Sales Revenues at the Potential Expense of Patient Safety:

Ibrutinib is a selective and irreversible inhibitor of Bruton’s tyrosine kinase (BTK) that entered phase 1 clinical trials in 2009 based on preclinical efficacy in models of B-cell malignancy and autoimmune disease.^{[1, 2]} The initial phase 1 trial showed clear efficacy in a number of lymphoid malignancies at doses as low as 1.25 mg/kg/d. Furthermore, full receptor occupancy was demonstrated at 2.5 mg/kg/d. Despite these pharmacological and early clinical findings, development of ibrutinib continued at doses of 420 mg qd and 560 mg qd, levels 3-4 fold higher than suggested by the pharmacological data. In addition, the absorption of ibrutinib is enhanced by administration of food, which may explain why even the lowest dose showed efficacy in some patients.

Ibrutinib is unique in having received four Breakthrough designations on the basis of its efficacy data. It was first approved in November 2013 for the treatment of mantle cell lymphoma at a dose of 560 mg qd, administered as four 140 mg capsules. Three months later, ibrutinib was approved for chronic lymphocytic leukemia (CLL) at a dose of 420 mg qd, again administered as multiple 140 mg capsules. Between July 2014 and August 2017, ibrutinib was approved for five addition indications, but it was not until December 2017 that its 70 mg capsule, necessary to permit safe administration of 70 mg qd in patients with B-cell malignancies receiving posoconazole or patients with moderate hepatic impairment, was approved.

Most recently, the manufacturer received approval of a new tablet formulation of ibrutinib in four different strengths: 140 mg, 280 mg, 420 mg, and 560 mg. Of note, these tablets of varying potencies are priced the same. It may initially appear to be appealing to have higher strengths as a single tablet, as opposed to 1-4 capsules per day. However, this new formulation is associated with removal of the 140 mg capsules (priced at about one third the cost of the new 140 mg tablet) from the market, as well as a marketing and pricing scheme that raises concerns regarding patient safety and access for lower socio-economic groups.

This flat pricing scheme appears to have been motivated by the manufacturer’s awareness of the increasing interest in utilizing lower doses of ibrutinib off-label.

The current ibrutinib label is very complex, as it identifies five potential dosages to be administered over an 8-fold range (70 mg, 140 mg, 280 mg, 420 mg, and 560 mg). The specific dosage to be prescribed depends on the indication, the patient’s prior toxicities, concomitant medications, occurrence of ibrutinib intolerance, and current hepatic function. These criteria are all dynamic, often not based on pharmacologic data, and thus frequent dosage adjustments may be required, both upwards and downwards. For example, many patients for whom ibrutinib is indicated (e.g., CLL, chronic graft-versus-host disease) are at increased risk of infection, and will require concomitant (and likely temporary) antifungals (e.g., posoconazole, fluconazole) or macrolide antibiotics (e.g., erythromycin). Furthermore, patients with concomitant cardiovascular disease may intermittently require calcium channel blockers (e.g., diltiazem, verapamil). Finally, these patients are also at risk for developing hepatic dysfunction, either due to disease (e.g., hepatic graft-versus-host disease) or other intercurrent illness. All of the aforementioned scenarios require rapid dosage reduction to as low as 70 mg qd, and potentially reinstitution of the prior dosage if and when the intervening event is reversed.

While the prescribing information is complex, prescribers and patients have had the flexibility of taking anywhere from one to four 140 mg capsules, readily permitting dose reduction to all but the lowest labeled dose (70 mg). However, the new formulation and its associated marketing scheme (You&i^TM) greatly impact the ability of the prescriber and patient to follow the prescribing information, resulting in the potential for a greatly enhanced risk of toxicities relative to that observed in the clinical trials which utilized multiples of the 140 mg capsules.

Delays in therapy at the new dose will be at least 2 days and usually more, because new drug will have to be secured by mail order, and will require significantly more participation by physicians and mid-level providers. Specifically, the new marketing and pricing scheme ensures that all patients are dispensed a single tablet (or capsule) a day at one of the five marketed strengths. Thus, patients will not be able to titrate their daily dosage on the advice of a physician (e.g., in the context of off-target toxicities and intercurrent illness, such as a fungal infection requiring an azole).

In order to ensure that all patients receive a single tablet rather than multiple 140 mg tablets, the manufacturer has priced all tablet strengths at the same price, so that a physician who wished to prescribe 420 mg as three 140 mg tablets would be unlikely to get payor approval to do so, since the cost would be 300% of the single 420 mg tablet. Furthermore, patients who have been on a daily dose of 140 mg now find that the cost of their 140 mg tablet is more than three-fold higher than the cost of their prior 140 mg capsule.

While flat pricing schemes are not uncommon, it is highly unusual to change from a linear (i.e., per mg) to flat pricing scheme after initial marketing approval, over an eight-fold range of daily dosages. Furthermore, this flat pricing scheme appears to have been motivated by the manufacturer’s awareness of the increasing interest in utilizing lower doses of ibrutinib off-label,^[3] based on a study initiated at MD Anderson in June 2016 and recently presented at the 2017 meeting of the American Society of Hematology. In this small pilot study, the dose was lowered from 420 mg to 280 mg, then to 140 mg qd, without any apparent loss of biological efficacy, not surprising given the initial phase 1 study.

The MD Anderson study was initiated based on the molecular pharmacology of ibrutinib. At the molecular level, a single ibrutinib molecule binds covalently to a single BTK molecule, thereby inactivating BTK. Hence a 1:1 stoichiometry is needed to inhibit the BTK target. Once this is achieved, free drug is only required if additional BTK protein is synthesized. Because BTK transcription is driven by NF-kappaB, a downstream target in the B-cell receptor pathway and suppressed by ibrutinib, it is believed that ibrutinib both inactivates BTK and inhibits BTK synthesis. In fact, after one cycle of ibrutinib at the standard dose, both BTK mRNA and protein levels decreased in circulating CLL lymphocytes.^[4] Such decline supports the use of a lower subsequent dose of ibrutinib, considering the 1:1 stoichiometry. Results of the pilot protocol (NCT02801578) suggest that after one cycle of the standard 420 mg dose of ibrutinib, the dose may be lowered to 140 mg qd for subsequent cycles without compromising the biological impact.^[3]

While clinical efficacy was not evaluated in the pilot protocol using a lower ibrutinib dose, in the real-world situation, as many as one-third of patients with CLL require a lower ibrutinib dose due to toxicity. This is a common occurrence and has been reported in the US^[5], UK^[6], Sweden^[7], and Poland^[8]. The dose decrease occurred after one or more cycles of full dose ibrutinib. Importantly, these patients had identical overall and progression-free survival as those who did not require dose reductions, further demonstrating the clinical utility and appropriateness of dose reductions in patients with CLL.

Given the expected frequency of dose adjustments, the manufacturer (and/or its marketing partner) has developed the You&i^TM program to allow patients to exchange their current tablets for those of a different strength. However, this program is inconsistent with rapid dose adjustments, since it requires completion of a form by the prescriber, signature of the form by a You&i^TM pharmacist (only available from 8 am to 8 pm Eastern Time, Monday to Friday), shipping of the new strength to the patient, and the requirement for return of the patient’s prior tablets to the manufacturer. In the event of a temporary dose reduction (e.g., 14 day course of antibiotics), the process would need to occur again. This is critical because prior studies have demonstrated that a gap of a week or more without ibrutinib can impact survival.^[9] Any putative convenience advantage of taking one pill a day is negated by the marked inconvenience to the patient of having to return pills every time there is a need for a dosage change. Furthermore, in the future, it is likely that many patients will be receiving combinations with other agents. Dosage adjustment in combination protocols is often much more complicated than for single agents.

It is worth comparing the prescribing information for ibrutinib with that of warfarin, which has been called “the most dangerous drug in America”.^[10] Warfarin is formulated in nine strengths ranging from 1-10 mg daily. However, prescribers have complete discretion to select the dose strength most appropriate for each individual patient, and may choose to prescribe a 2 mg strength for a patient whose daily dosage requirement ranges from 4-6 mg daily. Prescribers also choose to use every other day dosing on occasion. Needless to say, it would be not be possible to safely use warfarin if the prescriber had to order a new tablet strength for each and every dosage change.

In contrast to warfarin, we do not believe that physicians and patients will be able to prescribe and self-administer ibrutinib in accordance with the prescribing instructions without the ability to prescribe 140 mg tablets regardless of the daily dosage. When dose reductions are required and substitute tablets are not readily available, physicians will need to choose between continuing the higher dose (a major safety risk) or interruption of the dosing for as long as two weeks, which could potentially impact efficacy.^[9]

In this context, we urge the Food and Drug Administration to review the safety of the You&i^TM program in the context of the approved drug label, given that it creates a barrier to optimal prescribing for some patients. We further urge the FDA to recognize that the combination of the high price per pill and the flat pricing scheme are specific impediments to safe administration, and that ignoring the marketing approach for ibrutinib is antithetical to fostering optimally safe dosing and administration. We also urge clinical investigators to consider studies of every other day dosing of ibrutinib, given that it is an irreversible inhibitor of its target, and that its target’s turnover rate is relatively low and would likely permit effective dosing on this schedule.^[11] Of course, this would also result in a 50% reduction in treatment cost, despite You&i^TM.

References

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2. Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, Li S, Pan Z, Thamm DH, Miller RA, Buggy JJ. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010;107(29):13075-80.
   

3. Bose P, Chen L, Cruz N, Jiang Y, Thompson PA, Feng S, Kroll M, Jain N, Wierda WG, Keating MJ, Gandhi V. 4307 A Pilot Study of Lower Doses of Ibrutinib in Patients (pts) with Chronic Lymphocytic Leukemia (CLL). ASH 59th Annual Meeting & Exposition. 2017(Session: 642, CLL: Therapy, excluding Transplantation: Poster III).
   

4. Cervantes-Gomez F, Kumar Patel V, Bose P, Keating MJ, Gandhi V. Decrease in total protein level of Bruton’s tyrosine kinase during ibrutinib therapy in chronic lymphocytic leukemia lymphocytes. Leukemia. 2016;30(8):1803-4.
   

5. Mato AR, Nabhan C, Thompson MC, Lamanna N, Brander DM, Hill B, Howlett C, Skarbnik A, Cheson BD, Zent C, Pu J, Kiselev P, Goy A, Claxton D, Isaack K, Kennard KH, Timlin C, Landsburg D, Winter A, Nasta SD, Bachow SH, Schuster SJ, Dorsey C, Svoboda J, Barr P, Ujjani CS. Toxicities and outcomes of 621 ibrutinib-treated chronic lymphocytic leukemia patients in the United States: a real-world analysis. Haematologica. 2018.
   

6. Forum UC. Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients. Haematologica. 2016;101(12):1563-72.
   

7. Winqvist M, Asklid A, Andersson PO, Karlsson K, Karlsson C, Lauri B, Lundin J, Mattsson M, Norin S, Sandstedt A, Hansson L, Osterborg A. Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group. Haematologica. 2016;101(12):1573-80.
   

8. Iskierka-Jazdzewska E, Hus M, Giannopoulos K, Madro E, Holojda J, Piotrowska M, Zaucha JM, Piszczek W, Szeremet A, Wojciechowska M, Steckiewicz P, Knopinska-Posluszny W, Osowiecki M, Drozd-Sokolowska J, Kumiega B, Kyrcz-Krzemien S, Halka J, Dudzinski M, Wieszczy P, Robak T, Warzocha K, Jamroziak K. Efficacy and toxicity of compassionate ibrutinib use in relapsed/refractory chronic lymphocytic leukemia in Poland: analysis of the Polish Adult Leukemia Group (PALG). Leuk Lymphoma. 2017;58(10):2485-8.
   

9. Barr PM, Brown JR, Hillmen P, O’Brien S, Barrientos JC, Reddy NM, Coutre S, Mulligan SP, Jaeger U, Furman RR, Cymbalista F, Montillo M, Dearden C, Robak T, Moreno C, Pagel JM, Burger JA, Suzuki S, Sukbuntherng J, Cole G, James DF, Byrd JC. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood. 2017;129(19):2612-5.
   

10. Ornstein C. Popular Blood Thinner Causing Deaths, Injuries at Nursing Homes. ProPublica. 2015.

11. Daryaee F, Zhang Z, Gogarty KR, Li Y, Merino J, Fisher SL, Tonge PJ. A quantitative mechanistic PK/PD model directly connects Btk target engagement and in vivo efficacy. Chem Sci. 2017;8(5):3434-43.