Who Are the Key Lucentis Biosimilar Players to Watch?

Roche’s reference product Lucentis® (ranibizumab) seems to be the next likely target for biosimilar competition. Sales of the drug in the US were last reported to be $1.5 billion in 2017, but Roche’s revenues from Lucentis are expected to slip, owing to competition from Eylea® (aflibercept) primarily and some newer agents. And new Lucentis biosimilars will hasten that decline.

ranibizumab biosimilars

Ranibizumab is approved for use for several ophthalmologic indications, including wet age-related macular degeneration, diabetic retinopathy and diabetic macular edema, myopic choroidal neovascularization, and macular edema following retinal vein occlusion.

According to reporting by the UK-based Generics and Biosimilar Initiative (GaBI), the patents on Lucentis will expire in the US in June 2020 and in Europe in 2022. GaBI had found some 10 organizations or partnerships working on investigational ranibizumab biosimilars, but little updated information (some were reported as early as 2015).

Today, our research into the Lucentis biosimilar space revealed just a couple of active players, but with rapidly advancing plans. Here are the three initiatives reported publicly:

1. Coherus-Bioeq

This one is a little complex—stick with it, as it could be the first to obtain FDA approval, as early as later this year.

Formycon AG, a German manufacturer, gave Bioeq IP AG exclusive global commercialization rights to FYB201, Formycon’s ranibizumab biosimilar. In November 2019, with Formycon’s assent, Bioeq signed an agreement with Coherus Biosciences to commercialize the biosimilar in the US.

At the recent JP Morgan investor conference, Coherus President Denny Lanfear disclosed that Bioeq filed for FDA approval in December 2019. Coherus is expecting FDA acceptance of the application shortly, and a fourth quarter 2020 decision. This could set up a product launch, according to Coherus, in 2021.

Interestingly, Coherus originally had a different biosimilar ranibizumab in its own pipeline. This agent, CHS-3351, fell by the wayside a couple of years ago. The deal with Bioeq seems to have created a new ranibizumab opportunity for Coherus.

2. Xbrane-Stada Arzneimittel

Sweden-based Xbrane signed an agreement with the German generics manufacturer Stada Arzneimittel to co-develop Xbrane’s Lucentis biosimilar. This agent, currently dubbed Xlucane™, is being tested in a phase 3 trial involving 580 patients with age-related macular degeneration, which is slated for completion in February 2021 (interim results available in May 2020).

3. Biogen-Samsung Bioepis

Samsung Bioepis completed its phase 3 trial of SB11 in December 2019 (primary completion date of May 2019). This trial comprised 705 patients with neovascular age-related macular degeneration. SB11 seems poised to be submitted for approval via the 351(k) biosimilar pathway, and Samsung’s deal with Biogen (already a part owner of the joint venture with Samsung Biologics) for commercialization. Therefore, Biogen will take the marketing reins once an FDA decision has been given. If Samsung submits its filing in Q2 2020, a launch could be possible in Q2 2021, assuming a positive decision.

Are There Any Other Active Players Out There?

The development of PF582 by Pfenex has been on hold since 2018, after the company was handed back the full rights to the agent by former partner Hospira. Pfenex no longer lists this product (or any other biosimilar for that matter) on its pipeline. The drug had progressed through phase 1/2 studies, but has not advanced.

None of the other significant players in the biosimilar industry (including Pfizer, Sandoz, Mylan, Amgen, Celltrion, or Biocon) have publicly announced a ranibizumab biosimilar program at present.

United Kingdom to Save 75% on Annual Humira Spending

Since the October expiration of Abbvie’s EU patent, the potential Humirsavings seem to be truly mind-blowing. After implementing its contracts for adalimumab, the UK National Health Service (NHS) should save about three quarters of the $514 million (£400 million) it spends each year on this product alone.

In a fixed-budgeted system like that in the UK, the real implications of these savings become clear. According to the NHS, this additional $385 million (£300 million) will enable it to pay for 11,700 community care nurses or 19,800 treatments in patients with breast cancer.

And to earn these Humira SavingsHumira savings, the NHS does not exclude using the originator product Humira. It has signed contracts (with large price cuts) with Abbvie, as well as with biosimilar manufacturers Amgen, Biogen, Mylan and its partner Fujifilm Kyowa Kirin, and Sandoz.

Could the US see such savings on adalimumab in 5 years? Although the competition may be fierce when the brand loses patent protection in 2023, Abbvie has created a stepped-launch scenario with its licensing agreements. Rather than a jailbreak of competition, as we are seeing in the EU with patent expiration there in October 2018, the timing of the licensing agreements may limit the drop in per-unit price, at least for the first year or so.

After that time, payers will be able to choose from all biosimilar adalimumab manufacturers, which should then drive pricing down (or rebates up) considerably, resulting in long-sought lower net costs. However, this will happen only after years of price increases by Abbvie. Abbvie has not claimed, while it is drastically slashing its price in the EU, that it will be losing money. In part, that is because its US revenues on Humira will continue to be at over $10 billion a year. Furthermore, its revenues largely reflect pure profit on the manufacturing of the product today, as its research and development costs were covered 15 years ago and ongoing marketing costs are a tiny fraction of this figure.

Despite repeated protestations in the US that healthcare resources are not unlimited, our system is not based on a fixed budget. It is not disingenuous to consider savings in the terms posed by NHS. Defining the large savings in terms of other useful expenditures give people a concrete idea of how the money can be better used. The need for savings on drug expenditures is acute in this nation, and biosimilars will eventually lead the way.

Let’s not Knock Innovation, but Biosimilars Exist for the Sake of Competition

A recent Twitter conversation between a blogging colleague of mine and a German advocate of precision medicine propelled this post: What is the real benefit of biosimilars? Does biosimilar development detract from efforts to produce innovative medicines? Is the main societal benefit biosimilar cost savings?

biosimilar cost savings

Biosimilar Development Is Separate From Innovation Development

The main reason that the Biologics and Biosimilars Price Competition and Innovation Act (BPCIA) was signed into legislation was related to cost containment. For biologics, there was no pathway for the evaluation and approval for lower-cost copies in the US health system, akin to the generic-brand name dynamic for conventional drugs. Adding competition has been the first and only point. The specialty drug trend had been rising rapidly, and the long-term estimates were frightening: Costs associated with specialty drugs like biologics threaten to eat 48% of the total drug spending pie in the United States by 2020.

Two factors were responsible. The first, increasing specialty drug utilization, has been especially difficult to address. The pipeline is congested with biologics. Medical societies are increasingly incorporating biologics into their guidelines and clinical pathways. Prescribers have grown more comfortable with these agents, and payers have limited tools at their disposal to put the brakes on their use.

The second, price increases, are well known and publicized. Without competition, drug companies tend to test what the market will bear, and to this point, they have borne quite a bit. Unlike in Europe, where the tender system of pharmaceutical purchasing has resulted in better cost containment, the US payers have been accustomed to stomaching large price increases through increased use of rebate contracts with price guarantees. But the overall costs continue to rise, as contracts expire and new ones are drawn up. Thus, the list prices for drugs like Enbrel® and Humira® have skyrocketed, with Humira’s more than doubling in a few years.

There is no evidence to say that biosimilar manufacturers would have engaged in the development of innovative new agents had they not devoted resources to this area. Indeed, pure-play biosimilar makers, like Coherus or Adello, were only introduced to produce biosimilars. Other makers, such as Samsung Bioepis, are joint ventures of existing manufacturers to do the same. Biogen recently raised its stake in Samsung Bioepis to nearly 50% of the company’s shares. This could be construed as a case of an originator company pouring $700 million into a biosimilar manufacturer, which could be using that money directly for other purposes. Finally, firms like Apotex, Mylan, Sandoz, and Hospira (now part of Pfizer) are heavily involved in generic drug manufacturing. Biosimilar development was a natural extension for them. Even big pharma players, such as Amgen, Merck, and Pfizer, are more commonly engaged in biosimilar marketing partnerships rather than purely R&D efforts (e.g., Amgen/Allergan, Merck/Samsung Bioepis, Pfizer/Celltrion).

One can also make an argument that pharmaceutical innovation is more evident at the drug discovery level. These days, big pharma seems less interested in pursuing drug discovery than in purchasing it.

The Societal Benefits of Biosimilars

The EMA and FDA biosimilar pathways were created to introduce competition that would lower drug costs. This in turn would make innovative biologic therapy available to more patients. Biosimilar cost savings could drive greater access to important drug technologies.

With the EU’s longer and more extensive experience with biosimilar medications, costs have indeed been saved. Although this has varied by country, it is undeniable.

In the US, with very limited economic experience with biosimilars (filgrastim and infliximab), savings figures are more theoretical than real. Although the infusion of a biosimilar into the new market may reduce wholesale acquisition price of the reference drug a bit, it will have a greater effect on net pricing, after rebates. And, of more immediate importance, the new biosimilar has the potential to halt further price increases for the originator product. This aspect of biosimilars cost savings cannot be overemphasized. Between the first adalimumab biosimilar approval and the initial availability of these products in 2023, the list price of Humira can increase upwards of 40% (or more, if Abbvie veers from its pledge to limit price increases). The initial price of the first adalimumab biosimilar will thus be much higher than if it was launched last year. On the other hand, adalimumab biosimilars will launch in the EU in October of this year, which should effectively lower cost products and limit their EU members’ exposure to future Humira price increases.

Biosimilar cost savings can have real benefits in terms of improved access. Payers’ incentives to use biosimilars (if they are motivated to implement them) can result in lower patient cost sharing. For example, a fourth-tier biologic may be subject to a 20% cost share, whereas a third-tier biosimilar may carry a flat copay of $100. This can make a difference in terms of therapeutic choices available to patients.

In conclusion, the German correspondent is only partly right. Biosimilars are not innovative. They are highly complex, cost-control medications. Do they detract the focus of manufacturers from new innovative products? There’s no evidence of this. However, we are beginning to see limited evidence in the US of the societal benefits, namely cost savings, they can bring.

Fujifilm Gains Further Exposure in Biosimilar Partnerships

The biosimilar industry continues to make strange bedfellows. In July 2016, I reported in the Center for Biosimilars that a subsidiary of the Japanese camera maker, Fujifilm, had jumped into the biosimilar field. The Indian pharmaceutical company Biocon announced that it has launched its new insulin glargine biosimilar in Japan. Fujifilm Pharma Co, Ltd was named as the partner in this endeavor to commercialize the product in Japan.

Fujifilm Pharma is a producer of diagnostic and therapeutic radiopharmaceuticals, in addition to contrast media. This makes sense, as the parent is in the imaging business. Medical imaging can be a very natural extension of this activity. But biosimilars?

To reaffirm its strategy, Fujifilm announced a new partnership.  Its Fujifilm Kyowa Kirin Biologics subsidiary will manufacture a adalimumab biosimilar in the EU (filed for approval in the EU only) and will be commercialized by Mylan if approved. There is no information about whether Fujifilm will seek authorization to market this biosimilar in the US down the road.

Fujifilm Kyowa Kirin AstraZenecaTo further its chances of commercializing this biosimilar in the EU, Fujifilm Kyowa Kirin Biologics joined a lawsuit in April 2017 with Samsung Bioepis and its partner Biogen. The lawsuit, filed in the UK, sought to invalidate Abbvie’s two remaining adalimumab patents, and the UK court ruled in favor of the plaintiffs, opening the door to marketing next year in Europe. Fujifilm also has a bevacizumab biosimilar (FKB 238) in phase 3 clinical investigation.

The parent company has over 200 subsidiaries, and it can be complicated to track which ones are directly involved. For example, another Fujifilm company, Fujifilm Diosynth, does contract manufacturing of biologics. Yet, the phase 3 trial being carried out on FKB238 is sponsored by Centus Biotherapeutics Limited, which is a joint venture between Astra Zeneca and Fujifilm Kyowa Kirin Biologics. Centus seems to be involved only with the bevacizumab biosimilar, not with the adalimumab agent. Despite this web of intrigue, Fujifilm is not likely to be overexposed in the biosimilar marketplace. It is also unknown whether their efforts will be affected by the recent difficulties of its partners Biocon and Mylan with getting its pegfilgrastim biosimilar approved. It has been reported that Biocon will also benefit from this latest Mylan collaboration.

FDA Approves New Humira Biosimilar, Bypasses Advisory Board Route

Boehringer Ingelheim Pharmaceuticals, Inc. announced August 29 that it had received approval from the Food and Drug Administration (FDA) for its first biosimilar. Named Cyltezo™ (adalimumab-adbm), a biosimilar to Humira®, it is approved for several autoimmune disorders, including rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease in adults, plaque psoriasis, and ulcerative colitis.

The FDA approval bypassed the need for an Arthritis Advisory Committee review and recommendation, which the agency suggested may be increasingly common with future biosimilar approvals. One suspects that this is more likely with the licensing of the first biosimilar for a particular originator product, with the assumption of a comprehensive data package on submission.

Like Amgen’s Amjevita®, Boehringer’s biosimilar will likely enter a holding pattern until patent litigation is settled (or the patents expire) on AbbVie’s Humira. In the meantime, Boehringer indicated that it will seek approval for an autoinjector, to stand alongside its newly approved subcutaneous formulation.

Boehringer has also applied for approval with the European Medicines Agency, which is expected to decide on its approval before the end of this year. Samsung Bioepsis and partner Biogen earned its own European approval for Imraldi™ this week, another adalimumab biosimilar.