Gaining momentum on the road to accessible biosimilars

So, has the promise of potentially cheaper options fired up governments, regulators and healthcare insurers to ensure the growth of biosimilars? The reality is some uncertainty and caution but this apparent inertia has in fact been a period in which stakeholders have been working together to iron out the convoluted approvals processes and fragmented regulation surrounding biosimilars. But there are signs that this period may be coming to an end and that biosimilars will begin to contribute to a future of affordable medicine for treating advanced and chronic illness.

A landmark for complex biosimilars

When South Korean biotechnology company Celltrion recently submitted its copy of Johnson & Johnson’s biologic Remicade for FDA approval, it signalled — albeit quietly — a landmark in the history of biosimilars. Some biologics, such as vaccines and insulin, have been around since the 70s, but Celltrion’s monoclonal antibody (‘MAb’), known as Remsima, is the first complex molecule biosimilar of its kind to seek approval in the US, having already been submitted for approval in Europe in 20131. Why the fuss? Before turning to biosimilars, a brief recap of branded (i.e. original or innovative) biologics reminds us why this class of medicines promises to be so important to healthcare in 2030 and beyond.

Bigger, more complicated and with a different mode of tackling disease than small-molecule medicines, biologics have revolutionised the treatment of difficult-to-treat conditions such as rheumatoid arthritis, Crohn’s disease, Turner’s syndrome and cancer. Bristol-Myers Squibb’s oncology drug ipilimumab (marketed under the brand name YERVOY®), is a good example of why biologics have captured the imagination of the healthcare industry. Ipilimumab is prescribed for patients suffering advanced melanoma after prior treatments have failed. In conventional chemotherapy, the drug acts on rapidly dividing cells in the body (such as cancer cells) but its action is indiscriminate, destroying normal as well as abnormal cells. Ipilimumab — like other MAbs — targets specific proteins in the body, stimulating the immune system to fight the melanoma tumour cells by attaching to the body’s T-cells and blocking the action of the protein CTLA-4 which, in melanoma, is inhibited from recognising cancer cells. This allows production of more T-cells, some of which will fight off the malignant cells^2,3.

A follow-up review of 12 studies of advanced melanoma patients treated with ipilimumab demonstrated a long-term survival benefit for patients.

A follow-up review of 12 studies of advanced melanoma patients treated with ipilimumab demonstrated a long-term survival benefit for patients. Advanced melanoma is one of the most aggressive forms of cancer and historically, average survival was just six to nine months. In 1,861 ipilimumab-treated patients, the median overall survival was 11.4 months (95% confidence interval: 10.7 – 12.1), and three year overall survival rates were 22%⁴. This represents a significant data point for patients with this difficult-to-treat disease.

Compared to small-molecule (chemical-based) medicines, such as aspirin, larger biologics are difficult to manufacture, quality and safety assure, store and administer, as shown in Table 1.

The performance of biologics therefore comes at a financial cost. MAb-based rheumatoid arthritis medicines cost on average £9,500 per patient per year, compared with around £450 per year for conventional therapies such as corticosteroids, NSAIDs or immunosuppressant drugs⁶. Roche’s breast cancer drug Herceptin costs around $54,000 per year in the USA; in suitable patients, it is taken in conjunction with Roche’s newer biologic drug, Perjeta, which costs about $70,000 for a year’s treatment (though Perjeta is listed at ~$42,000 in the UK)⁷. Cerezyme, a biologic used to treat the rare condition Gaucher’s disease, may be as much as $150,000 for a year of treatment.

The proposed ‘antidote’ to this is biosimilars. Following in the slipstream of the branded biologics which are coming off patent, biosimilars are designed to offer a cost-effective alternative; an advantage to payers, prescribers and patients.

Beer, bread, cheese… and biosimilars

The simple nature and homogeneity of a small-molecule and its relatively easy chemically-manufactured process means that a generic drug can be considered a duplicate of its branded counterpart. Most generics contain the same active ingredient as the branded drug. Marketing approval is made on the basis of bioequivalence, in practice a relatively cheap and fast process for generics manufacturers. Biosimilars are a different matter; like biologics, they are produced in large bioreactors from living cells, such as yeast, bacteria or cultured animal cells, in a process which may take from several weeks to months to complete. Rather like making beer, bread or cheese, there is a degree of alchemy involved in producing a consistent biologic product. Science writer and editor Khadijah Britton sums up the dilemma perfectly: ‘Under the best conditions, [branded] biologic companies have a hard enough time proving equivalence between batches of the same medication, even though they themselves hold all of the intellectual property and often use the exact same equipment and scientists’⁸. Different manufacturing processes, using different cell sources, extraction and purification techniques in large, complex molecules have the potential to behave differently in clinical practice. Due to its size and structural complexity, a biosimilar can trigger an immune reaction or side effect not previously seen in a patient population when using the branded biologic.

Because ‘similar’ is not the ‘same’, safety and effectiveness can also vary from branded biologic to biosimilar. Significant financial resources are needed to demonstrate that a biosimilar is indeed similar to the branded biologic it follows and does not differ significantly in terms of quality, safety or efficacy. The European Medicines Agency, for example, requires all biosimilar manufacturers to implement post-market safety programmes, often as part of other additional risk minimisation measures.

So how does the ‘generic’ model — where the branded medicine is substituted with a generic medicine — work in the world of biologics and biosimilars, where the goal-posts appear to be moving? This is where it starts to get messy; automatic substitution or interchanging, as in the case of small-molecule generics, is not as straightforward in biosimilars. A review of European states, in Table 2, shows that different countries interpret regulatory guidance in different ways. French pharmacists, for example, are able to substitute a biosimilar for the branded biologic only at the initiation of a patient’s treatment and on condition that the prescribing physician has indicated on the prescription that the biologic can be substituted⁹. In some Scandinavian countries, pharmacists can only make a biosimilar substitution if the biosimilar appears on an ‘approved’ list. In the US, biosimilar legislation is set by the individual state; in April of 2014, Delaware became the latest US state to pass a bill allowing substitution by pharmacists, but as in France, only if the prescriber has not expressly prohibited substitution¹⁰.

With their unique living cell line, and difficult manufacturing and characterisation process, it is unsurprising that it feels as though there is a lack of clear policy and decision-making regarding legislation surrounding biosimilars, particularly in the US¹¹.

Enabling the future for biosimilars

What does the future hold for biologics and biosimilars? In Team Consulting’s recent survey of UK and US patients and medical specialists¹² there was almost unanimous consensus that medicine would not be cheaper in 2030. This is hardly surprising; pharmaceutical products are increasingly complex and our demand for safer drugs and evidence of associated benefits and risks has grown, and with it the regulatory burden. However, whilst the biosimilars landscape currently has a number of grey areas — scientific challenges and opaque regulatory policy — the commercial pressures are too great to prevent uptake in the market-place in the next 15 years. We should also recognise that enablers are needed to support progress in the biosimilar arena. These include creating a harmonised regulatory strategy, starting with established and common regulatory elements — such as the requirement for efficacy and immunogenicity data — to arrive at a greater degree of global consistency across borders. There are signs that regulators are trying to pick a legislative pathway which takes a pragmatic view of the clinical and scientific data required for a biosimilar product. Physicians need to feel confident when prescribing a biosimilar in the place of a biologic, and payers need to be assured that biosimilars represent value for money without compromising patient safety and efficacy. Ultimately, from the biosimilar developer’s perspective, the amount of investment required to get to market needs to make sense.

Understanding the role emerging markets can play is also critical. The early launch of biosimilars in India, Korea and other markets, provide opportunities to learn from real-world patient data. In addition, within highly-regulated markets, the push towards clinical trials data transparency will reinforce knowledge of both biologics and their biosimilar counterparts. Clinical trials investigating the impact of switching from biologic to biosimilar are underway. One example, a Norwegian study, will assess the safety and efficacy of switching from Remicade to Celltrion’s biosimilar Remsima in patients with rheumatoid arthritis, ulcerative colitis, Crohn’s disease and other auto-immune indications.

So how does the ‘generic’ model — where the branded medicine is substituted with a generic medicine — work in the world of biologics and biosimilars, where the goal-posts appear to be moving?

As market confidence grows in biosimilars, new innovations will emerge designed to ease the journey to affordable biosimilars, such as leaner manufacturing processes and smarter formulation. In the next 15 years, the gold standard of care for many conditions will be dominated by MAb biologics and biosimilars, resulting in medicines requiring careful storage, or reconstitution and typically administered to patients as long, slow infusions in a clinical setting. Research, such as that carried out by UK-based Arecor, has considered re-formulation in the context of greater stability, flexibility in administration, the ability to use significantly higher aqueous concentrations and the potential for patient self-administration, to overcome constraints and improve accessibility¹³.

It may be early days for biosimilars in Europe, the US and other highly-regulated markets, but the period of apparent inertia and legislative opaqueness is coming to a close. Instead, the prospect of biosimilars taking their place in a future of affordable medicine to treat complex and chronic disease is tantalisingly close.

This article was taken from issue 7 of Insight magazine. Get your free copy of the latest issue here.

References
1. ‘Celltrion submits biosimilar Remicade for US approval’, 14 August 2014, PMLive | http://te-am.co/1yV7MeK
2. Hanaizi, Z. et al, The European Medicines Agency review of ipilimumab (Yervoy) for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy: Summary of the scientific assessment of the Committee for Medicinal Products for Human Use. European Journal of Cancer 48 (2), 237–242 (2012)
3. The European Medicines Agency. ‘Yervoy: EPAR — Product Information Annex I & IIIB’. Last update: 11 March 2014 | http://te-am.co/1x8HSCV
4. Schadendorf, D., Hodi, F.S., Robert, C. et al, Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. Presentation at European Cancer Congress 2013
5. ‘Background paper on biosimilars’, 6 March 2012, Bio Deutschland | http://te-am.co/1t8vTBj
6. ‘TA195 Rheumatoid arthritis — drugs for treatment after failure of a TNF inhibitor and TA198 Rheumatoid arthritis — tocilizumab: costing template’, 24 August 2010, National Institute for Health and Care Excellence, http://te-am.co/10qEAQT
7. ‘Herceptin successor reaches UK shores, 14 March 2013, PharmaTimes digital | http://te-am.co/1zuec7P
8. ‘Biosimilars are back … Or are they?’, 2 August 2011, Britton,K., Scientific American blog | http://te-am.co/1EfNWhg
9. ‘France to allow biosimilars substitution’, 21 February 2014, GaBI (Generics and Biosimilars Initiative) Online | http://te-am.co/13E1aHB
10. ‘Delaware passes biosimilars substitution law’, 25 April 2014, GaBI (Generics and Biosimilars Initiative) Online | http://te-am.co/1wuHBMs
11. Leintz, C.J., Regulatory uncertainty vs legislative inevitability. Regulatory Rapporteur 11 (7/8) (2014)
12. ‘Patient and doctor perspectives’, 18 November 2014, Team Consulting Ltd | https://www.team-consulting.com/2030
13. Reese Saylor, T., Expanding medicine access through formulation, MedNous, (Sept 2014)