Are Biobetters Better?

Many companies are actively working on the development of 'biobetters' - improved versions of originator biological drugs - but are these drugs worth the investment?

Biosimilars and biobetters are both variants of a biologic drug, however, while biosimilars are close copies of the originator, biobetters have been improved, for example, in terms of efficacy, safety, tolerability or dosing regimen.

Regulators consider biobetters as new products and so afford them the same patent protection as any originator, however, this means they require the same clinical and non-clinical data packages. Conversely, a reduced clinical data package is an attractive element for the development of biosimilars.

Given the cost of development and the time pressure to bring a biobetter to market before biosimilars push prices down, some are asking a fundamental question – are biobetters worth the investment?

No better?

One way of improving an originator is through PEGylation – modifying a biological molecule with polyethylene glycol (PEG), a non-toxic, non-immunogenic polymer. This process can be used to change the properties of the molecule to, for example, increase drug stability and reduce drug administration frequency.

Such a technique has been used to adapt several molecules, including anaemia drug Mircera (methoxy polyethylene glycol-epoetin beta) and infection-fighting drug Neulasta (pegfilgrastim), a PEGylated version of Neupogen (filgrastim). Both products were developed to reduce dosing frequency without diminishing efficacy.

However, more convenient dosing schedules may reduce healthcare burden but do not always translate into value for payers. For example, in its guidance, the UK’s National Institute for Health and Care Excellence (NICE) found “no evidence to distinguish between ESAs (erythropoietic stimulating agents) in terms of efficacy”, while the Haute Autorité de Santé (HAS) in France concluded: “Mircera is not expected to have any additional impact on morbidity or patients' quality of life despite the fact that it is more convenient.”

Efficacy isn’t everything

Another method to modify a molecule is engineering to bring two chemical entities into one. In 2000, Herceptin (trastuzumab) received its first EU approval for use in HER2+ metastatic breast cancer, while, in 2013, Kadcyla (trastuzumab emtansine) received its first EU approval for HER2+ unresectable, locally advanced or metastatic breast cancer for patients who had previously received Herceptin and a taxane, separately or in combination. Kadcyla is the combination by biotechnical engineering of Herceptin and DM1 (a cytotoxic chemotherapy agent, derived from maytansine, a microtubule inhibitor).

When introduced, Herceptin represented a step change in the treatment of breast cancer and it remains the dominant standard of care. While, in its first pivotal trial (EMILIA), Kadcyla demonstrated superior efficacy over Tykerb (lapatinib) in second-line treatment, it failed to demonstrate superiority in a second trial, over Herceptin in first-line treatment (MARIANNE).

Here, it could appear that the biobetter is not in fact better than the originator, having failed to demonstrate superiority, but it is important to remember that as a second-line treatment for patients who have not responded to treatment, Kadcyla represents an improvement in standard of care and so remains an important treatment option. 

Later this year, results are expected in the phase III SOPHIA trial, which is pitting margetuximab plus chemotherapy against trastuzumab plus chemotherapy in the treatment of HER2+ metastatic breast cancer. Margetuximab is a modified monoclonal antibody that binds to the same target as trastuzumab on the HER2 receptor. It remains to be seen whether this biobetter will demonstrate superiority or whether it can find the niche of non-responders to which it will provide benefit.

The future of biobetters

Whether biobetters demonstrate improved value over originators, for patients, such new and innovative products provide value through improvements in convenience and by offering further treatment options should a disease progress.

For manufacturers, having a target in mind and optimizing the clinical trial program can support earlier market entry. In this respect, biobetters currently appear to be one way of maintaining market share and defending against biosimilar entry – if superiority can be achieved.

For payers, the issue becomes one of magnitude of improvement – how much more efficacious is a biobetter over its originator? Willingness to pay for a biobetter will be directly proportionate to this, so, if an originator takes patients 80 percent of the way to being cured, can the biobetter offer 90 percent? And, if so, what is a 90-percent cure worth?

Attaching a high price tag to a biobetter will hinder commercial success in a price competitive market, unless it can be justified on many levels, not just primary efficacy outcomes. Innovation typically affords new products with leverage to command higher prices but, in the biologics market, differentiation will be key, not simply innovation. Furthermore, pricing expectations will need to be realistic in a world where your comparators are fast going generic and biosimilar products are entering the market with around 30 percent lower prices.

Ensuring market access

Biobetters do have a chance for commercial success because existing treatments are not perfect. However, understanding the market and developing products that can offer parity in some clinical domains, and improvements in others, will be of value.

To achieve this, manufacturers must heed certain considerations to ensure market access:

Address an unmet need

Identify and address unmet needs by engaging with clinicians and payers – understand the elements that your product can address and those it cannot, and be clear that, while your product will not address every unmet need, some are more important to payers and clinicians than others. Your product should not add to any unmet needs; Mircera is an example where the reduction in frequency of administration both highlighted and met a previously unmet patient need.

Address non-responders to current treatment

Focus on patient sub-populations that may not be responding well, or well enough, to current standards of care. Defining and identifying the market segments with high unmet needs may require population and position scanning, as well as in-depth evaluation of various disease indications and patient types. As seen with Kadcyla, payers, patients and clinicians all benefit from the options in treatment available despite lack of superiority.

Time entry to market and negotiate from the start

Securing market access for a biobetter requires scanning the market landscape for competitor products. To establish market share over price-driven biosimilars, biobetters need to enter the market before the exclusivity period of the patented reference biologic expires, which is the only time that biosimilars can start commercialisation.

At the same time, be mindful that payers are likely tracking originator patent expiry and when biosimilars are likely to launch, so they will have these price tags in their minds. In countries such as Scotland, the HTA process picks the comparator based on market share, so getting in before biosimilars have established a long on the market, can mean the branded originator is still the comparator. This will help with gaining higher prices. However, once the biosimilar is on the market and its market share grows, it will be difficult to compete without pricing incentives. Biobetters may also need to compete with other innovative products. With all of this in mind, a solid economic-focused negotiation strategy will be necessary. 

Biobetters are enhanced versions of originator biologics, which potentially offer added value to patients and payers. Premium pricing will be a barrier to patients gaining access to these innovative treatments, and so manufacturers need to put together the right evidence and strategy to secure market access.

James Wright is a Consultant at Valid Insight.