JANSSEN-PHARMACEUTICAL

The Janssen Pharmaceutical Companies of Johnson & Johnson announced today results from the first randomised Phase 3 study investigating the subcutaneous (SC) formulation of DARZALEX^® ▼ (daratumumab) in the treatment of patients with newly diagnosed light chain (AL) amyloidosis, a rare and potentially fatal disease.^1,2 The data demonstrated daratumumab SC in combination with cyclophosphamide, bortezomib, and dexamethasone (D-CyBorD) resulted in a significantly higher haematologic complete response rate (CR), 53 percent vs. 18 percent (P <0.0001), compared to CyBorD.³ Additionally, treatment with D-CyBorD delayed the time to major organ deterioration (MOD), haematologic progression or death (MOD-PFS), and enhanced event-free survival (MOD-EFS) based on MOD-PFS criteria with the time to initiation of next therapy.³ The combination showed a safety profile consistent with daratumumab SC or CyBorD alone.³

The results are being highlighted during a press briefing at the 25^th European Hematology Association (EHA) Annual Congress today and will be presented during the late-breaking oral session on Sunday, June 14 at 03:00 p.m. CEST (Abstract LB2604 ).³

AL amyloidosis is a rare and potentially fatal multi-system disorder that occurs when the bone marrow produces abnormal pieces of antibodies called light chains, which clump together to form an amyloid.¹ This amyloid is deposited in tissues and vital organs and interferes with normal organ function.^1,2 As the disease progresses, many patients experience gradual deterioration to multiple organs, including the heart, kidneys, liver, nervous system and digestive tract.² Prognosis is dependent on multiple factors including the pattern and number of organs involved and the treatment regimen.^4,5 Patients with AL amyloidosis have a poor prognosis with an estimated median survival ranging from six months to three years depending on the patient population and data used.⁴ There are currently no therapy options approved by regulatory bodies such as the European Medicines Agency (EMA) or U.S. Food and Drug Administration (FDA) to treat this devastating disease.^6,7

“Due to widely varying symptoms of AL amyloidosis, which can be mistaken for more common conditions, patients are often faced with a delayed diagnosis of several years. These delays to diagnosis and treatment impact on emotional wellbeing, and lead to poorer outcomes for patients,” said Giovanni Palladini, M.D., Ph.D., acting director of the Amyloidosis Research and Treatment Center at the University Hospital San Matteo in Pavia, Italy and study investigator*. “Current therapies focus on slowing the production of amyloid protein and managing symptoms, but there is no approved treatment for AL amyloidosis. The results of the ANDROMEDA study have demonstrated the potential of daratumumab for newly diagnosed patients with AL amyloidosis, which could fulfil a great unmet need and alleviate the burden of organ damage for these patients.”

Results from the ANDROMEDA study showed that the primary endpoint, haematologic CR rate, was 53 percent for D-CyBorD and 18 percent for CyBorD (Odds Ratio=5.1; 95 percent confidence interval [CI], 3.2-8.2; P <0.0001).³ In addition, patients receiving D-CyBorD achieved higher rates of overall haematologic response (92 percent vs. 77 percent) and very good partial response or better (≥VGPR; 79 percent vs. 49 percent) than patients receiving CyBorD.³ Among the 195 patients who responded to treatment in the D-CyBorD arm, median time to ≥VGPR/CR was 17/60 days compared to the 193 patients in the CyBorD arm whose median time to ≥VGPR was 25/85 days.³

The six-month organ response rate nearly doubled for patients treated with D-CyBorD versus CyBorD, for both cardiac (42 percent vs. 22 percent; P =0.0029) and renal (54 percent vs. 27 percent; P <0.0001) responses.³ Additionally, MOD-PFS (Hazard Ratio=0.58; 95 percent CI, 0.36-0.93, P =0.0224) and MOD-EFS (Hazard Ratio=0.40; 95 percent CI, 0.28-0.57, P <0.0001) favoured the D-CyBorD arm, demonstrating substantially delayed major organ deterioration, haematologic progression, or death, as well as improved event-free survival.³ In addition, the D-CyBorD arm, which is delivered subcutaneously, helps to limit intravenous fluid overload, an important treatment factor in the setting of cardiac compromised patients.³

“Through the daratumumab development programme, Janssen has deep expertise in diseases where CD38 is highly expressed. Daratumumab’s mode-of-action gives us an opportunity to treat the underlying cause of AL amyloidosis and potentially bring a new therapy option to patients living with this rare disease,” said Patrick Laroche, M.D., Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag. “Since launch daratumumab has treated over 130,000 patients worldwide and has become the foundation of multiple myeloma treatment, and we will continue to investigate its potential in diseases in which CD38 is expressed.”

The most common Grade 3/4 treatment emergent adverse events occurring in more than 5 percent of patients for the D-CyBorD arm compared to the CyBorD arm, included lymphopenia (13 percent vs. 10 percent), pneumonia (8 percent vs. 4 percent), diarrhoea (6 percent vs. 4 percent), cardiac failure (6 percent vs. 5 percent), neutropenia (5 percent vs. 3 percent), syncope (5 percent vs. 6 percent) and peripheral oedema (3 percent vs. 6 percent).³ The study showed daratumumab SC had a low rate of administration-related reactions (ARR).³ Systemic ARRs in the D-CyBorD arm occurred in 14 patients (7 percent), all were Grade 1-2 and most occurred during the initial administration. A total of 56 deaths occurred (D-CyBorD, n=27; CyBorD, n=29).³

#ENDS#

In Europe, daratumumab is indicated:⁸

• in combination with lenalidomide and dexamethasone or with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant
• in combination with bortezomib, thalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant
• in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy
• as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy

About the ANDROMEDA Study^3,9

ANDROMEDA (NCT03201965 ) is an ongoing Phase 3, randomised, open-label study investigating the safety and efficacy of daratumumab SC in combination with cyclophosphamide, bortezomib and dexamethasone (CyBorD), compared to CyBorD alone, in the treatment of patients with newly diagnosed light chain (AL) amyloidosis.^3,9 The study included 388 patients with newly diagnosed AL amyloidosis with measurable haematologic disease and one or more organs affected. The primary endpoint was overall complete haematologic response rate (intent-to-treat / ITT). Secondary endpoints included major organ deterioration, progression-free survival, event free survival, organ response rate, overall survival, and time to haematologic response, among others.^3,9

About AL Amyloidosis

Light chain (AL) amyloidosis is a rare and potentially fatal haematologic disorder that can affect the function of multiple organs.^1,2 The disease occurs when bone marrow produces abnormal pieces of antibodies called light chains, which clump together to form a substance called amyloid. These clumps of amyloid are deposited in tissues and vital organs and interfere with normal organ function, eventually causing organ deterioration.^1,2 It is the most common type of amyloidosis. AL amyloidosis frequently affects the heart, kidneys, digestive tract, liver and nervous system and is potentially fatal if left untreated.^1,2 Diagnosis is often delayed and prognosis is poor due to advanced, multi-organ, particularly cardiac, involvement.^1,2 Approximately 30,000 to 45,000 patients in the United States and the European Union have AL amyloidosis.¹⁰

About daratumumab and daratumumab SC

Daratumumab is a first-in-class biologic targeting CD38, a surface protein that is highly expressed across multiple myeloma (MM) cells, regardless of disease stage.^8,11 Daratumumab is believed to induce tumour cell death through multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as through apoptosis, in which a series of molecular steps in a cell lead to its death.¹¹ A subset of myeloid derived suppressor cells (CD38+ MDSCs), CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) are decreased by daratumumab-mediated cell lysis.¹¹

In Europe, daratumumab has been approved in five indications, three of which are in the frontline setting, including newly diagnosed MM patients who are transplant eligible and ineligible.⁸ In June 2020 , daratumumab SC (daratumumab and hyaluronidase human-fihj) was approved the European Commission as the only subcutaneous CD38-directed antibody approved to treat patients with multiple myeloma.¹² Daratumumab SC is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme's ENHANZE^® drug delivery technology.¹²

Since launch, it is estimated that 130,000 patients have been treated with daratumumab worldwide.¹³

Daratumumab is being evaluated in a comprehensive clinical development programme across a range of treatment settings in MM, such as in frontline and relapsed settings.^{14,15,16,17,18,19,20,21} Additional studies are ongoing or planned to assess daratumumab SC’s potential in other malignant and pre-malignant haematologic diseases in which CD38 is expressed, such as smouldering myeloma and in AL amyloidosis.^22,23 For more information, please see https://www.clinicaltrials.gov/ .

For further information on daratumumab, please see the Summary of Product Characteristics at https://www.ema.europa.eu/en/medicines/human/EPAR/darzalex .

In August 2012 , Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive licence to develop, manufacture and commercialise daratumumab.²⁴

About the Janssen Pharmaceutical Companies of Johnson & Johnson

At Janssen, we’re creating a future where disease is a thing of the past. We’re the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology, and Pulmonary Hypertension.

Learn more at www.janssen.com/emea . Follow us at www.twitter.com/janssenEMEA for our latest news. Janssen-Cilag, Janssen Pharmaceutica NV, and Janssen Biotech, Inc. are part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

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Cautions Concerning Forward-Looking Statements

This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding the benefits of daratumumab for the treatment of patients with multiple myeloma. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialise, actual results could vary materially from the expectations and projections of Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behaviour and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 29, 2019, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in the company’s most recently filed Quarterly Report on Form 10-Q, and the company’s subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov , www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

ENHANZE^® is a registered trademark of Halozyme.
* Professor Giovanni Palladini has an ongoing contractual relationship with Janssen Pharmaceutica N.V.

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References

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² Merlini G, Comenzo RL, Seldin DC, Wechalekar A, Gertz MA. Immunoglobulin light chain amyloidosis. Expert review of hematology. 2014 Feb 1;7(1):143-56.
³ Kastritis, E. et al. Subcutaneous Daratumumab + Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in Patients with Newly Diagnosed Light Chain (AL) Amyloidosis: Primary Results from the Phase 3 ANDROMEDA Study [LBA]. To be presented at European Hematology Association 2020 Annual Congress.
⁴ McCausland KL, White MK, Guthrie SD, Quock T, Finkel M, Lousada I, Bayliss MS. Light chain (AL) amyloidosis: the journey to diagnosis. The Patient-Patient-Centered Outcomes Research. 2018 Apr 1;11(2):207-16.
⁵ Quock TP, Yan T, Chang E, Guthrie S, Broder MS. Epidemiology of AL amyloidosis: a real-world study using US claims data. Blood advances. 2018 May 22;2(10):1046-53.
⁶ European Medicines Agency. EU/3/19/2222 – AL Amyloidosis. Available at: https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3192222 Last accessed: June 2020.
⁷ Leng S, Bhutani D, Lentzsch S. Amyloid Therapy and Targets. Clinical Lymphoma, Myeloma and Leukemia. 2019 Sep 1;19:S49-52.
⁸ European Medicines Agency. DARZALEX summary of product characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/darzalex-epar-product-information_en.pdf Last accessed: June 2020.
⁹ ClinicalTrials.gov. A Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to CyBorD Alone in Newly Diagnosed Systemic Amyloid Light-chain (AL) Amyloidosis. NCT03201965. Available at: https://clinicaltrials.gov/ct2/show/NCT03201965 Last accessed: June 2020.
¹⁰ Lousada I, Comenzo RL, Landau H, Guthrie S, Merlini G. Light chain amyloidosis: patient experience survey from the Amyloidosis Research Consortium. Advances in therapy. 2015 Oct 1;32(10):920-8.
¹¹ Sanchez L, Wang Y, Siegel DS, Wang ML. Daratumumab: a first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma. J Hematol Oncol . 2016;9:51.
¹² Janssen EMEA. European Commission Grants Marketing Authorisation for DARZALEX®▼(daratumumab) Subcutaneous Formulation for all Currently Approved Daratumumab Intravenous Formulation Indications. Press Release June 04, 2020. Available at: https://www.janssen.com/emea/sites/www_janssen_com_emea/files/european_commission_grants_marketing_authorisation_for_darzalexrvdaratumumab_subcutaneous_formulation_for_all_currently_approved_daratumumab_intravenous_formulation_indications.pdf Last accessed: June 2020.
¹³ [Data on file]. DARZALEX: New Patient Starts Launch to Date. RF-124148
¹⁴ ClinicalTrials.gov. A study to evaluate daratumumab in transplant eligible participants with previously untreated multiple myeloma (Cassiopeia). NCT02541383. Available at: https://clinicaltrials.gov/ct2/show/NCT02541383 Last accessed: June 2020
¹⁵ ClinicalTrials.gov. A study comparing daratumumab, lenalidomide, and dexamethasone with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. NCT02076009. Available at: https://clinicaltrials.gov/ct2/show/NCT02076009 Last accessed: June 2020.
¹⁶ ClinicalTrials.gov. Addition of daratumumab to combination of bortezomib and dexamethasone in participants with relapsed or refractory multiple myeloma. NCT02136134. Available at: https://clinicaltrials.gov/ct2/show/NCT02136134 Last accessed: June 2020.
¹⁷ ClinicalTrials.gov. A study of combination of daratumumab and Velcade (bortezomib) melphalan-prednisone (DVMP) compared to Velcade melphalan-prednisone (VMP) in participants with previously untreated multiple myeloma. NCT02195479. Available at: https://clinicaltrials.gov/ct2/show/NCT02195479 Last accessed: June 2020.
¹⁸ ClinicalTrials.gov. Study comparing daratumumab, lenalidomide, and dexamethasone with lenalidomide and dexamethasone in participants with previously untreated multiple myeloma. NCT02252172. Available at: https://clinicaltrials.gov/ct2/show/NCT02252172 Last accessed: June 2020.
¹⁹ ClinicalTrials.gov. A study of Velcade (bortezomib) melphalan-prednisone (VMP) compared to daratumumab in combination with VMP (D-VMP), in participants with previously untreated multiple myeloma who are ineligible for high-dose therapy (Asia Pacific region). NCT03217812. Available at: https://clinicaltrials.gov/ct2/show/NCT03217812 Last accessed: June 2020.
²⁰ ClinicalTrials.gov. Comparison of pomalidomide and dexamethasone with or without daratumumab in subjects with relapsed or refractory multiple myeloma previously treated with lenalidomide and a proteasome inhibitor daratumumab/pomalidomide/dexamethasone vs pomalidomide/dexamethasone (EMN14). NCT03180736. Available at: https://clinicaltrials.gov/ct2/show/NCT03180736 Last accessed: June 2020.
²¹ ClinicalTrials.gov. Study of carfilzomib, daratumumab and dexamethasone for patients with relapsed and/or refractory multiple myeloma (CANDOR). NCT03158688. Available at: https://clinicaltrials.gov/ct2/show/NCT03158688 Last accessed: June 2020.
²² ClinicalTrials.gov. A Study of Subcutaneous Daratumumab Versus Active Monitoring in Participants With High-Risk Smoldering Multiple Myeloma. NCT03301220. Available at: https://clinicaltrials.gov/ct2/show/NCT03301220 Last accessed: June 2020.
²³ ClinicalTrials.gov. A Study of Daratumumab Monotherapy in Previously Untreated Patients With Stage 3B Light Chain (AL) Amyloidosis. NCT04131309. Available at: https://clinicaltrials.gov/ct2/show/NCT04131309 Last accessed: June 2020.
²⁴ Johnson & Johnson. Janssen Biotech announces global license and development agreement for investigational anti-cancer agent daratumumab. Press release August 30, 2012. Available at: https://www.jnj.com/media-center/press-releases/janssen-biotech-announces-global-license-and-development-agreement-for-investigational-anti-cancer-agent-daratumumab Last accessed: June 2020.

CP-161762
June 2020

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