Critical Path Institute will serve as the regulatory science core and NCC-PDI will serve as the medical device core.

From Children’s National, the investigators include: Peter Kim, M.D., Ph.D., vice president of the Sheikh Zayed Institute for Pediatric Surgical Innovation; Kolaleh Eskandanian, Ph.D., executive director of the Sheikh Zayed Institute and NCC-PDI and Johannes van den Anker, M.D., Ph.D., division chief of Clinical Pharmacology and vice chair of Experimental Therapeutics.

“We are pleased that this grant addresses innovative reengineering of the pediatric device trials system,” says Eskandanian. “In contrast with drug trials, device trials are generally less optimally understood in academic medical centers and clinical sites.”

She explains that children have medical device needs that are considerably different from adults. Designing devices for children requires considerations such as growth and development, anatomical and physiological differences. Often, the lack of available devices for children forces clinicians to use an adult device off-label or to improvise. Off-label use may be the only option, but such use can bring risks of serious adverse events that could be avoided if there were more FDA–approved pediatric devices.

“Thanks to partnership with I-ACT we will be able to address the pressing need to improve clinical trials and post-market monitoring of pediatric devices,” says Eskandanian.

Leading the network as principal investigator is Edward Connor, M.D., president of I-ACT for Children and an emeritus professor of Pediatrics, Microbiology, Immunology, and Tropical Medicine at George Washington University School of Medicine and Children’s National.

Work has been initiated to integrate network components and engage public and private shareholders. Next steps include selecting priority projects for implementation in 2018 and beyond, and scaling the network in North America and abroad.

Funding for this work was made possible, in part, by the Food and Drug Administration through grant 1 U18 FD 006297. Views expressed in written materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government.

Children’s National Chief of Allergy and Immunology helps move gene therapy forward

Catherine Bollard

Catherine Bollard, M.D., MBChB, Chief of the Division of Allergy and Immunology, recently shared her expertise on an FDA panel that unanimously expressed its support for a pediatric cancer T-cell therapy called CTL019.

On July 12, 2017, a U.S. Food and Drug Administration advisory committee unanimously expressed its support for CTL019 – a pediatric cancer T-cell therapy. If the FDA follows the advice from the 10-member Oncologic Drug Advisory Committee (ODAC) – which included Children’s National Health System’s Catherine Bollard, M.D., MBChB, Chief of the Division of Allergy and Immunology and Director of the Program for Cell Enhancement and Technologies for Immunotherapy – CTL019 will become the first gene therapy to hit the market.

“Many of these children with recurrent cancer are out of other options to treat their illness,” said Dr. Bollard. “We are encouraged by these findings and the potential for this therapy to improve outcomes and quality of life.”

CTL019 is a chimeric antigen receptor (CAR) T-cell therapy, comprised of genetically modified T cells that target CD19, an antigen expressed on the surface of B cells. Also known as tisagenlecleucel, the therapy targets a single type of cancer called acute lymphoblastic leukemia and was created by Novartis.

In clinical trials, CTL019 showed unparalleled effectiveness. Of the 68 patients who received the drug, 52 responded almost immediately, and their cancer disappeared within the first three months. Seventy-five percent of those patients remained cancer-free six months after treatment. The therapy has one main side effect: an immune reaction called cytokine release syndrome, which can be deadly, with extended spiking fevers and other symptoms.

However, because of CTL019’s high efficacy, FDA scientists asked the ODAC panel to focus on the therapy’s safety and manufacturing challenges rather than whether or not it works.

Several committee members, including Dr. Bollard, expressed apprehension about the T-cell subpopulations’ heterogeneity, which could affect safety and efficacy. Another issue for consideration by the ODAC panel was the long-term side effects of CTL019 and the possibility that the T-cell modification could go awry, causing secondary cancers in the future.

Despite these concerns, the committee concluded that the strong efficacy data and the near-term benefits of CAR-T therapy more than tipped the scales in favor of the therapy. ODAC members were also pleased with Novartis’ plan to minimize risk, which includes limiting CTL019 distribution to selected centers with CAR T-cell therapy experience, and extensive, long-term post-marketing surveillance plans.

The FDA is not required to follow the ODAC panel’s advice when making its final decision, but it often does so. A final decision by the FDA is anticipated by late September.

Read more about the story in the Philadelphia Inquirer, Medpage Today and Healio.com.

Children’s National Heart Institute experts partner with FDA and nation’s leading cardiology organizations to advance pediatric drug development

New joint health policy statement offers roadmap for immediate changes in clinical trial design to save children’s lives

Families with children suffering from rare and difficult-to-treat cardiovascular diseases may soon have better access to drugs to treat their often life-threatening conditions. For the first time, experts from the U.S. Food and Drug Administration (FDA), the American College of Cardiology, the American Heart Association and the American Academy of Pediatrics are working together to describe the challenges and opportunities to improve pediatric drug research as shared in a joint statement published online June 29 in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.

“Children should have access to the latest advances in treatment and the best care. By challenging the status quo and designing new, safe and effective alternative study designs, we can give them the best opportunity to grow up stronger,” notes David Wessel, M.D., executive vice president and chief medical officer, Hospital and Specialty Services at Children’s National Health System. Dr. Wessel is internationally recognized for his pioneering work in caring for children with heart disease. As the senior author of the new joint statement and principal investigator of the STARTS-1 trial, which is the catalyst for this collaboration, he says he is “optimistic about this forward progress.”

According to the statement, less than 50 percent of drugs approved for use in the United States have sufficient data to support labeling for dosing, safety and efficacy in children. Additionally, a 2008 report by Pasquali et al, which reviewed more than 30,000 records of hospitalized children with cardiovascular disease, found that 78 percent received at least one off-label medication and 31 percent received more than three.

There are numerous challenges in the development and approval of medications for children – especially those with rare diseases – but the paper’s lead author, Craig Sable, M.D., associate division chief of cardiology at Children’s National, says we can and need to do better.

“While randomized clinical drug trials remain the gold standard in advancing care for adults with cardiovascular disease, relying solely on these types of trials for children unnecessarily limits the drugs approved for use in children,” says Dr. Sable. “Through this unique collaboration that unifies the voice of leaders in pediatric cardiology and the FDA, our goal is to provide a framework to better define which drugs are needed and how we can create novel study designs to overcome the current trial barriers.”

To read more about the barriers and ideas presented, please find the full statement here.