The emergence of follow-on disease-modifying therapies for multiple sclerosis

Abstract

Medication prices are a major contributor to the high cost of care for multiple sclerosis. Three generic glatiramer acetate products have regulatory approval in North America, Europe, or Latin America. The pending expiration of patents for other disease-modifying therapies for relapsing multiple sclerosis creates the opportunity for development and regulatory approval of additional follow-on alternatives (generics or biosimilars), potentially providing lower prices and cost savings to payors and patients. However, the complexities of development, regulatory approval, and marketing of follow-on products have some important differences compared to those of new drugs. This topical review provides background and a status update on the development of follow-on disease-modifying medications to treat multiple sclerosis.

Keywords

Multiple sclerosis disease-modifying therapy generics biosimilars

Introduction

Currently, there are more than a dozen disease-modifying therapies (DMTs) with regulatory approval to treat multiple sclerosis (MS), with several additional approvals expected soon. People with MS and providers now have a range of therapeutic options from which to choose with different mechanisms of action, efficacy, safety profiles, and routes of administration. However, DMTs account for 64%–91% of direct medical costs in MS.¹ Despite the emergence of new therapies, which would be expected to increase competition and lower prices, MS DMT costs have continued to rise.² The development and regulatory approval of follow-on therapies (generics or biosimilars) is one potential solution to rising costs. However, the efficacy and safety of follow-on medications must be confirmed without removing the financial incentive to pharmaceutical companies for their development.

Requirements for regulatory approval

The process of regulatory approval for follow-on products (generics and biosimilars) differs from that of new drugs. Tables 1 and 2 provide definitions of key terms and concepts. The regulatory requirements for evaluation and approval are generally comparable in the United States, Western Europe, and other jurisdictions, though some differences in terminology, the specific regulations, and how those regulations are applied in practice exist. A comprehensive review of the similarities and differences is beyond the scope of this article. Nevertheless, it should be noted that there have been deviations in some countries from the standards established by the Food and Drug Administration (FDA), European Medicines Agency (EMA), and World Health Organization,³ which can be detrimental to the welfare of patients. Moreover, differences in patent laws have allowed follow-on products with no published studies confirming safety and efficacy to be marketed in some countries, in some cases prior to the original reference drug.³

Table 1.

Definitions.

Innovator drug (reference product) = the approved “brand” medicinal product
Follow-on drug = a general term used to encompass generics, complex generics, and biosimilars
Generic = copy of a brand-name drug that is the same in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use
Biologic = product with an active ingredient produced by or extracted from a biological source
Biosimilar (follow-on biologic) = generic version of a biologic
Subsequent entry non-biologic complex drug (complex generic): generic version of a complex drug, for example, glatiramer acetate, analogous issues as biosimilars

Table 2.

Key concepts.

• A follow-on product is not required to be identical to the reference product but “comparable” or “highly similar” with no clinically meaningful differences in safety, purity, and potency
• Equivalence limits generally are 80%–125%, but the actual limits are negotiated
• Development of a follow-on product is a compromise; success depends on ability to offer a similar, safe, and effective product at a cost saving
- Too relaxed requirements may jeopardize efficacy or safety
- Too stringent requirements create a disincentive to pharmaceutical companies
• Interchangeability is a higher standard than equivalence
- Expected to produce the same clinical result in any given patient
- If administered more than once, the risks in terms of safety or reduced efficacy for switching are not greater than with continued use of the reference product
- An interchangeable follow-on product may be substituted for the brand drug without authorization of the healthcare provider

In the United States, small-molecule drugs are approved under the Food, Drug, and Cosmetic Act and require a New Drug Application. Biologics are usually approved under the Public Health Service Act, which requires a Biologics License Application. Both new small-molecule drugs and biologics typically require two Phase 3 clinical trials to confirm safety and efficacy. MS DMTs meet this requirement by demonstrating superiority to placebo or a previously approved active comparator.

The 1984 Drug Price Competition and Patent Term Restoration (Hatch–Waxman) Act established the regulatory framework for approval of small-molecule generics through an Abbreviated New Drug Application (ANDA).⁴ Small-molecule generics are verified as being safe and effective by showing pharmaceutical equivalence (i.e. the same active ingredients, purity, strength, dosage, and route of administration) and bioequivalence (i.e. a similar rate, extent of absorption, and bioavailability) compared to the reference (approved brand or originator) drug. Together, these factors establish therapeutic equivalence; the safety and efficacy of the generic is inferred from the reference drug.⁵ In general, one small trial comparing the pharmacokinetics of the generic and reference drugs typically is required for approval. In some cases, the requirement for a bioequivalence study can be waived, based, in part, on the drug’s biopharmaceutical classification.⁶ There is general agreement, however, that drugs of Group II (low solubility/high permeability, e.g. fingolimod) and Group IV (low solubility/low permeability) should undergo bioequivalence studies.

The 2009 Biologics Price Competition and Innovation Act established the regulatory framework for abbreviated approval for biosimilars. Applicants must show that the biosimilar is “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and that for the treatment indication, there are no clinically meaningful differences in safety, purity, and potency of the drug.⁷ The Biologics Price Competition and Innovation Act stipulates that the FDA may require additional data comparing the safety, efficacy, and immunogenicity of a biosimilar to the reference drug to ensure that there are no clinically meaningful differences. Alternatively, the FDA may, at its discretion, waive any of the analytical, animal, or clinical studies otherwise required.

Because biologics have a more complicated molecular structure and are manufactured using complicated proprietary biological processes, demonstrating equivalence is more difficult than for small-molecule generics.⁸ Small alterations in the manufacturing process or packaging can result in subtle structural changes or minor impurities that can affect efficacy, toxicity, or, importantly, immunogenicity.⁹ Biosimilars are not strictly considered generic equivalents of the reference drug. Therefore, at least one human study typically is expected to assess pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy.

A nonbiological complex drug (NBCD) is a medicinal product in which the active ingredient is not a homo-molecular structure but consists of different, closely related, and often nanoparticulate structures that cannot be isolated or fully quantified, characterized, or described by physicochemical analytical means. Which structural elements impact therapeutic performance also may be unknown. Formal guidelines for subsequent entry (generic) NBCDs are not strictly defined, but many of the same issues apply as for biosimilars. The FDA, EMA, and other health authorities have approved some generic NBCDs, but whether something is evaluated as a small-molecule generic or NBCD is determined on a case-by-case basis.

Regulatory considerations that inform clinical trials

Successful development of follow-on drugs depends on providing similar, safe, and effective products at a cost saving. Regulatory requirements that are too relaxed may jeopardize appropriate evaluation of clinical safety and efficacy. Regulatory requirements that are too strict risk removing the financial incentive of pharmaceutical companies to develop them. The FDA¹⁰ and EMA¹¹ have published background material for the assessment of biosimilarity. If clinical studies are required, an equivalence design is often preferred to show that the follow-on product is neither less nor more efficacious than the reference drug within a predetermined range (defined by equivalence margins). Typically, the limits are set at 80%–125% for a particular parameter, but the specific limits for a particular follow-on product are determined in advance by the sponsor and regulatory agency.

Selection of appropriate clinical endpoints is also critical. The goal is not to establish safety and efficacy de novo, but to detect clinically relevant differences between the follow-on product and reference drug. The endpoints may be different from those used for regulatory approval of the reference drug.

After approval, it is expected that the follow-on product has a risk minimization plan comparable to that requested for the reference drug. A more difficult issue is what post-marketing surveillance or risk minimization plan (presumably to monitor for unanticipated differences in safety or efficacy) is appropriate for a follow-on product of a drug that was not requested to have a risk minimization plan.

The development and approval of follow-on glatiramer acetate products

Currently, the only follow-on MS DMT approved in North America and Western Europe is glatiramer acetate (GA). GA is a complex mixture of heterogeneous polypeptides formed from the random polymerization of L-glutamic acid, L-lysine, L-alanine, and L-tyrosine.¹² GA was originally developed in the 1960s to study features of myelin basic protein that induce experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The mechanisms by which GA produces clinical benefit are not fully understood, but are thought to include competition with myelin antigens at binding sites on antigen presenting cells, inhibition of T-cell activation, shift in T helper cells from a pro-inflammatory to anti-inflammatory phenotype, and neuroprotection through secretion of neurotrophic factors.¹² In clinical trials, GA reduced relapse rate, magnetic resonance imaging (MRI) lesion activity, and delayed conversion to clinically definite MS following clinically isolated syndrome compared to placebo and reduced relapse rate to a similar extent compared to interferon-beta.¹²

A 20-mg formulation of GA administered by daily subcutaneous injection was approved in the United States to treat relapsing MS in 1996 and in Europe in 2000. A 40-mg formulation administered three times per week was approved in 2014 following a trial demonstrating efficacy.¹³ Despite the advent of oral therapies and monoclonal antibodies, GA was still the most frequently prescribed MS DMT in 2014.¹⁴ The patent for brand GA 20 mg daily ended in 2014. The FDA approved a generic form of GA originally produced by Momenta in April 2015 based on demonstration of equivalent physicochemical characteristics, immunologic effects, and benefit in EAE.¹⁵ In October 2017, the FDA approved 20 mg and 40 mg formulations of a second generic GA originally produced by NATCO. The FDA approved the Momenta and NATCO GA products following ANDAs and did not require clinical trials.

In contrast, the EMA considered GA a NBCD and advised a third sponsor, Synthon, to perform a clinical trial to confirm equivalent efficacy, safety, and tolerability of its generic GA product. The GATE trial was a randomized, double-blind, placebo-controlled, Phase 3 trial.¹⁶ Trial participants were 18–55 years old with relapsing MS, ⩾1 relapse in the prior year, and 1–15 gadolinium-enhancing (GdE) lesions on screening MRI. They were randomized to generic GA 20 mg (n = 353), brand GA 20 mg (n = 357), or placebo (n = 84) by daily subcutaneous injection for 9 months. The primary endpoint, mean total number of GdE lesions on monthly MRIs during months 7–9, was significantly reduced in the combined GA-treated group and each GA group individually compared to placebo, confirming study sensitivity (i.e. that GA was efficacious in the study population). The point estimate and 95% confidence interval of the ratio of generic versus brand GA was 1.095 (0.883–1.360), within the prespecified equivalence margins (0.727–1.375), demonstrating equivalent efficacy. Tolerability and safety, including injection site reactions, were also similar in the generic and brand GA groups. In an open-label extension, all participants were treated with generic GA for 15 months.¹⁷ The mean numbers of GdE lesions during generic GA treatment in the extension were similar in months 12, 18, and 24 in participants originally treated with generic and brand GA. Annualized relapse rate, safety and tolerability, and incidence and titer of anti-GA antibodies also were comparable. The extension demonstrated that efficacy, safety, and tolerability of generic GA were maintained up to 2 years. Also, switching from brand to generic GA was safe and well tolerated. On the basis of these results, EMA and Health Canada approved 20 mg and 40 mg formulations of the Synthon product in 2016–2017.

The GATE trial introduced two key principles for MS follow-on drug trials. First, it utilized an equivalence design rather than the superiority design more familiar to the MS field. Demonstration of equivalent efficacy, safety, tolerability, and immunogenicity indicates that reported differences between the Synthon generic GA and brand GA¹⁸ are probably not clinically meaningful. Second, GATE was the first pivotal DMT trial in MS to use an MRI-related outcome as the primary endpoint. The primary endpoint and estimated statistical power in the GATE trial were based on the European/Canadian GA MRI study, which demonstrated that GA reduced GdE lesions on monthly MRI scans over 9 months compared to placebo and that the treatment effect became significant after month 6.¹⁹ Justification for an MRI-related outcome was based on two meta-analyses showing MRI lesion activity could serve as a surrogate for relapses in MS trials. The first, a meta-analysis of 23 clinical trials, showed a strong correlation between treatment effects on MRI lesion activity and clinical relapses at the trial level.²⁰ The second, a meta-analysis of 31 additional trials, showed that the magnitude of the treatment effect on MRI lesion activity in Phase 2 trials predicted the magnitude of treatment effect on relapse rate in subsequent Phase 3 trials.²¹

Rituximab as an example of biosimilar drug development

No biosimilars of biologic MS DMTs have been tested as yet. The development of biosimilars for rituximab for other indications provides a relevant example. Rituximab is a chimeric monoclonal antibody, approved to treat non-Hodgkin’s lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). It targets CD20, a transmembrane protein expressed on pre-B-cells, naïve B-cells, and memory B-cells.²² Studies over the past 10–15 years support an important role for B-cells in MS pathogenesis.²³ Also, it is now realized that many of the DMTs thought to work through T-cell-mediated immune mechanisms may exert their beneficial clinical effects, at least in part, through effects on B-cells.²⁴ The Phase 2 Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke (HERMES) trial demonstrated that a single course of rituximab rapidly and potently inhibited MRI lesion activity and clinical relapses for 48 weeks in participants with relapsing-remitting multiple sclerosis (RRMS).²⁵ Although rituximab does not have regulatory approval to treat MS, it is frequently used off-label and shows good effectiveness.²⁶ Recently, ocrelizumab, a humanized monoclonal anti-CD20 antibody with similar mechanism of action was approved to treat relapsing and primary progressive MS, based on the results of the Phase 3 OPERA I and II trials²⁷ and ORATORIO trial,²⁸ respectively.

The patent for brand rituximab expired in Europe in 2013 and in the United States in 2018. There are at least eight rituximab biosimilars currently in development.²⁹ Two were approved in 2017 by the EMA—CT-P10 (Celltrion) to treat NHL, CLL, and RA and GP2013 (Sandoz/Novartis) to treat NHL, CLL, RA, GPA, and MPA. In November 2018, the FDA approved CT-P10 to treat NHL.

A multicenter randomized trial compared the pharmacokinetics, efficacy, and safety of CT-P10 to brand rituximab in RA.³⁰ Participants with active RA were randomly assigned to receive 1000 mg of CT-P10 (n = 103) or rituximab (n = 51) at weeks 0 and 2 combined with methotrexate. Equivalence was demonstrated for the primary endpoints, area under the serum concentration-time curve from time 0 to last quantifiable concentration and maximum serum concentration after the second infusion. Pharmacodynamic effects (depletion of peripheral blood CD19+ B-cells), efficacy (measured by American College of Rheumatology response rates, European League Against Rheumatism responses, Disease Activity Score, Clinical Disease Activity Index, and Simplified Disease Activity Index), the proportions of participants with anti-drug antibodies, and safety/tolerability were also comparable. This trial illustrates demonstration of equivalence of a biosimilar product in an autoimmune indication.

Conclusion

The rising costs of prescription drugs are concerning for all parties involved in healthcare. This issue is especially relevant for MS. Introduction of follow-on drugs has the potential to increase competition and reduce costs, but, as detailed above, demonstrating equivalence of follow-on products to reference drugs is complex, especially for biologics and NBCDs. The processes for development and regulatory approval of follow-on products in MS are still evolving. In addition, competition leading to cost savings depends on having multiple alternatives to the brand drug. Typically, the first follow-on alternative is only moderately reduced in price. Only after additional follow-on products become available are significant price reductions seen, though not always.³¹ In fact, in some countries, follow-on products have prices comparable to or exceeding that of the brand drug.³

We are now at the early stages of development of follow-on MS DMTs, beginning with GA. The availability of follow-on versions of other drugs may be delayed. A ruling from the U.S. Patent and Trademark Office in July 2018 extended a patent on brand fingolimod from 2019 to 2027,³² and Biogen recently won a challenge to a patent on brand dimethyl fumarate that expires in 2028.³³ Drug costs at an individual level are also subject to insurance-related factors, which impose their own complications on cost and availability.³⁴ It is the responsibility of neurologists to continue to advocate for accessibility to DMTs based on objective evidence, value, and individual needs.³⁵

Footnotes

Acknowledgements

While this manuscript was in preparation, B.P.M. was supported by National Multiple Sclerosis Institutional Clinician Training Award ICT0002.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: B.P.M. reports personal compensation for consulting form Genentech and speaking for Genzyme and has stock in Pfizer. J.A.C. reports personal compensation for consulting for Alkermes, Biogen, Convelo, EMD Serono, ERT, Gossamer Bio, Mapi, Novartis, Pendopharm, and ProValuate; speaking for Mylan and Synthon; and serving as an editor of Multiple Sclerosis Journal.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Brandon P Moss

Jeffrey A Cohen

References

Adelman

Rane

Villa

KF.

The cost burden of multiple sclerosis in the United States: A systematic review of the literature. J Med Econ 2013; 16(5): 639–647.

Hartung

Bourdette

Ahmed

, et al. The cost of multiple sclerosis drugs in the US and pharmaceutical industry: Too big to fail? Neurology 2015; 84(21): 2185–2192.

Skromne-Eisenberg

Ordonez-Boschetti

Trevino-Frenk

Disease-modifying therapies in multiple sclerosis in Latin America. Mult Scler J Exp Transl Clin 2017; 3(3): 2055217317723369.

Food and Drug Administration. Federal Food, Drug, and Cosmetic Act, https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/FederalFoodDrugandCosmeticActFDCAct/default.htm (accessed 26 December 2018).

Center for Drug Evaluation and Research; U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for industry: Bioavailability and bioequivalence studies for orally administered drug products—general considerations, 1 March 2003, https://www.fda.gov/downloads/Drugs/Guidances/ucm154838 (accessed 10 December 2018).

International Council for Harmonisation of technical requirements for pharmaceuticals for human use. ICH harmonised guideline: Biopharmaceutics classification system-based biowaivers M9, 7 June 2018, https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M9/M9EWG_DraftGuideline_Step2_2018_0606.pdf (accessed 23 March 2019).

Biologics Price Competition and Innovation Act. Public Law 111-148, 7001-7003 S, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf (accessed 10 December 2018).

U.S. Food and Drug Administration. Guidance for industry: Scientific considerations in demonstrating biosimilarity to a reference product. Silver Spring, MD: U.S. Food and Drug Administration, 2015.

Chirino

Mire-Sluis

AR.

Characterizing biological products and assessming comparability following manufacturing changes. Nat Biotechnol 2004; 22(11): 1383–1391.

10.

Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry, April 2015, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory%20Information/Guidances/UCM291128.pdf (accessed 26 December 2018).

11.

European Medicines Agency and European Commission. Biosimilars in the EU. Information guide for healthcare professionals, https://www.ema.europa.eu/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf (2017, accessed 4 January 2019).

12.

Scott

LJ.

Glatiramer acetate: A review of its use in patients with relapsing-remitting multiple sclerosis and in delaying the onset of clinically definite multiple sclerosis. CNS Drugs 2013; 27(11): 971–988.

13.

Khan

Rieckmann

Boyko

, et al. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol 2013; 73(6): 705–713.

14.

Iqvia Institute for Human Data Research. Medicine use and spending in the U.S. A review of 2017 and outlook to 2022, April, https://www.iqvia.com/institute/reports/medicine-use-and-spending-in-the-us-review-of-2017-outlook-to-2022 (2018, accessed 26 December 2018).

15.

Anderson

Bell

Bishop

, et al. Demonstration of equivalence of a generic glatiramer acetate (GLATOPA). J Neurol Sci 2015; 359(1–2): 24–34.

16.

Cohen

Belova

Selmaj

, et al. Equivalence of generic glatiramer acetate in multiple sclerosis: A randomized clinical trial. JAMA Neurol 2015; 72(12): 1433–1441.

17.

Selmaj

Barkhof

Belova

, et al. Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results. Mult Scler 2017; 23(14): 1909–1917.

18.

Melamed-Gal

Loupe

Timan

, et al. Physicochemical, biological, functional and toxicological characterization of the European follow-on glatiramer acetate product as compared with Copaxone. Eneurologicalsci 2018; 12: 19–30.

19.

Comi

Filippi

Wolinsky

JS.

European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. Ann Neurol 2001; 49(3): 290–297.

20.

Sormani

Bonzano

Roccatagliata

, et al. Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: A meta-analytic approach. Ann Neurol 2009; 65(3): 268–275.

21.

Sormani

Bruzzi

MRI lesions as a surrogate for relapses in multiple sclerosis: A meta-analysis of randomised trials. Lancet Neurol 2013; 12(7): 669–676.

22.

Stashenko

Nadler

Hardy

, et al. Characterization of a human B lymphocyte-specific antigen. J Immunol 1980; 125(4): 1678–1685.

23.

McFarland

HF.

The B cell—Old player, new position on the team. N Engl J Med 2008; 358(7): 664–665.

24.

Longbrake

Cross

AH.

Effect of multiple sclerosis disease-modifying therapies on B cells and humoral immunity. JAMA Neurol 2016; 73(2): 219–225.

25.

Hauser

Waubant

Arnold

, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008; 358(7): 676–688.

26.

Granqvist

Boremalm

Poorghobad

, et al. Comparative effectiveness of rituximab and other initial treatment choices for multiple sclerosis. JAMA Neurol 2018; 75(3): 320–327.

27.

Hauser

Bar-Or

Comi

, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017; 376(3): 221–234.

28.

Montalban

Hauser

Kappos

, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017; 376(3): 209–220.

29.

Greenwald

Tesser

Sewell

KL.

Biosimilars have arrived: Rituximab. Arthritis 2018; 2018: 3762864.

30.

Yoo

Suh

Shim

, et al. A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2017; 76(3): 566–570.

31.

Food and Drug Administration. Generic drug facts, https://www.fda.gov/drugs/resourcesforyou/consumers/buyingusingmedicinesafely/genericdrugs/ucm167991.htm (accessed 26 December 2018).

32.

Bloomberg. Novartis Sues to block generic sales of top drug Gilenya for MS, 19 July, https://www.bloomberg.com/news/articles/2018-07-19/novartis-sues-in-bid-to-block-generic-sales-of-best-selling-drug (2018, accessed 1 January 2019).

33.

Food and Drug Administration. Appeals court upholds PTAB ruling in favor of Biogen’s MS Patent, 2 November, https://www.fdanews.com/articles/189010-appeals-court-upholds-ptab-ruling-in-favor-of-biogens-ms-patent (2018, accessed 1 January 2019).

34.

Esper

Hartung

Avitzur

The Patient Protection and Affordable Care Act and chronic neurological diseases. Benefits and challenges. JAMA Neurol 2015; 72(7): 739–740.

35.

Corboy

Halper

Langer-Gould

, et al. American Academy of Neurology position statement: Availability of disease-modifying therapies (DMT) for treatment of relapsing forms of MS, https://www.aan.com/siteassets/home-page/policy-and-guidelines/policy/position-statements/18_dmt-ms-ps_v304.pdf (2015, accessed 26 December 2018).