Dr Ivo Abraham Column: Not All Quiet on the Biologics Front—Biosimilars, Biobetters, and Bioparallels

Following a little hiatus since my last column because of major demands in my “day job” and some post-pandemic catching up on life, time to pick up the biosimilars thread again and explore some striking developments in follow-on biologics. Time to reuse this circa 2010 term (remember it?)—for better and for more.

Zymfentra (Remsima SC; infliximab-dyyb) is a subcutaneous formulation of Inflectra (Remsima; infliximab-dyyb), an biosimilar referencing Remicade (infliximab). Although Zymfentra is based on a biosimilar, the lack of a subcutaneous version of the originator meant that the FDA had to approve Zymfentra as a novel agent.

As I was finalizing and fact-checking this column, news came in that the FDA had approved Celltrion’s Remsima SC (Zymfrentra) for maintenance therapy in patients with moderately to severely active ulcerative colitis and Crohn disease. Zymfentra is a subcutaneous (SC) formulation of Inflectra, Celltrion’s intravenous (IV) infliximab biosimilar. There is an international twist to this: this SC formulation is approved in Europe, the Republic of Korea, Canada—as well as in other regions and countries—as a biosimilar referencing IV infliximab. The FDA noted that Remsima SC produced better clinical outcomes than Remsima IV and asked the manufacturer to submit a biologics license application. That gives us, here in the US, a quite unique biologic:

The first biobetter …

of a biosimilar …

of an originator product.

Over to PD-1 (and related) immune checkpoint inhibitors (ICI), the biologics that have brought us such great advances in cancer care and so much hope to so many patients. Biosimilars of pembrolizumab (Keytruda) and nivolumab (Opdivo) are being developed and tested around (most of) the globe in anticipation of a biosimilars market that may well turn out to be larger than the adalimumab biosimilar market.

This is a biosimilars market to be followed—but, as we approach the third decade of biosimilars, they may have their own competition.¹ By my count, 3 Chinese PD-1 ICIs are being reviewed by the FDA (toripalimab, tislelizumab, camrelizumab), following 1 (sintilimab) that failed to be approved. A lot more biologics (as well as non-biologics such as tyrosine kinase inhibitors) are being readied to cross the Eastern Hemisphere.

Let’s call them bioparallels, for reasons I’ll try to explain. Yes, they are new biological molecules, but the ambition is not early-in-class innovation but later-in-class market entry—with a solid shake. Unlike biosimilars, they are approved as new biologic agents. Like biosimilars, they may prove to be market disruptors. Most likely, they will compete on price for the clinical benefit they bring—without the constraints of needing to be equivalent in efficacy and safety.

Lower on the innovation scale.

Higher on the market access scale.

Do we need regulatory pathways for biobetters and bioparallels?

That might not be a bad idea, but this should be approached cautiously— which will take time. We can expect the FDA to continue its case-by-case review and require a biologics license application, rightfully so. Other regulators around the globe may follow the FDA in this or they may not. Alternately, regulators may take the non-inferiority route and require that (presumed) biobetters cannot fail a non-inferiority trial (this might challenge us to come up with another term; tongue-in-cheek, how about “bionotworsers”?)

Some tough questions will need to be addressed and ICIs may well be the class of biologics that serves as the proving ground. Should any future bioparallel, by extrapolation, get the full label of the initial generation of this class of agents? Would vertical by-indication trials be required? Would basket trial evidence be sufficient? Should this apply to both monotherapy regimens and combination therapies—considering, in the case of ICIs, all the evidence accumulating that adding targeted agents or chemotherapy agents, or even radiotherapy, to an ICI may yield better outcomes?

Things are not all quiet on that front. In a thoughtful 2022 perspective paper in the New England Journal of Medicine entitled “The Wild West of checkpoint inhibitor development”, Julia Beaver and Richard Pazdur from the FDA Oncology Center of Excellence raised some fair concerns—not only about source and quality but also about generalizability: “sponsors based in China seeking U.S. approval on the basis of clinical trials conducted outside the United States”, some of which are for “diseases occurring predominantly in Asia” applying “a strategy of duplicating the trial of an approved checkpoint inhibitor that led to U.S. approval for the indication in question” as opposed to “non-inferiority trials comparing the new agent with the approved antibody”; adding the need to demonstrate “the results’ generalizability to the U.S. population.”²

Consider this both caution and direction—not a door shut.

Case-by-case for now

Regulatory innovation evolving into the future

Accommodating current research and development in biobetters and bioparallels

Beyond the China factor

Just as much as we need to be fair to the US, we need to avoid being unfair to China (as well as Asia and other regions). Innovation is rising in Asia – in China, the Republic of Korea, and Japan on the higher-income country end as well as in India on the middle-income end, to name just a few. It is not a China thing, it is a globalization-of-science thing and China happens to be one of a growing number of active and productive countries.

The data are getting a bit old, but a study by Yu and colleagues published in Nature Reviews Drug Discovery in 2020 underscores this.³ China has the highest median recruitment rate for PD-1/PD-L1 inhibitor trials: 1.50 patients per trial site per month (PSM) for monotherapies and 1.02 PSM for combination therapies. Compare this to 0.22 and 0.21 for the US, 0.30 and 0.23 for 6 major markets (France, German, Italy, Japan, Spain, United Kingdom) and 0.36 and 0.24 for an Asia-Pacific region (Australia, Hong Kong, Republic of Korea, New Zealand, Taiwan, Thailand).

There are other notable developments. As David Cyranoski wrote in Nature, in 2015 the China FDA (NMPA) ordered pharmaceutical manufacturers to “re-evaluate the authenticity, integrity, and compliance of clinical trial data” in all pending new drug applications, with major consequences if the CFDA found violations.⁴

In response, “more than 80% of the applications were voluntarily withdrawn” and “one-quarter of the remainder was subsequently rejected because of problems with authenticity.” Today, Chinese or Chinese-led trial results are being presented at key international meetings and published in major international journals. China joined the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use in 2017 and is now aligned with international standards for clinical trial conduct and pharmaceutical product registration. This is critical for both regulatory review and international credibility.

There is another reason why not only China but also Japan and the Republic of Korea want to export their drugs. To be listed on their respective country’s reimbursement formulary, pharmaceutical companies were required to reduce prices, in some cases drastically so. If a drug is good, perhaps even great, why not export it to benefit more patients elsewhere—and make up for loss in the domestic market along the way?

For the sake of transparency and assurance, I am not getting paid by China and I have never been to China. Neither am I getting paid by Japan or the Republic of Korea, though I have visited these countries on several occasions.

Out: naïve skepticism, geopolitical prejudice

In: responsible science, thorough regulation

Beyond the incremental benefit factor

At a 2022 ASCO session, survival data of the CHOICE-01 trial of toripalimab (Coherus Biosciences/Shanghai Junshi Biosciences) vs placebo in combination with chemotherapy in first-line treatment of non-small cell lung cancer without EGFR/ALK mutations were presented. This trial of 465 patients randomized 2:1 found significant survival improvements. A discussant noted that these findings were “unlikely to move the field forward”, that there was no need for “additional trials incorporating new PD-1 or PD-L1 agents compared to standard chemotherapy doublet” as they “do not provide an incremental benefit” and that “if this drug were to be approved, I frankly wouldn’t be able to appreciate significant differences between this trial versus landmark trials that have been performed”.⁵ The discussant added that this drug could only “be valuable if it shows better efficacy.”

So, what? If toripalimab achieves “only” satisfactory outcomes—regardless of whether they are better, similar, or in parallel with other PD-1 inhibitors? I am not an oncologist, but I don’t think that better therapeutic outcomes are the only metric to adopt a drug. Just-as-good is good enough. It will help patients just as well.

The discussant missed an elementary point: the value equation is about the bidirectional relation of cost (on a gradient from low to high) and efficacy (on an analogous gradient). Value is a ratio, not a count. It is not about efficacy alone. Achieving a similar benefit at lower cost is positive value. Even if efficacy were “only” similar (and not better) but cost is lower, there is positive value. If efficacy were higher and cost the same or lower, there would be positive value as well—in a different direction. The only negative value would be if efficacy were lower, regardless of cost.

Value misunderstood

What is my point here?

Upfront, you can accuse me of bias. As the disclosure statement below indicates, Matrix45 has contracts with Celltrion and Coherus Biosciences, I am an equity owner in Matrix45, and I am involved in projects involving both companies. I am using my (rather) deep insights in the respective products to provide as objective information as possible.

The point is: there will be well over 1.9 million new cancers diagnosed in the US this year. Most of them will get just-as-good treatment. It will cost a lot of money to care for them. Lower-priced just-as-good (or perhaps a bit better) treatment will save money. That money can re-allocated budget-neutrally to treating more patients. You’ve heard me say that before, and you’re hearing me say it again from a different—global—angle. For whatever you think it is worth. I can only lay out the facts.

Just-as-good creates choice

Choice breeds competition

Competition drives innovation

References

1. Abraham I. Preparing for the third decade of biosimilars. Expert Opin Biol Ther. 2023;23(8):651-652. doi:10.1080/14712598.2023.2247916
2. Beaver JA, Pazdur R. The wild west of checkpoint inhibitor development. New Engl J Med. 2023;386:1297-1301. doi:10.1056/NEJMp2116863
3. Yu JX, Hodge JP, Oliva C, et al. Trends in clinical development for PD-1/PD-L1 inhibitors. Nat Rev Drug Discov. 2020;19(3):163-164. doi:10.1038/d41573-019-00182-w
4. Cyranoski D. China cracks down on fake data in drug trials. Nature. 2017;545:275. doi:10.1038/nature.2017.21977
5. Bassett M. Another China-developed PD-1 inhibitor makes its case in NSCLC. Medpage Today. March 16, 2022. Accessed October 26, 2023. https://www.medpagetoday.com/hematologyoncology/lungcancer/97708

Bio

Ivo Abraham is Chief Scientist of Matrix45 and professor of pharmacy, medicine, and clinical translational sciences at the University of Arizona, where he is associated with the Center for Health Outcomes and PharmacoEconomic Research and the University of Arizona Cancer Center. He has worked in biologicals since the late 1990s and in biosimilars since their introduction in the European marketplace—collaborating closely with Karen MacDonald (also his wife) on large international and national observational studies as well as economic evaluations of biosimilars. On both the private and academic sides, their group published the first economic evaluations of biosimilars—a line of studies that continues to date and has been instrumental in the breakthrough and market adoption of biosimilars in Europe and the United States. More recently, Matrix45 has ventured into biosimilars in emerging markets, including low- and middle-income countries. He may be reached at cntr4biosim@matrix45.com.

Perspective

I am a strong proponent of biosimilars, biobetters, and bioparallels (let’s call them bioXs). That does not mean I am against innovation; on the contrary. There would be none of these drugs without the innovators. I have worked on several of these innovators and am working now on innovators that someday may have bioXs. I am of the generation that has had the immeasurable pleasure of seeing treatments emerge (and some fail) for diseases that over 40 years ago had the poorest of poor prognoses, but are now treatable.

Innovation in therapeutics (that is, the originator products) is about moving the boundaries of hope. BioXs are a channel for spreading more hope to more patients globally.

Statement of disclosures of relevance to this monthly column

I am contracted by a USDHHS contractor to consult on a project on the cost of bringing biosimilars to market.

Matrix45, LLC and predecessor companies in which Karen MacDonald and I hold or have held equity, have been contracted for research, analytics, dissemination, consulting, and training services by Janssen/Johnson & Johnson, Amgen, Novartis, and Roche on the originator side and by Sandoz/Novartis, Coherus Biosciences, Mylan/Viatris/Biocon, Hospira/Pfizer, and Teva on the biosimilars side; with past and current conversations with Merck KGaA, Celltrion, Apobiologix, Apogenix, Fresenius-Kabi, and Spectrum. By company policy, associates of Matrix45 cannot hold equity in sponsor organizations, nor provide services or receive compensation independently from sponsor organizations. Matrix45 provides its services on a non-exclusivity basis.

All contributions to this column are prepared independently, without funding from sponsors, and without any other form of compensation.

Links to prior columns

The 2022 WHO Biosimilar Guidelines—Loosening the Reins or Changing the Track? Part 2

The 2022 WHO guidelines on biosimilars: loosening the reins or changing the track? Part 1

Biologics and biosimilars: harnessing regulatory data for value, access, equity and parity

1 billion people can access biosimilars; what about the other 7 billion?

Biosimilars and the commoditization of treatments

When more may yield less: price erosion of biosimilars following US market entry

It’s what we do with the savings: economics and equity

Good bait and fair switch: biosimilar interchangeability, substitution, and choice

To try or not to try, that’s not the question: phase 3 trials of biosimilars and beyond

The enemy of your enemy should be your friend: why biosimilar companies should collaborate