FibroGen, Inc. The Next Big Biotech Blow-Up November 4, 2019 - - PowerPoint PPT Presentation

PLAINVIEW

The Next Big Biotech Blow-Up November 4, 2019

FibroGen, Inc.

PLAINVIEW

Legal Disclaimer

As of the date of this presentation, Plainview LLC, other research contributors, and others with whom we have shared our research (the “Authors”) have short positions in and may own option interests on the stock of the Company covered herein (FibroGen, Inc.) and stand to realize gains in the event that the price of the stock declines. Following publication, the Authors may transact in the securities of the Company. The Authors have obtained all information herein from sources they believe to be accurate and reliable. However, such information is presented “as is”, without warranty of any kind – whether express or implied – and without any representation as to the results obtained from its use. All expressions of opinion are subject to change without notice, and the Authors do not undertake to update this presentation or any information contained herein. This is not a recommendation to buy or sell any security.

1

PLAINVIEW

Table of Contents

❑ Executive Summary ❑ FibroGen Overview ❑ Roxadustat

• MACE/mortality imbalances appear to be a class effect
• Roxadustat’s MACE HR is inferior to EPO
• Roxadustat’s MACE HR is inferior to placebo
• MACE+ inflated by prohibiting IV iron & using placebo comparator
• HIF-PH inhibitor mechanism of action is flawed
• Roxadustat does not work in EPO-hyporesponsive patients

❑ Pamrevlumab

• CTGF is a biomarker, not a principal mediator
• No value in IPF even if Phase 3 trial succeeds
• No evidence pamrevlumab works in DMD
• Pamrevlumab doesn’t work in pancreatic cancer

❑ Concluding Thoughts & Looking Forward ❑ Appendix 1: Roxadustat Trial References ❑ Appendix 2: Daprodustat & Vadadustat Trial References

2

PLAINVIEW

Executive Summary

PLAINVIEW

Executive Summary – Roxadustat

• HIF-PH inhibitors all demonstrate a strong adverse safety signal: Published

roxadustat Phase 2/3 trial data shows 11/983 roxadustat patients died vs. 0/419 control and 23/983 roxadustat patients experienced MACE incidents

• vs. 1/419 control. Competing HIF-PH inhibitor drugs daprodustat and

vadadustat also reported imbalances, and we believe this is a class effect driven by HIFs’ well-documented off-target effects

• Daprodustat: 9/677 daprodustat patients died compared to 1/192 control patients,

and 14/677 daprodustat patients reported MACE incidents compared to 2/192 control patients

• Vadadustat: Most adverse event data was withheld, but Akebia reported 5/522

vadadustat patients died compared to 1/243 control patients and 7/522 vadadustat patients reported MACE incidents compared to 1/243 control patients

4 Executive Summary

PLAINVIEW

Executive Summary – Roxadustat

• Roxadustat failed to achieve MACE non-inferiority in DD-CKD: FibroGen Management

has withheld the DD-CKD time-to-MACE hazard ratio and instead repeatedly told investors that the number of MACE events was lower for roxadustat than EPO. Many interpreted this as meaning that the MACE hazard ratio for roxadustat was <1. This is wrong– the total number of events is only lower because the roxadustat discontinuation rate is much higher than EPO as evidenced by all prior roxadustat trials. In the China Phase 3 DD-CKD trial, the roxadustat discontinuation rate was 3.4x the EPO discontinuation rate. Dropouts become immune to future events (but are also censored from the hazard ratio analysis and do not affect it). All available evidence indicates that roxadustat failed to meet the DD-CKD primary safety endpoint

• Roxadustat failed to achieve MACE non-inferiority in NDD-CKD: FibroGen Management

has withheld the primary NDD-CKD safety endpoint (time-to-MACE hazard ratio) and instead told investors that a “conservative” post-hoc intention-to-treat (“ITT”) analysis demonstrated noninferiority. ITT is the opposite of conservative: in contrast to the primary safety endpoint (Kaplan-Meier analysis), ITT does not censor study dropouts which dilutes any drug-driven safety signal by padding safety statistics with patients who are not taking the drug. All available evidence indicates that roxadustat failed to meet the NDD-CKD primary safety endpoint

5 Executive Summary

PLAINVIEW

Executive Summary – Roxadustat

• FibroGen’s reported control arm MACE+ results are inflated and irrelevant to

approval: MACE+ obscures MACE by including congestive heart failure/unstable angina hospitalizations which are frequently driven by anemia rather than

• thrombosis. Due to differences in mechanism of action, IV iron is frequently

required for EPO to work, but not for HIF-PH inhibitors. In FibroGen’s Provenzano et al 2016, prohibition of IV iron resulted in an EPO Hb response rate of only 33% compared to 79% Hb response rate in the clinical-dose roxadustat group– despite screening out all EPO hyporesponders during enrollment. In its Phase 3 trials, FibroGen manipulated MACE+ by prohibiting IV iron, which artificially boosted the frequency of anemia among control arm patients as evidenced by its significantly higher transfusion rate. GSK’s daprodustat trials also demonstrated that restricting IV iron inflates control group “+” events (see slide 49) but has no impact on MACE

• incidents. FibroGen’s Q2 2019 10-Q (p. 47) ominously revealed that the EMA will

be reviewing MACE results, and it is naïve to think that any regulatory agency would overlook a strong adverse MACE safety signal because of engineered “+”

• events. We believe MACE inferiority will lead to regulatory rejection in the US/EU

and minimal uptake followed by inevitable approval revocation in China & Japan

Executive Summary 6

PLAINVIEW

Executive Summary – Roxadustat

• EPO is safer than HIF-PH inhibitors because of its specificity to erythropoiesis:

While EPO and HIF are part of the same pathway, HIF is upstream and activates many unnecessary genes while EPO circumvents that activity and is highly specific to erythropoiesis. In slides 53-65, we summarize the findings of more than a dozen studies implicating HIF-1α, HIF-2α and HIF-PH inhibitors in hypertension, fibrosis, immune suppression and other effects that likely contributed to MACE

• Roxadustat and HIF-PH inhibitors are not capable of treating EPO hypo-

responders: FibroGen cites the study Provenzano et al 2016 as showing that roxadustat worked in EPO hyporesponders– but that study screened out EPO hyporesponders during enrollment and subsequently censored all roxadustat non- responders from the relevant analysis. An intellectually honest study published by GSK showed that daprodustat does not work in EPO hyporesponders, which is almost certainly true for the entire HIF-PH inhibitor class

Executive Summary 7

PLAINVIEW

Executive Summary – Pamrevlumab

• Pamrevlumab, an anti-CTGF (connective tissue growth factor) antibody, has

been FibroGen’s drug in search of a disease for years. Multiple trials for pamrevlumab in fibrotic diseases have been initiated and concluded or terminated without disclosing results

• CTGF is portrayed by FibroGen Management as the central mediator of

fibrosis, but the rest of the research community assigns it a minor role, with TGF-β1 implicated as the master regulator of fibrosis

• There is no consensus in the research community that CTGF has a key role in

fibrosis in IPF, cancer, Duchenne Muscular Dystrophy or any other disease

• state. CTGF rarely receives meaningful mention in publications not

sponsored by FibroGen, and seems to be merely associated with fibrosis as a biomarker in the same way that many other extracellular matrix (“ECM”) components are associated with fibrosis

Executive Summary 8

PLAINVIEW

Executive Summary – Pamrevlumab

• We believe pamrevlumab is worth nothing in any of the indications FibroGen

is currently testing it in

• In FibroGen’s pancreatic cancer trial, there was no difference in ORR

between pamrevlumab + chemotherapy (21% ORR) vs. chemotherapy alone (23% ORR). OS and PFS were conspicuously withheld. The scientific concept behind using pamrevlumab for pancreatic cancer (targeting stromal growth) has been tried multiple times and has consistently failed

• Management withheld all relevant DMD data during the recent PPMD 2019

presentation after running a trial for 3.5 years; this tells us that pamrevlumab did not show the hoped-for benefit

• We have serious doubts about pamrevlumab’s efficacy in treating IPF due to

its mechanism of action failing to demonstrate benefit in fibrotic diseases in the past and the published lack of dose response in IPF

9 Executive Summary

PLAINVIEW

Executive Summary – Pamrevlumab

• Management appears to share our doubts about pamrevlumab in IPF: FibroGen is

currently only running a single Phase 3 trial now even though two Phase 3 trials would be required for approval and each trial is expected to take four years

• FibroGen withheld efficacy results of a placebo-controlled study designed to test

whether pamrevlumab added any benefit when stacked with current IPF standard-

• f-care (Esbriet and Ofev); this indicates that pamrevlumab failed to show any

benefit

• That failure likely informed the decision to structure the Phase 3 trial as placebo-

controlled with background Esbriet/Ofev prohibited. This would make pamrevlumab unsellable even with Phase 3 success:

• Pamrevlumab would be a branded IV formulation with no evidence of additive benefit,

superiority, or even non-inferiority vs. oral Esbriet/Ofev, at least one of which will likely soon go generic

• Possibly competing against new drugs for IPF that show additive benefit with Esbriet/Ofev

10 Executive Summary

PLAINVIEW

FibroGen Overview

PLAINVIEW

FibroGen Overview

• $3.7bn market capitalization
• Founded in 1993
• FibroGen’s flagship drug is roxadustat, an HIF-PH inhibitor designed to treat
• anemia. We estimate roxadustat makes up 85-90% of FibroGen’s current

enterprise value. FibroGen is scheduled to present its key major adverse cardiovascular event (MACE) data at ASN 2019 (2:00 PM Friday, November 8): a make-or-break moment for the drug and the company

• FibroGen is also developing pamrevlumab, an anti-CTGF antibody, for three

indications: idiopathic pulmonary fibrosis (IPF), pancreatic cancer, and Duchenne’s Muscular Dystrophy (DMD). We estimate pamrevlumab makes up the remainder of FibroGen’s current enterprise value. Pamrevlumab’s Phase 3 trials are expected to read out in 2022 (pancreatic cancer) and 2023 (IPF)

12 FibroGen Overview

PLAINVIEW

Roxadustat Overview

• Roxadustat is a hypoxia-inducible factor prolyl hydroxylase (“HIF-PH”) inhibitor
• HIF is a transcription factor that can stimulate erythropoiesis, while HIF-PH is an

enzyme that binds to and triggers the degradation of HIF through hydroxylation and ubiquitination

• In normal circumstances, HIF is inhibited by HIF-PH. However, HIF-PH requires
• xygen to function, hence HIF activity is “induced” by hypoxia
• Roxadustat is designed to inhibit HIF-PH, mimicking the effects of hypoxia and

leading to increased erythropoiesis to treat anemia

• FibroGen has completed pivotal trials for roxadustat in the treatment of anemia in

patients with chronic kidney disease and has guided to submitting an NDA for dialysis-dependent and non-dialysis-dependent chronic kidney disease (DD-CKD & NDD-CKD) in October 2019 and to submitting an MAA in the EU by the end of Q1 2020

13 FibroGen Overview

PLAINVIEW

Pamrevlumab Overview

• Pamrevlumab (FG-3019) is an antibody designed to inhibit connective tissue

growth factor (“CTGF”)

• FibroGen presents CTGF as a principal cause of fibrosis in organs as well as a

key target in pancreatic cancer

• FibroGen has been conducting clinical trials with pamrevlumab since 2003
• Past indications FibroGen has posted pamrevlumab trials for and

subsequently scrapped include liver fibrosis, diabetic nephropathy, and focal segmental glomerulosclerosis (FSGS)

• Idiopathic pulmonary fibrosis (“IPF”) and locally advanced pancreatic cancer

(“LAPC”) are the current lead indications for pamrevlumab

• LAPC Phase 3 results expected in 2022
• IPF Phase 3 results expected in 2023

14 FibroGen Overview

PLAINVIEW

Roxadustat

PLAINVIEW

Roxadustat Table of Contents

❑MACE/mortality imbalances appear to be a class effect

• There is a large MACE/death imbalance favoring control group across roxadustat trials as well as trials for competing HIF-

PH inhibitors vadadustat and daprodustat, indicating a class effect

❑Roxadustat’s MACE HR is inferior to EPO

• FibroGen’s claim of numerically lower events in DD-CKD is a product of the much-higher dropout rates seen in roxadustat

groups across trials. Based on published clinical data, we believe roxadustat’s MACE risk is significantly higher than EPO, which is why FibroGen has withheld it and provided bizarre excuses for the lack of disclosure

❑Roxadustat’s MACE HR is inferior to placebo

• FibroGen has withheld the NDD-CKD MACE HR and instead told investors that the post-hoc ITT MACE HR was non-

inferior to placebo. ITT analysis is inappropriate & misleading because it dilutes the safety signal with dropouts. As with DD-CKD, we believe roxadustat failed to achieve MACE non-inferiority in the NDD-CKD setting

❑MACE+ inflated by prohibiting IV iron & using placebo comparator

• IV iron is a critical part of EPO treatment but is not necessary for HIF-PH inhibitors to achieve efficacy. FibroGen

manipulated MACE+ by barring IV iron in its trials and using a placebo comparator in NDD-CKD, driving up anemia-related “+” events in the control groups

❑HIF-PH inhibitor mechanism of action is flawed

• HIF-PH inhibitors (including roxadustat) act upstream of EPO and are less specific to erythropoiesis. HIFs & HIF-PH

inhibitors have been implicated in hypertension, fibrosis, immune suppression, and other adverse effects that could increase risk of MACE

❑Roxadustat does not work in EPO-hyporesponsive patients

• FibroGen’s claim that roxadustat can treat EPO-hyporesponsive patients is based on a misleading study where EPO

hyporesponders as well as roxadustat non-responders were removed from the analysis

16

PLAINVIEW

Point #1: MACE/Mortality Imbalances Appear to be Class Effect

• Published data shows large MACE & mortality imbalances across FibroGen’s

trials

• 11/983 roxadustat patients died compared to 0/419 control patients
• 23/983 roxadustat patients experienced MACE incidents compared to 1/419 control

patients

• These imbalances were also seen in competitor GSK and Akebia’s HIF-PH

inhibitor trials

• 9/677 daprodustat patients died compared to 1/192 control patients
• 14/677 daprodustat patients experienced MACE incidents compared to 2/192 control

patients

• 5/522 vadadustat patients died compared to 1/243 control patients
• Akebia withheld nearly all adverse event data outside of deaths but reported 7/522

MACE incidents in vadadustat patients compared to 1/243 in control patients

17 MACE/Mortality Imbalances Appear to be Class Effect

PLAINVIEW

MACE/Mortality Rate Consistently Higher in Roxadustat Group

• We compiled all FibroGen’s published clinical data in the table below.

Roxadustat consistently yielded worse MACE rates compared to EPO/placebo despite higher dropout rates. This included 11/983 deaths on roxadustat compared to 0/419 deaths on EPO/placebo and 23/983 total MACE incidents compared to 1/419 for EPO/placebo

MACE/Mortality Imbalances Appear to be Class Effect 18

1 In the poster discussing the Japan Phase 3 DD-CKD trial results, the authors did not provide a complete SAE breakdown, and it is possible that additional MACE incidents occurred that were not disclosed

PLAINVIEW

Roxadustat Trial References

MACE/Mortality Imbalances Appear to be Class Effect 19

Trial Source Where to Find MACE in Each Publication China Phase 3 – DD-CKD Chen et al 2019 SAEs on p. 13 of Supp. Appendix Japan Phase 3 – DD-CKD ASN 2018 Akizawa Poster (not available online) Table 5 of poster China Phase 2 – DD-CKD Chen et al 2017 No reported events US Phase 2 – DD-CKD Provenzano et al 2016 SAEs listed in Table 5 of paper US Phase 2b – NDD-CKD Provenzano et al 2016 SAEs listed in Supplemental Table 5 US Phase 2 – ID-CKD Besarab et al 2016 SAEs listed on pp. 15-16 of Appendix US Phase 2a – NDD-CKD Besarab et al 2015 No reported events China Phase 3 – NDD-CKD Chen et al 2019 No reported events China Phase 2 – NDD-CKD Chen et al 2017 No reported events

• Sources for the numbers in the prior slide are provided below. The relevant

excerpts from each publication (including the Akizawa poster) are provided in the Appendix at the end of this presentation along with brief discussion

PLAINVIEW

Roxadustat MACE Events by Category

MACE/Mortality Imbalances Appear to be Class Effect 20

1 In the poster discussing the Japan Phase 3 DD-CKD trial results, the authors did not provide a complete SAE breakdown, and it is possible that additional MACE incidents occurred that were not disclosed

PLAINVIEW

MACE Imbalance Even Worse After Adjusting For Treatment Duration

• However, event count understates

how poorly roxadustat faired:

• The average treatment duration

based on trial design was longer for control group patients than roxadustat patients (see table)

• The dropout rate was 40% higher in

the roxadustat group compared to the control (see slide 18)– meaning that actual average treatment duration is even lower in roxadustat patients relative to control

MACE/Mortality Imbalances Appear to be Class Effect 21

• One concern with dividing total events by total patients is that the varying

trial durations and enrollment sizes lead to different treatment durations for the patient groups which could make absolute event rates misleading

Note: 1 US Phase 2 DD-CKD and US Phase 2b NDD-CKD trials each included two different trial durations. These are combined in the prior two slides

PLAINVIEW

Class Effect: Higher MACE/Mortality Rates Also True for Daprodustat

MACE/Mortality Imbalances Appear to be Class Effect 22

• Daprodustat also saw much higher rates of discontinuation, MACE, and

death compared to control. See Appendix at the end of this presentation for sources, relevant excerpts & brief discussion

PLAINVIEW

Class Effect: Higher MACE/Mortality Rates Also True for Vadadustat

• Akebia has withheld much of its safety data, but based on what is publicly

available, vadadustat presents MACE/death imbalances similar to roxadustat and daprodustat. See Appendix at the end of this presentation for sources, relevant excerpts & brief discussion

MACE/Mortality Imbalances Appear to be Class Effect 23

PLAINVIEW

Death Imbalance in Additional Daprodustat Trial

• GSK also conducted a trial to reduce ischemic events in patients undergoing

aortic aneurysm repair where patients were either dosed with daprodustat

• r placebo. Daprodustat appeared to have a detrimental effect: 22% (6/27)
• f daprodustat patients died compared to 7.1% (2/28) of placebo patients
• Caveats:
• The death imbalance was not statistically significant due to low N
• The doses of daprodustat used in this trial (300 mg loading & 100 mg QD) were higher

than the doses used for treating anemia, so it is not an apples-to-apples comparison– but it is still certainly troubling

MACE/Mortality Imbalances Appear to be Class Effect 24

PLAINVIEW

MACE Inferiority Even with Questionable In-House Adjudications

• In FibroGen’s publication Besarab et al 2015, the authors claimed that there

were no cardiac SAEs in the roxadustat group. Curiously, one of the non- cardiac SAEs in the roxadustat group was deemed to be “dyspnea secondary to worsening congestive heart failure” while another SAE was ruled “noncardiac chest pain” with no further commentary

• Phase 3 safety results are generally worse for drugs with hazardous

mechanisms of action because:

• Enrollment is expanded to meet powering requirements, frequently leading to sicker

patients who are more susceptible to adverse events

• Adverse event adjudication switches from local principal investigator/sponsor to a

blinded third party that is impartial and not invested in the success of a drug

MACE/Mortality Imbalances Appear to be Class Effect 25

PLAINVIEW

Greatest Phase 2 to Phase 3 Turnaround of All Time?

• Given the extraordinarily poor Phase 2 safety results reported despite in-

house adjudications, roxadustat achieving MACE noninferiority in Phase 3 would be the greatest Phase 2 to Phase 3 turnaround of all time

• We find it highly unlikely that roxadustat inexplicably achieved the safety

improvements necessary to reach non-inferiority in Phase 3 after reporting much worse safety in its prior trials

• Management’s blatantly misleading statements and refusal to disclose the

actual MACE hazard ratios greatly reinforce our view. First rule of biotechnology investing: if Management withholds clinical data, that data is always bad

MACE/Mortality Imbalances Appear to be Class Effect 26

PLAINVIEW

Point #2: Roxadustat’s MACE HR is Inferior to EPO

• During May 2019 call to discuss pooled safety results for roxadustat, analysts repeatedly

asked about the MACE hazard ratios in DD-CKD. FibroGen Management refused to provide the hazard ratios, but instead said that the total number of MACE incidents was lower for roxadustat in DD-CKD, leading many to erroneously conclude that the hazard ratios were <1

• This conclusion is wrong. The event counts are distorted by the fact that the dropout rate for

the roxadustat group was much higher than the dropout rate for the control group. Dropouts become immune to MACE and reduce total possible events but are censored in calculating hazard ratios. Roxadustat dropout rates have been far higher than EPO across FibroGen’s trials: in the China Phase 3 DD-CKD trial, the roxadustat discontinuation rate was 3.4x the EPO discontinuation rate. The gap in dropouts appears to increase as trial duration increases

• We believe the hazard ratio was not disclosed because roxadustat is inferior to EPO– not due

to Management’s bizarre claims of being restrained by AstraZeneca and needing to discuss statistical analysis with the FDA well after the trial concluded

• FibroGen has confirmed that the roxadustat NDA & MAA are for the DD-CKD and NDD-CKD

indications; the ID-CKD safety data is too underpowered to show MACE noninferiority and is irrelevant to drug approval

27 Roxadustat’s MACE HR is Inferior to EPO

PLAINVIEW

“My Dog Ate My Pivotal Trial Results”

• The initial FibroGen press release revealed that roxadustat achieved non-inferiority

for MACE+ and that MACE showed “no clinically meaningful difference” in DD-CKD and NDD-CKD, but did not state that MACE achieved non-inferiority

• On the Q1 2019 call discussing the pooled Phase 3 results, FibroGen first claimed that

“we have to yet agree with our regulator on specific [MACE] analyses to be done.”

• Minutes later, FibroGen Management implied that AstraZeneca was preventing

FibroGen from calculating/sharing the MACE hazard ratios (but mysteriously not the MACE+ hazard ratios or any of the other statistics they provided): “We don't expect that MACE will be particularly different than this [MACE+]. It's just that with U.S., we have an agreement with our partner, AstraZeneca, to evaluate under the totality of evidence basis.”

• These excuses are absurd. MACE is a subgroup of MACE+, so if FibroGen had

calculated the MACE+ hazard ratios, then FibroGen must have also calculated the MACE hazard ratios. Even suspending reality and assuming FibroGen could not produce a hazard ratio, they could have easily provided a Kaplan-Meier plot or basic statistical measures such as means/medians to show the data– no complex analysis required

28 Roxadustat’s MACE HR is Inferior to EPO

PLAINVIEW

Event Count Misdirection

• When pressed on hazard ratios, FibroGen Management switched the

discussion from hazard ratios to the misleading number of events:

“So with the MACE+ data, I believe we have numeric advantage in these categories. So there’s 5 categories…Every one of them, we have numeric advantage over ESA. Is that clear enough?”

• This was repeated multiple times, and seemed to placate some investors

and analysts, with the underlying assumption being that if the total number

• f events was lower, then the hazard ratio must be <1
• This assumption is wrong
• The primary safety endpoint for DD-CKD and NDD-CKD is MACE hazard ratio,

not total number of MACE events per group

Roxadustat’s MACE HR is Inferior to EPO 29

PLAINVIEW

Much Higher Dropout + Lower Number of Events = HR Inferiority

• The number of events can be lower in the roxadustat group despite HR inferiority because

roxadustat has consistently seen far more patient dropouts compared to EPO

• Looking at FibroGen’s public EPO-controlled DD-CKD trial data, the dropout rate in the roxadustat

group is up to 3.4x as high as the dropout rate in the EPO group, with the difference increasing with duration:

• Looking at the 19-26 week trials, we see that the median discontinuation rate for roxadustat

patients is 21.2% compared to 8.7% for placebo, or 2.43x as high. The dropout discrepancy appears to increase with increased duration and the median duration was significantly higher in the DD-CKD Phase 3 trials: FibroGen reported a mean duration of treatment of 1.9 years in the SIERRAS trial and 1.8 years in HIMALAYAS

• The consistently higher dropout rates should also be alarming to investors given that safety is the

key endpoint

Roxadustat’s MACE HR is Inferior to EPO 30

PLAINVIEW

Hazard Ratio Refresher

• Hazard ratios (HRs) measure the likelihood of a specific event occurring in
• ne population compared to the likelihood of the same event occurring in

another population over a given time horizon

• HRs are not the total number of events in one group divided by the other
• group. “Total events” is not a useful measure (particularly in the case of

roxadustat) because dropouts become immune to survival endpoints due to censoring and would inappropriately benefit their group by reducing total possible events

• Dropouts are addressed by using Kaplan-Meier estimate censoring: once a

patient drops out, he/she is censored from future event probability

• calculation. The operating assumption is that dropouts would have had the

same probability of experiencing an event in the future as the rest of the population

Roxadustat’s MACE HR is Inferior to EPO 31

PLAINVIEW

Hazard Ratio Refresher

• HRs can be thought of as the tangent slope of the Kaplan-Meier (K-M) event

curve for one group divided by the tangent slope of the K-M curve for the

• ther group. The relative slope represents the relative probability of an

event occurring: if Survival Curve 1 (SC1) has a slope of -5% (meaning that,

• n average, 5% of the population experiences the event per time period)

and Survival Curve 2 (SC2) has a slope of -10% (meaning that, on average, 10% of the population experiences the event per time period), the event is twice as likely to occur during a given time period in the Survival Curve 2

• group. The HR for SC1 would be 0.5 and the HR for SC2 would be 2.0
• The tangent slope is rarely (if ever) constant, and so each K-M curve

generates a range of slopes (and thus hazard ratios) which can be used to calculate confidence intervals

Roxadustat’s MACE HR is Inferior to EPO 32

PLAINVIEW

Hazard Ratio Refresher

• In a simple example, we look at two populations where one population has an

event rate of 5%/year and a dropout rate of 5%/year while the other population has an event rate of 7.5%/year and a dropout rate of 15%/year. Despite having a lower total event count, the hazard ratio for the second population is much higher and the K-M curve plainly illustrates worse survival:

Roxadustat’s MACE HR is Inferior to EPO 33

Higher Event Rate + Higher Dropout Rate = Lower Event Count & HR>1

PLAINVIEW

High Dropout Rate Suppresses MACE Event Count

• Another HIF-PH inhibitor, Bayer’s molidustat, reported comparable MACE

event rates between the trial group and control in Macdougall et al 2019. However, we think this is attributable to the astronomically higher dropout rate in the molidustat group (38% vs. 11%), not to any difference between molidustat and the other HIF-PH inhibitors. The control completion rate was nearly 50% higher than molidustat (89% control vs. 62% molidustat)

Roxadustat’s MACE HR is Inferior to EPO 34

PLAINVIEW

ID-CKD: Powering Insufficient to Draw Conclusions

• FibroGen claims that roxadustat achieved “directionally lower MACE risk than

EPO” in the ID-CKD subpopulation

• FibroGen’s decision to frame the ID-CKD hazard ratio as showing “directionally

lower” MACE risk without any mention of non-inferiority indicates that the confidence interval did not achieve non-inferiority

• We can roughly estimate the confidence interval for the ID-CKD data based on

prior confidence interval of the CHOIR trial, which enrolled a similar size population (CHOIR n = 1,432, FibroGen ID-CKD n = 1,526)

• The hazard ratio in the CHOIR trial was 1.28 with a 95% confidence interval of

(1.03, 1.75). With the same confidence interval range of (-0.25,+0.47), roxadustat would have needed to achieve an HR of 0.83 just to prove non-inferiority

• The confidence interval for ID-CKD is likely even wider than the CHOIR trial due to

1) ID-CKD patients experiencing more frequent events compared to the stable dialysis patients enrolled in CHOIR and 2) roxadustat’s high dropout rate

Roxadustat’s MACE HR is Inferior to EPO 35

PLAINVIEW

ID-CKD MACE: Not a Primary Safety Endpoint

• We find it highly unlikely that HIF-PH inhibitors can achieve superiority or even

non-inferiority vs. EPO in any setting given the preponderance of clinical evidence from FibroGen, Akebia, and GSK that HIF-PH inhibitors increase MACE risk relative to EPO

• We note that in FibroGen’s prior uncontrolled ID-CKD roxadustat trial, 3% (2/60) of

roxadustat patients experienced MACE events (both deaths) within 12 weeks

• It is far more likely that the “directionally lower MACE risk” is the product of the

higher variance in the ID-CKD pool fueled by more frequent events and a smaller N

• Regardless, the ID-CKD results are insufficient to support an NDA in terms of
• powering. As FibroGen has stated multiple times (including on the most recent

August 8, 2019 Q2 2019 conference call), the NDA is to be submitted for the DD- CKD and NDD-CKD indications– not for ID-CKD

Roxadustat’s MACE HR is Inferior to EPO 36

PLAINVIEW

Point #3: Roxadustat’s MACE HR is Inferior to Placebo

• FibroGen Management refused to disclose the NDD-CKD MACE hazard ratio,

but instead said that under a “conservative” post-hoc intention-to-treat (ITT) analysis, roxadustat achieved non-inferiority

• The difference between standard Kaplan-Meier analysis and ITT analysis is that

Kaplan-Meier censors patients after drug discontinuation while ITT does not

• Evaluating safety using an ITT analysis is the opposite of conservative: ITT

analyses include dropouts who are no longer taking study medication, which dilutes any drug-driven safety signal

• If Management calculated the ITT MACE HR (HR including dropouts), then

Management must have also calculated the primary safety endpoint: the MACE hazard ratio corrected for study dropouts via censoring. We believe FibroGen withheld the primary safety endpoint because roxadustat failed to achieve non- inferiority to placebo

37 Roxadustat’s MACE HR is Inferior to Placebo

PLAINVIEW

NDD-CKD MACE HR Failed to Achieve Non-Inferiority

• Like DD-CKD, FibroGen declined to provide the MACE HR for NDD-CKD. We

chalk this up to roxadustat failing to achieve MACE non-inferiority compared to control

• This is not surprising: if roxadustat could not show MACE non-inferiority to

EPO and EPO is known to increase MACE risk, one would expect that roxadustat would also be inferior to placebo in terms of MACE risk

• FibroGen did not tout a lower event count for roxadustat in NDD-CKD– we

believe this is at least in part because the NDD-CKD placebo dropout rates were closer to roxadustat than the DD-CKD EPO dropout rate (see slide 18), and thus the event count for NDD-CKD was not as skewed by dropouts

Roxadustat’s MACE HR is Inferior to Placebo 38

PLAINVIEW

Intention-To-Treat Vs. Kaplan-Meier

• Instead of providing the actual NDD-CKD MACE HR, FibroGen told investors

that the NDD-CKD ITT MACE HR was non-inferior to placebo

• Intention-to-treat (“ITT”) is typically used for evaluating drug efficacy

(particularly in cancer) in order to avoid survivorship bias in determining how effective a drug is: patients who respond to a drug are more likely to continue taking it than patients who do not respond

• ITT is completely inappropriate for evaluating safety because it dilutes the

safety data by including safety data of patients who are not taking the drug

• The standard method for evaluating safety measures such as MACE is a

Kaplan-Meier (K-M) analysis. K-M analyses accounts for dropouts by censoring them. Patients are included in the safety population until they stop taking the drug after which they are excluded from analysis– because they are no longer taking the drug

Roxadustat’s MACE HR is Inferior to Placebo 39

PLAINVIEW

Roxadustat NDD-CKD NDA Based On K-M HR, Not ITT HR

• On the Q2 2019 call, Management discussed the results of its pre-NDA FDA

meeting (emphasis added): “And in terms of the way that the time to MACE primary endpoint is being analyzed in nondialysis, this will account for differential drop out between our drug and placebo, whereas you know that because placebo doesn't work in treating anemia, placebo patients had a tendency to drop out earlier. And we have reached agreement on statistical method that accounts for that.”

• Management did not mention “ITT” at any point during the Q2 2019 call
• Differential dropout rates are accounted for via Kaplan-Meier censoring; ITT

is diluted by dropouts. Barring some other nonconventional way of accounting for dropouts, this confirms that the NDA will use the conventional Kaplan-Meier analysis MACE HR rather than the ITT MACE HR

Roxadustat’s MACE HR is Inferior to Placebo 40

PLAINVIEW

Roxadustat Clinical Data Summary

• All evidence points to roxadustat producing significantly higher MACE HR

compared to EPO/placebo:  Dropout rate is much higher in roxadustat group vs. EPO group across trials for all HIF-PH inhibitors, pointing to serious safety issues and allowing for lower total event rates and statistically significant inferiority at the same time  Reported MACE rate of 23/983 in roxadustat vs. 1/419 in control  Reported mortality rate of 11/983 in roxadustat vs. 0/419 in  Similar MACE/mortality imbalances in competing HIF-PH inhibitors, indicating class effect  FibroGen Management made misleading statements & refused to disclose actual MACE HRs

Roxadustat’s MACE HR is Inferior to Placebo 41

PLAINVIEW

Point #4: MACE+ Inflated by Prohibiting IV Iron & Using Placebo Comparator

• The principal safety concern for ESAs/HIF-PH inhibitors is increased risk of

thrombosis which manifests as MACE: stroke, myocardial infarction, and death

• The “+” in MACE+ is hospitalizations for congestive heart failure/unstable

angina– which are frequently driven by anemia rather than thrombosis. Looking at MACE+ instead of MACE masks the real risk (potentially fatal blood clots) with temporary symptoms driven by an unrelated cause

• FibroGen prohibited IV iron, a key part of EPO therapy that is not necessary for

HIF-PH inhibitors. Doing so increased anemia in control groups and thus artificially inflated the control group MACE+ rates in the DD-CKD trials

• In the NDD-CKD trials, a placebo comparator combined with the IV iron ban

inflated control group anemia and MACE+ rates

• MACE+ noninferiority will not make regulators overlook clear MACE inferiority

42 MACE+ Inflated by Prohibiting IV Iron & Using Placebo Comparator

PLAINVIEW

EPO Requires IV Iron & Roxadustat Does Not

• Iron is a key component of hemoglobin
• Using exogenous EPO in patients skips

steps of the HIF pathway, including those that enhance iron absorption and transport in the body

• Because iron absorption/transport is not

enhanced in EPO patients, IV iron supplementation is frequently essential in EPO patients to ensure sufficient iron is available for erythropoiesis

• HIF-PH inhibitors (including roxadustat)

drastically reduce the need for IV iron by improving iron absorption/transport

MACE+ Inflated by Prohibiting IV Iron & Using Placebo Comparator 43

PLAINVIEW

Prohibiting IV Iron Inflated Anemia Rate in Control Group

• FibroGen noted in its December 2018 topline press release that

“…roxadustat-treated patients had a 33% reduction in the risk of blood transfusion compared to epoetin alfa (HR=0.67) in the time to first blood transfusion during treatment, p=0.0337.” Note that a 33% reduction in risk in the roxadustat population equates to a ~50% increase in risk in the EPO population (1/.67 = 1.49)

• FibroGen attributes the decreased risk of rescue therapy to roxadustat’s

ability to treat EPO-resistant patients. This claim is wrong– as we show in Point #6 of this presentation, HIF-PH inhibitors do not work in true EPO hyporesponders

• The difference is attributable to the fact that IV iron is a key part of EPO

therapy and it was prohibited (except as rescue therapy) in FibroGen’s trials

MACE+ Inflated by Prohibiting IV Iron & Using Placebo Comparator 44

PLAINVIEW

Prohibiting IV Iron Increases Anemic Events By Reducing EPO Efficacy

• In the roxadustat Phase 2 trial (Provenzano et al 2016), the investigators

prohibited IV iron use in both groups

• The EPO Hb response rate was only 33% compared to 79% Hb response rate in the

high-dose roxadustat group.* However, this trial screened out all EPO hyporesponders prior to randomization–the fact that only 33% of EPO patients in the trial achieved Hb responses is reflective of the impact of prohibiting IV iron, not the efficacy of EPO treatment, and demonstrates that restricting IV iron has a far greater impact on EPO patients than on roxadustat patients

• This demonstrates the enormous impact that prohibiting IV iron has on successful

treatment with EPO: Kharagjitsingh et al 2005 conducted a retrospective study and concluded that the true EPO hypo-response rate is only 3.3% (57/1,677 patients) with an even lower incidence rate of 16.7 per 1,000 patient-years

MACE+ Inflated by Prohibiting IV Iron & Using Placebo Comparator 45

*Roxadustat was dosed at 1.5-2.0 mg/kg in the high-dose group, comparable to roxadustat’s Phase 3 dosing of 100 mg starting dose in patients <60 kg and 120 mg in patients >60 kg)

PLAINVIEW

Anemia Drives CHF/Unstable Angina

• In Bhavanadhar et al 2016, the authors found that 58.2% of patients hospitalized

for unstable angina were experiencing anemia. The authors noted that anemia drives angina and CHF, citing the textbook Clinical Hematology (Wintrobe 2008): “It is well established in patients with known CVD that anaemia has adverse effects on myocardial oxygenation resulting in provocation or acceleration of angina, and may worsen Congestive Heart Failure (CHF).”

• Anemia, unstable angina, and CHF symptoms are all caused by reduced
• xygenated blood flow and present with similar symptoms. They also frequently
• ccur concurrently, making it difficult if not impossible for adjudicators to

distinguish between hospitalization for anemia and hospitalization for angina/CHF unrelated to anemia

MACE+ Inflated by Prohibiting IV Iron & Using Placebo Comparator 46

PLAINVIEW

Anemia Vs. Unstable Angina/CHF

• Symptoms of anemia, unstable angina, and CHF are all very similar and

frequently occur concurrently, raising issues with adjudicating “+” events for MACE+:

MACE+ Inflated by Prohibiting IV Iron & Using Placebo Comparator 47

Dyspnea Fatigue Weakness Edema Chest Pain Dizziness Anemia Unstable Angina CHF

PLAINVIEW

Prohibiting IV Iron Contradicts Real-World Practices

• Macdougall 2017 provides a concise summary of prior trials comparing IV

iron with oral/no iron in patients on EPO and shows that IV iron enhanced Hb responses with lower EPO requirements compared to oral or no iron

• Dosing anemic hemodialysis patients with EPO + IV iron is standard practice:

the USRDS 2018 data report found that in May 2017, 78% of dialysis patients were on EPO and 62% of dialysis patients were on IV iron

• Iron is required to complete erythropoiesis, and prohibiting parenteral iron

paints an unrealistically favorable picture of roxadustat’s relative efficacy

MACE+ Inflated by Prohibiting IV Iron & Using Placebo Comparator 48

PLAINVIEW

Prohibiting IV Iron Inflates EPO Group “+” in MACE+

• GSK has published results for two 24-week trials of its HIF-PH inhibitor

daprodustat vs. EPO: one where IV iron was not restricted (Meadowcroft et al 2018), and one where IV iron was restricted (Holdstock et al 2018)

• MACE rates were higher for daprodustat in both trials, but MACE+ was lower

for daprodustat in the iron-restricted trial. In the iron-restricted trial, 2/170 daprodustat patients reported “+” events vs. 4/80 EPO patients

• In the trial where iron was not restricted, the “+” event rates were similar.

3/177 daprodustat patients reported “+” events vs. 1/39 EPO patients

MACE+ Inflated by Prohibiting IV Iron & Using Placebo Comparator 49

PLAINVIEW

Prohibiting IV Iron Also Forces Increased EPO Dosing

• In its May press release, FibroGen

touted that in one Phase 3 DD-CKD trial, EPO dosing increased by 57% over 52 weeks while roxadustat dosing stayed stable: “In SIERRAS, roxadustat dose requirements remained stable over time, while epoetin alfa dose requirements increased by 57% over 52 weeks in the epoetin arm.”

• This is evidence of the adverse effect of

restricting IV iron on EPO patients;

• ther EPO trials show stable EPO dosing
• ver 52 weeks (and beyond). See right

for the EPO dosing from the CHOIR trial:

MACE+ Inflated by Prohibiting IV Iron & Using Placebo Comparator 50

Source: CHOIR Trial (Singh et al 2006) EPO dosing is stable @ 52 weeks in CHOIR trial while prohibiting IV iron forced a 57% increase in EPO dosing in FibroGen’s SIERRAS trial

PLAINVIEW

Increased EPO Dosing Worsens Event Profile

• In the CHOIR trial,

investigators found that the high Hb group experienced composite events significantly more frequently compared to the low Hb group, with a hazard ratio of 1.34 (1.03 to 1.75)

• Patients in the high Hb

group were, on average, receiving roughly double the EPO dose of the low Hb group (see prior slide)

MACE+ Inflated by Prohibiting IV Iron & Using Placebo Comparator 51

Source: CHOIR Trial (Singh et al 2006)

PLAINVIEW

MACE is Principal Measure of Safety

• FibroGen’s MACE+ results are a red herring driven by FibroGen’s decisions to

1) prohibit patients from using parenteral iron and 2) use placebo comparators in the NDD-CKD trials, which artificially inflated the anemia rates in the control groups and thus control group MACE+ rates

• The primary concern with EPO and HIF-PH inhibitors is that they can cause

thrombosis leading to MACE; the “+” in MACE+ is particularly irrelevant to this given FibroGen’s trial protocol

• We note that the primary safety endpoint for the FDA NDA is MACE and on
• p. 47 of its Q2 2019 10-Q, FibroGen (for the first time) disclosed that the

EMA will be reviewing MACE as well

• The entire point of a primary safety endpoint is to weed out unsafe drugs–

MACE inferiority would show that roxadustat is not safe regardless of MACE+

MACE+ Inflated by Prohibiting IV Iron & Using Placebo Comparator 52

PLAINVIEW

Point #5: HIF-PH Inhibitor Mechanism of Action is Flawed

• EPO is part of the HIF pathway and lies downstream from HIF. HIFs have been

shown to induce hypertension, fibrosis, immune suppression, and other adverse effects through EPO-independent mechanisms

• HIF-PH inhibitors are flawed compared to EPO because EPO is highly specific to

erythropoiesis and HIFs are not

• The pro-HIF-PH inhibitor theory is that administering HIF-PH inhibitors lowers

total EPO exposure, which improves safety. The anti-HIF-PH inhibitor thesis is that the pleiotropic effects of HIFs are more dangerous than higher EPO exposure

• The large MACE & mortality imbalances and higher dropout rates in published

HIF-PH inhibitor trial data show that HIFs’ problematic effects vastly outweigh lower systemic exposure to EPO

53 HIF-PH Inhibitor Mechanism of Action is Flawed

PLAINVIEW

Review: The HIF-EPO Pathway

• Under normal conditions

(normoxia), HIF-α (HIF-1α and HIF- 2α) is eliminated via ubiquitination by the Von Hippel Lindau E3 ligase (VHL) after being tagged by prolyl hydroxylase domain-containing proteins (PHD)

• Under hypoxic conditions, HIF-

PHDs cease to function, which allows for HIF-α to enter the nucleus and activate gene transcription: mimicking this by blocking PHDs is the intended mechanism of action of roxadustat and other HIF-PH inhibitors

HIF-PH Inhibitor Mechanism of Action is Flawed 54

Source: Chen & Lou 2017

PLAINVIEW

Review: The HIF-EPO Pathway

• With the inhibition of HIF-

PHs, HIF stimulates transcription of target genes

• In addition to the ESA

(EPO) and iron homeostasis genes in the diagram, HIF-α (HIF-1α & HIF-2α) also activates transcription of other genes that serve no purpose in erythropoiesis

• These include genes

linked to hypertension, fibrosis, and other adverse effects

HIF-PH Inhibitor Mechanism of Action is Flawed 55

Source: FibroGen presentation

PLAINVIEW

Hypoxia Induces Hypertension

• Patients with sleep apnea (a disorder where breathing repeatedly stops and

starts while the patient is sleeping) are exposed to repeated hypoxia and

• ffer insight into the effects of chronic activation of the HIF pathway
• Studies identify sleep apnea as a major contributor to increased risk of

hypertension and MACE:

• Peppard et al 2000 found a dose-response association between hypoxic events and

hypertension in sleep apnea patients

• Lin et al 2017 compared outcomes for 2,699 patients with obstructive sleep apnea

(OSA) and 13,490 non-OSA patients, and found that the MACE incidence rate was 1.95-fold in OSA patients compared to non-OSA

• Yacoub et al 2018 estimated the prevalence of sleep apnea in drug-resistant

hypertension at 80%

HIF-PH Inhibitor Mechanism of Action is Flawed 56

PLAINVIEW

HIF-1α is Implicated in Hypertension

• Yamashita et al 2001: HIF-1α binds to an ET-1 promoter, which activates ET-1

expression in endothelial cells. ET-1 acts as a potent vasoconstrictor, and is linked to hypertension & heart failure progression

• Diebold et al 2010: HIF-1α activates NOX4 gene, which leads to increased reactive
• xygen species and pulmonary arterial smooth muscle cells which have been

implicated in pulmonary hypertension

• Eckle et al 2014: HIF-1α is a transcriptional regulator of the A2B adenosine

receptor (ADORA2B) which modulates development of pulmonary hypertension by mediating the release of hyaluronan, an extracellular matrix component implicated in development of pulmonary hypertension

• Nanduri et al 2015: HIF-1α upregulation leads to a transcriptional imbalance

favoring pro-oxidant genes, and those genes drive increased generation of reactive

• xygen species which cause hypertension

HIF-PH Inhibitor Mechanism of Action is Flawed 57

PLAINVIEW

HIF-2α is Implicated in Pulmonary Hypertension

• Cowburn et al 2016: The rise in right ventricular systolic pressure (RVSP) normally
• bserved following chronic hypoxic exposure was absent in mice with pulmonary

endothelial HIF-2α deletion without affecting hypoxic Hb response, implicating HIF-2α

• Kapitsinou et al 2016: Inactivation of PHD2 (a target of roxadustat and other HIF-

PH inhibitors) led to a 118% increase in right ventricular systolic pressure, and the development of pulmonary hypertension was dependent on HIF-2α

• Bryant et al 2016: Deletion of HIF in mice protected them from development of

pulmonary hypertension following induction of lung fibrosis via bleomycin. HIF deletion also protected mice from pulmonary hypertension following chronic hypoxia

• Dai et al 2016: Removing PHD2 (HIF-PH inhibitor target) from mice led to severe

HIF-2α-mediated pulmonary arterial hypertension, with 12/15 mice dying within 5 months vs. 0/15 control mice

HIF-PH Inhibitor Mechanism of Action is Flawed 58

PLAINVIEW

HIFs & HIF-PHis are Implicated in Fibrosis

• Higgins et al 2004: HIF-1α induces CTGF transcription, which may mediate

pro-fibrotic effects of TGF-β1

• Higgins et al 2007: HIF-1α leads to fibrosis by stimulating epithelial-to-

mesenchymal transition by upregulating lysyl oxidase genes and increasing expression of extracellular matrix modifying factors

• Ueno et al 2011: TGF-β1 upregulates 58 genes through an HIF-1α-dependent

mechanism, including pro-fibrotic genes such as PAI-1

• Baumann et al 2016: HIF-1α stimulates COL1A2 transcription which is

implicated in renal fibrosis. HIF-1α knockout conferred renal protection to mice

• Li et al 2019: HIF-PH inhibition led to tubulointerstitial fibrosis via HIF-1α-

induced transcription of KLF5 which promotes fibrosis via TGF-β1

HIF-PH Inhibitor Mechanism of Action is Flawed 59

PLAINVIEW

HIF-1α Implicated in Atherosclerosis through Multiple Pathways

• Gao et al 2012

postulated that HIF- 1α is involved in the development of atherosclerosis via multiple pathways (see diagram)

HIF-PH Inhibitor Mechanism of Action is Flawed 60

Source: Gao et al 2012

PLAINVIEW

HIF-PH Inhibition Has Many Off-Target Effects

• Prolyl-hydroxylase domains

are not exclusive to regulating HIFs: Strowitzki et al 2019 summarizes other prolyl hydroxylase targets that would be impacted by HIF-PHis, including NF-κB (via IKKb), p53, FOXO3a, MAPK6, Cep192, and ZHX2. The authors note that “hundreds

• f genes have been reported

to be sensitive to hypoxia.”

HIF-PH Inhibitor Mechanism of Action is Flawed 61

Source: Strowitzki et al 2019

PLAINVIEW

…And Roxadustat/HIF-PHis Aren’t Even Specific to HIF-PHs

• HIF-PH inhibitors (roxadustat in particular) are not specific to the HIF-PHs:

Kiriakidis et al 2017 found that dosing mice with 10 mg/kg roxadustat led to a 50% decline in C1q secretion, negatively impacting immune responses.

• The authors concluded that this was likely due to roxadustat also inhibiting

the collagen prolyl-4-hydroxylases, which are necessary for formation of C1q

HIF-PH Inhibitor Mechanism of Action is Flawed 62

PLAINVIEW

HIF-PH Inhibition Suppresses Innate Immune System

HIF-PH Inhibitor Mechanism of Action is Flawed 63

3,4-DHB is an HIF-PH inhibitor. Administration of 3,4-DHB in septic (CLP or PCI) mice led to significantly worse survival outcomes compared with control

• Kiriakidis et al 2017 also noted that the study Schindler et al 2016 found that HIF-

PH inhibition in septic mice led to significantly higher mortality rates. This is likely a product of the HIF-PHi-induced immune suppression via C1q suppression (see prior slide):

PLAINVIEW

Other Adverse Effects of HIFs

• Cheng et al 2014 concluded that HIF-1α collaborates with Notch-1 to induce

neuronal death in ischemic strokes, and that inhibiting HIF-1α decreased neuronal death

• While companies developing HIF-PH inhibitors have not admitted to any pro-
• ncogenic safety signals, HIF is also strongly implicated in cancer
• It has also been shown that HIF-1α and HIF-2α expression in tumors is associated with

worse progression-free survival and overall survival

• Peloton Therapeutics’ HIF-2α inhibitor PT2385 produced a 22% monotherapy ORR in

2L+ ccRCC patients while its HIF-2α inhibitor PT2977 produced a 24% ORR in 2L+ mRCC patients

HIF-PH Inhibitor Mechanism of Action is Flawed 64

PLAINVIEW

HIF Exposure Greatly Outweighs Reduced EPO Exposure

• There are likely multiple factors driving the imbalance in deaths, MACE and

dropout rates between HIF-PH inhibitors and EPO

• The pro-roxadustat/HIF-PH inhibitor thesis is that EPO exposure is the

principal culprit in deaths/MACE in both EPO and HIF-PH inhibitor patients and HIF-PH inhibitors can achieve equivalent increases in Hb with lower EPO exposure; therefore, HIF-PH inhibitors should reduce MACE risk

• The dramatic MACE/death imbalance seen in clinical data showed that this

theory was wrong. The consistently higher dropout rate in the HIF-PH inhibitor groups across trials also pose additional safety concerns, and the real-world safety difference is even greater than FibroGen’s trials suggest due to FibroGen’s disingenuous decision to prohibit IV iron, which inflated EPO dosing in the control group far beyond where it would have been under real-world conditions

HIF-PH Inhibitor Mechanism of Action is Flawed 65

PLAINVIEW

Point #6: Roxadustat Does Not Work in EPO Hyporesponders

• FibroGen references two pieces of evidence to show that roxadustat can

adequately treat EPO hyporesponders. Both are misleading and wrong:

• Provenzano et al 2016 showed that roxadustat seemed to have similar impact on patients

regardless of CRP levels, with the implicit assumption that CRP is the key determinant of EPO

• hyporesponsiveness. The problem is that Provenzano 1) screened out EPO hyporesponders

during enrollment and 2) did not include the roxadustat non-responders (16%, 9/58) in the

• analysis. The only real takeaway is that roxadustat works in 100% of the subgroup that

roxadustat works in

• In multiple studies, roxadustat patients achieved higher Hb levels compared to EPO patients.

This was a result of FibroGen prohibiting use of IV iron, a critical part of EPO therapy– not of superior efficacy. Competitor HIF-PH inhibitor trials permitting IV iron showed no difference in Hb

• GlaxoSmithKline conducted a study of its HIF-PH inhibitor daprodustat among

EPO-hyporesponsive patients, and found that daprodustat produced no Hb response in those patients. This is likely true for the entire HIF-PH inhibitor class

66 Roxadustat Does Not Work in EPO Hyporesponders

PLAINVIEW

FibroGen’s EPO Hyporesponse Theory

• Inflammation drives an increase in hepcidin, which binds to ferroportin and thus

suppresses absorption and extracellular release of iron

• HIFs are known to decrease hepcidin levels; this improves iron transport for

patients

• The theory presented by FibroGen is that the principal cause of EPO

hyporesponsiveness is inflammation limiting iron absorption and transportation, and using HIF-PH inhibitors helps combat this by decreasing hepcidin levels and increasing iron absorption/transport

• FibroGen’s principal support for this theory comes from Provenzano et al 2016,

where the authors measured inflammation based on C-reactive protein (CRP) levels and used CRP as a proxy for EPO hyporesponsiveness. The theory is that inflammation (high CRP) causes EPO hyporesponse, so therefore if roxadustat works in patients with high CRP levels, then this means it will work in EPO

• hyporesponders. As we show, the study was extremely misleading and wrong

Roxadustat Does Not Work in EPO Hyporesponders 67

PLAINVIEW

Problem #1: Provenzano Excluded Roxadustat Non-Responders

• There are two problems with the Provenzano et al 2016 analysis: first, the

authors excluded all the patients who discontinued roxadustat due to lack of efficacy:

Roxadustat Does Not Work in EPO Hyporesponders 68

Excluding patients for lack of efficacy makes the subsequent declaration that CRP levels do not affect roxadustat efficacy completely meaningless– of course roxadustat works for all patients after excluding the 16% of patients it did not work for!

PLAINVIEW

Problem #2: Provenzano Excluded EPO Hyporesponders from Enrolling

• The second problem is that EPO hyporesponders were explicitly excluded

from the trial!

• From the S1 Supplement to Provenzano 2016:

Roxadustat Does Not Work in EPO Hyporesponders 69

Hard to conclude that a drug works in EPO hyporesponders when EPO hyporesponders are excluded from enrolling in the trial

PLAINVIEW

HIF-PH Inhibitors Do Not Work in EPO-Hyporesponsive Patients

• GlaxoSmithKline conducted an

intellectually honest study of its HIF-PH inhibitor daprodustat among erythropoietin- hyporesponsive patients, and saw no change in Hb after transitioning EPO-hyporesponsive patients to daprodustat

Roxadustat Does Not Work in EPO Hyporesponders 70

Source: Cizman et al 2018 Virtually no change in Hb at all time points

PLAINVIEW

Iron-Mediated EPO Hyporesponses Already Solved…With IV Iron

• The need for HIF-PH inhibitors to modulate iron transport is an invented

problem: the iron transport problem has already been solved with IV iron, which leaves no benefit to using HIF-PH inhibitors except in FibroGen’s unrealistic trials where patients are denied IV iron except as emergency rescue therapy

• IV iron avoids the problems with iron transport/absorption by putting the

iron directly into the bloodstream. Ueda & Takasawa 2018 conducted a meta-analysis of nine studies comparing use of IV iron and oral iron in anemic CKD patients, and concluded that “One of the reasons accounting for superiority of IIT [IV iron therapy] over OIT [oral iron therapy] to maintain tHb [target Hemoglobin] in CKD patients may be the difference in the efficacy of IIT and OIT in CKD patients in the presence of concomitant inflammation that increases ferritin and hepcidin.”

Roxadustat Does Not Work in EPO Hyporesponders 71

PLAINVIEW

Higher Hb Levels in Roxadustat Group Due to Study Design, Not Efficacy

• Another part of FibroGen’s roxadustat pitch is that roxadustat is capable of

achieving higher Hb levels than EPO

• In reality, this appears to be driven by the previously-discussed decision to

prohibit IV iron rather than efficacy

• For instance, in Provenzano 2016, the authors concluded that the Hb

responder rate for the EPO group was 33% compared to 79% for the pooled high-dose roxadustat group. This doesn’t make sense at all considering that the supplement to Provenzano 2016 (relevant graphic on slide 69) showed that EPO hyporesponders were already screened out of the trial– unless the EPO hyporesponses were driven by prohibition of IV iron

Roxadustat Does Not Work in EPO Hyporesponders 72

PLAINVIEW

Competitor Trials Show HIF-PHi & EPO Hb Responses Are Similar

• Examining competitors’ long-term DD-CKD trials, we see no meaningful

difference between Hb levels achieved in drug vs. control groups (see below table). Roxadustat utilizes the same mechanism of action and we believe the claimed benefit is primarily a function of FibroGen suppressing the results of the EPO group by withholding IV iron

Roxadustat Does Not Work in EPO Hyporesponders 73

PLAINVIEW

Pamrevlumab

PLAINVIEW

Pamrevlumab Table of Contents

❑ Pamrevlumab Background: Lots of Trials, Few Results ❑ CTGF is a Biomarker, Not a Principal Mediator ❑ No Value in IPF Even If Phase 3 Trial Succeeds

• FibroGen withheld results from a trial comparing pamrevlumab + SoC vs. placebo + SoC,

indicating that the trial likely failed. This means that pamrevlumab offers no additive benefit to SoC which is likely going generic before pamrevlumab could possibly make it to market

• We have concerns about pamrevlumab’s efficacy and Management appears to share our

concerns: FibroGen only initiated a single Phase 3 despite long trial duration (4+ years expected) and a precedent that clearly shows two Phase 3 trials are required for approval. At best, pamrevlumab will get approval for IPF in 9-10 years

❑ No Evidence Pamrevlumab Works in DMD

• Provided virtually no data during recent presentation given 3.5 years after initiating trial

❑ Pamrevlumab Doesn’t Work in Pancreatic Cancer

• FibroGen’s pancreatic cancer trial results showed no difference in ORR between

pamrevlumab and control. PFS and OS were withheld, and the claimed resection benefit is wildly misleading

• Targeting the stroma has already been tried via hedgehog inhibitors and has failed

75

PLAINVIEW

Pamrevlumab Background

• Previously known as FG-3019
• Currently in development for Duchenne muscular dystrophy (DMD), locally

advanced pancreatic cancer (LAPC), and idiopathic pulmonary fibrosis (IPF)

• Was previously in development for diabetic nephropathy, focal segmental

glomerulosclerosis (FSGS), and Hepatitis B

• Paucity of published clinical data despite 16 years in the clinic
• Currently in Phase 3 trials for IPF and LAPC
• LAPC Phase 3 trial expected to reach primary completion in September 2022
• IPF Phase 3 trial expected to reach primary completion in March 2023

76 Pamrevlumab Background

PLAINVIEW

Lots of Trials, Few Results Over 16 Years

• December 2003: Phase 1 in IPF posted
• January 2005: Phase 1 in diabetic nephropathy initiated
• March 2008: Phase 1 for pamrevlumab in diabetes mellitus & diabetic

nephropathy initiated

• April 2008: Phase 1 trial in FSGS initiated
• December 2008: Phase 1 trial in pancreatic cancer initiated
• February 2009: Phase 2 RCT in CKD initiated (terminated)
• August 2010: Phase 2 RCT in Hepatitis B initiated (terminated)
• March 2011: Phase 2 for IPF initiated
• July 2014: Phase 1/2 controlled trial for pancreatic cancer initiated
• November 2015: Phase 2 trial in DMD initiated
• May 2019: Phase 3 trial in locally advanced pancreatic cancer initiated
• June 2019: Phase 3 trial in IPF initiated

Pamrevlumab Background 77

PLAINVIEW

Management’s Sleaziness Permeates Into Pamrevlumab

• In a February 2016 investor call, Fibrogen Management told investors that they were

“encouraged” by Phase 2 results for pamrevlumab for liver fibrosis resulting from Hepatitis B and implied that pamrevlumab was reversing fibrosis: “The result showed a trend for dose response improvement in liver fibrosis at doses of FG- 3019 similar to those now being tested in other diseases. We are encouraged by these results, and we continue to evaluate options for trial of FG-3019 in subjects with advanced liver fibrosis due to NASH. In addition, we are evaluating the potential for trial of FG-3019 in subjects with advanced liver fibrosis due to hepatitis C, where it appears that the fibrosis may not resolve after cure of the hepatitis with current potent anti-viral therapy.”

• In reality, Management had already prematurely terminated the HBV trial in June 2015

for futility (note that the primary completion date is June 2015)-- eight months before claiming to be “encouraged” by the results. The promised additional trials in HBV/HCV/NASH never came to fruition

• Management also ran a six-month Phase 2 trial in diabetic nephropathy and terminated

the trial 18 months later (January 2011)– after the scheduled primary completion date. No results or explanation for termination were ever given outside of the termination being a “strategic decision”. Diabetic nephropathy is an enormous indication, so this strategic decision was likely driven by lack of efficacy

Pamrevlumab Background 78

PLAINVIEW

Lots of Trials, Few Results

• Pancreatic Cancer: FibroGen issued a press release touting that 33.3% of

pamrevlumab patients achieved clinical resection compared to 7.7% of control, a meaningless product of data-mining. The PR left out the fact that ORR was 23% in the control group compared to 21% in the pamrevlumab group which was published in an ASCO 2018 poster. PFS and OS data were never published

• DMD: In a bizarre presentation at PPMD 2019, FibroGen avoided disclosing

efficacy endpoints in the uncontrolled trial– instead only stating that certain endpoints performed better than cherry-picked publications

• IPF: As part of the PRAISE trial, FibroGen conducted an RCT comparing

pamrevlumab + standard-of-care vs. placebo + standard-of-care. No efficacy results were ever announced or published. This trial is key because it informs whether pamrevlumab adds any benefit to standard-of-care, which is expected to go generic before pamrevlumab could possibly make it to market

Pamrevlumab Background 79

PLAINVIEW

Point #1: CTGF is a Biomarker, Not a Principal Mediator

• FibroGen paints connective tissue growth factor (CTGF) as the principal cause of

fibrosis; most other research implicates TGF-β1 as the master regulator of fibrosis and research papers and primers on the subject pay little attention to CTGF

• In drug development, validated targets are quickly copied; often before they are

even proven in humans. Pamrevlumab has been in the clinic for 16 years with no imitators. Many drug developers are targeting fibrotic diseases but outside

• f FibroGen, none are targeting CTGF
• While we don’t dispute that CTGF mediates some effects, we believe its impact

is not clinically significant and that CTGF is more of a biomarker of fibrosis than a key driver of fibrosis

80 CTGF is a Biomarker, Not a Principal Mediator

PLAINVIEW

What is CTGF?

• CTGF is an extracellular matrix protein (“ECM”) and “connective tissue

growth factor” is a misnomer: “the name CTGF (connective tissue growth factor)…implies activities and a mechanism of action akin to those of classical growth factors, a notion that has not been supported by experimental evidence to date.” (emphasis added, Chen & Lau 2009)

• Fibrosis involves the growth and proliferation of many ECM proteins and

CTGF is only one of them

• Pamrevlumab’s lack of monetizable or even decisive clinical results after 16

years of trials suggests that the impact of targeting CTGF is simply not meaningful for patients suffering from fibrosis

• Based on published research, we believe that CTGF is more of a biomarker of

fibrosis and pancreatic cancer than a valid target with clinical value

CTGF is a Biomarker, Not a Principal Mediator 81

PLAINVIEW

How FibroGen Describes CTGF (Central Mediator of Fibrosis)

CTGF is a Biomarker, Not a Principal Mediator 82

Source: FibroGen 2010 Publication

PLAINVIEW

How Fibrosis Researchers Describe CTGF (They Don’t)

• CTGF is not thought to be

a principal cause of fibrosis and is rarely discussed meaningfully in publications not sponsored by FibroGen. To the right is an illustration of the fibrotic pathway taken from Meng et al 2016; CTGF is nowhere to be found.

CTGF is a Biomarker, Not a Principal Mediator 83

PLAINVIEW

Point #2: No Value in IPF Even If Phase 3 Trial Succeeds

• We question whether pamrevlumab will succeed in its IPF Phase 3 trial given that:
• Pamrevlumab showed no dose response in IPF
• It is not clear why pamrevlumab would work in IPF after failing in other fibrotic indications
• As part of the PRAISE trial, FibroGen conducted an RCT comparing pamrevlumab + SoC vs.

placebo + SoC in IPF which concluded in 2017– and never announced or published the efficacy results, a near-certain sign that pamrevlumab added no benefit to SoC. This likely informed the decision to prohibit use of SoC as background therapy in the Phase 3 trial

• The lack of additive benefit to SoC makes pamrevlumab an impossible sell even assuming

Phase 3 success:

• Pamrevlumab offers no value. At least one of the current SoCs is widely expected to go generic before

pamrevlumab makes it to market. With no head-to-head or combination therapy data, there is no reason for payors to cover pamrevlumab as an alternative or for anyone to prescribe it

• Pamrevlumab is less convenient. Pamrevlumab requires Q3W IV administration compared to QD oral
• dosing. Patients are more likely to prefer daily oral dosing
• Management’s decision to only run a single four-year Phase 3 trial now when two Phase 3s

are required for approval indicates that Management shares our skepticism about IPF

84 No Value in IPF Even if Phase 3 Trial Succeeds

PLAINVIEW

No Pamrevlumab Dose Response in IPF

• The lines, p-value, and blue

shading FibroGen drew into the graph are lipstick on a pig: anyone can look at this graph and plainly tell that there is virtually no relationship between change in Forced Vital Capacity (FVC; measure of lung volume) and drug concentration.

No Value in IPF Even if Phase 3 Trial Succeeds 85

Source: FibroGen September 13, 2017 8-K

PLAINVIEW

Missing Trial Results Likely Due to Missing Efficacy

• FibroGen conducted an RCT comparing pamrevlumab +

pirfenidone/nintedanib compared to placebo + pirfenidone/nintedanib. It was a 24 week study with an additional 4-10 weeks of screening/follow-up. Enrollment completed on December 16, 2016, and the trial should have concluded in mid-2017

• The efficacy endpoint results were never disclosed, indicating that

pamrevlumab did not offer any benefit to patients over placebo

• This likely informed the Phase 3 trial design in which FibroGen decided to

prohibit use of pirfenidone/nintedanib as background therapy

No Value in IPF Even if Phase 3 Trial Succeeds 86

PLAINVIEW

Prohibiting Standard-of-Care is Blatantly Unethical

• There is strong evidence that pirfenidone (and to a lesser extent, nintedanib)

significantly increases survival for IPF patients. It is unethical to enroll a placebo group where patients are denied access to these drugs. This will make it very challenging to fully enroll the trial and we think it is very likely that FibroGen’s first Phase 3 trial will take significantly longer than the estimated four years to reach the primary endpoint

• Nathan et al 2017 conducted a pooled analysis of pirfenidone Phase 3 trials

and found that the all-cause mortality hazard ratio for pirfenidone was 0.52 (0.31, 0.87)

• Lancaster et al 2019 conducted a pooled analysis of nintedanib Phase 2/3

trials and found that the all-cause mortality hazard ratio for nintedanib was 0.70 (0.46, 1.08)

No Value in IPF Even if Phase 3 Trial Succeeds 87

PLAINVIEW

Generic IPF Competition

• It is very likely that pirfenidone, nintedanib, or both will be generic by the

time the first pamrevlumab Phase 3 trial concludes

• Paragraph IV filings have been submitted for both pirfenidone and

nintedanib

• At least one company has submitted a Paragraph IV filing for nintedanib
• Pirfenidone is particularly vulnerable, as the composition of matter patent

covering the drug has long been expired. At least 18 generic manufacturers have filed Paragraph IVs for pirfenidone, including:

No Value in IPF Even if Phase 3 Trial Succeeds 88

• Laurus Labs
• Aurobindo
• Lupin
• Micro Labs
• Apotex
• Granules Pharmaceuticals
• Alembic Pharmaceuticals
• Hetero Labs
• Amneal Pharmaceuticals
• Torrent Pharmaceuticals
• Teva
• Accord Healthcare
• Macleods Pharmaceuticals
• Cipla
• Aizant Drug Research Solutions
• Shilpa Medicare
• Scigen Pharms
• Sandoz

PLAINVIEW

Phase 3 Trial Design is Clinically Irrelevant

• While using a placebo control group makes it much easier for pamrevlumab

to show benefit, it also makes the results clinically irrelevant

• Competing IPF drugs in Phase 3 (PRM-151 and GLPG1690) are testing for

efficacy in combination with pirfenidone/nintedanib: without proving superiority or additive benefit to those drugs, there is no selling point

No Value in IPF Even if Phase 3 Trial Succeeds 89

PLAINVIEW

GLPG1690 Effective in Small IPF Study

• GLPG1690 is an oral autotaxin inhibitor. Galapagos theorizes that autotaxin

production of lysophosphatidic acid has a pathogenic role in IPF, and that inhibiting autotaxin could slow IPF progression

• The FLORA trial was a Phase 2a study in which Galapagos enrolled 23

patients (17 in GLPG1690 group, six in control group)

• GLPG1690 achieved a mean increase in FVC of 25 mL compared to a -70 mL

decline in FVC in the control group (Maher et al 2018, ppFVC not provided)

• While the FLORA trial excluded patients on pirfenidone/nintedanib, the two

Phase 3 trials (ISABELA1 and ISABELA2) are enrolling patients on background pirfenidone/nintedanib therapy

No Value in IPF Even if Phase 3 Trial Succeeds 90

PLAINVIEW

PRM-151 Succeeded in IPF With Background Therapy

• PRM-151 is recombinant human serum amyloid P, and the theory behind its

use in fibrosis is that PRM-151 can prevent differentiation of cells into M2- macrophages and fibrocytes, reducing fibrosis in patients

• The Phase 2 results for PRM-151 (Raghu et al 2018) show that it produced a

statistically significant benefit in ppFVC in patients allowed background pirfenidone/nintedanib, with 48% lower decline in ppFVC over 28 weeks (- 2.5% vs -4.8%, p = 0.001)

• 78% of enrolled patients were receiving concurrent pirfenidone or

nintedanib

• 95% (74/78) of PRM-151 patients completed treatment compared to 95%

(37/39) of control patients and SAEs occurred in 8% of PRM-151 patients and 10% of control patients, indicating that the drug was well-tolerated

No Value in IPF Even if Phase 3 Trial Succeeds 91

PLAINVIEW

Needs Two Phase 3 Trials For Approval…Only Running One

• As is clear from precedents pirfenidone/nintedanib and GLPG1690, two

pivotal trials are required for IPF approval. FibroGen is only running one: the ZEPHYRUS trial

• Galapagos is running two concurrent Phase 3 trials (ISABELA1 and ISABELA2) for

GLPG1690

• InterMune conducted three Phase 3 trials for pirfenidone in IPF (one of which failed

to achieve primary efficacy endpoint)

• Boehringer Ingelheim conducted two Phase 3 trials for nintedanib in IPF
• Running a single trial now implies that Management will wait for that trial to

read out before deciding on a second Phase 3 trial. A projected 2023 initial Phase 3 readout and a 4-year estimated trial timeline puts earliest potential FDA approval for pamrevlumab in IPF at nearly a decade from today

• The decision to only run one trial in the face of multiple competitors speaks

to a major lack of confidence in pamrevlumab’s IPF prospects

No Value in IPF Even if Phase 3 Trial Succeeds 92

PLAINVIEW

Point #3: No Evidence Pamrevlumab Works in DMD

• FibroGen presented “preliminary” results of its uncontrolled Phase 2

Duchenne’s Muscular Dystrophy (DMD) study at PPMD on June 28, 2019

• The trial began recruiting in November 2015 and enrollment was completed in

April 2018. All patients had been enrolled >1 year by June 2019

• Virtually no actual data was shared in the presentation. FibroGen instead

shared abstract comparisons with historical precedents without revealing actual trial datapoints from the pamrevlumab DMD trial in an apparent attempt to imply efficacy without proving efficacy

93 No Evidence Pamrevlumab Works in DMD

PLAINVIEW

Primary Endpoint & Most Secondary Endpoints Not Disclosed

• The trial description for pamrevlumab in DMD lists a primary endpoint

(annual change in FVC) and 12 secondary endpoints

• FibroGen did not disclose the primary endpoint change– other than to say

that change in ppFVC was higher than the change in ppFVC seen in a selected prior DMD publication

• Only two of the 12 secondary endpoints were disclosed (LVEF and change in

performance of upper limbs), though other metrics were said to be higher or lower than arbitrary historical precedents

• If the data were favorable, FibroGen would have shared it instead of making

abstract comparisons with favorable historical precedents and withholding numerical data. All patients had been enrolled in the trial >1 year as of April 2019; there should have been ample data to share in June 2019

No Evidence Pamrevlumab Works in DMD 94

PLAINVIEW

Cherry-Picking Example

• It’s been known since 1989 (see Mendell et al 1989) that glucocorticoid

steroid treatment delays muscle loss and the onset of respiratory decline in DMD patients

• In FibroGen’s trial, 100% of the patients were given steroids (see Slide 7 of

the PPMD presentation)

• FibroGen compared its ppFEV1 endpoint with the DELOS trial publication

(Meier et al 2017), a trial in which patients were prohibited from taking glucocorticoids

• Cross-trial differences such as baseline characteristics and background

medications make the comparisons FibroGen provided completely meaningless

No Evidence Pamrevlumab Works in DMD 95

PLAINVIEW

Point #4: Pamrevlumab Doesn’t Work in Pancreatic Cancer

• FibroGen’s ASCO 2018 poster showed that patients in the pamrevlumab arm

achieved a 20.8% (5/24) ORR vs. 23.1% (3/13) ORR in the control arm

• “Eligibility for surgical resection” is not a valid primary endpoint and FibroGen’s

focus on the metric is classic data-mining misdirection in a small-N trial. Legitimate endpoints are ORR, PFS, and OS. PFS and OS were listed among the trial efficacy endpoints, but were conspicuously absent from all disclosures indicating that, like ORR, pamrevlumab showed no benefit in PFS and OS

• A large meta-analysis (Gillen et al 2010) showed a near-identical rate of surgical

resection following chemotherapy as pamrevlumab + chemotherapy achieved in FibroGen’s trial (33.2% vs 33.3%) – cementing that it is highly unlikely pamrevlumab offers any benefit

• The scientific thesis behind using pamrevlumab in pancreatic cancer (targeting

the stroma) has been tried multiple times in pancreatic cancer and never succeeded

96 Pamrevlumab Doesn’t Work in Pancreatic Cancer

PLAINVIEW

Clinical Data Shows No ORR Benefit in Pancreatic Cancer

• The RECIST ORR was 20.8% (5/24) in the pamrevlumab arm and 23.1%

(3/13) in the control arm, as shown in FibroGen’s ASCO 2018 poster

• ORR is especially significant considering that the trial enrolled patients with

localized pancreatic cancer– if a drug doesn’t appear to have an additive impact on the target tumor in a localized cancer then it is almost certainly accomplishing nothing

• PFS and OS were listed among the efficacy endpoints but were never

disclosed, strongly indicating that, like ORR, pamrevlumab showed no benefit in PFS or OS

• Instead of disclosing ORR/PFS/OS in its press release, FibroGen only

disclosed the proportion of patients who achieved surgical resection in the trial for each group: a blatant attempt at data mining to misdirect investors

Pamrevlumab Doesn’t Work in Pancreatic Cancer 97

PLAINVIEW

Resection Rate On Par With Historical Precedent

• In the Phase 1/2 pancreatic cancer trial, resection was achieved in 33.3%

(8/24) of the pamrevlumab group patients compared to 7.7% (1/13) of control group

• Gillen et al 2010 conducted a meta-analysis of 111 studies (n=4,394) and

found that among pancreatic cancer patients who were initially deemed non-resectable, 33.2% received resection following chemotherapy– nearly identical to the 33.3% achieved in the pamrevlumab trial

• We also note that FibroGen’s ASCO poster indicates that none of the three

patients in the control arm who saw RECIST responses were deemed eligible for resection. This seems unlikely unless the RECIST responses were significant enough that resection no longer made sense for those patients– in which case the resection rate in the control group is ironically obscured by efficacy

Pamrevlumab Doesn’t Work in Pancreatic Cancer 98

PLAINVIEW

FibroGen’s Pancreatic Cancer Theory

• The theory behind combining

pamrevlumab with chemotherapy is that the reason outlook is so bleak for pancreatic cancer patients is because the exceptionally dense extracellular matrix associated with pancreatic cancer blocks a chemotherapeutic or immune response in those patients

• However, it is widely thought that

the principal culprit behind the enhanced ECM is a constitutively active hedgehog signaling pathway, not CTGF

Pamrevlumab Doesn’t Work in Pancreatic Cancer 99

Source: Stromal biology and therapy in pancreatic cancer

PLAINVIEW

Prior Attempts to Target Stroma in Pancreatic Cancer Have Failed

• Given that the hedgehog pathway is thought to be the principal driver of

pancreatic cancer stroma growth, prior drugs have attempted to disrupt the hedgehog pathway with hedgehog inhibitors

• All of them have failed in the clinic:
• Vismodegib (GDC-0449): Showed no benefit in ORR, PFS, or OS in an N=106 RCT trial

presented at ASCO 2013

• Saridegib (IPI-926): Company halted pancreatic cancer trial prematurely after

preliminary interim analysis showed a “difference in survival favoring the placebo plus gemcitabine arm due to a higher rate of progressive disease in the saridegib plus gemcitabine arm.”

• M402: Pancreatic cancer trial was terminated following interim futility analysis

Pamrevlumab Doesn’t Work in Pancreatic Cancer 100

PLAINVIEW

Concluding Thoughts & Looking Forward

PLAINVIEW

Concluding Thoughts – Roxadustat

• The problem with HIF-PH inhibitors is that they are not as specific to

erythropoiesis as EPO and have potent off-target effects

• Clinical data supports this, with higher MACE, mortality, and dropout rates

reported across the board for roxadustat, vadadustat, and daprodustat

• We believe roxadustat missed the primary safety endpoints for both DD-CKD and

NDD-CKD, and based on prior MACE data and FibroGen’s reticence, it was probably by a wide margin

• MACE+ was manipulated by prohibiting IV iron in both DD-CKD and NDD-CKD and

using a placebo comparator in NDD-CKD to increase anemia rates in the control

• groups. It would be naïve to think that a regulatory agency would ignore a

significant MACE safety signal because of MACE+ even if the trials had not been rigged to increase “+” events in the control groups

• Given its apparent MACE safety inferiority to EPO, we believe roxadustat will be

rejected in the US/EU and that it is only a matter of time until roxadustat is pulled from market in China/Japan. Once the safety data becomes public, no ethical doctor will prescribe it

102 Concluding Thoughts & Looking Forward

PLAINVIEW

Concluding Thoughts – Pamrevlumab

• Research not sponsored by FibroGen indicates that CTGF is simply not a principal

mediator of fibrosis, and 16 years of drug trials has provided little to refute that thesis

• The IPF Phase 3 trial design makes pamrevlumab an impossible sell even if it

works; by prohibiting background therapy and comparing pamrevlumab to placebo, there will be no evidence of superiority or additive benefit to the current standard of care (pirfenidone/nintedanib), one or both of will likely be generic by the time FibroGen’s drug makes it to market. Further, the decision to only run a single Phase 3 trial now means that in an optimal scenario, pamrevlumab might make it to market a decade from now

• We do not believe pamrevlumab works in pancreatic cancer given the similar ORR

between groups in the Phase 2 trial, failure to disclose PFS/OS, and history of failures for similar strategies targeting the stroma

• With 3.5 years of clinical data and virtually no clinical endpoint data disclosed, we

do not believe pamrevlumab works in DMD

Concluding Thoughts & Looking Forward 103

PLAINVIEW

FibroGen Management’s Unscrupulous Practices

• Selective disclosure to manipulate shareholder perception
• Withheld key MACE hazard ratios and instead made misleading disclosures about the pooled safety

profile of roxadustat engineered to create the illusion that roxadustat succeeded where it failed

• Failed to mention ORR/PFS/OS for pamrevlumab in pancreatic cancer press release, and instead

focused on an obscure metric where pamrevlumab happened to outperform placebo by chance

• Failed to disclose the actual clinical endpoints in the DMD trial, and instead provided abstract and

useless cross-trial comparisons

• Failed to disclose the efficacy endpoint results of the IPF trial comparing pamrevlumab + SoC vs.

placebo + SoC

• Unethical trial design to artificially inflate results
• Prohibiting IV iron in the roxadustat trials in order to try to create the illusion of efficacy benefit over

the control arm as well as inflate relative safety. This forced higher EPO dosing in control groups which has been unequivocally shown to lead to worse safety outcomes

• Prohibiting background therapy and using a placebo control in the IPF trials despite clear evidence of

survival benefit from standard-of-care pirfenidone/nintedanib

• Pure dishonesty
• Claimed to be “encouraged” by results from pamrevlumab’s HBV trial in February 2016 despite having

already terminated the trial for futility eight months prior

• Claimed MACE was “trending favorably” and blamed FDA/AstraZeneca for lack of MACE HR disclosure

Concluding Thoughts & Looking Forward 104

PLAINVIEW

What’s Next?

• ASN 2019 (November 7-10 2019): FibroGen is expected to present several

roxadustat posters as well as full MACE safety data for roxadustat on November 8 from 2:00 to 2:15 PM

• FibroGen indicated in its Q2 2019 press release that it would be submitting

the US NDA for roxadustat in October 2019 with the European MAA following soon after

• If the FDA accepts the roxadustat NDA, an advisory committee meeting for

roxadustat will likely be scheduled for mid-late 2020

• Pamrevlumab readouts:
• Pancreatic Cancer Phase 3 trial: primary completion estimated at September 2022
• IPF Phase 3 trial: primary completion estimated at March 2023

105 Concluding Thoughts & Looking Forward

PLAINVIEW

Appendix 1: Roxadustat Trial References

PLAINVIEW

Overview of Roxadustat Trials

Appendix 1: Roxadustat Trial References 107

Note: 1 In the poster discussing the Japan Phase 3 DD-CKD trial results, the authors did not provide a complete SAE breakdown, and it is possible that additional MACE incidents occurred that were not disclosed

PLAINVIEW

Roxadustat Trials: Individual MACE Components

Appendix 1: Roxadustat Trial References 108

Note: 1 In the poster discussing the Japan Phase 3 DD-CKD trial results, the authors did not provide a complete SAE breakdown, and it is possible that additional MACE incidents occurred that were not disclosed

PLAINVIEW

Roxadustat Trial References

Appendix 1: Roxadustat Trial References 109

Trial Source Where to Find MACE in Each Publication China Phase 3 – DD-CKD Chen et al 2019 SAEs on p. 13 of Supp. Appendix Japan Phase 3 – DD-CKD ASN 2018 Akizawa Poster (not available online) Table 5 of poster China Phase 2 – DD-CKD Chen et al 2017 No reported events US Phase 2 – DD-CKD Provenzano et al 2016 SAEs listed in Table 5 of paper US Phase 2b – NDD-CKD Provenzano et al 2016 SAEs listed in Supplemental Table 5 US Phase 2 – ID-CKD Besarab et al 2016 SAEs listed on pp. 15-16 of Appendix US Phase 2a – NDD-CKD Besarab et al 2015 No reported events China Phase 3 – NDD-CKD Chen et al 2019 No reported events China Phase 2 – NDD-CKD Chen et al 2017 No reported events

PLAINVIEW

China Phase 3 DD-CKD Trial (Chen 2019)

Appendix 1: Roxadustat Trial References 110

• MACE Incidents:
• Roxadustat: Three strokes

and one myocardial infarction (4/204)

• Epoetin alfa: None (0/100)
• Source: Chen et al 2019

Basilar artery aneurysm, brain stem infarction, and lacunar infarction count as strokes

PLAINVIEW

Japan Phase 3 DD-CKD Trial (ASN 2018 Akizawa Poster)

Appendix 1: Roxadustat Trial References 111

• MACE Incidents:
• Roxadustat: At least one stroke and separate two deaths (3/150)
• Control: None reported (0/152)
• Source: ASN 2018 Akizawa Poster (relevant excerpt below)

Based on the disclosure below, we know at least

• ne other roxadustat

patient suffered from a stroke (cerebral infarction) and that patient was not

• ne of the two who died

(no stroke reported in death descriptions)

PLAINVIEW

China Phase 2 DD-CKD Trial (Chen 2017)

• MACE incidents
• Roxadustat: None (0/65)
• EPO: None (0/22)
• No SAEs of any kind were reported

for either group

• Trial was only six weeks
• The patient population from the AE

table is different from the trial design numbers due to including 9 patients enrolled in a PK sub-study; we did not include those 9 patients in calculating MACE frequency

• Source: Chen et al 2017

Appendix 1: Roxadustat Trial References 112

PLAINVIEW

US Phase 2 DD-CKD Trial (Provenzano 2016, 1/2)

• MACE incidents:
• Roxadustat: 2 strokes, 2 myocardial infarctions, 3 deaths (7/108)
• EPO: 1 myocardial infarction, 0 strokes, 0 deaths (1/36)
• Source: Provenzano et al 2016

Appendix 1: Roxadustat Trial References 113

PLAINVIEW

US Phase 2 DD-CKD Trial (Provenzano 2016, 2/2)

• There were 3 deaths in the roxadustat group, which were described on pp. 7-8 of

Provenzano et al 2016. None of which were attributed to patients who also experienced myocardial infarction or stroke and therefore all three are separate MACE incidents: Three roxadustat-treated participants died during the study: a 68-year-old man with known heart failure and coronary and peripheral arterial disease had an unwitnessed death, a 77- year-old man with methicillin-resistant Staphylococcus aureus sepsis, and a 58-year-old man with preexisting allergy to dialysis and cardiovascular disease (acute myocardial infarction, stent, and transient ischemic attacks) prior to enrollment who presented volume

• verloaded with respiratory failure in whom dialysis was delayed, leading to cardiac arrest.
• We include all three deaths in our MACE tally. As we noted on slides 62-63, Kiriakidis et

al 2017 showed that roxadustat and other HIF-PH inhibitors compromise immune systems by blocking the complement pathway, and the study Schindler et al 2016 found that HIF- PH inhibition in septic mice led to significantly higher mortality rates. We think it is very possible that the sepsis death was drug-related

Appendix 1: Roxadustat Trial References 114

PLAINVIEW

US Phase 2b NDD-CKD (Provenzano 2016, 1/2)

Appendix 1: Roxadustat Trial References 115

• MACE incidents:
• Roxadustat: 2 strokes

(excluding one that

• ccurred outside of

study period), 1 myocardial infarction (two but one led to death), 4 deaths (excluding one that

• ccurred outside of

study period). Total: 7/145

• No control group
• Source: Provenzano et

al 2016

PLAINVIEW

US Phase 2b NDD-CKD (Provenzano 2016, 2/2)

• There were five total deaths in the NDD-

CKD Phase 2b trial, which are described in Supplemental Table 6 of the appendix to the study (see right table)

• One of the deaths occurred in a patient

who suffered from a myocardial infarction and one occurred in a patient who suffered from a cerebellar infarct (stroke): the first was counted as a death for the purpose of computing MACE and excluded from MI to avoid double-

• counting. The stroke death was not

counted and the stroke was excluded from the MACE incidents due to

• ccurring outside of the study period

Appendix 1: Roxadustat Trial References 116

PLAINVIEW

US Phase 2 ID-CKD (Besarab 2016, 1/2)

• MACE Incidents:
• Roxadustat: 0 myocardial

infarction, 0 strokes, 2 deaths

• No control group
• There was a patient who

suffered from a myocardial infarction and died; the MI was not counted in MACE to avoid double-counting the patient

• Source: Besarab et al 2016

Appendix 1: Roxadustat Trial References 117

PLAINVIEW

US Phase 2 ID-CKD (Besarab 2016, 2/2)

• Two patients on roxadustat died in the ID-CKD trial.
• Deaths are discussed on pp. 1228-1229 of publication:

Two patients died: one during treatment and one during follow-up. Both deaths were determined by the investigators as unrelated to roxadustat. A 67-year-old patient receiving PD with a long history of hypertension was found dead at home (suspected cause: acute heart failure) 5 days after last roxadustat dose taken on study day 26. A 75-year-old patient in the no-iron cohort with a history of hypertension, ischemic and congestive heart disease, and cor pulmonale from chronic obstructive pulmonary disease responded to initial therapy; week 8 Hb levels were 10.4 g/dl (dose of 1.33 mg/kg). The patient was hospitalized

• n day 72 for worsening heart failure and began receiving warfarin for atrial fibrillation.

Last roxadustat dose was given on day 84 (end of treatment). On day 85, the patient’s Hb dropped from 9.9 to 5.5 g/dl from acute gastric ulcer bleeding, which led to two red blood cell transfusions. Despite these transfusions, acute myocardial infarction occurred on day

• 89. The patient died the next day.
• We include both patients in our tally of deaths; the first patient died while on the study

drug and the second patient’s death was apparently driven by the sharp drop in Hb which

• ccurred immediately after ceasing roxadustat

Appendix 1: Roxadustat Trial References 118

PLAINVIEW

US Phase 2a NDD-CKD (Besarab 2015)

• MACE Incidents:
• Roxadustat: None
• Placebo: None
• There were no deaths or MACE incidents reported in this trial. SAEs are

briefly discussed on p. 1670 of the publication: Serious AEs (SAEs) were reported by four (5%) roxadustat-treated subjects and one (4%) placebo patient; the SAEs in roxadustat treated subjects included vascular access complications, femoral neck fracture, noncardiac chest pain and dyspnea.

• Source: Besarab et al 2015

Appendix 1: Roxadustat Trial References 119

PLAINVIEW

China Phase 3 NDD-CKD Trial (Chen 2019)

• MACE Incidents
• Roxadustat: None
• Placebo: None
• There were no deaths or MACE incidents

reported during the randomized portion of the trial; during a subsequent 18-week

• pen-label portion with 131 patients (all

taking roxadustat), two roxadustat patients

• died. We did not include these deaths in
• ur tables/analysis
• Source: Chen et al 2019

Appendix 1: Roxadustat Trial References 120

PLAINVIEW

China Phase 2 NDD-CKD (Chen 2017)

• MACE incidents
• Roxadustat: None
• EPO: None
• Trial was only eight weeks
• Source: Chen et al 2017

Appendix 1: Roxadustat Trial References 121

PLAINVIEW

Appendix 2: Daprodustat & Vadadustat Trial References

PLAINVIEW

Overview of Daprodustat Trials

Appendix 2: Daprodustat & Vadadustat Trial References 123

PLAINVIEW

Daprodustat Sources

Appendix 2: Daprodustat & Vadadustat Trial References 124

Daprodustat Trial Source Where to Find MACE in Each Publication US Phase 2a – NDD-CKD (vs. placebo) Holdstock et al 2016 No events reported US Phase 2a – DD-CKD (vs. EPO) Holdstock et al 2016 No events reported US Phase 2a – NDD-CKD (vs. placebo) Brigandi et al 2016 Table 3 on p. 5 of publication US Phase 2a – DD-CKD (vs. placebo) Brigandi et al 2016 No events reported Japan Phase 2 – DD-CKD (vs. placebo) Akizawa et al 2016 SAEs discussed on p. 6 of publication US Phase 2a – DD-CKD (no control) Cizman et al 2018 Table S1 from Supplementary Data Japan Phase 3 – DD-CKD (no control) https://clinicaltrials.gov/ct2/show/re sults/NCT02829320 No events reported US Phase 2b – NDD-CKD (vs. EPO) Holdstock et al 2018 Table 6 on p. 7 of publication US/Int’l Phase 2b – DD-CKD (vs. EPO) Meadowcroft et al 2018 Table 5 on p. 8 of publication

PLAINVIEW

Daprodustat Phase 2a NDD & DD-CKD (Holdstock 2016)

• NDD-CKD MACE Incidents:
• Daprodustat: None (0/52)
• Control: None (0/19)
• DD-CKD MACE Incidents:
• Daprodustat: None (0/60)
• EPO: None (0/20)
• No death or other MACE incidents were

reported in this trial. See right for summary of SAEs taken from p. 19 of Supplementary Appendix to Holdstock 2016

• Source: Holdstock et al 2016

Appendix 2: Daprodustat & Vadadustat Trial References 125

PLAINVIEW

Daprodustat US Phase 2a – NDD & DD-CKD (Brigandi 2016)

• NDD-CKD MACE Incidents:
• Daprodustat: One MI (1/61)
• Control: None (0/9)
• DD-CKD MACE Incidents:
• Daprodustat: None (0/31)
• Control: None (0/6)
• No MACE incidents were

reported among DD-CKD patients, one severe acute coronary syndrome (myocardial infarction) reported in NDD-CKD

• group. See right for

summary of SAEs from p. 5

• f publication
• Source: Brigandi et al 2016

Appendix 2: Daprodustat & Vadadustat Trial References 126

PLAINVIEW

Daprodustat Japan Phase 2 – DD-CKD (Akizawa 2016)

• MACE Incidents
• Daprodustat: None (0/78)
• Placebo: One stroke (cerebral

hemorrhage) (1/19)

• SAEs discussed on p. 6 of

Akizawa 2016 (see right for relevant excerpt)

• Source: Akizawa et al 2016

Appendix 2: Daprodustat & Vadadustat Trial References 127

PLAINVIEW

Daprodustat US Phase 2a DD-CKD (Cizman 2018)

• MACE Incidents:
• Daprodustat: 1 myocardial infarction

(1/15)

• No control group
• Adverse events reported in Table S1

from the Supplementary Appendix to Cizman 2018 (see right) as well as at https://clinicaltrials.gov/ct2/show/stud y/NCT02075463

• Source: Cizman et al 2018

Appendix 2: Daprodustat & Vadadustat Trial References 128

PLAINVIEW

Daprodustat Japan Phase 3 – DD-CKD (clinicaltrials.gov)

• MACE incidents:
• Daprodustat: None (0/28)
• No control
• No MACE incidents were reported in this trial. SAEs provided below
• Source: https://clinicaltrials.gov/ct2/show/results/NCT02829320

Appendix 2: Daprodustat & Vadadustat Trial References 129

PLAINVIEW

Daprodustat US Phase 2b – NDD-CKD (Holdstock 2018)

• MACE Incidents:
• Daprodustat: Four deaths & one

myocardial infarction (5/170)

• EPO: One death (1/80)
• MACE summary from Holdstock

2018 provided to the right

• Source: Holdstock et al 2018

Appendix 2: Daprodustat & Vadadustat Trial References 130

PLAINVIEW

Daprodustat US Phase 2b – DD-CKD (Meadowcroft 2018)

• MACE Incidents:
• Daprodustat: Five deaths & two

myocardial infarctions (7/177). One patient suffered from a myocardial infarction and later died and was excluded from the MI count to avoid double- counting

• EPO: No MACE incidents (0/39)
• Table 5 from p. 8 of Meadowcroft 2018

provided to the right

• Source: Meadowcroft et al 2018

Appendix 2: Daprodustat & Vadadustat Trial References 131

PLAINVIEW

Overview of Vadadustat Trials

Appendix 2: Daprodustat & Vadadustat Trial References 132

PLAINVIEW

Vadadustat Sources

Appendix 2: Daprodustat & Vadadustat Trial References 133

Vadadustat Trial Source Where to Find MACE in Each Publication US Phase 2a – NDD-CKD (vs. placebo) Martin et al 2017 Not disclosed – one death reported US Phase 2 - DD-CKD (no control) Haase et al 2018 Table of AEs on p. 8 of publication US Phase 2b - NDD-CKD (vs placebo) Pergola et al 2016 Not disclosed – three deaths reported Japan J01 – NDD-CKD (vs. EPO) Akebia Press Release Not disclosed – one death reported Japan J02 – PD-CKD (no control) Akebia Press Release Not disclosed – one death reported Japan J03 – DD-CKD (vs. EPO) Akebia Press Release Not disclosed Japan J04 – DD-CKD (no control) Akebia Press Release Not disclosed

PLAINVIEW

Vadadustat US Phase 2a – NDD-CKD (Martin 2017)

• MACE incidents were not disclosed, but p. 5 of Martin 2017 reveals that

SAEs were reported in 7/72 (10%) of vadadustat patients and 1/19 (5%) of control patients. Specific SAEs were not disclosed

• One patient in the vadadustat group died (1/72) compared to zero patients

in the control group (0/19)

• Source: Martin et al 2017

Appendix 2: Daprodustat & Vadadustat Trial References 134

PLAINVIEW

Vadadustat US Phase 2 DD-CKD (Haase 2018)

• MACE Incidents:
• Vadadustat: 2

myocardial infarctions, 0 strokes, 0 deaths (2/94)

• No control
• Adverse event table

provided on p. 8 of Haase 2018 (see right)

• Source: Haase et al

2018

Appendix 2: Daprodustat & Vadadustat Trial References 135

PLAINVIEW

Vadadustat US Phase 2b – NDD-CKD (Pergola 2016)

• MACE incidents were not disclosed
• There were three deaths in the vadadustat group (3/138) compared to zero

deaths in placebo (0/72) which are discussed on pp. 4-5 of Pergola 2016

• SAEs were reported in 33/138 (24%) of vadadustat patients compared to

11/72 (15%) of placebo patients

• Source: Pergola et al 2016

Appendix 2: Daprodustat & Vadadustat Trial References 136

PLAINVIEW

Vadadustat Japan Trials: J01, J02, J03 & J04 Studies (Akebia PR)

• MACE incidents were not disclosed
• One death was reported in the control group in the J01 trial and one death

was reported in the vadadustat group in the J02 trial

• Source: Akebia Press Release

Appendix 2: Daprodustat & Vadadustat Trial References 137