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Source: Gail Dutton of The Life Sciences Report (9/9/15)

CAR T-cell therapies show amazing potential in treating blood cancers, but there’s a lot of work to do before the cells are ready for commercialization. Alan Leong, senior analyst with BioWatch, tells The Life Sciences Report about the latest in CAR T-cell therapeutics and how some companies are hedging their bets by developing bispecific antibodies. He also describes the reality behind the growing excitement in regenerative medicine, and what investors should know about some very innovative, but often overlooked, small companies.
The Life Sciences Report: To begin, tell our readers about chimeric antigen receptor (CAR) T-cells and why they are generating so much excitement in the oncology field, particularly among companies targeting hematologic (blood) cancers. Alan Leong: We’re seeing remarkable and well-documented response rates for CAR T-cell therapies. These therapeutics are still in the early stages of their lifecycles, so they are likely to evolve and be refined over the next five to 10 years. What is amazing is the incredible array of companies developing CAR T- cell therapies. They include Juno Therapeutics (JUNO:NASDAQ), Kite Pharma (KITE:NASDAQ), Bellicum Pharmaceuticals Inc. (BLCM:NASDAQ), Intrexon Corp. (XON:NYSE), bluebird bio Inc. (BLUE:NASDAQ), Celgene Corp. (CELG:NASDAQ), Selexis SA (private) and many others. These companies are very good at stimulating T cells to be highly active cancer cell killers. Each company is trying to develop its own process and targets, but what excites everyone is the chance to target the CD3 receptor to activate T cells.

“RepliCel Life Sciences Inc. is a very provocative, very interesting company.”

Activating T cells through the CD3 receptor, however, has drawbacks that may limit CAR T-cell therapeutics to hematologic cancers. Because CD3 activation highly stimulates the T cells, we sometimes see something called cytokine release syndrome. In this syndrome, the body mounts an extreme response, in which T cells target major organs in an autoimmune shutdown. This reaction is potentially fatal, so currently, when the leading CAR T-cell companies enroll patients in a CAR T-cell trial, those patients are put into intensive care wards immediately. Companies are trying to find solutions to minimize that risk. If they succeed, they may be able to target solid tumors. If I had a caution about CAR T-cell therapy, it would be that the cost is extremely high. To put this in context, Provenge (sipuleucel-T), by Dendreon Corp. (DNDN:NASDAQ), debuted in 2010 at $93,000 ($93K) for a three-infusion regimen, and was criticized for being so expensive. CAR T-cell therapy is much more complex and, therefore, even more expensive. In some cases CAR T-cell therapies also are less homogenous, so there may be substantial batch-to-batch variation. TLSR: If the CAR T-cell therapeutics are as effective as early results indicate they may be, would their higher costs be worthwhile for payers? AL: Right now, the actual costs of CAR T-cell therapeutics are somewhat opaque, but people are talking about an initial price of $250K per patient. Some suggest payers will provide reimbursement based on Gilead Sciences Inc.’s (GILD:NASDAQ) Sovaldi (sofosbuvir) experience: A 12-week regimen for that hepatitis C therapeutic costs $84K. I always retort, “Well, if there were three or four Sovaldis out at the same time, would they have paid it?” The answer is no.

“When it goes head-to-head against tenofovir, ContraVir Pharmaceuticals Inc.’s CMX157 is a slam dunk.”

I think we’ll see some interesting movement over the next year or two as people raise questions regarding the ability to commercialize CAR T-cell therapies. Nonetheless, this is a time to be excited. We’re seeing response rates we only dreamed of years ago. TLSR: Do you see any alternative therapies in development? AL: We’re entering the age of targeted medicines. This is an exciting time. In the past decade Seattle Genetics (SGEN:NASDAQ) brought out Adcetris (brentuximab vedotin), which elicits amazing response rates in lymphomas. Then Medivation Inc. (MDVN:NASDAQ) introduced a prostate cancer medication. Now we have a plethora of targets and technologies.

“Celator Pharmaceuticals Inc.’s acute myeloid leukemia therapy shows superior delivery and uptake by cancer cells.”

CAR T-cell therapy is expensive, but many companies are creating bispecific antibodies that may recreate what CAR Ts do at a fraction of the cost. Bispecific antibodies are engineered to go after two or more targets. In their favor, bispecifics are much less expensive and much more standardized than CAR Ts, so they probably don’t have to be as effective to be commercially successful. They just have to be effective. Therefore, I raise a caution regarding CAR Ts and bispecifics because they’re going after very similar targets. Perhaps both can be successful. TLSR: Are you seeing any trends among all the companies that have the CAR T-cells out in late-stage research? AL: On the business side, we’re seeing an interesting number of collaborations occurring with one major partner or multiple smaller partners. That’s true for bispecifics, too. Juno and bluebird each recently concluded deals with Celgene. So companies are getting support, whether from the equity markets or from partners, to help them reach their next milestones. That funding is being used primarily to improve their processes. That includes identifying the source of the cells; the most effective methods to condition, transect or modify the cells to become CAR T cells; criteria to select T cells; and the best ways to replicate them in vitro. The methodologies used today will continue to improve.

“Sunesis Pharmaceuticals Inc. was encouraged by European Union regulatory staff to submit for approval of Qinprezo.”

Juno has an autologous process, where the blood is taken out of each patient. Other companies are trying to develop allogeneic processes, to eventually make off-the-shelf products viable. The challenge is how to standardize and optimize each process so that it becomes scalable and cost effective. Scientists throughout the industry also are working to control the dangerous side effect of cytokine release syndrome. Some are inserting a suicide gene so that, within 30 minutes, they can infuse a solution that will kill or deactivate specific CAR T cells. Bellicum is known for that approach, although Juno and others also have CAR T-cell lines that incorporate suicide genes. Companies are trying to find additional methods to inhibit the strength or the application of the CAR T cells in healthy tissue. We’re all crossing our fingers. TLSR: What regulatory challenges do you foresee for this new technology? AL: CAR T-cell therapeutics will experience issues that are typical to any first-in-class therapy. The FDA must give them an extra look. CAR T-cell therapies are very new and very complicated. As much as we’re concerned about evaluating response rates and safety, I’m just as concerned that these therapeutics pass the FDA’s manufacturing inspection. This is an issue for any new drug. For CAR Ts the hurdles may be a bit more significant because the manufacturing process is so complex. But these are issues any first-in-class therapy must contend with. TLSR: Briefly, what makes the process so complex? AL: For years, there have been many attempts to activate T cells. There was a suspicion that, if we could get the T cells really alive, we would see interesting response rates. The ground is littered with predecessors. Juno, among others, found the right therapeutic package. It stimulated the right molecule and developed the compound in a way that elicited great responses. Really, Juno hit the jackpot. The CAR T-cell therapy that emerged from that early work is a first-generation, combination gene/cell therapy. It’s amazing science, but I often wonder if, 10 years from now, we’ll look back and consider it Rube Goldberg science. I hope, in 10 years, that processes will be much more advanced. TLSR: Tell us about some of the companies you are following. AL: There are a great number of interesting companies. Some of these are very early stage, but they caught my eye because of what they imply. I recently looked at Inmedix LLC (private). I’m still analyzing it, but the results of some of its early work are surprisingly robust. There is a whole area of research that looks at the status of a person’s autonomic nervous system, which governs involuntary body functions such as breathing, heartbeat and digestion, and determines whether there is variability within that system, or whether the system is heightened. It also considers the status of the sympathetic nervous system, which controls the body’s reactions to stress. Some of these things are intuitive. For example, if you think of the “fight or flight response,” you can see that the immune system gets upregulated. Those changes trigger other changes in the human body.

“We’re seeing remarkable and well-documented response rates for CAR T-cell therapies.”

For example, Seattle-area rheumatologist Andrew Holman, M.D., with his associates, studied autoimmune disease to determine whether autonomic status can guide therapeutic decisions. The resulting method enables physicians to prescribe the right drug the first time for 80% of their rheumatoid arthritis patients. Without it, they must try multiple regimens until one works. An 80% hit rate is almost unheard of, so I’d like to see the studies replicated. The research protocol is straightforward, relying upon one very strong predictive variable rather than many, and the therapy is very simple. It combines the right autoimmune medication with something, like a benzodiazepine, that stabilizes the autonomic nervous system. Earlier versions used a selective beta blocker and saw some very good effects. Inmedix is a private company at this point, but if its additional data is good, the company may interest very early investors. It’s a very interesting play. TLSR: What about public companies? AL: I have a number of them. On the regenerative side, RepliCel Life Sciences Inc. (RP:TSX.V; REPCF:OTCQB) and Capricor Therapeutics (CAPR:NASDAQ) are very interesting. I’ve been watching the regenerative arena carefully. The interesting thing is the idea that we can rejuvenate parts of the human body or even, perhaps eventually, the entire human body. Most people agree that’s a disruptive development and worthy of further development. Many think regenerative medicine is too early in its lifecycle to seriously be considered as an investment opportunity. But while some applications are in the distant future, others just need refinement. Some regenerative medicine therapeutics, especially those treating major organs or in some of the boutique areas of the sector, are being commercialized now. People, including scientists, who haven’t followed regenerative medicine often are surprised at how far some companies have gotten in terms of results, costs and manufacturability. RepliCel caught my attention because of its hair regeneration or restoration technology. That may not be the application that first goes commercial, but it’s interesting, and there’s a lot of money in this area. About a year ago, BioWatch asked the former president of a cosmetic therapy professional organization to describe the typical hair replacement procedure. It’s incredibly invasive. RepliCel has a way of using dermal-related cells that is far less invasive.

“Many companies are creating bispecific antibodies that may recreate what CAR Ts do at a fraction of the cost.”

RepliCel’s technology can be used to regenerate hair, and a related technology can be used to repair tendons for patients with tendinitis or major tendon injuries. Interestingly, because of the nature of the cells it is using and its process, cost and scale aren’t issues. Other scientists give it a thumbs up, saying the science is good. The company is currently in a set of Phase 1 and 2 trials for both the hair regeneration and for tendon repair. Early results seem to be very good. RepliCel is under the radar. It based in Vancouver, British Columbia, and trades off the Canadian exchange and over the counter in the U.S. at very low prices. Keep an eye out for the next set of results and for a move to a major stock exchange. For those who want to get in very early, this is a very provocative, very interesting company.

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