On the Biotechnology Frontier: Personalized Medicine, A Discussion with E.J. Brandreth

Favrille, a San Diego-based biopharmaceutical company, is one of a handful of firms on the forefront of personalized medicine. Because personalized treatment is tailored to an individual's biology, it has the potential to be far more effective than current approaches to disease management.

Favrille focuses on developing and commercializing patient-specific therapies for immune system diseases. Its lead drug candidate FavId, is an active immunotherapy for the treatment of B-cell non-Hodgkin's lymphoma. The company has completed patient enrollment in a pivotal Phase 3 trial and plans to unblind the study during the first half of 2008.

In the following interview, EJ Brandreth, the senior director of quality at Favrille, talks about potential new cancer treatments, regulatory challenges, and the wonder of disposables.

Where do we stand in the evolution of personalized medicine?

Personal medicine has been in development since the late 1980s. No one yet has a personalized product approved for the treatment of cancer, but four or five companies are near the end of Phase 3 trials, and over the next several years, we expect to see approvals come through. There's a big difference between personalized treatment, and personalized products. Personalized treatment is where the doctor prescribes the best treatment for you based on your genetic profile; personalized products involve a drug that is actually made just for you and you alone.

What has been the biggest breakthrough leading to personalized medicine?

By far, it has been the ability to rapidly sequence a patient's DNA, identify the sequences of interest, and produce recombinant protein at a scale appropriate to the need. Over the last five to 10 years, we learned how to go into a tumor and analyze a sample from a patient. Pathologists and doctors are now able to look at the DNA sequences (biomarkers) of cancer patients, which tell them what the best treatments would be for the patient. This information directs the physician on which general therapeutic can be used. If personalized products are not available yet, doctors can identify which general therapy—chemotherapy, antibodies, or radiation—would be the most statistically effective for a particular cancer type, based on their genetic screening.

Quick Recap

What is Favrille's current focus?

Our lead product candidate, FavId, is specific to a patient's cancer—B-cell non-Hodgkin's lymphoma. This is a cancer of the lymphoid system and the tumor cells produce an antibody that is specific to the patient and to the tumor. Due to the advancements in high-throughput sequencing, sequence databases and plasmid generation, and expression in an insect cell system, it is possible to generate large amounts of the specific antibody produced by those cancer cells. These antibodies are then given back to the patient, so his or her immune system mounts a defense against those antibodies, and therefore against that tumor. This type of treatment should also work on other immune-system cancers.

QA: How much difference is there between the antibodies of one patient and the antibodies of another?

While all antibodies have a common structure involving two heavy and two light chains, there are variable regions that are unique to each patient's lymphoma tumor. The probability of identical sequences in any two lymphomas is extremely unlikely.

In addition to DNA sequencing, what other developments have led to these advancements?

In addition to DNA sequencing, the use of expression systems that do not require cell transformation has been a major advancement, such as the use of baculovirus in an insect cell culture. This dramatically reduces the time in cell processing for the production of recombinant proteins.

On the analysis end, it is new equipment, like DNA sequencers that have become far more efficient and sophisticated. They can analyze multiple samples simultaneously. In the future, we'll be able to increase what we're doing today, logarithmically with computers, and with equipment using microcapillaries. We can now process a thousand samples in the amount of time that one sample took in the past.

What are some of the manufacturing developments that have led to personalized therapies?

After we receive a biopsy sample, sequence the DNA, and determine the relevant sequence for the patient's antibody, we generate a plasmid that is integrated into a virus specific for insect cells. The use of this viral and insect cell system has been a big breakthrough. We use insect cells—Fall Armyworm (Spodoptera frugiperda) and Cabbage Looper (Trichoplusia ni)—with a baculovirus vector. The virus replicates within the insect cells and they produce antibodies with a glycosylation pattern that we believe is best suited for eliciting the immune response we are seeking. In fact, we can generate and harvest a cell culture in a fraction of the time it would take using mammalian cells.

So, how long will it take you to develop a therapeutic for a cancer patient?

Our proprietary production system allows for manufacturing a patient's FavId and returning it to the patient's physician in eight weeks. Mammalian cell production systems require 4–6 months.

Does the manufacture of patient-specific therapies require unique facilities and regulatory considerations?

Safety is always the number one concern, and with insect cells, there is a slightly lower risk of viral contamination for humans compared with mammalian cells.

One of the biggest measures we can take to ensure safety is segregating patient-specific lots. There are different approaches to this. One is through facility design.

We have already completed the construction of a commercial facility. The biggest regulatory concern is segregating the lots of patients' antibodies. We have a dedicated area for the final production phases of each lot, and will be processing and releasing up to 80 lots per week. In any given day, we could have more than 500 lots at various stages of production in the facility. Those are staggering numbers.

The other measure is establishing a dedicated tracking number and bar code for the biopsy sample when it comes through the door, and then following it all the way to the final vial shipped out to the patient.

Another major consideration is scale. We have essentially the same stages as other typical recombinant protein biotech companies: cell culture, purification, formulation and filling, but at a very small scale. We are only making enough vials for one patient.

How do you scale up?

You have to scale up horizontally, not vertically. We have multiples of small pieces of equipment: dozens of laminar air flow hoods and purification skids.

Do you use disposables?

Our entire process uses disposable technology. There are virtually no cleaning validation issues, to avoid the possibility of cross-contamination. The disposable industry has evolved to the point where lots of equipment is available that is presterilized and single-use, and that eliminates validation concerns for cleaning and sterilizing.

What type of testing will be done?

We sequence the patient's DNA at the beginning of the process, and verify it at the end, to make sure the sequence matches what came in. Otherwise, the testing is fairly typical for protein products.

The benefit of patient-specific therapy is doing everything at small scale. When you get to process validation, you can validate at actual commercial scale. In general, the biotech industry has to use scale-down models to validate the process.

Are there any shortfalls of production at small scale?

The only thing that doesn't become easier at small scale is certain aspects of compliance, such as batch records. If you were making Herceptin or Rituxan in a 12,000-L bioreactor, you would have a large batch record; it's the same size batch record if you're only making 12 L for a patient lot: the size of the bioreactor has come down, but you still have the same compliance issues.

How much protein does each batch or lot yield? How does this quantity relate to the dosage needed for the patient? Does the patient receive dosing over an extended period?

The process was identified as being sufficient to produce enough product to treat a patient for at least three years. Patients with indolent non Hodgkin's lymphoma are faced with eventual disease progression in most cases. FavId is designed to extend the time to progression for patients with follicular lymphoma, one of the most common types of lymphoma. Each patient receives six initial monthly subcutaneous injections of FavId along with four daily subcutaneous injections of Luekine (GM-CSF), a cytokine intended to enhance the immune system response to FavId. If the patient's disease is stable or in remission, then he or she moves into maintenance therapy and receives bi-monthly injections for one year and then quarterly injections until disease progression.

Is this type of production economically feasible? How does your cost of goods compare with those for mass-produced biologics?

It really is a completely different business model than mass-produced biologics, and until a few years ago, it was not economically feasible. Today, by using our proprietary processes including the use of baculovirus and insect cell cultures, we have rapid turnaround time for the product, and "time is money." Moreover, the availability of affordable disposable materials and equipment has helped to make this new approach to medicine practical and affordable.

How will personalized medicine affect patient care?

We have found that there is great variability within one type of cancer: there are many types of breast cancer, colon cancer, etc. This is because there is variability in the types of mutations leading to cancer; we need personalized therapy to address the specific tumor. It used to take too long to sequence the DNA and generate the protein. It was too expensive and time consuming.

We have completed over 300 lots for our Phase 3 trial; we have an impressive data base before going commercial. That's rare for the biotech industry, which often has only 5–10 lots at commercial scale when they apply for a license, because each lot is so expensive.

This means we're sitting on 300+ cell culture runs, purification runs, and aseptic fills. If you look at final product testing, which requires 10–20 tests, and multiply that by 300, there is a huge amount of quality control testing data available.

How long do you think you will get approval?

Assuming positive data from our ongoing registration trial, we anticipate approval in early 2009.

Is it challenging to get approval (of product or process) because your clinical trial patient numbers are so small per lot?

We have a process that is shown to be reproducible for the wide variety of patient tumors we receive. Our historical data should demonstrate a very robust and licensable product. The clinical data will speak for itself; a safe and effective product should get rapid approval. Once approved, we anticipate rapid market penetration.

How long do you think personalized medicine will become a routine, or even a central part of production and a business model in the industry?

The use of personalized treatments is already occurring and the use of personalized products is in its infancy, but I expect in 10 years we will see this as a significant sector of the biotech industry.