By Anna Rose Welch, Director, Cell & Gene Collaborative
In October, I had the opportunity to moderate a panel for the DIA Biosimilars Conference. The topic of discussion was what the next five years will bring the biosimilars industry. As you can imagine, the experts hailing from IQVIA, a small/mid-size biosimilar player (Polpharma Biologics), a device manufacturer (Owen Mumford), and a CMC consulting firm (Ulteemit BioConsulting) had a lot to say on this topic. In addition to outlining future pipeline opportunities, product and device selection considerations, and streamlined manufacturing strategies, we also couldn’t overlook what has become an intriguing topic: value-added and “biobetter” products.
Differentiation is a broad, somewhat tricky term — especially in the biosimilar space. In the novel biologics space, differentiation can mean altering a product’s excipients or strength, or it can be as complex as a molecular change that improves a product’s overall clinical efficacy. However, to be approved as a biosimilar, a candidate must be highly similar from a bioequivalence, PK/PD perspective with the same dosage, strength, and presentation. Some small differences in terms of the device and an improved safety profile can be acceptable. There are some biosimilar manufacturers that have made known their intentions to pursue not just a biosimilar development strategy, but also a value-added strategy for a number of their biosimilar molecules. (Please note, these efforts may not all be approvable as a biosimilar unless the originator has made the same change.)
As IQVIA’s Aurelio Arias argued in a recent IQVIA webinar (and in part one of this series), the pharma industry’s increasing drive toward patient centricity combined with the pressures of biosimilar competition promises a future of improved originator and off-patent biologics. In fact, he anticipates some element of differentiation will be critical for biosimilar manufacturers targeting highly competitive molecules in the future. Following my previous article based on Arias’ presentation, I wanted to share the main differentiation-centric takeaways I gleaned from the DIA panel. This topic could easily have taken an entire day to discuss; however, there were a few tidbits of knowledge each expert offered, adding more color around the types of differentiation biosimilar companies can pursue and its overall impact on product/device selection and the manufacturing process.
Product Selection: Is Niche The Way To Go?
Given the high cost of development for what will ultimately be a discounted product, it makes sense that biosimilar companies must carefully scrutinize each potential pipeline candidate. As Alex Moulson, VP strategy, portfolio, and programs of Polpharma Biologics, shared, this involves closely considering a product’s overall market opportunity, presentation(s), clinical trial endpoints, and manufacturability. Not only does the product need to have market longevity alongside newer, innovative biologics, but the overall development timeline and regulatory requirements and nuances will be key, too.
For example, a novel product that has two different formulations (IV and subcutaneous) and several different presentations (i.e., autoinjector, prefilled syringe, and a vial) could result in a big development headache for a biosimilar manufacturer. In fact, this already complex array of product offerings, coupled with, for instance, increasingly used diagnostic tools, will translate into a more complicated regulatory and market access landscape to manage. There may also be differences in approvals and availability of the different presentations and formulations between the U.S. and EU.
That said, the product-related challenges facing a biosimilar company from the get-go could also mean that this is a unique and important candidate to pursue, Moulson admitted. “Such a molecule could really turn off a lot of other biosimilar manufacturers, meaning you’d be entering the market with a lower number of competitors.” As such, differentiation isn’t necessarily limited to the look and feel of the product, but it can also be embodied through a company’s approach to product selection. The smaller the number of competitors for a molecule, the bigger the slice of the pie for each manufacturer to expand its market presence and recoup its initial investments.
In terms of differentiating the product itself, Moulson argued it can definitely be a “ticket to play,” especially if a manufacturer doesn’t wish to base competition solely on price. The delivery of the product is one of the key factors she typically considers for differentiation. “If you’re making a similar product in a similar device, the biggest differentiating factor that will encourage the health provider to select your biosimilar is a lower price,” she said. “Ultimately, differentiation can bolster your product in a healthcare provider’s eyes.” Outside of gaining a commercial boost, however, Moulson cautioned that a manufacturer should not anticipate higher reimbursement for the added-value. “You’re not going to get better pricing, but sometimes this is something you simply have to do to de-risk the development of a molecule,” she explained, especially in a crowded market.
Device Differentiation: What Innovations Are On The Horizon?
Given that most of the biosimilar products on the U.S. market today are administered intravenously, the device has not been the subject of much discussion. Seeing as more physician and patient-administered products are coming off patent in the upcoming years, however, I wanted to ensure the industry is keeping its eyes on this important piece of the puzzle.
George I’ons, head of product strategy and insights for Owen Mumford, walked us through some of the biggest considerations a company must make about the device platform. While many earlier players were drawn to the more cost-effective predeveloped devices, I’ons pointed out that, in a lot of cases, being predeveloped didn’t necessarily mean the device was the best fit for the product right out the gate. He foresees the need for a more mature approach to device development moving forward, especially as biosimilar makers begin investing in products with lower sales volumes. There will also need to be more attention paid to future-proofing a device platform.
“If you have more than one injectable in your pipeline, or even if you have goals to evolve a particular product to increase injection volume, for example, you have to ask if you’re picking a platform that will streamline the process for any future innovation,” he explained. “If your platform isn’t future-proofed, you may have to create a whole new work stream to reinvent what you’ve just done for your future products. You ultimately want to ensure that your device doesn’t corner you into only one option.”
In addition to future-proofing the workstream, I’ons touched upon originator manufacturers’ ongoing investments in digital and connected health. Such efforts are being deployed to improve patient outcomes, adherence, and physician reporting. As I’ons argued, this type of differentiation is critical for biosimilar makers to keep their eyes on, as “it moves the goalpost on the pricing conversation away from unit cost toward overall product value and patient centricity.” Though we’ve been seeing an influx in this type of innovation, particularly among originator companies in the diabetes space, there still remains room for improvement in the future. For example, as IQVIA’s Arias pointed out, there’s more work to be done in improving device-to-device communication — for example, how well a pump communicates with a patient’s cell phone and/or a pharma company’s app.
Another factor I’ons is watching is the steady progression toward sustainable (as in green) devices. The pharma industry has developed the mindset that disposable is the way to go. However, I’ons anticipates that, in the device space, we will begin to see more focus on creating reusable or semi-reusable systems, which, in turn, could lower overall injection costs.
“Biobetter” Manufacturing: When Is It Worth The Added Risks?
At the end of the day, the pipeline and differentiation decisions a biosimilar manufacturer makes will have implications on the overall manufacturing process. Previous articles on this site have explored some of the potential process improvements coming down the line for biosimilar manufacturers, as well as the industry’s perceived hang-ups when it comes to being truly innovative with manufacturing.
Polpharma’s Moulson already confirmed that manufacturability of a molecule is one of the key criteria she examines in selecting a future biosimilar pipeline candidate. Mike Ultee, principle of Ulteemit BioConsulting, confirmed that selecting mAbs provides biosimilar makers a more straightforward development journey compared to that of other novel molecules (i.e., fusion proteins). However, for companies planning to invest in a “biobetter,” there will be a very different manufacturing risk profile. “Developing a biobetter falls between the risk of developing a brand-new product and a biosimilar,” Ultee clarified. “We know a lot about the originator molecule, its indications, and problem areas, and therefore, probably the biobetter. But in changing the molecule itself, you lose the opportunity to approve that molecule as a biosimilar using the abbreviated development pathway.”
On the surface, these changes may seem slight. For example, it may simply mean altering the sequence of three amino acids (out of several hundred) in the molecule. But that seemingly tiny tweak can eliminate a serious side effect of the original drug. Any changes to the molecule itself will also require manufacturers to carefully evaluate the overall impact on the manufacturing process. “Can you use the same techniques to produce, purify, and stabilize the molecule?” Ultee offered. “Are you going to be able to formulate and fill-finish the product in the same way?”
At the end of the day, the biggest question that must be answered by a manufacturer and the target markets is what level of difference will truly be meaningful for patients. A small change that doesn’t result in much more of a clinical benefit is unlikely to convince payers and healthcare providers that its worth changing patients to the newer version. On the other hand, “If you really address serious concerns with that product, I think you can make a case for pursuing a biobetter,” he concluded.