Download to your free Sample Pages

Malignant melanoma Pipeline
DMKC0063157 | Published on 07/10/2014
Table 2: Recently discontinued drugs in melanoma
Drug (molecule) Company
Indication
Phase
(melanoma)
Allovectin
Vical
First-line Stage IV
Mechanism of
Formulation
Drug class
Intratumoral
Immunotherapy
Intravenous
Targeted
action
III
(velimogene
HLA-B7 gene
therapy
aliplasmid)
Genasense
Genta
First-line Stage IV
III
Bcl-2 antisense
Eli Lilly
Second-line Stage
III
Apoptosis stimulator Intravenous
(oblimersen)
Tasisulam
(LY573636)
IV
PL
E
Source: Datamonitor Healthcare
Targeted/cytotoxic
SA
M
Over the past few years the attrition rate of pipeline drugs for melanoma has been relatively high. The
hard-to-treat nature of melanoma means that although some pipeline drugs may demonstrate activity
in these tumors, they have not demonstrated enough of an effect to gain regulatory approval.
“Melanoma is a very tough disease to treat and over the past 40 years we have learned that it is not
very easy to achieve a survival advantage. Even though some of these drugs may have a benefit, it is
not strong enough of an effect to translate into a survival advantage. Mechanistically and
scientifically speaking I don’t think that we can explain the failures.”
US key opinion leader
ALLOVECTIN (VELIMOGENE ALIPLASMID; VICAL)
ALLOVECTIN FAILED TO MEET THE PRIMARY ENDPOINT OF ITS PHASE III TRIAL
In August 2013, Vical announced that Allovectin had failed to meet the objective response rate
primary endpoint and the overall survival secondary endpoint in its Phase III clinical trial (Vical press
release, 2013). Allovectin was being investigated against dacarbazine or temozolomide for the
treatment of patients with recurrent metastatic melanoma (ClinicalTrials.gov identifier:
NCT00395070). Based on the outcome of this trial, Vical has now discontinued its Allovectin program
and is focusing its resources on its infectious disease vaccine programs (Vical press release, 2013).
Vical previously announced the termination of a Phase III low-dose Allovectin trial after an initial
review showed that it would not meet the primary endpoints of objective response rate and/or time to
Downloaded by Lisa.Hearn on 05/11/2014
© Informa UK Ltd. This document is a licensed product and is not to be reproduced or redistributed
8
Malignant melanoma Pipeline
DMKC0063157 | Published on 07/10/2014
EARLY-PHASE OPPORTUNITIES
Melanoma has a history of being difficult to treat due to the physiology of its tumors (Tsao et al.,
2012). However, the approvals of Yervoy (ipilimumab; Bristol-Myers Squibb) and Zelboraf
(vemurafenib; Roche/Daiichi Sankyo) in 2011 have revitalized the melanoma development market.
Pharmaceutical companies are now taking note of the interesting molecular targets, novel treatment
strategies, and the high levels of unmet need in this indication. Growing interest in melanoma will
dramatically increase competition in this market, but will also drive improvements in the clinical
treatment of a historically hard-to-treat indication.
E
Datamonitor Healthcare has evaluated the commercial potential of the early-phase melanoma
pipeline for assets with a known mechanism of action, target indication, and/or likely therapeutic use
on the market. To access Datamonitor Healthcare’s forecast of each product, please see the
accompanying datapack.
PL
Please note, due to the low incidence rates of melanoma in Japan, Datamonitor Healthcare has not
surveyed Japanese health professionals about their approaches in the treatment of melanoma. In the
early-phase opportunities datapack, sales of individual drugs in Japan are included as part of the "rest
of world" sales figure.
Targeted therapies and immunotherapies dominate the early-phase melanoma pipeline
SA
M
Targeted therapies and immunotherapies constitute the largest share of the melanoma early-phase
pipeline. The large proportion of targeted therapies in development for melanoma is in line with other
oncology indications, as treatment shifts away from standard cytotoxic therapies towards targeted
therapies and personalized medicine. However, the melanoma pipeline also contains a large number of
immunotherapies, including vaccines and immunomodulators.
It is well documented that melanoma is an immunogenic tumor due to its ability to undergo
spontaneous regression associated with lymphocyte infiltration (Sznol, 2009; Komenaka et al., 2004).
As a result, this indication has historically seen a larger number of immunotherapies in the earlyphase pipeline compared to other tumor types. Although many immunotherapies and vaccines have
struggled to make it to market, the approval of the targeted immunomodulator Yervoy demonstrated
the potential of this drug class and increased developer interest in these drugs.
Downloaded by Lisa.Hearn on 05/11/2014
© Informa UK Ltd. This document is a licensed product and is not to be reproduced or redistributed
12
Malignant melanoma Pipeline
DMKC0063157 | Published on 07/10/2014
TARGET PRODUCT PROFILE
Yervoy (ipilimumab; Bristol-Myers Squibb)
Yervoy (ipilimumab; Bristol-Myers Squibb) is an intravenous fully humanized immunoglobulin G1
(IgG1) monoclonal antibody that targets human cytotoxic T-lymphocyte-associated antigen-4 (CTLA4). CTLA-4 is present on activated T-cells and is a negative regulator of T-cell activation within the
immune response. Ipilimumab was designed to inhibit the activity of CTLA-4, which allows for an
active immune response against cancer cells (Yervoy prescribing information, 2014).
E
Datamonitor Healthcare has chosen Yervoy as one of the comparator therapies for metastatic
melanoma as it was the first drug to demonstrate an improvement in overall survival in this patient
group. As a result, the approval of Yervoy in 2011 altered the initial treatment of Stage IV melanoma
patients who previously had limited treatment options. The Phase III clinical trial showed median
overall survival was 10 months for patients receiving Yervoy compared to 6 months receiving gp100.
Furthermore, patients that respond to the treatment demonstrate a relatively long duration of
response (Yervoy prescribing information, 2014).
PL
Despite the improved overall survival Yervoy has distinct limitations due to severe autoimmune
toxicity, a delayed response, and a response rate of less than 15%, which are compounded by the high
cost of the treatment (Hodi et al., 2010). This has an impact on uptake as physicians must cautiously
select patients that are healthy enough to tolerate and potentially respond to the drug. However, the
improvement in overall survival means that if patients respond this is an attractive treatment option.
SA
M
Yervoy’s drug profile is shown in the table below.
Downloaded by Lisa.Hearn on 05/11/2014
© Informa UK Ltd. This document is a licensed product and is not to be reproduced or redistributed
23
Malignant melanoma Pipeline
DMKC0063157 | Published on 07/10/2014
CLINICAL TRIAL DESIGN
Clinical trials
This section identifies and defines key endpoints currently used in melanoma clinical trials, and the
trial designs used to demonstrate superior (or in some cases possibly equivalent) performance
compared to existing treatments.
CLINICAL TRIAL DESIGN
SA
M
PL
E
A good clinical trial design depends on factors such as patient selection, patient number, trial
duration, dosing regimens, and endpoints that best reflect the effectiveness of the investigated drug.
Randomized trials are usually considered the best approach to eliminate any bias, and are the
preferred basis for approval by the US Food and Drug Administration (FDA) (Roberts et al., 2003). The
success of a clinical trial and its ability to support a potential subsequent approval also depends on
the use of an appropriate comparator. The historical unmet need for effective therapy and
consequently lack of standard of care for metastatic melanoma has resulted in no real definitive
comparator therapy. However, before new drug approvals in 2011, dacarbazine was often considered
the foundation of many melanoma treatment regimens. As a result, despite its low response rate
(12–20%), dacarbazine has often been used as the comparator therapy in late-stage melanoma
clinical trials (Bedikian et al., 2006). For example, the Phase III trial that supported the US approval of
Zelboraf (vemurafenib; Roche/Daiichi Sankyo) in the first-line treatment of BRAFV600E-positive
metastatic melanoma compared Zelboraf with monotherapy dacarbazine (Zelboraf prescribing
information, 2014). In contrast, Yervoy (ipilimumab; Bristol-Myers Squibb) was approved on the back
of a Phase III trial comparing the drug to gp100, which was deemed to be an equivalent to best
supportive care (Yervoy prescribing information, 2014).
The table below shows the design of the BRIM3 Phase III clinical trial of Zelboraf in melanoma.
Downloaded by Lisa.Hearn on 05/11/2014
© Informa UK Ltd. This document is a licensed product and is not to be reproduced or redistributed
31