Subcutaneous Formulation of DARZALEX®▼(Daratumumab) Combination Resulted in Deep and Rapid Haematologic Responses and Improved Clinical Outcomes in the Treatment of Patients with Newly Diagnosed Light Chain (AL) Amyloidosis

ANDROMEDA study investigated the first and only subcutaneous anti-CD38 monoclonal antibody in treatment of rare multi-system disease with a high unmet medical need for which there are currently no approved therapies Data selected as late-breaking abstract and featured in press briefing at EHA

BELGIUM, BEERSE, June 13, 2020 – 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.^[i],[ii] 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.[iii] 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.[iv]^,[v] 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.[vi]^,[vii]

“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[1]. “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

[1]Professor Giovanni Palladini has an ongoing contractual relationship with Janssen Pharmaceutica NV

[i] Desport E, Bridoux F, Sirac C, Delbes S, Bender S, Fernandez B, Quellard N, Lacombe C, Goujon JM, Lavergne D, Abraham J. Al amyloidosis. Orphanet journal of rare diseases. 2012 Dec;7(1):54.

[ii] 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.

[iii] 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.

[iv] 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.

[v] 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.

[vi] 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.

[vii] Leng S, Bhutani D, Lentzsch S. Amyloid Therapy and Targets. Clinical Lymphoma, Myeloma and Leukemia. 2019 Sep 1;19:S49-52.