Company Announcement
- DARZALEX (daratumumab) approved by U.S. FDA in combination with lenalidomide and dexamethasone, or
bortezomib and dexamethasone for relapsed or refractory multiple myeloma
- Financial guidance updated to include milestone payments totaling USD 65
million
Copenhagen, Denmark; November 21, 2016 – Genmab A/S (Nasdaq
Copenhagen: GEN) announced today the U.S. Food and Drug Administration (FDA) has approved the use of DARZALEX®
(daratumumab) in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients
with multiple myeloma who have received at least one prior therapy. In July 2016,
daratumumab was granted a Breakthrough Therapy Designation (BTD) in this patient population. In August 2012, Genmab granted
Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize DARZALEX.
Genmab will receive milestone payments totaling USD 65 million from Janssen associated with the first
commercial sale of the daratumumab in combination with lenalidomide and dexamethasone and in combination with bortezomib and
dexamethasone in the United States. As this will occur quickly after this approval, Genmab is improving its financial
guidance for the year. See the Outlook section of this announcement for more information.
“This is an exciting day for patients with multiple myeloma in the U.S., who will now have the opportunity to
receive DARZALEX at an earlier point in treatment of their disease,” said Jan van de Winkel, Ph.D., Chief Executive Officer of
Genmab. “We believe daratumumab has the potential to become a backbone therapy for multiple myeloma.”
The approval was based on data from two Phase III studies: the CASTOR study of daratumumab in combination with
bortezomib and dexamethasone versus bortezomib and dexamethasone alone in patients with relapsed or refractory multiple myeloma,
and the POLLUX study of daratumumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone
in patients with relapsed or refractory multiple myeloma.
Data from the Phase I study of daratumumab in combination with pomalidomide and dexamethasone in relapsed or
refractory multiple myeloma was also submitted as part of the supplemental Biologics License Application (sBLA) for daratumumab in
the newly approved indications in August 2016. The FDA granted a Standard Review for the use of daratumumab in combination with
pomalidomide and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received at
least two prior therapies, including a proteasome inhibitor and an immunomodulatory agent. The FDA assigned a Prescription Drug
User Fee Act (PDUFA) target date of June 17, 2017 for the combination of daratumumab with pomalidomide and
dexamethasone.
DARZALEX was initially approved by the FDA in November 2015 for the monotherapy treatment of patients with
multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an
immunomodulatory agent, or who are double-refractory to a PI and immunomodulatory agent.
OUTLOOK
| MDKK |
Revised Guidance |
Previous Guidance |
| Revenue |
1,650 – 1,700 |
1,200 – 1,250 |
| Operating expenses |
(800) – (850) |
(800) – (850) |
| Operating income |
825 – 875 |
375 – 425 |
| Cash position at end of year* |
3,650 – 3,750 |
3,650 – 3,750 |
| *Cash, cash equivalents, and marketable
securities |
Genmab is improving the 2016 financial guidance it published on November 2, 2016, due
to the inclusion of daratumumab milestones totaling USD 65 million. The milestones are associated with the first commercial sale of
DARZALEX in combination with lenalidomide and dexamethasone, and bortezomib and dexamethasone, for the treatment of patients with
multiple myeloma who have received at least one prior therapy in the U.S. following FDA approval in this indication.
Operating Result
We expect our 2016 revenue to be in the range of DKK 1,650 – 1,700 million, an increase of DKK 450 million
compared to the previous guidance. We have increased our projected daratumumab milestones to DKK 1,020 million (previously
DKK 570 million) due to inclusion of USD 65 million in milestone payments triggered by the first commercial sale of DARZALEX
in combination with lenalidomide and dexamethasone, and bortezomib and dexamethasone, for the treatment of
patients with multiple myeloma who have received at least one prior therapy. We expect DARZALEX
royalties to remain in the range of DKK 400 – 450 million, based on an estimated USD 500 – 550 million of DARZALEX sales in 2016.
The remainder of the revenue mainly consists of Arzerra® royalties, DuoBody® milestones, and non-cash
amortization of deferred revenue.
We anticipate that our 2016 operating expenses will remain in the range of DKK 800 – 850 million.
As a result of the increased revenue, we now expect the operating income for 2016 to be approximately DKK 825 –
875 million, compared to DKK 375 – 425 million in the previous guidance.
Cash Position
There is no change to the projected cash position at the end of 2016 of DKK 3,650 – 3,750 million as we expect to
receive payment for the additional milestones shortly after year-end.
Outlook: Risks and Assumptions
In addition to factors already mentioned, the estimates above are subject to change due to numerous reasons,
including but not limited to the achievement of certain milestones associated with our collaboration agreements; the timing and
variation of development activities (including activities carried out by our collaboration partners) and related income and costs;
DARZALEX and Arzerra sales and corresponding royalties to Genmab; fluctuations in the value of our marketable securities; and
currency exchange rates. The financial guidance assumes that no significant agreements are entered into during 2016 that could
materially affect the results.
About the CASTOR study
The Phase III CASTOR study included 498 patients who had relapsed or refractory multiple myeloma. Patients
were randomized to receive either daratumumab combined with subcutaneous bortezomib (a type of chemotherapy, called a proteasome
inhibitor) and dexamethasone (a corticosteroid), or bortezomib and dexamethasone alone. The study met the primary endpoint of
improving progression free survival (PFS); Hazard Ratio (HR) = 0.39, 95% CI 0.28-0.53, p<0.0001. The median PFS for patients
treated with daratumumab has not been reached, compared to median PFS of 7.2 months for patients who did not receive
daratumumab. Daratumumab also significantly increased the overall response rate (ORR) (79% vs. 60%, p<0.0001), including
doubling rates of complete response (CR) or better (18% vs. 9%) and rates of very good partial response (VGPR) or better (57% vs.
28%). The most common grade 3 or 4 adverse events in patients treated with daratumumab in combination with bortezomib and
dexamethasone compared to those who only received bortezomib and dexamethasone were thrombocytopenia (47% vs 35%), anemia (13% vs
14%) and neutropenia (15% vs 5%). Daratumumab-associated infusion-related reactions were reported in 45% of patients, were mostly
grade 1/2, and occurred predominantly during the first infusion. This is consistent with the reported safety profile of daratumumab
monotherapy and background bortezomib/dexamethasone therapy.
About the POLLUX study
The Phase III POLLUX study enrolled 569 patients who had relapsed or refractory multiple myeloma. Patients
were randomized to receive either daratumumab combined with lenalidomide (an immunomodulatory drug) and dexamethasone (a
corticosteroid), or lenalidomide and dexamethasone alone. The study met the primary endpoint of improving progression-free
survival (PFS) (Hazard Ratio (HR) = 0.37; 95% CI 0.27-0.52; p<0.0001) for patients treated with daratumumab versus patients who
did not receive daratumumab. Patients who received treatment with daratumumab in combination with lenalidomide and
dexamethasone had a 63% reduction in risk of their disease progressing, compared to those who did not receive daratumumab. The
median PFS for patients treated with daratumumab in combination with lenalidomide and dexamethasone has not been reached, compared
to an estimated median PFS of 18.4 months for patients who received lenalidomide and dexamethasone alone. Additionally, daratumumab
significantly increased ORR (91% vs. 75%, p<0.0001, including doubling rates of CR or better (42% vs. 19%), as well as rates of
VGPR or better (75% vs. 43%). The most common grade 3 or 4 adverse events in patients treated with daratumumab in combination with
lenalidomide and dexamethasone versus those who received only lenalidomide and dexamethasone were neutropenia (53% vs 40%),
thrombocytopenia (13% vs 15%), and anemia (13% vs 19%). Daratumumab-associated infusion-related reactions occurred in 48% of
patients, were mostly grade 1/2, and occurred predominantly during the first infusion. Overall, the safety profile was consistent
with known toxicities of daratumumab monotherapy and combination therapy of lenalidomide and dexamethasone.
Both the CASTOR study and the POLLUX study were published in The New England Journal of Medicine in
August 2016 and October 2016 respectively.
About multiple myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess
proliferation of plasma cells.1 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and
lymphoma.2 Approximately 30,330 new patients are expected to be diagnosed with multiple myeloma and approximately 12,650
people are expected to die from the disease in the U.S. in 2016.3 Globally, it was estimated that 124,225 people would
be diagnosed and 87,084 would die from the disease in 2015.4 While some patients with multiple myeloma have no
symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation,
kidney problems or infections.5 Patients who relapse after treatment with standard therapies,
including proteasome inhibitors or immunomodulatory agents, have poor prognoses and few treatment options.6
About DARZALEX® (daratumumab)
DARZALEX® (daratumumab) injection for intravenous infusion is indicated in the United States for the
treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome
inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory
agent.7 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug
Administration (FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe for use as
monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI
and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. For
more information, visit
www.DARZALEX.com.
Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is
believed to induce rapid tumor cell death through programmed cell death, or apoptosis,7,8 and multiple immune-mediated
mechanisms, including complement-dependent cytotoxicity,7,8 antibody-dependent cellular
phagocytosis9,10 and antibody-dependent cellular cytotoxicity.7,8 In addition, daratumumab therapy
results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and
B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were accompanied by increases in CD4+ and
CD8+ T cell numbers in both the peripheral blood and bone marrow.7,11
Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop,
manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline
settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and
pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma, non-Hodgkin’s lymphoma and solid
tumors.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS - None
WARNINGS AND PRECAUTIONS
Infusion Reactions – DARZALEX® can cause severe infusion
reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also
occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior
to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion.
Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs
and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and
nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.
Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients
during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed.
Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the
infusion rate when re-starting the infusion.
To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following
DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion
medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled
corticosteroids for patients with chronic obstructive pulmonary disease.
Interference with Serological Testing - Daratumumab binds to CD38 on
red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive
indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks
detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not
impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has
received DARZALEX. Type and screen patients prior to starting DARZALEX.
Neutropenia - DARZALEX may increase neutropenia induced by background
therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for
background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX dose delay may be required to allow
recovery of neutrophils. No dose reduction of DARZALEX is recommended. Consider supportive care with growth factors.
Thrombocytopenia - DARZALEX may increase thrombocytopenia induced by
background therapy. Monitor complete blood cell counts periodically during treatment according to
manufacturer’s prescribing information for background therapies. DARZALEX dose delay may be required to allow recovery of
platelets. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions.
Interference with Determination of Complete Response - Daratumumab is
a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation
(IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete
response and of disease progression in some patients with IgG kappa myeloma protein.
Adverse Reactions – In patients who received DARZALEX in combination
with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (92%),
thrombocytopenia (73%), upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough
(30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse events was
49%. Serious adverse reactions were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia
(3%).
In patients who received DARZALEX in combination with bortezomib and dexamethasone, the most frequently
reported adverse reactions (incidence ≥20%) were: thrombocytopenia (90%), neutropenia (58%), peripheral sensory neuropathy (47%),
infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea
(21%). The overall incidence of serious adverse events was 42%. Serious adverse reactions were upper respiratory tract infection
(5%), diarrhea (2%) and atrial fibrillation (2%).
In patients who received DARZALEX as monotherapy, the most frequently reported adverse reactions (incidence
≥20%) were: neutropenia (60%), thrombocytopenia (48%), infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%),
pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). Serious adverse reactions were reported in 51 (33%)
patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia
(3%).
DRUG INTERACTIONS
Effect of Other Drugs on daratumumab: The coadministration of lenalidomide or bortezomib with DARZALEX did not
affect the pharmacokinetics of daratumumab.
Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX with bortezomib did not affect the
pharmacokinetics of bortezomib.
About Genmab
Genmab is a publicly traded, international biotechnology company specializing in the creation and development of
differentiated antibody therapeutics for the treatment of cancer. Founded in 1999, the company has two approved antibodies,
Arzerra® (ofatumumab) for the treatment of certain chronic lymphocytic leukemia indications and DARZALEX® (daratumumab) for the
treatment of heavily pretreated or double refractory multiple myeloma. A subcutaneous formulation of ofatumumab is in development
for relapsing multiple sclerosis. Daratumumab is in clinical development for additional multiple myeloma indications and for
non-Hodgkin’s lymphoma. Genmab also has a broad clinical and pre-clinical product pipeline. Genmab's technology base consists
of validated and proprietary next generation antibody technologies - the DuoBody® platform for generation of bispecific antibodies,
and the HexaBody® platform which creates effector function enhanced antibodies. The company intends to leverage these
technologies to create opportunities for full or co-ownership of future products. Genmab has alliances with top tier pharmaceutical
and biotechnology companies. For more information visit
www.genmab.com.
Contact:
Rachel Curtis Gravesen, Senior Vice President, Investor Relations & Communications
T: +45 33 44 77 20; M: +45 25 12 62 60; E: r.gravesen@genmab.com
This Company Announcement contains forward looking statements. The words “believe”, “expect”, “anticipate”,
“intend” and “plan” and similar expressions identify forward looking statements. Actual results or performance may differ
materially from any future results or performance expressed or implied by such statements. The important factors that could cause
our actual results or performance to differ materially include, among others, risks associated with pre-clinical and clinical
development of products, uncertainties related to the outcome and conduct of clinical trials including unforeseen safety issues,
uncertainties related to product manufacturing, the lack of market acceptance of our products, our inability to manage growth, the
competitive environment in relation to our business area and markets, our inability to attract and retain suitably qualified
personnel, the unenforceability or lack of protection of our patents and proprietary rights, our relationships with affiliated
entities, changes and developments in technology which may render our products obsolete, and other factors. For a further
discussion of these risks, please refer to the risk management sections in Genmab’s most recent financial reports, which are
available on www.genmab.com. Genmab does not undertake
any obligation to update or revise forward looking statements in this Company Announcement nor to confirm such statements in
relation to actual results, unless required by law.
Genmab A/S and its subsidiaries own the following trademarks: Genmab®; the Y-shaped Genmab
logo®; Genmab in combination with the Y-shaped Genmab logo™; the DuoBody logo®; the HexaBody logo™;
HuMax®; HuMax-CD20®; DuoBody®; HexaBody® and UniBody®. Arzerra®
is a trademark of Novartis AG or its affiliates. DARZALEX® is a trademark of Janssen Biotech, Inc.
1 American Cancer Society. "Multiple Myeloma Overview." Available at
http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-what-is-multiple-myeloma. Accessed June 2016.
2 National Cancer Institute. "A Snapshot of Myeloma." Available at
www.cancer.gov/research/progress/snapshots/myeloma. Accessed June 2016.
3 American Cancer Society. "What are the key statistics about multiple
myeloma?" http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-key-statistics. Accessed June
2016.
4 GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence
Worldwide: Number of New Cancers in 2015. Available at:
http://globocan.iarc.fr/old/burden.asp?selection_pop=224900&Text-p=World&selection_cancer=17270&Text-c=Multiple+myeloma&pYear=3&type=0&window=1&submit=%C2%A0Execute.
Accessed June 2016.
5 American Cancer Society. "How is Multiple Myeloma Diagnosed?"
http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-diagnosis. Accessed June 2016.
6 Kumar, SK et al. Risk of progression and survival in multiple myeloma
relapsing after last therapy with IMiDs and bortezomib: a multicenter international myeloma working group study.
Leukemia. 2012; 26:149-57.
7 DARZALEX US Prescribing Information, November 2015.
8 De Weers, M et al. Daratumumab, a Novel
Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors. The Journal of
Immunology. 2011; 186: 1840-1848.
9 Overdijk, MB, et al. Antibody-mediated phagocytosis contributes to the
anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015; 7: 311-21.
10 Khagi, Y and Mark, TM. Potential role of daratumumab in the
treatment of multiple myeloma. Onco Targets Ther. 2014; 7: 1095–1100.
11 Krejcik, MD et al. Daratumumab Depletes CD38+ Immune-regulatory Cells,
Promotes T-cell Expansion, and Skews T-cell Repertoire in Multiple Myeloma. Blood. 2016; 128: 384-94.
Company Announcement no. 55
CVR no. 2102 3884
Genmab A/S
Bredgade 34E
1260 Copenhagen K
Denmark
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