Mechanism of Action of NINLARO^® (ixazomib)

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The camera opens on the Takeda logo.

For two decades, Takeda has been a trusted partner and leader in the fight against multiple myeloma with a relentless focus on innovation,…

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The logo begins to fade and the camera now shows a shot of a thigh bone.

…including pioneering proteasome inhibition with the first ever proteasome inhibitor, or PI…

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The camera zooms into the bone marrow.

…in 2003 and subsequently bringing an oral proteasome inhibitor to patients in 2015 [1] [2].

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We see plasma cells dividing uncontrollably.

Multiple myeloma is a cancer of the bone marrow, characterized by the irregular expansion of plasma cells [3][4].

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We crash zoom further into a plasma cell of the tumor to see the proteasome.

The ubiquitin proteosome pathway allows for the degradation of proteins. The 26S proteasome is composed of a 20S proteolytic core [5].

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We see a glow to indicate the protein function.

Therapeutic targeting of the proteasome has been a cornerstone of multiple myeloma treatment…

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A call out appears on screen in time with the VO with the words ‘Arrests cell growth and causes cell death.’

… because the disruption of proteasome activity arrests cell growth and causes cell death [5].

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The call outs disappear and the individual subunits of the proteasome are visible. Labels appear on screen for the two alpha subunits, for the two beta subunits and the two 19S regulatory complexes that cap the barrel.

This 20S core is made up of individual subunits which mediate proteolytic cleavage [5].

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The labels disappear and the 19S subunit is highlighted to draw attention.

When proteins are marked for degradation, they are recognized by the 19S cap and directed to the core of the proteasome [5].

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The Beta subunits of the proteasome are now highlighted.

Proteolytic cleavage is mediated through Beta subunits [5].

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The compound comes into frame, and we see a hero shot (NINLARO 4mg) as well as the NINLARO logo.

NINLARO or ixazomib is the only oral proteasome inhibitor and is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is not recommended for use in the maintenance setting or in newly diagnosed multiple myeloma in combination with lenalidomide and dexamethasone outside of controlled clinical trials [1].

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The compound binds to the proteasome inhibitor through the Beta 5 subunit.

In vitro, NINLARO is a reversible proteasome inhibitor that preferentially binds to the Beta 5 subunit of 20S [1].

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The proteasome is no longer functioning due to the presence of the compound.

It inhibits the chymotrypsin-like activity of the Beta 5 subunit [1] …

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The environment turns slightly darker, and we see a build-up of proteins within the cell.

…disrupting the elimination of proteins which leads to cytotoxicity…

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We zoom out slightly to view the mass of tumour cells. Cells in the tumour begin to disintegrate as cancer cell death is shown.

…inducing the apoptotic cascade and killing myeloma cells [6] .

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We crash zoom back out of the bone marrow environment.

N/A

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We see the MM patient (who is in their 70s) reading the drug packaging.

As part of an all-oral regimen, in combination with lenalidomide and dexamethasone, NINLARO may be a convenient option for patients at first relapse with multiple myeloma Ninlaro is not recommended for use in the maintenance setting or in newly diagnosed multiple myeloma in combination with lenalidomide and dexamethasone outside of controlled clinical trials.  [1] [7] .

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We see a mosaic of patients enjoying their life outside example: diverse people gardening, elderly couple on a cruise, playing with grandchildren.

The Ninlaro regimen may help facilitate long-term treatment until disease progression due to the convenience of oral administration and manageable safety profile [1].

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On screen text with a graphic to indicate patients

The NINLARO regimen may be prescribed to patients at first relapse who are experiencing an indolent relapse or elderly with an active lifestyle [1][3].

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On-screen scrolling text in line with the VO, moving into ISI information.

NINLARO is also associated with these serious adverse reactions and drug interactions:

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

• Thrombocytopenia has been reported with NINLARO. Platelet nadirs typically occurred

between Days 14-21 of each 28-day cycle and recovered to baseline by the start of the

next cycle. Grade 3 thrombocytopenia was reported in 17% of patients in the NINLARO

regimen and Grade 4 thrombocytopenia was reported in 13% in the NINLARO regimen.

During treatment, monitor platelet counts at least monthly, and consider more frequent

monitoring during the first three cycles. Manage thrombocytopenia with dose

modifications and platelet transfusions as per standard medical guidelines.

• Gastrointestinal Toxicities, including diarrhea, constipation, nausea and vomiting were

reported with NINLARO and may occasionally require the use of antidiarrheal and

antiemetic medications, and supportive care. Diarrhea resulted in the discontinuation of

one or more of the three drugs in 3% of patients in the NINLARO regimen and 2% of

patients in the placebo regimen. Adjust dosing for Grade 3 or 4 symptoms.

ADVERSE REACTIONS

The most common adverse reactions (≥ 20%) in the NINLARO regimen compared to placebo in

combination with lenalidomide plus dexamethasone, respectively were thrombocytopenia (85%,

67%; pooled from adverse event and laboratory data), neutropenia (74%, 70%; pooled from

adverse event and laboratory data), diarrhea (52%, 43%), constipation (35%, 28%), peripheral

neuropathy (32%, 24%), nausea (32%, 23%), edema peripheral (27%, 21%), rash (27%, 16%),

vomiting (26%, 13%), and bronchitis (22%, 17%). Serious adverse reactions reported in ≥ 2% of

patients in the NINLARO regimen included diarrhea (3%), thrombocytopenia (2%), and

bronchitis (2%).

• Thrombotic Microangiopathy has been reported with NINLARO. Fatal cases of

thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic

uremic syndrome (TTP/HUS), have been reported in patients who received NINLARO.

Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop

NINLARO and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting

NINLARO. The safety of reinitiating NINLARO therapy in patients previously

experiencing TTP/HUS is not known.

• Peripheral Neuropathy was reported with NINLARO. The most commonly reported

reaction was peripheral sensory neuropathy (24% and 17% in the NINLARO and

placebo regimens, respectively). Peripheral motor neuropathy was not commonly

reported in either regimen (<1%). Peripheral neuropathy resulted in discontinuation of

one or more of the three drugs in 4% of patients in the NINLARO regimen and <1% of

patients in the placebo regimen. During treatment, monitor patients for symptoms of

neuropathy and consider adjusting dosing for new or worsening peripheral neuropathy.

• Hepatotoxicity has been reported with NINLARO. Drug-induced liver injury,

hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have

each been reported in <1% of patients treated with NINLARO. Hepatotoxicity has been

reported (10% in the NINLARO regimen and 9% in the placebo regimen). Monitor

hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms.

• Embryo-fetal Toxicity: NINLARO can cause fetal harm. Advise pregnant women of the

potential risk to a fetus. Advise females of reproductive potential to use effective nonhormonal

contraception during treatment with NINLARO and for 90 days following the

last dose. Advise males with female partners of reproductive potential to use effective

contraception during treatment with NINLARO and for 90 days following the last dose.

• Increased Mortality in Patients Treated with NINLARO in the Maintenance

Setting: In two prospective randomized clinical trials in multiple myeloma in the

maintenance setting, treatment with NINLARO resulted in increased deaths. Treatment

of patients with NINLARO for multiple myeloma in the maintenance setting is not

recommended outside of controlled trials.

• Peripheral Edema was reported with NINLARO. Evaluate for underlying causes and

provide supportive care, as necessary. Adjust dosing of NINLARO for Grade 3 or 4

symptoms or dexamethasone per its prescribing information.

• Cutaneous Reactions, including a fatal case of Stevens-Johnson syndrome, were

reported with NINLARO. If Stevens-Johnson syndrome occurs, discontinue NINLARO

and manage as clinically indicated. Rash, most commonly maculo-papular and macular

rash, was reported with NINLARO. Rash resulted in discontinuation of one or more of

the three drugs in <1% of patients in both regimens. Manage rash with supportive care

or with dose modification if Grade 2 or higher.

DRUG INTERACTIONS: Avoid concomitant administration of NINLARO with strong CYP3A

inducers.

USE IN SPECIFIC POPULATIONS

• Lactation: Advise women not to breastfeed during treatment with NINLARO and for 90

days after the last dose.

• Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with

moderate or severe hepatic impairment.

• Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe

renal impairment or end-stage renal disease requiring dialysis. NINLARO is not

dialyzable. [1]

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-

617-6468 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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The graphics disappear and we are back on the previous footage of the patient mosaic.

The Ninlaro regimen may provide the benefits of long-term proteasome inhibition, defined as treatment until disease progression [1].

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Continuation of previous frame, closing on NINLARO and Takeda logo.

The Ninlaro regimen may offer extended efficacy and manageable tolerability for the types of patients with relapsed multiple myeloma you see everyday [1][8][9][10][11].

References

1. NINLARO. Prescribing Information. Takeda Pharmaceuticals America, Inc.; 05/2022: https://www.ninlaro.com/prescribing-information.pdf. Accessed September 2022.
2. VELCADE. Prescribing Information. Takeda Pharmaceuticals America, Inc.; 08/2022: https://www.velcade.com/files/pdfs/VELCADE_PRESCRIBING_INFORMATION.pdf. Accessed September 2022.
3. Raedler LA. Ninlaro (Ixazomib): First Oral Proteasome Inhibitor Approved for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma. Am Health Drug Benefits. 2016;9(Spec Feature):102-105.
4. Mahindra A, Hideshima T, Anderson KC. Multiple myeloma: biology of the disease. Blood Rev. 2010;24 Suppl 1:S5-S11.
5. Moreau P, Richardson PG, Cavo M, Orlowski RZ, San Miguel JF, Palumbo A, Harousseau JL. Proteasome inhibitors in multiple myeloma: 10 years later. Blood. 2012;120(5):947-959.
6. Chauhan D, Hideshima T, Mitsiades C, Richardson P, Anderson KC. Proteasome inhibitor therapy in multiple myeloma. Mol Cancer Ther. 2005;4(4):686-692.
7. Muz B, Ghazarian RN, Ou M, Luderer MJ, Kusdono HD, Azab AK. Spotlight on ixazomib: potential in the treatment of multiple myeloma. Drug Des Devel Ther. 2016;10:217-226.
8. Moreau P, Masszi T, Grzasko N, et al; for TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374(17):1621-1634.
9. Terpos E, Ramasamy K, Maouche N, et al. Real-world effectiveness and safety of ixazomib-lenalidomide-dexamethasone in relapsed/refractory multiple myeloma. Ann Hematol. 2020;99(5):1049-1061.
10. Minarik J, Pika T, Radocha J, et al. Survival benefit of ixazomib, lenalidomide and dexamethasone (IRD) over lenalidomide and dexamethasone (Rd) in relapsed and refractory multiple myeloma patients in routine clinical practice. BMC Cancer. 2021;21(1):73.
11. Hájek R, Minařík J, Straub J, et al. Ixazomib-lenalidomide-dexamethasone in routine clinical practice: effectiveness in relapsed/refractory multiple myeloma. Future Oncol. 2021;17(19):2499-2512.