LIFESCI ADVISORS
June 5, 2013
Data Released at ASCO Demonstrates the
Severe Unmet Need in Brain Cancer;
DelMar Presented Promising Early Data
DelMar Note
Andrew I. McDonald, Ph.D.
(646) 597-6987
andrew@lifesciadvisors.com
Jerry Isaacson, Ph.D.
jerry@lifesciadvisors.com
The annual American Society of Clinical Oncology meeting
was held recently in Chicago. New data on the use of
Roche/Genentech’s Avastin in brain cancer was released,
revealing that Avastin is not a safe or effective choice as a
first-line treatment in this indication. New compounds with
differing modes of action are needed; DelMar’s VAL-083 is
a promising candidate for patients with brain cancer.
Key Points of Discussion
Avastin is Not a Choice for First-Line Brain Cancer.
Every year, the most promising new data and ideas for
cancer treatment are presented at the American Society for
Clinical Oncology’s annual meeting. This year’s meeting,
held from May 31 to June 4, 2013, featured a number of
important story lines, and one important development was
the evolving role of Roche/Genentech’s Avastin
(bevacizumab) in cancer treatment. This is and will
continue to be an important tool in the fight against cancer,
but as time goes on we are finding that the initial level of
excitement around Avastin was overblown. This was
confirmed resoundingly in October 2011, when the FDA
removed the breast cancer indication from Avastin’s label.
Recently released data has some speculating that the FDA
will make a similar move with Avastin’s indication for the
brain cancer glioblastoma multiforme (GBM). Considering
the lack of treatment options for this cancer, we think a
label change is unlikely, but the data illustrates both that
Avastin is not a good choice in the first line for GBM and
that new, better treatments are needed.
Avastin as Part of a First-Line GBM Regimen –
RTOG 0825 Trial. Two large studies presented at ASCO
tested Avastin in the first-line setting for GBM, as part of a
Ticker
DMPI
Price
$1.95
Market Cap (M)
$60
EV (M)
$52
Shares Outstanding (M)†
30.6
Fully Diluted Shares (M)
56.9
Avg. Daily Vol.
19,026
52-week Range:
$1.25-2.50
Cash (M)
$8.3
Net Cash/Share
$0.26
Debt (M)
$0.26
Short Interest (M)
N/A
†The number of shares outstanding is
inclusive of exchangeable shares held by
Canadian holders of the pre-IPO private
entity.
FY Dec
EPS:
2010A
2011A
2012A
Q1
N/A
N/A
N/A
Q2
N/A
N/A
N/A
Q3
N/A
($0.03)A
($0.05)A
Q4
N/A
N/A
N/A
FY
N/A
($0.16)A
($0.15)*
*9-months ended 9/30/12
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June 5, 2013
combination that also includes Temodar (temozolomide) and radiation. One of the trials, known as
RTOG 0825, was sponsored by the National Cancer Institute and randomized 637 newly diagnosed
GBM patients to treatment Temodar and radiation plus either Avastin or placebo.1 The co-primary
endpoints for the trial were overall survival (OS) and progression-free survival (PFS). An important
secondary endpoint was the impact of O6-methylguanine-DNA methyltransferase (MGMT)
methylation on the results.2
The results of this trial did not support the use of Avastin in this patient population. Regarding OS,
there was no statistical difference between the control and Avastin-added arms, at 16.1 months
versus 15.7 months (p=0.11), and actually numerically favored the placebo arm. The addition of
Avastin did have a significant impact on PFS, at 10.7 months versus 7.3 months for placebo
(p=0.004) although these results did not meet a pre-determined PFS endpoint. There was an
increase in grade 3 or higher adverse events (AEs) for the Avastin arm, including neutropenia,
hypertension, and deep vein thrombosis/pulmonary embolism. MGMT status was not predictive of
the results, however patients with MGMT methylation trended towards lower OS in the Avastin arm
when compared to placebo.
Roche AVAglio Study of Avastin in Combination with First-Line Therapy. The second study
relating to Avastin in brain cancer was conducted by Roche and was known as AVAglio. 3 The
treatment protocol for this trial was very similar to RTOG 0825, with either Avastin or placebo being
added to standard of care, which included Temodar and radiation. The co-primary endpoints of PFS
and OS were also the same. This trial enrolled 921 patients, and there was a significant increase in
PFS of 10.6 months for the Avastin arm versus 6.2 months for the placebo arm (p=0.001)4.
These results should be viewed in light of multiple factors. First, it is clear from these data that
Avastin is not a good choice for the first-line treatment of GBM. This program has been seen as the
most promising development for GBM for many years now, so these disappointing results further
highlight the need for better treatments. Second, we see that Avastin has an impact on PFS but no
impact on OS. So, as has happened in other indications, the drug is clearly affecting the tumor but
this does not translate to a survival benefit. One hypothesized reason for this is that while Avastin
affects the tumor for some time, eventually it comes back more aggressively. This was also observed
in breast cancer with Avastin. It has also been hypothesized that Avastin, an antibody which can’t
enter the brain, may therefore not be able to directly affect the tumor so that any effect it is having is
systemic and therefore not as potent.
We conclude from this data that a valuable market opportunity and an important unmet medical
need remain in GBM. Multiple companies are exploring small molecule as well as antibody
1
http://clinicaltrials.gov/show/NCT00884741
http://meetinglibrary.asco.org/content/111571-132
3
http://clinicaltrials.gov/show/NCT00943826
4
http://meetinglibrary.asco.org/content/114612-132
2
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approaches to treating this deadly cancer, and immunotherapies are also being tested. Hopefully
more than one of these will emerge as good treatment options for patients with GBM. As we are
seeing in prostate cancer, these new therapies should and will also be tested in various combinations.
It is possible that a combination of an immunotherapy and a traditional drug such as VAL-083 may
prove to be very useful in this indication, but only time will tell.
Importance of MGMT Status in Treating GBM. As mentioned above, the RTOG 0825 trial for
Avastin included effect of MGMT methylation as a secondary endpoint. MGMT is a DNA repair
enzyme that can inhibit the ability of the front-line treatment Temodar to induce cell death in tumor
cells of patients with GBM. DelMar’s VAL-083 induces cell death in tumors via a mechanism that is
independent of MGMT expression, making VAL-083 a potential treatment for Temodar resistant
tumors that express MGMT.
Pre-clinical research presented at the 2012 American Association for Cancer Research,5 and also at
ASCO, directly addressed the effect of VAL-083 on cells expressing MGMT. The study
demonstrated that both temozolomide and VAL-083 can induce cell death in cells that do not
express MGMT, but only VAL-083 induces death in MGMT-expressing cells. Therefore, VAL-083
may be an effective therapy for patients who express MGMT but do not respond to Temodar
treatment. This raises the possibility of using the MGMT status of patients in the selection criteria
for future trials, and also of using VAL-083 in combination with Temodar.
DelMar Presented VAL-083 Phase I/II Dose Escalating Study at ASCO. DelMar initiated a
Phase I/II clinical trial of VAL-083 in November 2011. The study is an open label, single-arm,
safety, tolerability and pharmacokinetic study of VAL-083 for adult patients with recurrent
malignant glioma or secondary brain tumors that have failed both Temodar and Avastin, unless
contraindicated. The trial protocol calls for administration of VAL-083 on the first 3 out of every 21
days. The primary endpoint for the Phase I/II trial is to establish the maximum tolerated dose
(MTD) of VAL-083. Secondary endpoints include monitoring antitumor activity, progression free
survival (PFS), and pharmacokinetics of the treatment.
Once the MTD is established, additional patients will be enrolled to begin the Phase II portion of
the study; radiographic response (the ability of the drug to shrink the tumor as shown brain scans)
and PFS will be monitored as the primary endpoints. These endpoints have been used by the FDA
in the past to approve products such as Temodar and Avastin for refractory GBM. At the outset of
this trial, patients with malignant glioma or secondary brain tumors were treated together. However,
DelMar recently announced that the trial would be broken into two arms so these different patient
groups may be evaluated separately. The concern is that patients with secondary brain tumors may
Hu, K., et al., 2012. VAL083, a novel N7 alkylating agent, surpasses temozolomide activity and inhibits cancer stem
cells providing a new potential treatment option for glioblastoma multiforme. American Association for Cancer
Research, 2012 Annual Meeting. Abstract #811.
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be heavily pre-treated and therefore may experience myelosuppression and a smaller MTD than
GBM patients.
Updated data presented at ASCO revealed that 2/8 patients with GBM experienced a response and
1/6 patients with secondary brain tumors experienced a response. Patients characteristic and
responses are summarized in the table below.
Figure 1: VAL-083 Patient and Response Summary
Source: DelMar ASCO Presentation6
We expect that DelMar will present interim data from this trial at upcoming conferences including,
possibly, the Society for Neuro-Oncology (SNO) conference in November. If patient enrollment
continues at the current pace, we would not be surprised to see DelMar find the MTD for VAL-083
in time for the SNO meeting. Based on historical precedent, we also anticipate that clinical response
rates above 20% may be sufficient for approval of new therapies in refractory GBM. Notably,
DelMar’s data achieve this level or response.
Upcoming Expected Milestones


2H 2013 – Expected completion of Phase I of the Phase I/II trial of VAL-083 in GBM.
1H 2014 – Potential expansion of VAL-083 Phase II trial to a registration study.
About DelMar: More information on DelMar Pharmaceuticals can be found in our Initiation of
Coverage Report at http://lifesciadvisors.com/clients/delmar/.
6
http://www.delmarpharma.com/DelMarASCO2013-11x17.pdf
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