Follow Up Results from the REP 301 Trial: Safety and Efficacy of REP 2139 and PegylatedInterferon Alpha-2a in Caucasian Patients with Chronic HBV / HDV Co-infection

INTRODUCTION RESULTS

CONCLUSIONS

MATERIAL & METHODS

ACKNOWLEDGEMENTS

DISCLOSURES

Contact information: availlant@replicor.com

M. Bazinet1, V. Pantea2, V. Cebotarescu2, L. Cojuhari2, P. Jimbei3, J. Albrecht4, P. Schmid4, A. Krawczyk5, H. Karimzadeh6, M. Roggendorf6, A. Vaillant1

1. Replicor Inc. Montreal, Canada; 2. Department of Infectious Diseases, N. Testemitanu State University of Medicine and Pharmacy, Chisinau, Republic of Moldova; 3. Toma Ciorbǎ Infectious Clinical Hospital, Chisinau, Republic of Moldova. 4. National Genetics Institute, Los Angeles, USA, 5. Universitätsklinikum Essen, Institute for Virology, Essen, Germany 6. Institute for Virology, Technische Universität München, Munich, Germany.

AIMS

Infectedhepatocyte

Subviral particles(bulk of serum HBsAg)

cccDNA

HDV virus (SVP-like)

HDVRNP

HDVRNA

Release of HBV sub viral particlesRelease of HDV

Follow up(4, 12 and 24 weeks) Pegylated interferon α-2a

180 μg qW SC 48 weeks

REP 2139-Ca500mg qW IV 15 weeks

REP 2139-Ca250mg qW IV 15 weeks

Poster#1848

HBV / HDV co-infection represents a significant unmet medicalneed, causes rapid progression of liver disease and has noapproved therapy. The nucleic acid polymer (NAP) REP 2139blocks HBsAg release and can eliminate serum HBsAg in chronicHBV and HBV / HDV co-infection (Vaillant 2016 Antiviral Res. 133:32-40). In the completed phase II proof-of-concept REP 301protocol (NCT02233075), the safety and antiviral efficacy of REP2139 in combination with pegylated interferon alpha 2a (peg-INF)was evaluated in 12 Caucasian patients with HBV / HDV co-infection. Final safety and efficacy data and 6 month follow-upresults from this trial are presented.

REP 2139 inhibits the release of HBV subviral particles, amechanism which may also function in the release of HDV virions(Bonino et al., 1986 J. Virol. 58: 945-950, see Figure 1.). The goalof this study was to assess the effect of REP 2139 therapy in HDVinfection.

Figure 1. Release of HBV subviral particles and HDV utilize a similarmechanism. RNP = ribonuclear protein complex.

Patients received 500mg REP 2139-Ca (calcium chelate complex)once weekly for 15 weeks by IV infusion, followed by combinedtherapy for 15 weeks with a reduced dose of 250mg REP 2139-Cawith peg-INF (180ug SC qW) (see Fig. 2). Patients thentransitioned to 33 weeks of peg-INF monotherapy. HDV RNA, HBVDNA, HBsAg and anti-HBs are followed every two weeks usingstandard assays (Robogene RT-PCR [MKI], Abbott RealTime HBV,Abbott Architect). Follow up evaluations were scheduled 4, 12and 24 weeks following cessation of all treatment.

Figure 2. REP 301 trial design

Infectious DiseaseClinic

Toma CiorbăHospital

Figure 3. Serum HBsAg levels during treatment and follow-up. HBsAgstatus is indicated in green in the legend. Boxes highlight patientswith no detectable HBsAg at 24 weeks of follow-up. Light blue lineindicates threshold for a complete HBsAg response (1 IU / ml)

Figure 6. Serum HBV DNA levels during treatment and follow-up. HBVDNA status at 24 weeks of follow-up is indicated in green in thelegend. Boxes indicate patients that are HDV RNA negative (TND).TND = target not detected.

Figure 5. A) Serum anti-HBs levels during treatment and follow-up.Anti-HBs status at 24 weeks of follow-up is indicated in green in thelegend. Boxes indicate patients with no HBsAg present. B) Serum anti-HBs levels during treatment and follow-up in HBsAg responders (left)and non-responders (right).

Figure 4. A) Serum HDV RNA levels during treatment and follow-up.HDV RNA status at 24 weeks of follow-up is indicated in green in thelegend. Non-highlighted boxes indicate patients with no HBsAgpresent. Highlighted boxes indicate patients that are HDV RNAnegative but HBsAg positive. B). Confirmatory HBV RNA assessmentsfrom two independent test labs. TND status is indicated in green inthe legend. Highlighted patient (orange in legend) is HDV RNA TNDat TUM but HDV RNA positive at ESSEN. TND = target not detected,FW = follow-up week, TW = treatment week.

Figure 8. Hematological observations during treatment and follow-up.Figure 7. A) Serum transaminase flares in HBsAg responders (left) andpartial responders (right). B) Liver function during treatment andfollow-up.

REP 2139-Ca

Peg-IFN Follow-up

HBsAg status

0.000.000.00

0.00

0.00

2392646

13896214

149431225

29724

Anti-HBs status 24W follow-up (mIU / ml)

75851354013566

1772

32543

1.071.42

< 0.1< 0.10.190.3

< 0.1

HDV RNA status 24W follow-up (IU / ml) TNDTNDTND

TND

TND

TND1390

465,000TND2250

173,280,000

REP 2139-Ca

Peg-IFN Follow-up

REP 2139-Ca

Peg-IFN Follow-up

REP 2139-Ca

Peg-IFN Follow-up

A

B CONFIRMED TNDFW 4TW 63FW 4FW 4FW 4FW 4

TW 54

TW 54

TW 50

CONFIRMED TNDFW 24FW 24FW 24FW 24FW 24FW 24

FW 24

FW 12

A

B

HBV DNA status 24W follow-up (IU / ml) TNDTNDTND

TND

TND

1310

1510282310

Partial responder (HBsAg > 1 IU / ml)Complete responder(HBsAg < 1 IU / ml)

HBsAg complete responders (HBsAg < 1 IU / ml) HBsAg partial responders (HBsAg > 1 IU / ml)

The authors would like to thank Dr. Hrvoje Mijočević for his assistance with theconfirmatory HDV RNA assays at TUM.

M.Bazinet and A.Vaillant are employees and shareholders in Replicor Inc.M. Roggendorf is a member of Replicor’s SAB.H. Karimzadeh is a consultant for Replicor.

REP 2139-Ca

Peg-IFN Follow-up

REP 2139-Ca

Peg-IFN Follow-up

HBsAg complete responders (HBsAg < 1 IU / ml) HBsAg partial responders (HBsAg > 1 IU / ml)

REP 2139-Ca

Peg-IFN Follow-up

A

B

• REP 2139 simultaneously clears serum HBsAg and HDVRNA.

• Universal clearance of HDV RNA during therapy indicates adistinct activity of REP 2139 against HDV upstream ofvirion secretion.

• Improved action of peg-IFN is correlated with HBsAgreduction below 1 IU / ml.

• Despite the suboptimal combination regimen used, 5/12patients maintained HBsAg loss and 7/12 patientsmaintained undetectable HDV RNA 24 weeks aftertreatment withdrawal.

• Longer concomitant therapy with REP 2139 and peg-IFN isexpected to increase the rate of functional control of HBVand HDV infection.

(final confirmatory results pending) (final confirmatory results pending)

REP 2139-Ca

Peg-IFN Follow-up

24Wfollow-up(IU / ml) Ba

selin

e(IU

/ m

l) Max. logreduction

on therapy

139982726428261

12382

5854

1751116426

208698314

134307836

20473

6.146.446.45

6.09

5.78

3.483.00

1.325.440.653.612.52