PCI Biotech Holding — Regulatory Filings 2021

Nov 8, 2021

Photochemical internalization (PCI) of gemcitabine in locally advanced inoperable Cholangiocarcinoma - a new technique with promising clinical activity

Jörg Trojan, Universitätsklinikum Frankfurt

Advisory role

Amgen, AstraZeneca, Bayer Healthcare, Bristol Myers-Squibb, Eisai, Insitute for Quality and Efficency in Health Care (IQWiG), Ipsen, Merck Serono, Merck Sharp & Dome, Lilly Imclone, PCI Biotech, onkowissen.de, Roche, Servier

Speakers honoraria

Amgen, Bayer Healthcare, Bristol Myers-Squibb, Daichi Sankyo, Eisai, Ipsen, Merck Serono, Merck Sharp & Dome, Lilly Imclone, Roche, Servier, streamedup!

Research grants

Ipsen, Roche

FIRST-IN-MAN STUDY PUBLISHED IN LANCET ONCOLOGY¹

► With independent expert commentary²

"The results of this phase 1, first-in-man, dose-escalation trial… …are encouraging.

Overall, the results… …suggest that photochemical internalization might have a role in the treatment of early lesions and palliation of advanced disease… These findings provide the basis for further studies."

3

¹Sultan et al (2016) Lancet Oncology 17(9):1217-1229 ² Madsen (2016) Lancet Oncology 17(9):1173-1174

BILE DUCT CANCER (CHOLANGIOCARCINOMA, CCA):

► Life threatening and poor outcomes

► Survival: Poor Prognosis

• 5 years survival (Europe), 5% to 17% depending on CCA ¹
• ► Cholangiocarcinoma includes:
  • Intra-hepatic tumours (iCCA): 10%¹
  • Extra-hepatic tumours
    • Perihilar/Klatskin tumours, (pCCA): 60-70%¹
    • Distal tumours dCCA: 20-30%¹
• ► Classification based on different evolving systems² :
  • Primary tumours, localisation, size/number, accessibility, vascular invasion
  • Regional lymphatic nodes and distant metastasis
• ► Diagnosis: no straightforward clinical features
  • Peak age for CCA is the seventh decade
  • Late stage and rapid deterioration

Perihilar bile duct cancer is the main target for PCI treatment

BILE DUCT CANCER – PCI TREATMENT

Three step treatment procedure

• ► The aim is to increase the treatment effect of gemcitabine by increasing intracellular gemcitabine concentration
• ► Fimaporfin is a photosensitiser that is inert until activation by light (652 nm)

PCI-triggered endosomal release

BILE DUCT CANCER – PCI TREATMENT

• ► Three step treatment procedure
• ► PCI Treatment in CCA/bile duct cancer

Three step PCI treatment procedure:

• Fimaporfin injection
• Gemcitabine infusion
• Illumination as a short add on procedure during standard ERCP

► Main aim for PCI treatment in CCA is to enhance the effect of gemcitabine locally at the tumour target

Perihilar bile duct cancer is the main target for PCI treatment

PCI treatment procedure

►Laser treatment

catheter

BILE DUCT CANCER – PHASE I STUDY

► Patient population

• ► Phase I dose escalation (different doses of light and fimaporfin) : 16 patients
• ► Phase I extension (up to two PCI treatments) : 7 patients were included
• ► Patients included were
  • locally advanced cholangiocarcinoma with stenosis in the perihilar or distal region
  • treatment naïve
  • adenocarcinoma
  • ECOG 0-1
  • stented

BILE DUCT CANCER – PHASE I STUDY

• ► Safety and Phase II recommended dose established
• ► Dose escalation with one PCI treatment, followed by an extension part for safety of two PCI treatments

Dose escalation part (N=16)

• Standard 3+3 design, with one PCI treatment
• 4 dose escalation cohorts
• No Dose-Limiting Toxicity (DLT) were observed
• No unexpected safety concerns
• Serious Adverse Events (SAEs) primarily cholangitis, similar to the frequency, severity and pattern reported in the literature for perihilar bile duct cancer
• Transient light sensitivity from PCI treatment considered acceptable in context of the encouraging signs of antitumour activity

Extension part (N=7)

• Explored safety of two PCI treatments (N=5)
• Same dose as dose escalation cohort IV, but up to two treatments
• No new safety signals

BILE DUCT CANCER – PHASE I DOSE ESCALATION RESULTS

► Early signs of anti tumour activity – 11 evaluable patients of 16 included

All radiologically evaluable patients from all dose escalation cohorts in Phase I

BILE DUCT CANCER – PHASE I DOSE-ESCALATION STUDY

► Early signs of anti tumour activity – median Overall Survival of 22.8 months at selected dose

Parameters	Cohort IV (N=6)	Phase I – all dose-escalation cohorts (N=16)
Median Overall Survival (mOS)	22.8 months	15.4 months

• Study closed and Cohort IV dose selected for the pivotal RELEASE trial
• Encouraging Phase I results paved the way for a pivotal trial, with potential for accelerated approval
• No new safety signals with two treatments in the Phase I Extension up to two treatments allowed in RELEASE

Case Study Report from 3 patients

• Dechene et al 2020
• Endoscopy International Open

novation for Photochemical internalization and gemcitabine combined with first-line chemotherapy in perihilar cholangiocarcinoma: observations in three patients O	Chican
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Author s
Alexander De chêne', Stefan Kasper', Hans Olivecrona', Joerg Schirra4, Joerg Trojan3
Institutions
1 Dept. of Gastroenterology and Endocrinology, Klinikum
Nümberg, Paracelsus Medical University, Nürnberg, ABSTRACT
2 Dept of Medical Oncology West German Cancer Center, Photochemical Internalization (PCI) is a technology to in-
duce a localized, intracellular enhancement of therapeutics
3 PCI Biatech AS, Oslo, Norway that are processed through endosomal pathways, including 4 Medical Department II, University Hospital, Ludwig
gemcitabine in malignant cells. In addition to a direct pho- Maximillians-University, Munich, Germany totoxic and tumoricidal effect, PC specifically disrupts en-
5 Goethe University Medical Center, Frankfurt, Germany dosomal membranes and, thereby, the compartmentaliza-
tion of certain cytotoxic compounds to enhance a drug's in- submitted 6.3.2020
tended intracellul ar target reach within the tissue treated. accepted after revision 17.8.2020
Non-resectable extrahepatic cholangiocarcinoma (eCCA) is
a common primary turnor and gemcitabinel cisplatin che- Bibliography
motherapy is widely considered standard of care for it. PCI Endoscopy International Open 2020: 08: E1878-E1883 is well suited as an endoscopic intervention, and clinical ob- DOI 10.1055/a-1276-6366 servations in three subjects participating in a phase I/II a ISSN 2364-3722
dose escalation safety trial are described. The trial included 2020. The Author(s).
patients with perihilar, non-resectable CCA suitable for Hes is an open active atticle published by Thums a under that more of the Crodine standard-of-care chemotherapy. Per protocol, a single
Communis Attriad in Alan Development ve Nan Communist Lionne, pennesing copying endoscopic PCI procedure with ge mcitabine was conducted and my malaction as long an the uniqual veril is spare propriate credit. Continet a at the initiation of standard ge mcitabine /cisplatin the rapy. y not in mad for communial paryones, or adapted, merined, therefor med ar
bed upst. (/etps://a.selsse:am.tran.com.tran.com/loyato.all/4.0/) Sixteen patients enrolled in the initial dose escalation phase
of the trial, which later was extended to explore the safety Corresponding author
of a second PCI procedure during chemotherapy.
Hans Ofvecrona, MD, PhD, PCI Biotech AS, Oslo, Norway While limited to a case series, the various clinical observa- Fax: 44767115400 tions described here serve to illustrate the effects of loca- ho@pcibiotech.com
lized, perihilar turnor targeting in appropriate patients by
any safe methodology, including PCI. As previously indica-
ted by clinical data using other localized treatment modal-
ities, adding a directed, turnor-targeting treatment to sys- temic therapy to ameliorate the progressively expanding extrahepatic turnor burden can have important effects on
the overall outcome of systemic treatment in many pa-
tients who have incurable eCCA.
Introduction
Perihilar cholangiocarcinoma (CCA) is an a denocarcinoma with variable histological characteristics arising from the proximal quent, most patients present with obstructive jaundice or cho-
portion of the common bile duct, including the main left or langitis on the basis of a primarily non-resectable, advanced- right hepatic ducts or their confluence. Surgical resection is stage turnor and an expected survival of 6 to 12 months [1, 2]. the only curative option, but because early symptoms are infre-
Standard of care is billiary drainage and systemic therapy, most often gemcitabine/cisplatin chemotherapy, result ing in a medi-
an overall survival of almost 12 months [3].
Carcisto Almander at it. Photozhersical internal setiment Endrecay international Onen 2020: 00: E18PA-E1340 E11878-21441 . E1300

Case report 2

• Patient – male 78 years old – 7 cycles of chemotherapy and one PCI treatment

Case report summary

• No bleeding episodes (in contrast to intraductal RFA)
• PFS of PCI with Gem followed by GemCis is very promising
• Two rounds of PCI might further enhance this benefit

► RELEASE study are currently recruiting for patients

► Study design

Up to 2 PCI treatments in RELEASE incorporated into the SoC of gemcitabine and cisplatin

• ► Patient population
• ► Inoperable cholangiocarcinoma
• ► Perihilar or distal stenosis requiring stenting
• ► Adenocarcinoma
• ► Metastatic disease is allowed (except for bone and CNS)
• ► At least one radiological lesion that is measurable or evaluable by RECIST
• ► Eligible for gemcitabine and cisplatin treatment
• ► Up to 2 cycles of gemcitabine + cisplatin may have been initiated before study entry
• ► Adequate biliary drainage (up to 5 x ULN of bilirubin is acceptable)
• ► ECOG 0-1

► Status

• ► 47 sites active for recruitment in Europe, USA and Asia
• ► FPFV May 2019 (Europe)
  • First patient in Asia Oct 2020
  • First patient in USA Apr 2021
• ► https://clinicaltrials.gov/ct2/show/NCT04099888