Safety of novel therapies

Flora Peyvandi Angelo Bianchi Bonomi Hemophilia and Thrombosis Center,

Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and

University of Milan, Italy

7 March 2017 – Brussels, BelgiumEHC – Clinical Trials in Haemophilia

DISCLOSURES

Conflict Disclosure - if conflict of interest exists

Research support Ablynx, Alexion, Kedrion Biopharma, and Novo Nordisk

Director, officer, employee No

Shareholder No

Honoraria Ablynx, Bayer, Grifols, Novo Nordisk, and Sobi

Advisory committee Ablynx, F. Hoffmann-La Roche Ltd

Consultant Freeline, Kedrion Biopharma, LFB, Octapharma

• Assessment of quality in terms of safety and efficacy is veryimportant for all new therapeutic products

• All adverse events occurring in relationship with any use of theproduct should be recorded and reported

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Drug safety

Safety and efficacy evaluation

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• Pre-clinical studies

• Assess biological activity and safety in two or more species (one rodent, one non-rodent)

• Clinical studies

• Premarketing: efficacy and safety evaluation - in healthy subjects - patients

• Postmarketing: assessment of safety and efficacy in a large group of subjects

Clinical safety of FVIII and FIX concentrates

• Viral contamination

• Immunogenicity

The occurrence of neutralizing antibodies is a majorcomplication of haemophilia treatment, in particular in patientswith severe hemophilia A

• Adverse events

Development of hypersensitivity/anaphylactic reactions for FIXconcentrates, thrombogenicity is also considered

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• The current regulatory process obtains important data to ensure thesafety of novel drugs almost exclusively during premarketing testing

• Premarketing trials frequently do not have sufficient power to detectreliably important adverse drug reactions

• Trials are usually powered for the intended therapeutic effect andunderpowered for side effects that are rarer

• Registration trials are often performed in a relatively healthy subset ofpatients with the condition of interest

Premarketing trials

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• Postmarketing surveillance has been introduced to fill this gapby evaluating the safety of medicinal products and to determinethe unexpected effects after marketing authorization

• Therefore, we need to optimize strategies to evaluate the safetyof novel drugs

Postmarketing surveillance

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• PEGylated• Fusion protein

- Fc- Albumin

New drugs in hemophilia

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Novel hemostasis enhancing agents

• Inhibition of TFPI- anti-TFPI (Concizumab)

• Inhibition of antithrombin (AT)- ALN-AT3 (Fitusiran)

• Bispecific antibody- ACE910 (Emicizumab)

Extended half-life (EHL)

Metabolism of PEGs

• PEG is a polymer made up of identical ethylene glycol subunits

• PEG is efficiently filtered by renal glomeruli but depends on its molecularweight

• Ultrafiltration of PEG with molecular weight >30 kDa is dramaticallyslowed down

Flora Peyvandi (Nakaoka R et al. J Control release 1997;46:253-261; Caliceti P and Veronese FM. Adv Drug Deliv Rev. 2003;55:1261-1277)

The fate of PEGylated proteins

• PEGylated proteins are usually removed from circulation through the existingprotein-related mechanisms, target-mediated uptake (including receptor-mediated uptake) as well as pinocytosis

• PEGylated protein is internalized and can be transported to the endosomesand then to the lysosomes

Flora Peyvandi (Baumann et al. Drg Discov Today 2014;10:1623–1631)

• The lack of mammalian enzymes capable ofdegrading PEG results in the gradualaccumulation of PEG within lysosomes

• In the late 1970s Davis and Abuchowski generated the firstPEGylated molecule, introducing PEG molecules to bovine serumalbumin

• Currently, there are 11 approved PEGylated drugs in the US andEurope

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PEGylated products

(Ivens IA et al Tox Pathol 2015; 43: 959-983)

Results of preclinical studies

Safety of PEG-protein conjugatesAnimal studies

• Cases of cellular vacuolation of renal cortical tubular epithelium,spleen and of the choroid plexus epithelial (ependymal cells) havebeen observed in repeat-dose toxicity studies conducted with proteinsPEGylated with molecules ≥ 40 kDa

• Potential risk of PEG accumulation is associated with long-term andchronic administration

(Bendele et al. Proteins. Toxicol Sci 1998;42:152–157; Young et al. Transl Res. 2007;149:333-342; Ivens IA et al Tox Pathol 2015; 43: 959-983)

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Status of extended half-life drugs

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Animal studies with PEGylated products

(Baumann A et al Blood 2014 124:1473; Offenberg H et al. J Thromb Haemost 2015; Suppl.2: 558; Rasmussen et al Toxicol Pathol 2016;44:726-737; Stidl R et al Haemophilia 2015; 1-11)

Safety of extended half life drugs

• Toxicity (kidney, liver, and brain)

• Immunogenicity against the tag (PEG), Fc, or albumin

• Immunogenicity (inhibitors)

• Allergic reactions

• Any other undesired reaction

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• long term postregistration surveillance is required to understand theeffect of long term PEG exposure

(Garay et al. Expert Opin. Drug Deliv. 2012;9:1319-1323)

• Some studies have reported the development of anti-PEG antibodies

• Plasma half-life of PEG-asparaginase and PEG-uricase were dramatically

shortened in some patients

• anti-PEG antibodies were detected in the patients plasma before the

treatment

• The widespread use of PEG polymers in healthy-care products, cosmetics

and foods could elicit anti-PEG antibodies in some individuals

anti-PEG antibodies

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Antibodies anti-PEG

(Reding MT et al. J Thromb Haemost. 2016 Dec 19. doi: 10.1111/jth.13597; Giangrande P et al Thromb Haemost 2017; 117: 252–261; Konkle BA et al Blood. 2015;126:1078-1085; Collins PW et al. Blood. 2014;124:3880-3886)

Safety of fusion proteins

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Linker

Recombinant coagulationFVIII or FIX Fc or Albumin

• Immunogenicity

• Potential for neo-epitopes in linker fusion protein

• No antibodies against FVIII and FIX fusion proteins have beenreported yet

(Strohl WR E et al. Biodrugs. 201;29:215-239)

Neutralizing and non-neutralizing antibodies

(Reding MT et al. J Thromb Haemost. 2016 Dec 19. doi: 10.1111/jth.13597; Giangrande P et al Thromb Haemost 2017; 117: 252–261; Konkle BA et al Blood. 2015;126:1078-1085; Collins PW et al. Blood. 2014;124:3880-3886; Mahlangu J et al Blood. 2014;123:317-325; Powell JS et al. N Engl J Med 2013;369:2313-

23; Santagostino E et al. Blood. 2016;127:1761-1769)

More than 25 years has been required to demonstrate an increased immunogenicity of certain drugs in PUPs

Adverse events extended half life drugs

• Hypersensitivity/anaphylactic reactions with one pegylated FVIII

• No drug-related serious adverse events

• No deaths

• For extended half-life rFIX concentrates, no thrombotic events

Hemostasis enhancing agents

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• The inhibition of natural anticoagulants is a promising approach for restoringhemostatic balance and correcting thrombin generation in hemophiliapatients

• Inhibition of TFPI- monoclonal antibody (anti-TFPI)

• Inhibition of antithrombin (AT)- small interference RNA (siRNA)

• The inhibition of natural anticoagulants may lead to an increasedthrombogenicity

- Particularly in association of replacement therapy during an acute bleedingand surgery

- No assays to monitor the hemostatic efficacy of novel bypassing drugs

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Novel alternative therapeutic strategy

• ACE910 is a chimeric bi-specific humanized antibody directed againstFIXa and FX

• Two cases of thromboembolic events and two cases of thromboticmicroangiopathy

• These events were seen with the concomitant use of multiple doses of abypassing agent (FEIBA and Novo’s NovoSeven ) with ACE910

• All of these adverse events have resolved

- two of the patients have restarted ACE910 and have not experienceda recurrence of the adverse event to date

Bispecific antibody - ACE910

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The current recommendation is to avoid the use of one specific bypassingagent and if necessary, to use it starting with the lower range of therecommended labeled dose and perform dosing under monitoring

Conclusion

• The availability of a large number of new products in the treatment ofhemophila requires a systematic postmarketing surveillance

• The ISTH-SSC is proposing a standardized data collection toolcontaining a minimum set of items

• All hemophilic patients, regardless of severity and age, using a newdrug for the first time should be registered

• This data collection system should be available in all HemophiliaTreatment Centres in the world

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Recommendations

• Implement the standardized data collection system over extended timeperiods in each patient using a novel hemostatic agent in eachHemophilia Treatment Centre

• Regularly merge and analyze datasets from all Hemophilia TreatmentCentres (e.g, annually)

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• Detect even low frequency adverse effects, not identified inpremarketing clinical trials