Biosimilar and drug repositioning. Giuseppe Curigliano MD, PhD University of Milano and European Institute of Oncology

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1 Biosimilar and drug repositioning Giuseppe Curigliano MD, PhD University of Milano and European Institute of Oncology

2 Biosimilar Landscape in Europe 32 Biosimilar Products Are Currently Approved by the EMA for Use INN A list of biosimilars approved by EMA as of March, 2018 Number of Products Approval Adalimumab 2 Mar-17 Enoxaparin sodium 2 Sep-16 Epoetin alpha 3 Aug-07 Epoetin zeta 2 Dec-07 Etanercept 1 Jan- 16 Filgrastim 7 Sep-08 to Sep-14 Follitropin alfa 2 Sep-13, Mar-14 Infliximab 3 Sep-13, May -16 Insulin glargine 2 Sep-14, April-17 Rituximab 1 Feb-17 Somatropin 1 Apr-06 Trastuzumab 2 Dec-17 EPAR. earchgenerict. ype=biosimilars&keyword=biosimilar&alreadyloaded=true&curl=pages%2fmedicines%2flanding%2fepar_search.jsp&status=authorised&treenum ber=&searchtab=searchbyauthtype&pageno=1. Accessed May 3, 2107.

3 Biosimilar Landscape in Europe (cont) 18 additional biosimilar applications are currently under review by the EMA: One approved A list of biosimilars under review by EMA as of March, 2018 Common Name Number of Applications Adalimumab 2 Bevacizumab 2 Etanercept 1 Insulin glargine 1 Insulin lispro 1 Pegfilgrastim 2 Rituximab 5 Trastuzumab 3 EMA. Accessed May 3, 2017.

4 Issued By WHO US FDA EMA What is a biosimilar? Definition A biotherapeutic product similar to an already licensed reference biotherapeutic product in terms of quality, safety, and efficacy A product highly similar to the reference product without clinically meaningful differences in safety, purity, and potency A biosimilar is a product that demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety, and efficacy, based on a comprehensive comparability exercise

5 Generic and biosimilar Small-molecule Drug Biologic Drug Living systems (eg, cultured Produced from Chemical synthesis animal and plant cells) Characterization Adequately characterized with limited physicochemical methods Comprehensive physicochemical analysis and bioassays necessary More sensitive to Manufacturing Easy to reproduce manufacturing conditions Safety Considerations Target-specific and off-target toxicity Target-specific and off-target toxicity Immunosuppression and immunogenicity reactions

6 Generics Generic and biosimilar Synthetic (chemistry) Small, simple, uniform Predictable, easy to characterize Biosimilar Biosynthetic (living organisms) Large, complex, heterogenous 3D structure more perturbable Difficult to fully characterize

7 Generic and biosimilar Biologic Drug Herceptin (trastuzumab) Chemical Formula: C 6470 H N 1726 O 2013 S 42 Molecular Weight: 148 kilodaltons Small-Molecule Drug Aspirin Chemical Formula: C 9 H 8 O 4 Molecular Weight: 180 daltons

8 Biologics Are More Difficult to Produce Than Small-Molecule Drugs Small-Molecule Production Steps 1 Biologic Production Steps 2 Chemical synthesis via multiple chemical processes Produced product analyzed Final formulation is analyzed and packaged for distribution Clone gene into a vector Transfect into a vector cell, screen, subclone, and produce master and working cell banks Cell culture expansion up to commercial scale Purify protein in an advanced multistep process Analyze the protein for quality and establish desired quality attributes Final formulation analysis and packing of protein suitable for transport, storage, and final use 1. Strober B, et al. J Am Acad Dermatol. 2012;66(2): ; 2. Kuhlmann M, Covic A. Nephrol Dial Transplant. 2006;21(suppl 5):v4-v8.

9 Factors That Impact Immunogenic Potential Glycoforms Glycoforms are glycoprotein molecules with the same protein component, but different ensembles of sugar chains. Rudd, P. M., et al. (1997) The glycosylation of the complement regulatory protein, human erythrocytes CD59. J. Biol. Chem. 272:7229. Structural Properties Sequence variation (human; bacterial) Glycosylation Schellekens H. Nat Rev Drug Discov. 2002;1(6): Immunogenic Potential Other Factors Contaminants and impurities (from initial production or downstream processing) Formulation Route of application Dose Length of treatment Assay technologies Patient characteristics Unknown factors

10 Oncology Biologics: Patent Expiration Dates United States Europe Many Biologic Patents Will Expire Soon 1,2 *; Over $90B of Biologic Products Will Be Off Patent by Epoetin alfa Filgrastim Rituximab Cetuximab Infliximab Trastuzumab Pegfilgrastim Adalimumab Cetuximab Rituximab Darbepoetin Bevacizumab Darbepoetin Infliximab Trastuzumab Adalimumab Bevacizumab Pegfilgrastim * Patent expirations are listed as provided in reference 2. 1.Datamonitor. Biosimilars: Market Entry Strategies. HC ; Publication Date: 20 December Gal A, et al. In: Biosimilar: Quo Vadis-A Snapshot of the Biosimilar Industry Halfway Through Its Formation. New York: Bernstein Research; June 2011.

11 The Cost Burden Associated With Biologics: US Example Drug Expenditures for Top 20 Oncology Drugs in US Outpatient Clinics in ,2 Drug Type Total ($M) Bevacizumab Biologic 1,884 Rituximab Biologic 1,466 Trastuzumab Biologic 931 Docetaxel Nonbiologic 688 Pemetrexed Nonbiologic 579 Oxaliplatin Nonbiologic 508 Gemcitabine Nonbiologic 463 Cetuximab Biologic 329 Bortezomib Nonbiologic 327 Leuprolide Nonbiologic 220 Paclitaxel-albumin Nonbiologic 212 Bendamustine Nonbiologic 208 Azacitidine Nonbiologic 148 Liposomal doxorubicin Nonbiologic 130 Decitabine Nonbiologic 92 Topotecan Nonbiologic 86 Fulvestrant Nonbiologic 81 Panitumumab Biologic 70 Ixabepilone Nonbiologic 60 Temsirolimus Nonbiologic 48 1.Zelenetz AD, et al. J Natl Compr Canc Netw. 2011;9(suppl 4):S1-S22. 2.Doloresco F, et al. Am J Health Syst Pharm. 2011;68(10): Biologics ($M) Top 3 US Expenditures Were Biologics $4.679,36 55% Nonbiologics ($M) $3.848,21 45% Biologics accounted for more than half (55%) of the total expenditures for the top 20 oncology drugs in outpatient clinics in ,2

12 Source CBO 1 PCMA 2 EGA 3 IGES Institut GmbH 4 Biosimilars Have the Potential to Lower Healthcare Costs Range of Estimates on the Cost Savings That Could Be Realized by Healthcare Systems With The Availability of Biosimilars Estimated Biosimilar Savings Savings of $25 billion during in US following implementation of bill S Medicare Part B: $14 billion over 10 years 1.6 billion, assuming a 20% discount for just 6 biologic drugs 11.8 to 33.4 billion between in 8 EU countries CBO, Congressional Budget Office; EGA, European Generic Medicines Association; PCMA, Pharmaceutical Care Management Association. 1. Congressional Budget Office. S Biologics Price Competition and Innovation Act of June 25, 2008; 2. Engel and Novitt, LLP. Report to PCMA on Potential Medicare Savings. January 2, 2007; 3. European Generic Medicines Association. The Future of Pharmaceuticals: Generic Medicines Enhancing Pharmaceutical Competition and Ensuring Healthcare Sustainability. Brussels, Belgium: EGA; 2007; 4. Haustein R, et al. GaBI J. 2012;1(3-4):

13 Biosimilarity 1,2 Bioequivalence 3 Equivalence 4 Noninferiority 4 Impact on sample size 5 Comparative Clinical Trials Are Required to Prove Biosimilarity Requires demonstration of bioequivalence and efficacy and safety using either equivalence or noninferiority Pertains to pharmacokinetic testing, most often C max and AUC Statistical testing showing new product is no better and no worse than a reference product Statistical testing showing new product is at least as good as a reference product Sample size required for equivalence > sample size required for noninferiority 1. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product [draft guidance]. Rockville, MD: FDA; EMA. Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues. London, UK: EMA; FDA. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. Rockville, MD: FDA; ICH. ICH Harmonised Tripartite Guideline: Statistical Principles for Clinical Trials E9. Brussels, Belgium: ICH; Da Silva et al. Biol Blood Marrow Transplant. 2008;15(1, suppl):

14 Biosimilar Regulatory Guidance Length of immunogenicity study and comparative vs noncomparative phase Position on interchangeability Request for pharmacovigilance study Extrapolation of indication (Extrapolation possible if sensitive clinical test model, similar MOA, and similar safety and immunogenicity issues in different population) FDA 1 EMA 2 WHO 3 (Extent and timing of program will vary) (Draft guidelines: produce same clinical effect with no safety, efficacy difference on switching) (Product dependent; 1-year follow-up data required pre-license for chronic administration) Not under EMA jurisdiction 1. FDA Web site. How Drugs are Developed and Approved. Last updated January 3, Accessed April 30, EMA. Accessed April 30, WHO. Expert Committee on Biological Standardization: Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs). Geneva, Switzerland; (Length dependent on duration of therapy and expected antibody development time)

15 PD, pharmacodynamics; PK, pharmacokinetics. Biosimilar Regulatory Guidance The level of evidence required for biosimilar approval is different from originator biologics Standard Biologics 1,2 Clinical studies Clinical pharmacology PK/PD Nonclinical Analytical Bioequivalence in Healthy Volunteers Analytical Small Molecule Generics 1,4 Comparative Clinical studies Biosimilars 1-3 Comparative clinical pharmacology PK/PD Nonclinical Analytical Confirm safety profile and efficacy in a disease population (dose ranging not necessary) 1. EMA, Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1) ; EMA/CHMP/BWP/247713/2012. Released 22 May Accessed 7/7/ chneider CK, et al. Nat Biotechnol 2012;30: McCamish M. Presented at EMA Workshop on Biosimilars; London; October Berghout A. Biologicals. 2011;39: US Food and Drug Administration ted New Drug Applications (ANDA): Generics. Acc Totality of evidence

16 Biosimilar Regulatory Guidance The goal of the clinical program is NOT to independently reestablish safety and effectiveness, but to demonstrate biosimilarity Since biosimilars are not identical to their reference products, phase 1 and phase 3 comparative clinical trials are generally required The scope and number of clinical trials required for biosimilar approval is determined on a case-by-case basis Depends on residual uncertainty after analytical characterization and human PK assessment When a biosimilar is approved, there is an expectation that there will be no clinically meaningful differences in safety, immunogenicity, and/or efficacy

17 Biosimilar Regulatory Guidance Superiority: Experimental intervention is superior to the control intervention Not useful when evaluating biosimilars Noninferiority: Experimental intervention is non-inferior to the control intervention May be adequate for the evaluation of immunogenicity or other safety outcomes Equivalence: Experimental intervention and the control intervention are equivalent More commonly used as demonstrating that the biosimilar is equivalent to the reference product is the goal

18 Biosimilars: Balancing Risk and Benefit in the Approval Process Approval Process Requires Too Large Amount of Data Biosimilar Development and Regulatory Approval Process Approval Process Requires Too Little Amount of Data Zelenetz AD, Ahmed I, Braud EL, et al. J Natl Compr Canc Netw. 2011;9(Suppl 4):S1-S22. Benefits: Greater HCP confidence in biosimilar product Greater acceptance and uptake of biosimilar Fewer safety concerns Risks: Higher development costs Lower pharmacoeconomic benefit over innovator Benefits: Lower development costs Greater pharmacoeconomic benefit over innovator product Risks: Lower HCP confidence in biosimilar product Less acceptance and uptake of biosimilar? Greater safety concerns

19 What EMA Guideline on Biosimilar Antibodies Says? The guiding principle is to demonstrate similar efficacy and safety compared to the reference medicinal product Therefore, in general the most sensitive patient population and clinical endpoint is preferred Comparability should be demonstrated in scientifically appropriately sensitive clinical models and study conditions

20 Key Differences in Requirement and Study Design for Biosimilar and Innovator Clinical Trials Patient population Clinical design Study endpoints Safety Immunogenicity (tested in most sensitive population) Biosimilar Sensitive and homogeneous patient population Comparative versus innovator (equivalence studies) Sensitive Clinically validated PD markers; ORR, pcr Similar safety profile to innovator Similar immunogenicity profile to innovator Innovator Any/Sensitive population Superiority vs standard of care Clinical outcomes data (OS, PFS) or accepted/established surrogates Acceptable risk/benefit profile vs standard of care Acceptable risk/benefit profile vs standard of care Extrapolation Possible if justified Not allowed

21 Key Considerations for Biosimilar Trials Topic Metastatic Population Neoadjuvant/Adjuvant population PK PD Clinical efficacy/safety Immunogenicity Affected by patient s health status & tumour burden Difficult to select homogeneous group Need to control and stratify for multiple factors (eg, prior use of chemotherapy, performance status). Population with heterogeneous characteristics affecting final clinical outcome. Immune system affected by performance status and concomitant chemotherapies received Healthy Volunteers Homogeneous population can be selected Variability is also observed Clinically validated PD marker not available Populations less likely to be confounded by baseline characteristics and external factors Sub-group of patients with higher responses could be identified (e.g. hormone receptor negative patients) Immune system impaired during chemotherapy cycles, but likely to recover to normal status thereafter

22 Efficacy of Biosimilars: Sensitive endpoints EMA guidelines identify ORR as a sufficiently sensitive endpoint for clinical trials of biosimilar antibodies Very often ORR does not correlate to survival Survival endpoints such as overall survival or progression-free survival may provide superior data, but may take too long for a biosimilar antibody trial Which endpoint should be used in a biosimilar antibody trial remains a controversial issue Current clinical trials of biosimilar trastuzumab use response and safety as primary endpoints The goal of biosimilar trials is to demonstrate comparability, which ORR allows, not necessarily efficacy

23 Response Rate: Pros and Cons PROS Indicator of drug activity when it is present Samples sizes typically smaller than with time-to-event endpoints A faster method of assessing drug activity than survival CONS Subject to measurement error and bias RR does not necessarily indicate improved patient outcome Association with overall survival questionable Is ORR sufficiently sensitive endpoint for approval of biosimilar antibodies?

24 Traceability of Biologic Products Clear identification of the product administered is essential to pharmacovigilance, traceability, and assessment of causality Emphasis on prescribing by brand name Section 4.4 of MabThera SmPC: In order to improve the traceability of biological medicinal products, the trade name of the administered product should be clearly recorded (or stated) in the patient file 1 Ensure manufacturers can deliver drug supply to prevent product switching in patients diminished ability to trace long-term product safety 2 and added cost-burden for national health system 3 1. MabThera SmPC Available at Accessed 15 May AFSSAP Expert Report July Available at: Accessed 15 May Accessed 15 May 2013.

25 Accurate Identification of the Drug Given to a Patient Is Essential in order to support pharmacovigilance monitoring, the specific medicinal product given to the patient should be clearly identified. Physician should be well advised to always document exactly which biological is used for an individual patient. In the Adverse Drug Reaction (ADR) report.inn, brand name, manufacturer, lot number, country of origin should be included to ensure a proper root cause analysis EMA Guideline on Similar Biological Medicinal Products CHMP/437/04, October 2005; Ehmann, F., Schneider K. HPE 2011;56:32-35.

26 Postmarketing Surveillance Post approval, biosimilars must undergo at least one year of post-marketing surveillance to detect incidence of immunogenicity and other adverse events This includes detailed risk management plans that should be followed by both physicians and pharmacists

27 Extrapolation of Indications Risk assessment of immunogenicity requires Multidisciplinary approach Related pivotal aspects that must be considered are Rate of occurrence and clinical consequences of unwanted immunogenicity If they can be prevented If they can be measured If they can be treated; is there a therapeutic alternative? In oncology setting it can be challenging How to distinguish loss of clinical response due to natural progression (unavoidable) from neutralization by anti-mab antibody response (potentially treatable)

28 Automatic Substitution Automatic substitution = substitution by a pharmacist without the physician's consent Generic drugs may be automatically substituted for reference drugs because they are the same Biosimilars are similar to the originator drugs, not identical, and there is currently no scientific basis to substitute different products Regulatory decisions on substitution are left to individual countries

29 What Every Oncologist Should Know MYTH 1: Cheaper = potentially less safe Biosimilars are expected to be priced approximately 20% to 30% lower than their reference biologic, which has the potential to translate into substantial cost savings to the health care system. However, the reduced cost of these agents does not automatically imply a reduction in safety standards.

30 What Every Oncologist Should Know MYTH 2: Confirmatory trials are too small to detect clinically meaningful differences A properly powered clinical trial to determine absolute equivalence between a biosimilar and its reference biologic would require thousands or even tens of thousands of patients, substantially larger than the size of the confirmatory trials required by the FDA for approval of a biosimilar. However, such trials are not necessary. A biosimilar agent is an highly similar to the reference product notwithstanding minor differences in clinically inactive components with no clinically meaningful differences in safety, purity, and potency

31 What Every Oncologist Should Know MYTH 3: Pharmacovigilance will be poor without different nonproprietary names Nonproprietary names, (e.g., filgrastim) serve to indicate the active ingredient in a brand name product, and are designed to reduce confusion regarding the therapeutic class to which a drug belongs. There is currently an ongoing debate regarding the nonproprietary naming convention to be applied to biosimilars, with some arguing that biosimilars for a given reference biologic should share the same nonproprietary name as the reference drug, as is the case with generics, while others argue that each biosimilar should be issued a distinct nonproprietary identifier.

32 What Every Oncologist Should Know MYTH 4: Extrapolation is dangerous without clinical trials for each indication Some clinicians have expressed concern that because the mechanisms of action of most biologic agents are not fully understood. However, if a confirmatory trial is conducted in the most sensitive or representative patient population, and solid comprehensive evidence from structural and functional assays is provided demonstrating a high degree of similarity between the biosimilar and reference biologic, it is very unlikely that clinically meaningful differences would be detected in subsequent trials to confirm additional indications of the reference agent

33 Conclusions The aim of clinical trials with biosimilars is to show equivalence and not patient benefit If biosimilars are approved, several challenging issues will need to be addressed such as maintaining appropriate pharmaco-vigilance, extrapolating across indications, and automatic substitution and switching Slight alteration in manufacturing of biologics can lead to clinically relevant changes, particularly concerning potency. With many biologics going off patent in the near future, an opportunity exists to expand access through the availability of biosimilars. They can be the future of sustainable cancer care

34 Drug repositioning Drug repositioning (also known as drug repurposing, re-profiling, re-tasking) is the application of known drugs and compounds to treat new indications (i.e., new diseases). A significant advantage of drug repositioning over traditional drug development is that since the repositioned drug has already passed a significant number of toxicity and other tests, its safety is known and the risk of failure for reasons of adverse toxicology are reduced. More than 90% of drugs fail during development

35 Drug repositioning

36 Drug repositioning Using drug repositioning, pharmaceutical companies have achieved a number of successes; for example, Pfizer's Sildenafil developed to treat pulmonary arterial hypertension and repositioned for erectile dysfunction Celgene's thalidomide developed to treat pregnancy associated nausea and the repositioned as antiangiogenic for MM and for severe erythema nodosum leprosum.

37 Drug repositioning Plerixafor, initially developed as an HIV drug to block viral entry in the cell via the chemokine co-receptor CXCR4, failed in its initial medical indication. Nevertheless, it was noticed that the drug induced peripheral blood leukocytosis within which peripheral blood CD34 hematopoietic stem cells were found. On basis of this observation, the drug has been re-purposed as a stem cell mobilizing drug Another example of drug repurposing is that of gabapentin, and its chemical cousin pregabalin. Originally developed as anti-epileptics, they have found more use treating anxiety disorders and neuropathic pain than as seizure medications.

38 Drug repositioning

39 Drug repositioning Drug repurposing programs in oncology have been limited thus far, and have provided very few suc- cesses. Academic and independently driven preclinical and clinical research programs should be promoted both nationally and internationally. For these programs to be successful and ulti- mately bring benefit to patients with cancer, the design and the quality of repurposing trials will need to be optimal. Broad communication of the results of well-performed repurposing trials will also be necessary to ensure they become practicechanging.

40 Giuseppe Curigliano MD, PhD

41 Thank you