Overview
If one were to have asked
drug development teams at the leading pharma companies 5 years ago whether they
were focused on developing kinase inhibitors specifically for genetically
defined populations, the answer would have been “no” across the board. Of
course, there was an interest in targeting the driver mutations that were
beginning to be reported from genomics studies, but companies were hesitant to
define their target patient population too narrowly and limit their market
opportunity.
Blueprint recognized
however that in order to achieve meaningful efficacy, kinase inhibitors would
need to be toxic to cancer cells but not to the rest of the body, and that the
only way to do this would be to inhibit target kinases specifically in
genetically defined patient populations. While other kinase inhibitors could be
dosed only so high before causing general toxicities to the patient,
Blueprint’s inhibitors would be so specific that they would be able kill the
tumor cells before causing unacceptable side effects. Other companies have
since caught on to this strategy, but Blueprint was one of the first and
remains amongst the best in the targeted kinase inhibitor space.
Blueprint’s oncology drug
development model focuses on 3 key pillars:
1)
Leverage a proprietary
library of kinase inhibitors with activity across the human kinome to discover
highly targeted drug candidates.
2)
Develop small
molecule inhibitors with exquisite selectivity to cancer driving kinases, with
preferential targeting of specific mutations in order to achieve greater
potency with reduced toxicity.
3)
Predict and
pre-emptively address on site mechanisms of resistance, thereby reducing the
rate of resistance/relapse in the clinic.
Blueprint’s lead programs
include:
1.
BLU-285 for KIT
D816V mutated Systemic Mastocytosis and for PDGFRa D842V mutated
gastrointestinal stromal tumors (GIST).
2.
BLU-554 for
hepatocellular carcinomas (HCC) with aberrant FGFR4 signaling.
3.
A third drug
currently in lead optimization for non small cell lung cancers with RET
fusions.
4.
An undisclosed
partnered program partnered with Alexion for a rare genetic disorder.
This review focuses on
the first two compounds, as they represent the most advanced programs in the
pipeline.
Given that their kinase
inhibitors are significantly more specific than other inhibitors currently in
the clinic, and given that preclinical testing in vivo has demonstrated highly
encouraging results, DEC believes that Blueprint has a higher likelihood of
increasing in value than other biotech stocks in similar stages of
development. Key risks to monitor
include competition from companies developing similar inhibitors and
unanticipated toxicities that may emerge in the clinic.
Unmet Medical Need
As with other aggressive
cancers with unmeant need, treatment failure for Blueprint’s indications is
common and most often results in mortality. New and effective treatments are
severely needed.
Prognoses for target indications:
- Advanced forms of Systemic
Mastocytosis (SM): 3-5 year median overall survival prognosis. Target indications are highlighted in the
figure below. The blue line represents expected US mortality. The green line
represents aggressive SM.
Image from: Blood. 2013. How I treat patients
with indolent and smoldering mastocytosis (rare conditions but difficult to
manage).
- GIST:
Metastatic/recurrent GIST will result in mortality in an average of 5 years.
- HCC: 5 year survival
rates are less than 15%.
Available Treatments
BLU-285 (SM): 4. For the 94% of patients with the D816V
mutation, imatinib is ineffective and fallback treatments such as
interferon-alpha or cytoreductive therapy do not likely impact survival rates.
4.
BLU-285 (GIST): About 5-6% of frontline GIST patients carry
PDGFRa D842V mutations. There is no effective treatment for these patients.
Another 80% have KIT driven GIST. Imatinib and then sunitinib are used to treat
these patients, but ultimately they develop KIT Exon 17 mutations (including
D816V) for which there are no current effective treatments.
BLUE 554. Intermiediate/ advanced HCC is treated with
chemotherapy and then sorafenib, but these treatments do not prolong survival
in a meaningful way (~3 months for sorafenib). There is no specific treatment
for the 30% of HCC patients driven by aberrant FGFR4 signaling.
Economic Opportunity
In oncology, efficacy
drives pricing. And some of the recently approved efficacious kinase inhibitors
have been priced well above $100,000 / year. In order to make a conservative
assessment, the price of Blueprint’s drugs is modeled at $85,000 a year. Based on the estimated patient numbers in the
US, EU, and Japan, the total market opportunity is as follows:
·
BLU-285 for SM: 4,500
mutation positive patients / year x $85,000 = $380M
·
BLU-285 for GIST:
7,100 mutation positive patients / year x $85,000 = $600M
·
BLU-554 for HCC:
24,000 mutation positive patients / year x $85,000 = $2,000M
Taking into account the
possibility of competition and a total market penetration of 30%, Blueprint’s
drugs are well positioned to exceed the billion-dollar mark in annual revenues.
Competition
Blueprint faces
competitors for all of its drugs in development. Based on the high quality of
its compounds, the company’s inhibitors are well positioned to compete for
first-in-class (for SM) and/or best-in-class (for GIST and HCC) status for
their respective indications. While competition is one of the key risks that
the company faces, Blueprint is creating a track record of developing superb
drugs that are amongst the best for their respective indications.
BLU-285 for SM and GIST:
-
Plexxikon: A Phase
I trial for PLX9486 was recently launched in March 2015 for KIT mutated GIST
and other KIT mutated tumors. Though no selectivity data have been disclosed,
this molecule is a direct competitor of BLU-285 in the GIST space, and is
slightly ahead in timing for GIST (but not SM). If PLX9486 is not as selective
as this compound then it may not be possible to achieve as potent inhibition as
with BLU-285.
-
Deciphera:
DCC-2618 is being developed as an inhibitor of both mutant and normal KIT for
SM. Unlike BLU-285, however, this compound also inhibits VEGFR2, PDGFRs, TIE2,
and FMS with the goal impacting the tumor microenvironment. It is 50 fold less
potent than BLU-285 against D816V. While these additional kinases may provide
efficacy advantages, broad targeting will limit the ability of achieving
specific and potent on target inhibition due to dose limiting toxicities. The
program is in preclinical development.
-
Arog: Crenolanib
is being developed for multiple cancers with KIT, PDGFRA, and FLT3 tumors. The
IC50 for KIT-D816V is 10 fold lower than for BLU-285. While an IC50 for
PDGFRa-D842V is not available, limited benefit in a exploratory clinical study
of 12 patients (1 PR and 6 SDs ) with this mutation may indicate insufficient
potency against this target.
BLU-554 for HCC:
-
AstraZeneca: In
2013 data were presented on AZ709, which was reported to be a potent inhibitor
of FGFR4. However, limited anti-proliferative activity was reported in HCC cell
lines. It remains unclear whether this compound was pursued for further FGFR4
optimization.
-
Esai: An FGFR4
selective inhibitor appears to be under development for HCC with initiation of
Phase I clinical trials by end of 2015. Selectivity vs FGFR1-3 has not been published,
but this compound may be a direct competitor of BLU-554.
-
Novartis: FGF401
has recently initiated a Phase I/II trial for HCC patients with FGFR4 over
activation. Novartis claims that this
inhibitor is 1,000 fold selective for FGFR4 over FGFR1-3. If confirmed, this
compound comprises a direct competitive threat to BLU-554.
Probability of Clinical Success
Efficacy
BLU-285
Successful clinical
efficacy for BLU-285 is predicted based on two key bodies of evidence. First,
the efficacy of targeting KIT for SM and KIT or PDGFRa for GIST has been
validated with the approved kinase inhibitors imatinib and sunitinib, which
achieve good response rates of tumor regression in these populations. BLU-285 potently
inhibits KIT and PDGFRa mutations that confer resistance to imatinib and
sunitinib, suggesting that efficacy will also be achieved.
The second line of evidence
for predicting success in the clinic comes from highly promising preclinical
data published by Blueprint. In an SM mouse xenograft model with tumor cells
driven by the KIT-D816V mutation, once daily oral dosing achieved dose
dependent anti-tumor activity, including tumor regression at the 30 mg/kg dose.
In comparison, the approved agent dasatinib, which inhibits KIT-D816V but has
10 fold lower potency (IC50 = 2.6) than BLU-285, barely slowed tumor growth and
displayed significant toxicity when dosed twice daily at 25 mg/kg. In a second
study looking at mortality, treatment with BLU-285 extended survival from 7 to
22 days at the highest dose.
With respect to GIST, a
mouse xenograft model with patient derived tumor cells driven by KIT-D816V
further supports outstanding efficacy of BLU-285. As seen in the figure below,
an oral dose of 30 mg/kg achieves marked tumor regression.
BLU-554
Although efficacy in HCC
with FGFR4 inhibitors has yet to be demonstrated in the clinic, there is strong
evidence that supports FGFR4 as an effective target in genetically defined
patients. A significant number of patients with HCC have been found to harbor
extra copies of the gene that encodes for FGF19, the secreted protein that
activates FGFR4 signaling. And a recent study carried out by Blueprint in
collaboration with scientific colleagues has identified an additional set of
HCC patients that over-express FGF19 in liver cells. Combined, up to 30% of HCC
patients show evidence of FGF19 mediated FGFR4 signaling, suggesting that FGFR4
hyperactivity plays a key role in the development of this cancer. This
hypothesis has been further validated in a mouse model that develops liver
cancer in response to FGF19 over-expression.
Blueprint has also
generated highly promising preclinical data with their drug for this
indication. While many companies have begun developing FGFR4 inhibitors, most
of these also inhibit FGFR1, 2, and 3, which will likely result in dose
limiting toxicities. In contrast, BLU-554 is highly selective for FGFR4, with
significant potency at single digit nanomolar concentrations (see IC50 below),
and limited off-target kinase inhibition up to a 3,300 nanomolar concentration.
Finally, very promising
preclinical data have been generated in two xenograft mouse models with tumors
driven by FGFR4 signaling. In an FGF19 amplified model, a dose of 100 mg/kg
twice daily, which was well tolerated, was able to achieve complete tumor
remission that lasted for 30 days post finalization of dosing. In a second
model based on FGF19 over-expression, control of tumor growth was also
achieved, albeit at higher doses. The approved drug sorafenib was used as a
control. At doses that produced significant toxicity, only modest control of
tumor growth was achieved with sorafenib.
Preclinical Safety
BLU-285
The safety profile of
BLU-285 is expected to be comparable or better than imatinib and other approved
kinase inhibitors with potency against KIT and PDGFRa. BLU-285 achieves 50%
inhibition of the target mutated kinases KIT-D816V and PDGFRa-D842V at
concentrations of ~0.25 nanomolar. Although the exact figures are not
published, efficacy against the conformationally distinct, unmutated KIT and
PDGFRa proteins is likely less. For example, the company is considering
carrying out combination trials with BLU-285 and imatinib to cover mutated and
unmutated KIT.
The compound is so
selective that at a 10,000 fold higher concentration (3 micromolar) only 12
other kinases are inhibited. This
selectivity is likely superior to that of imatinib, sunitinib, and especially
sorafenib – compounds used in the SM and GIST setting, and which have
acceptable safety profiles for use in the clinic.
BLU-554
As BLU-554 displays
exquisite selectivity for FGFR4, the probability of off-target toxicities is
limited relative to currently approved kinase inhibitors. Thus, a review of
possible on-target toxicities is required.
Knockouts of FGFR1 and 2
in mice are embryonic lethal, while those for the null FGFR3 display severe
developmental skeletal deformities. Knockout mice of FGFR4, the target of
BLU-554, do not display a developmental phenotype, suggesting significantly
better safety profile for an FGFR4 specific inhibitor vs a pan FGFR inhibitor.
In adult mice, FGFR4 is
expressed primarily in the liver. Null mice develop no histopathological
changes in this organ however, and display normal blood chemistry. FGFR4, via
its ligand FGF19, serves as a negative feedback loop for bile acid synthesis.
In the null mouse, bile acid is produced in excess. Consequences of this could
be diarrhea and an increased risk of colon cancer (hypothesized to be driven by
the bile acid deoxycholate based on epi studies). This adverse event could likely be managed
with clinically approved bile acid sequestrants.
Team Experience
Financial Health
With its recent IPO,
Blueprint currently holds approximately $200M in cash to fund its activities.
Based on the company’s published operating expenses and anticipated increases
in expenditures as clinical trials are commenced, the company likely has
sufficient cash on hand to fund corporate activities through the end of 2017
(that is, beyond significant value creation milestones).
Meaningful Milestones
Blueprint anticipates opening Phase 1, dose
escalation trials by September for BLU-285 in SM and GIST, and for BLU-554 in
HCC. Because genetically targeted patient populations will be treated with the
compounds in early trials, significant anti-tumor efficacy may be seen during
dose escalation. If observed, well-documented cases of tumor regression would
represent significant value inflection points for the company. Evidence of
efficacy would likely be reported in the 2nd half of 2016.
For BLU-285 in SM, over 90% of subjects will
likely carry the KIT-D816V mutation, meaning that a majority may benefit from
the drug once therapeutically meaningful doses are achieved. For BLU-285 in
refractory/relapsed GIST, a fraction of subjects (> 20%) will carry the
KIT-D816V or PDGFRa-D42V target mutations. An efficacy signal may be detected
in these patients, but more meaningful data will be achieved once a dose
expansion cohort is initiated in subjects who carry these mutations. This
cohort will commence once a maximum tolerated dose is achieved (possibly toward
the middle of 2016).
For BLU-554, it’s anticipated that about 1 in
3 subjects enrolled during the dose escalation Phase 1 trial will have FGFR4
hyperactivity. Although an efficacy signal may be seen early, more conclusive
evidence will come once a maximum tolerated dose is reached and an expansion
cohort is initiated in patients with the target mutation. As with BLU-285,
proof of concept efficacy and safety data for BLU-554 are expected for the
second half of 2016.
Platform Potential
With over 500 kinases encoded in the human
genome, and key roles for many kinases reported across disease indications like
oncology, immunology, and genetic disorders, Blueprint’s platform of kinase
inhibitors that allows the company to drug over 80% of all human kinases will
likely yield promising drug programs for years to come. One particularly
promising area for further exploration of the platform is in the space of
cancer immunotherapies.
