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February 09, 2016 - 11:02 pm Posted in Featured comments0 Comments

“No single player can do this alone.”
- Axel Hoos, Head, Immuno-Oncology, GSK

By Neil Canavan

New York - Stakeholders of every stripe in the cancer immunotherapy space gathered at the New York Academy of Medicine, February 2nd and 3rd, for the second annual Immuno-Oncology 360° meeting. The FDA was there, as was Wall Street, big pharma, and small biotech, academia sent several top clinical researchers, and, most poignantly, the very first successfully treated CAR-T patient also found time to attend (Emily Whitehead, age 10).

This remarkable group of people had gathered to discuss a remarkable thing: the possibility of actually curing cancer.

“I’m using the word ‘cure’ now,” said Axel Hoos, MD, PhD, senior vice president, Oncology Research and Development, GlaxoSmithKline. “It’s a word we have been shying away from for a long time in oncology, but now – we may actually have an opportunity to cure patients of metastatic disease.”

Dr. Hoos, a co-organizer of the IO 360° meeting along with James Gully of the NCI, played a significant role in the clinical development of the drug that kicked off the IO revolution: ipilimumab. Improvements in overall survival seen with this drug in patients with metastatic melanoma were without precedent; some patients are so far out in time from their last treatment (over 10 years) as to be considered effectively cured.

Ipilimumab (Ipi), the first “checkpoint inhibitor,” was approved in 2011. And since then the field has exploded.

In 2015, a second checkpoint was approved (pembrolizumab), and then a third (nivolumab), and there are many checkpoints in the near-term pipeline. Beyond that there are the so-called CARs, the first CD19 flavored, and now a whole menu, and now also, the first oncolytic virus treatment has been approved (T-Vec), and bi-specific antibodies are in late stage development, and vaccines – yes, vaccines – vaccines are back and it is all getting to be just a bit too much…

“The pace of progress has been so amazing,” said Dr. Hoos. “We’re almost not able to catch up in terms of even doing events that report on that progress.” Yet with each advance, each new opportunity, there are new questions, such as: How to safely use these drugs; who is more likely to respond; what combinations should be tried; how are IO trials different from targeted therapies; what is the FDA thinking about all this… How do you set a price on cure?

“The purpose of this event is to try to address some of the needs of all stakeholders,” said Dr. Hoos. “From the business angle to the bedside, all the way to the last basic aspects of science.”

On to Business
Topics presented at IO 360° ran the gamut from regulatory perspectives to imaging software. However, the focus here will be on aspects of business development in cancer immunotherapy, and certain themes that emerged during the meeting regarding: Combinations, Collaborations, Contractions, and Cost.

Peter Thompson, of the healthcare hedge fund, Orbimed, led off the business discussions. “There is no question that (IO) is really different,” he said. “The results from the (pivotal ipilimumab/nivolumab) Checkmate studies… This is dramatically different than what we’ve seen before.” And there are a lot of implications.

One of the top concerns is with the FDA, though Thompson insists that, given the complexity of IO, the FDA is doing a pretty good job. “There’s been a lot of (IO) approvals, and relatively quickly. The FDA has been working very hard to try to adapt the regulatory space at a pace that is commensurate with the evolution of our understanding of the science.”

More than ever, it’s critical that IO players be in constant communication with the FDA concerning trial design, in particular, having clearly defined endpoints according to the science.

“Recall that the initial results for Ipi were a bit challenging to interpret,” said Thompson. “The overall response rate wasn’t really much to go on, in fact, Ipi and (tremelimumab) had similar data sets, yet one organization walked away from the one drug, and the other continued.”

The problem wasn’t a lack of efficacy, it was a lack of understanding of how IO works. Simply put, immunotherapy takes longer, and works in different ways than targeted treatments. Responses to IO therapies are so different in fact that a new response criteria is now recognized as the standard for IO investigations (irRC; Immune-Related Response Criteria).

One of the many open questions going forward is how to design a trial for the multitude of upcoming IO/targeted therapy combinations. Think of all the opportunities for different trial designs: IO versus targeted treatment; IO/targeted versus targeted/targeted; novel/novel IO agents versus IO approved agent/novel IO…

Moreover, is an overall survival endpoint even valid for a drug that is potentially curative?

As GSK’s Dr. Hoos suggests, “With the increasing survival rates we’re seeing with these drugs you may not be able to use overall survival as a primary endpoint if you need to wait ten years for the data. It is not realistic—it requires us to rethink the way we measure activity.”

As these novel therapeutic trails continue to be blazed, the only and best advice for now is to talk to the FDA early, and often.

Gobble gobble
While the FDA grasps for an understanding of utterly novel technologies, pharma has been trying to figure out how to either become competitive, or vault ahead of the competition. To wit, a spate of recent deals:

• Merck buys IOmet Pharma (January 2016; IDO inhibitor asset)
• Merck buys cCAM Biotherapeutics (July 2015; checkpoint asset)
• BMS buys Flexus Biosciences (February 2015; IDO asset)
• Novartis buys CoStim Pharmaceuticals (February 2014; PD-1 asset)
• AstraZeneca buys Amplimmune (August 2013; PD-1 asset)

Note that all five transactions involved checkpoint inhibitors.

“Checkpoints will be the foundational components of IO regimens going forward,” said Jeff Bockman, of the healthcare consultancy, Defined Health. “It’s like taxanes in the chemotherapy arena – it’s always a taxane plus something else.”

So does everyone need a checkpoint? Business trends seem to suggest so. For example, the acquisition of Bionovion (checkpoint asset) in late 2015 by Aduro: “It’s a real advantage if you bring something like this in to your franchise and have the ability to control, say, anti-PD-1 and to combine it with whatever novel agents you have, rather than go outside,” said Bockman.

Michael King, senior biotech analyst at JMP Securities agrees. “PD-1 is such an axis—it would be like treating HIV without having a nuke backbone—it’s a foundational therapy.” King believes that in the checkpoints setting, and in the field overall, smaller players will be snapped up. “When you think about the technical complexity, the capital allocation needed to be directed toward developing follow-on therapies, the ability to go in and negotiate with payer groups, be it US or elsewhere… there will be more upward consolidation.”

Diversify or die
Smaller players can take heart in the example of Agenus, under the leadership of Robert Stein.

“As soon as I got involved in this space it became clear that combinations would be required,” said Stein. “And it won’t be the same combination for every patient—not like in HIV or HCV—for cancer you have to know the mutational landscape of neoepitopes (mutations that are likely to be unique to a given patient).”

“It was also clear that we need to shape the immune response, or disarm the tumor if it has deployed a defense mechanism—that’s the reason to get into the checkpoint modulator space.” To that end, Agenus is in checkpoint partnerships with Incyte, and Merck, and to help mine for neoepitopes Agenus just acquired Phosimmune.

At GSK (they of the deep pockets) the admonition that “we can’t do this alone” is interpreted as “no modality can do this alone,” and in recognition of that understanding, GSK is developing potentially overlapping assets and recognizing what it already has in-house.

“There are so many new technologies pushing out,” said Dr. Hoos. “Bispecific antibodies, oncolytic virus, vaccines, and CARs, are all just the part of the story. To be successful in the long run we need to integrate all this information and recognize the modalities we have available so we maximize their potential.”

Furthermore, maximizing potential does not mean getting really good at one thing – that won’t fly after your IO IPO:

“Not that many companies, after they go public, use their funding to make other M&A and BD decisions,” said Mark Simon, Torreya Partners. And in the IO space that’s a problem. “If you look, for example, at Bellicum, and some of the other CAR-T companies like Juno, they were very aggressive in bringing in other technologies. Others were more complacent,” he said. “Time will tell which approach is better, but history has shown that the ones who get out there and realize that there are good technologies outside their walls generally do better.”

Vaccines
“Vaccines are being reevaluated,” said Defined Health’s Bockman. “Single epitope, whole cell tumor lysates, tumor RNA, DNA, peptides, danger signals, costims, adjuvants… it’s a very diverse space.” Yet, there is no small amount of trepidation from investors when presented with vaccine opportunities. “There’s still a lot of misperception and baggage from the past,” but going forward the writing on the wall is clear: vaccines failed for lack of understanding about the immune system, and the checkpoints, and now with that knowledge in hand…

“I don’t see pulses raging just yet for cancer vaccines companies,” said JMP’s Mike King, “but I don’t think it would take a whole lot of data to move that needle.”

Miscellaneous
A few end notes, consensus observations, and advice on overcoming boredom:

• The therapeutic potential for CAR-T programs is difficult to estimate—suffice it to say it is extreme. Marketability, however, is an open question. How many CAR-T manufacturing facilities will be needed? Will Novartis have one, and Juno another, or, if technology allows, will each company have one at the patient’s bedside? What about off-the-shelf CAR-T cells, does that make more sense? Will allogenic CAR-T cells be as effective?

• How are investigations with IO/targeted combinations going to be prioritized? There are literally hundreds of potential combinations, and there is not enough money, nor are there enough patients to test them all. Deep knowledge of your drug’s mechanism will be critical in making the right choices.

• For IO drugs there may not be a maximum tolerated dose. As IO expert, Dr. Jedd Wolchok of Memorial Sloan Kettering Cancer Center stated, “We’re still figuring out how to use these drugs.” For instance, the dose of PD-1 for lung cancer is much less than that used in melanoma patients. Trial designs will have to take this into account.

• Cost. How do you price cure? Or, perversely, as one panelist pointed out, how do you adjust for the lost revenue from patients in the relapsed/refractory disease setting if those patients are being cured instead?

• In the case of Emily Whitehead, what do you do when you’re with your parents? You play Candy Crush on your iPhone just like any other perfectly healthy 10-year-old would do.

For more information on the IO 360° conference:

http://theconferenceforum.org/conferences/immuno-oncology-360/overview/

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