How Are Service Companies Responding to the Increased Interest in New Modalities, and What Regulatory and Market Hurdles Still Exist?

Moderator Dan Stanton, with Juan Cordova (Abzena), Dawn Ecker (BDO), and Scott Miller (Carbogen Amcis AG)

Moderator Dan Stanton led the second roundtable discussion at the BPI Theater at CPhI, which focused on emerging therapies and specifically how service companies are responding to the increased interest in developing new modalities.

More Monoclonal Antibodies
In Ecker’s presentation earlier that afternoon, her data had suggested that monoclonal antibodies (MAbs) have not yet peaked. Stanton began by asking the panelists to comment on this notion and how they see MAbs continuing to emerge.

Ecker replied that MAbs will continue to be useful tools. “They still will be produced and used as therapies,” she said, “because our limitations of knowing what we can block or trigger within a disease state are not even close to being understood.”

Cordova pointed to how the cost to develop and manufacture a conventional MAb has shifted over the past 20 years. He believes that the biggest hurdle for MAbs is finding the right target. “How has the cost shifted?” he asked. “Is the main hurdle now just finding the antigen, or is it the cost of goods to get into the clinic?”

Ecker responded, “I’m pretty certain the cost has come down for that process. It’s also evident that there are so many MAb companies with platforms that it must be a reasonable cost to develop and screen for all targets.”

Miller added that from a contract manufacturer’s perspective, customers tend to underestimate the difficulty of finding an antibody that offers the performance they are looking for. Often they have to switch manufacturers at the last minute, adding significant delays in development.

Gauging Market Scope
With an abundance of MAbs still in the pipeline, Stanton asked whether the extent to which a given modality is represented in development is proportionate to the number of service companies servicing that technology. Most CMOs in the biologics space, for example, are likely to focus on antibodies. Stanton asked the panel whether they see a change in proportions happening.

Ecker agreed that it is a proportional case, stating that a CMO needs enough projects to fill its pipeline or that CMO will cease to exist. Stanton opened the question to Miller and

Cordova. “With only four antibody–drug conjugates (ADCs) commercially available — is that proportionate?”

Miller pointed out that one company, Hanson Way, has developed a software platform that analyzes the industry. He estimates that 160 ADCs currently are in clinical development from early phase through phase 3, “so there is evidence of huge interest in the area.”

Cordova added, “I think the gene therapy space is similar, with the recent approval for Sparks Therapeutics. There is that big shift toward gene therapy, and companies are trying to grow in that space and establish at least a presence. Some hurdles that exist in that space lie around the ability to generate a robust platform process like we currently have for MAbs. We don’t have that for many viral vectors.”

Evolution of ADCs
Stanton wondered how ADC development has changed in the 20 years since Mylotarg (gemtuzumab ozogamicin) arrived on the market. Cordova pointed out that the conjugation technologies used for early FDA-approved ADCs were more straightforward chemistries than those in development now. “Since then, the field definitely has innovated its conjugation technologies toward very site-specific approaches that generate much more homogeneous therapies.” He added that investment in novel conjugation technologies is shifting toward even more complex approaches.

“We are seeing a lot of innovation looking at novel antibody conjugation methods or site-specific conjugation,” added Miller. “I also have seen that there doesn’t seem to be a consensus about what a good drug–antibody ratio (DAR) is. It may well depend on what the target, the drug linker, or the actual payload is.” He also pointed to approaches using antibody fragments as another area of interest.

Cordova agreed that the industry now is addressing different indications along with different methods of action — no longer thinking of antibodies as only targeting agents. “I think that’s one of the topics here — how our service companies deal with new modalities. We are seeing that maybe gene therapy also can be approached by nonviral-vector–mediated vehicles.”

Adapting Technologies for Emerging Therapies
Stanton asked whether the panelists’ companies can adapt easily or even repurpose some technologies to feed all these new modalities.

Cordova believes that gene therapy processes can seem very similar to conventional up- and downstream recombinant production and purification processes. On the upstream side, however, gene therapy technology is not quite yet using suspension-cell cultures that yield high titers. “We’re mostly limited, at least in my experience, to adherant-cell cultures in reactors that are somewhat difficult to scale. On the downstream side, viral-vector purification is very similar to conventional downstream processing of recombinant proteins. Depending on the viral vector being used, you may or may not have an affinity resin, but you still have the advantage of normal tangential-flow filtration (TFF) separations, which is very similar to adapting those systems or unit operations from recombinant protein production and purification.” Abzena has not developed gene therapies yet, but Cordova feels that doing so may be on the horizon for his company.

Then Stanton asked Miller, “Adapting your bioconjugation technologies to feed a whole host of different emerging therapies — is that something that is possible or actively happening?

Miller believes that the basic bioconjugation approach itself can be applied to other types of small and large molecules as well as other types of chemistries that couple two different biomolecules with each other for other indications. “If you have the skill set and the analytical skills, then you can apply it to a broad spectrum of large molecules, whereas historically, you were working only with small molecules.”

Enough Interest for Emerging Therapies?
Stanton asked all the panelists about emerging therapies such as chimeric-antigen receptor T (CAR-T) cell therapies, gene therapies, and messenger RNA (mRNA). “How “emerged” are they? Is there enough interest in these areas that service companies are interested in supporting them?”

Ecker thinks that such products are still in the early stages of development. From a growth perspective, she feels that they are similar to the MAb sector years ago when “everybody wanted in, and there were lots of technology problems that we couldn’t quite overcome.” It remains a challenge to produce large quantities of gene therapies, for example.

Cordova commented that the cost of goods (CoG) for gene therapies is much higher than for conventional MAbs. “In my experience, a total yield of 30% for a downstream process purifying a gene therapy is considered quite good — compared with a minimum yield above 60% for a conventional MAb. Some of the gene therapy quantities produced for phase 1 processes are much smaller than those of conventional recombinant proteins, but this is also because the indications require smaller doses anyway. “There is some ground to be made up in the affordability that some of these new modalities necessitate to get to the clinic,” he said.

Citing as an example Spark Therapeutics, which generated great interest when it received approval for its gene therapy from the US Food and Drug Administration (FDA), Stanton questioned whether or not regulatory approval instantly drives investment in service companies to support these modalities. “Is it really proof of a breakthrough that will lead to a whole support network looking into them?”
Cordova’s initial reaction was that “Yes, companies see this as a space that can grow and has gained FDA approval, which is incentive for establishing a presence in that area. A lot of the companies initially are much like Spark Therapeutics: small companies that started with development of these technologies in an academic setting.” That success is starting to encouarge investment from the big players.

Ecker pointed out that Spark was not truly the first gene therapy approval. The ultimately withdrawn Glybera (alipogene tiparvovec) proved it was possible, just not at a fiscally responsible price. “In part, as we work on our technologies and on getting our CoG down, especially in healthcare today, having certain types of structures in place may fuel the venture,” she said. “But if we find out that these are all very high priced for very short periods of time, I’m not sure that investment would continue.”

Can Emerging Therapies Be Affordable?
Also pointing to the Glybera (alipogene tiparvovec) example, Stanton said that it suffered from both CoG and pricing issues. He noted that the market itself wasn’t ready to take on such a product nearly a decade ago, and that price clearly will be a major issue going forward. Avexis is about to have its gene therapy approved at US$5 or $6 million dollars per patient. So he asked, “How is industry really going to cope with this change in payment conditions?

We’re talking healthcare providers and government payment issues, and
someone is going to have to pay for them. To me that seems to be one of the biggest hurdles stopping some of these emerging therapies from taking off.”

Cordova agreed and expressed that it would incentivize development to improve CoG. With so much room for growth, he’s excited about this area.Miller added that, as shown by the development of ADCs, once technology is fully developed and with proven clinical and commercial successes, efficiencies will emerge to reduce costs. He suspects that if a company can demonstrate clinically that a medicine will save or truly extend lives for long periods, then there will be a justifiable return on even large investments.

Stanton remarked on the paradigm shift in the way people think about paying for such therapies. “If you look at gene therapy, that’s a one-off cure for disease. Perhaps $5 or 6 million is more cost effective than a long-term regimen or MAb at whatever price.”

Looking Ahead
Stanton closed the roundtable discussion by asking panelists what emerging therapies and service issues they expect to be discussed at the BioProcess International Theater a decade from now, in 2029.

Ecker believes that by then, there will be discussion of gene therapies as a standard of care for a number of indications. “By that point, we will have done some great things to get these therapies to people.”

Cordova feels somewhat confident that attention will be on personalized medicine by 2029. “Whether it’s self-therapy or a different therapy, I think personalized medicine is on the horizon.”