A team of genome engineers at a startup biotech has been working for years to create a cell therapy with the hope that it will cure an aggressive form of cancer. After much grueling trial and error at the editing bench, they are ready to evaluate their drug candidate in clinical trials. Things are going well, and they’re ecstatic to see that tumors are shrinking, T cell counts are rising, and the disease is retreating. But there’s a cloud on this bright horizon. A side effect is showing up with some of the patients in the trial, one which might have long-term consequences for their well-being. The scientists have an idea: What if they can flip what they call an “off-switch” on one pair of genes they’ve identified that could turn off this side effect of the drug while retaining the new drug’s curative powers? It sounds like an easy fix but its implementation is going to take a long time.
In the current regulatory environment, after an important discovery is made, a trial alteration is required, which is a costly and lengthy process that limits the ability to bring novel unique therapies quickly to patients with high unmet needs. If those genome engineers at the startup want to make even the slightest improvement to their drug candidate, which may attenuate the previously mentioned serious side effect, they’ll be required to start all over again with a 2.0 version. This kind of versioning is customary in the biotech industry and can often be a race against time.
An era of inter-disciplinary advances
In our current climate of drug innovation, pharmaceuticals are being developed through hyper-precise genetic editing. No longer relegated to a siloed discipline, blockbuster drugs are being developed by the team efforts of gene therapy, cell therapy, gene editing, protein engineering, synthetic biology and artificial intelligence. These combined disciplines provide limitless capabilities to develop new therapies. This agile capacity could make in-trial drugs incrementally safer and more effective.
An example of what can emerge from this multidisciplinary world, that is making it relevant, is the invention of allogeneic CAR-T cell therapies. An artificial gene coding for a designed Chimeric Antigen Receptor (the CAR part of the word) is delivered by a synthetic vessel called lentivirus into T cells, white cells which are our bodies’ immune response fighters. Then, through synthetic biology, T cells are edited out (or in) to gain or lose specific functions. This process is made possible by using a gene editing tool called TALEN, which are enzymes that can be engineered to cut specific sequences of DNA. The engineering of TALEN is powered by deep learning algorithms. We may refer to the treatments that arise from this work as “cell therapy” or “gene therapy,” but it’s high concentration of sophisticated technologies working together.
A new therapeutic model
In 2015, during the annual meeting of the American Society of Hematology (ASH), the complete remission of the first patient treated with off-the-shelf CAR-T cells was announced. It took nearly 20 years of trial and error at the editing bench to go from concept to the first patient treatment. Now, five years later, the number of ongoing trials in the sector of cell and gene therapy is rapidly increasing. A report released in March 2020 by the Pharmaceutical Research and Manufacturers of America (PhRMA) identified 362 investigational cell and gene therapies currently in clinical development, a 20% increase since 2018.
Though the increase in trial numbers and the multitude of advances in the way we utilize gene and cell therapies seem positive, there is not a direct correlation between the advance in research we see in the lab and the way patients are treated in the clinic. Furthermore, the drugs that these patients receive were invented many years ago. To prove this point: Approved cellular therapies providing revolutionizing cures, like the first two autologous CAR-T products Yescarta and Kymriah, were invented over 15 years ago, and have side effects, due to the CAR-T persistence resulting in B cell aplasia (disappearance of B cells). Improvements have yet to be implemented in the compound and will need to be evaluated in a clinical setting.
The current paradigm in pharmaceutical development is that patients will get the “Older Gen” drugs with the afferent side effects rather than the “Next Gen” therapies that could solve the issue, because of the length, cost and complexity of the current regulatory framework not allowing for the implementation of improvements in the drug development phase.
Better treatments, ready sooner
While rapid, responsive versioning is the norm in other industries, like software, computer or rocket science development, the obvious difference in the pharmaceutical sector is that there are distinct ethical and safety concerns in conducting responsive versioning in trials on human beings; the safety of patients in clinical trials is paramount. That being said, what if we could expedite the process and bring innovation to patients faster within a fitted regulatory framework?
In recent years, several new clinical processes were created, intended to streamline and expedite drug development and clinical trial evaluation. To name a few: the creation of Phase 0, basket, and umbrella clinical trials. Though Phase 0 trials seem to address the expedition of the trials themselves, if any changes are made within this phase, a full IND application with the usual three pre-approval phases is still required to “re-version” your Phase 0 trial. Essentially, with simple proposed modifications, you are being asked to start from scratch, from a regulatory standpoint.
When the chance for failure in clinical trials (specifically in anti-cancer drug clinical trials) is so high (failure rate is more than 90%) and when more than half of these new drug candidates in oncology fail during later stages of clinical development, the path to expediting the implementation of versioning and revision during early-stage trials is fundamental to address patients’ needs, in a timely manner.
If a mechanism existed, by which series of versions of a product line could be tested, then adapt it or tune it up, according to the response observed in clinical trials, patients would have access to innovation faster and the modern medicine will progress further at a quick pace. Of course, preclinical proof of concept requirements and CMC must be part of the regulatory equation, but the ability to streamline testing of various versions of a therapeutic concept in the clinic could trigger a huge developmental acceleration to the benefit of patients.
The proposal would be to open a new era in drug development and adapt the regulatory environment to the speed of innovation and its opportunities in the interest of patients. The current regulatory framework and IND process (Investigational New Drug) seems set in stone for a single product development.
What if different versions of a product candidate could enter in clinical development phase under the same Investigational New Therapy (INT) number? In this INT, and under an initial umbrella Core Protocol (without making any shortcuts on product candidates manufacturing, quality and control or preclinical assessment of any of the versions of the therapy), incremental versions of the product candidate could enter in small clinical cohorts. Once there is a sign of meaningful efficacy and good safety profile on one of the versions, then this version of product candidate would be pushed into expansion and pivotal trial targeting a registration. In jurisdiction without the IND concept, the proposed Core Protocol will be associated with a Core Product Dossier holding the required information for each of the product candidate versions.
The goal of this process would be to get away from the track to get onto a larger road, with boundaries, where nimbleness is allowed to adapt the right version before moving to commercialization. This would be in the best interest of patients to get the latest therapy faster in a safe setting.
André Choulika is a virologist and a biotechnologist. He is the founder & CEO of Cellectis, a biotechnology company. He is also one of the inventors of nuclease-based genome editing in the 90s.
Biotech Voices is a contributed column from select Endpoints News readers. Read previous pieces here.
