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Kyprolis – Questions And Answers About The FDA Approval

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Published: Jul 25, 2012 1:31 pm; Updated: Jul 26, 2012 12:08 pm

Last week, the U.S. Food and Drug Administration (FDA) approved Kyprolis (carfilzomib) for the treatment of multiple myeloma patients who have received at least two prior therapies (see related Beacon news).

In this article, The Beacon addresses important questions multiple myeloma patients have been asking about the FDA decision.

What exactly did the FDA approve?

The FDA approved Kyprolis for the treatment of multiple myeloma patients meeting specific criteria.  The patients must have received at least two prior therapies.  These two therapies must have included Velcade (bortezomib) and an immunomodulatory agent, meaning either Revlimid (lenalidomide), thalidomide (Thalomid), or pomalidomide.  And the patients must have demonstrated disease progression on or within 60 days of completing their last therapy.

The last requirement means that, to be treated with Kyprolis, myeloma patients must be refractory (no longer responding) to an ongoing current therapy, or to a therapy that was stopped within the last 60 days.

What impact will the FDA decision have on myeloma patients in the United States?

Prior to the FDA decision, Kyprolis was only available through clinical trials studying Kyprolis, or through an expanded access program offered by Onyx (NASDAQ: ONXX), the company that developed and will market Kyprolis, for patients who had no other available treatment options.

With the FDA approval, physicians will be able to prescribe Kyprolis to myeloma patients throughout the U.S., without any clinical trial participation requirement.

Although Kyprolis has been approved by the FDA for a specific set of myeloma patients, once a drug is approved in the U.S., physicians have substantial freedom to prescribe the drug as they deem appropriate.  However, Medicare, Medicaid, and private insurance companies may decide to restrict reimbursement of Kyprolis treatment to patients meeting the FDA criteria described above.

How does Kyprolis work?

Kyprolis, along with Velcade (bortezomib), belongs to a class of drugs known as proteasome inhibitors.  They work by preventing the breakdown of protein in cancer cells, triggering their death.   Kyprolis is administered by infusion.

How is Kyprolis pronounced?

kai-PRO-lis

When will Kyprolis be available?

Kyprolis will be available on the U.S. market August 1 of this year.

What is the recommended dosing for Kyprolis?

Kyprolis’s recommended dosing is 20 mg/m2 six times per 28-day cycle for the first cycle and 27 mg/m2 six times per cycle thereafter for all patients able to tolerate the higher dose.

How effective is Kyprolis?

A Phase 2 study of Kyprolis, called 003-A1, showed that among 266 relapsed and refractory myeloma patients treated with carfilzomib, 23 percent experienced at least a partial response to carfilzomib, for a median duration of 7.8 months (see related Beacon news).  Patients in this study had a median of five previous lines of therapy.

What are the side effects of Kyprolis?

The most common side effects of Kyprolis are fatigue, low red blood cell counts, nausea, low platelet counts, difficulty breathing, diarrhea, and fever.  These side effects occured in at least 30 percent of patients treated with Kyprolis in the 003-A1 clinical trial.

The prescribing information for Kyprolis also includes warnings that Kyprolis can cause life-threatening heart- and lung-related side effects.  The first sentence of the “Warnings and Precautions” section of the prescribing information, for example, states that “Death due to cardiac arrest has occurred within a day of Kyprolis administration.”

Patients being treated with Kyprolis should therefore be monitored carefully for heart- and lung-related complications.  For patients who experience serious side effects of this kind, Kyprolis should be discontinued or withheld until the complication resolves.

The prescribing information for Kyprolis does not, in contrast, contain a warning about the risk of peripheral neuropathy (pain, tingling, or loss of sensation in the extremities), which often is experienced by patients receiving Velcade.  Less than 1 percent of the patients treated with Kyprolis in the 003-A1 trial experienced severe peripheral neuropathy.

How much will Kyprolis cost?

Kyprolis will cost $10,000 per 28-day cycle at the recommended dose for a patient of average size.

At that price and based on FDA-approved dosing schedules, Kyprolis will be the most expensive drug approved in the U.S. for multiple myeloma.

In comparison, Velcade costs between $4,000 to $8,000 per 28-day period, depending on the frequency of dosing, and Revlimid costs $7,900 per 28-day period at the FDA-approved 21-out-of-28-day dosing.

Will Onyx offer a patient assistance program for Kyprolis?

Onyx will offer a patient and caregiver assistance program, called Onyx 360.  The program will include treatment, payment, reimbursement, and emotional support to myeloma patients and caregivers.

What additional testing is the FDA requiring Onyx to complete?

Kyprolis was approved through the FDA’s accelerated approval process, which allowed Onyx to file for approval based on Phase 2 trial data.  Normally, the FDA requires new drug applications to be based on data from more extensive Phase 3 clinical trials.

Therefore, Onyx is expected to complete additional Phase 3 trials of the drug,  and the FDA will review those results to verify the clinical benefit of Kyprolis.  If these trials confirm the safety and efficacy of Kyprolis, the FDA will grant it a traditional approval.  If not, the FDA could remove the drug from the market.

Onyx must complete a Phase 3 trial, called ASPIRE, to confirm the clinical benefit of Kyprolis.  The study is comparing the combination of Kyprolis plus Revlimid and dexamethasone to Revlimid and dexamethasone alone for the treatment of relapsed and refractory myeloma patients.

Onyx must also complete several studies to demonstrate the safety of Kyprolis.

The company must conduct a study to determine the effect Kyprolis has on cardiac and pulmonary (lung) function.  Results from a Phase 3 trial called ENDEAVOR, which will evaluate Kyprolis plus dexamethasone versus Velcade plus dexamethasone, will be analyzed to determine the impact Kyprolis has on heart and lung function.

Two studies will also evaluate Kyprolis at a higher-than-approved dose of 20 mg/m2 during the first cycle and 56 mg/m2 during subsequent cycles.

Onyx must also conduct one or more clinical trials to assess the safety of Kyprolis in patients with impaired kidney function.

What impact will the FDA decision have on myeloma patients outside the U.S.?

Kyprolis is not currently approved outside of the U.S. and is therefore not available to myeloma patients outside of the U.S. other than through clinical trials.

Myeloma patients throughout Europe and Korea are still being recruited for a Phase 3 trial, called FOCUS, comparing treatment with Kyprolis versus best supportive care.  In addition, patients in Japan are being recruited for a Phase 1/2 study (description in Japanese) of Kyprolis for relapsed and refractory myeloma patients; the study is being conducted by Onyx’s partner Ono Pharmaceutical.

Onyx intends, however, to file for approval of Kyprolis in Europe based on results of the Phase 3 ASPIRE trial.  Initial results are expected in early 2013 and full results in 2014.

Given that the ASPIRE trial investigates the efficacy and safety of Krypolis in relapsed and refractory myeloma patients, Kyprolis is likely to initially be approved in Europe for those patients.

In Europe and many other countries, in contrast to the U.S., physicians are generally limited to using drugs only for their approved uses.

For more information, see the Kyprolis prescribing information (pdf).

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11 Comments »

  • Gary said:

    What a wonderful elucidation of the issues surrounding Kyprolis. I sincerely hope that other patients do not experience the severe heart issues that I did. Medicare and my secondary insurance provider will be happy that I am not adding $10,000 every month to their costs. Wow is that expensive. They are probably still celebrating in the ONYX suites. Wish I had bought the stock but I thought the side effects would torpedo it. Wrong again.

  • nancy shamanna said:

    I think that when you read that 23% of patients, who were already on several other therapies and relapsed, achieved at least a partial response of about 8 months, it makes on realize just how difficult it can be to treat such patients. The news that we got about the trials on patients who had carfilzomib for initial therapy seemed to be much more positive, showing a CR in what has to be record time! The side effects do sound very severe, and we have the personal accounts of Gary to verify this. It sounds like the new drug is going to be a help in reaching patients who needed to try more, different drugs. The chemo drugs are so powerful though, that of course they have to be approached with caution. I will look forward to the day when the new drug is available in Canada also, although I guess I shouldn’t be holding my breath really on that! All of these processes take time.

    I should say that I bought and sold Onyx twice this spring, but missed the big run up…I wouldn’t even have made enough to cover one week of therapy though!! Last spring I was interested in silver stocks, but this year they aren’t moving at all! Best to stick with safer investments, such as dividend paying stocks, or forms of ‘fixed income’,
    which is what we do, mostly!

    Anyways, thanks for the good article, Julie! That is most informative.

  • Shail said:

    Please let us know when shall this medicine be available in asia- India. We are desperately waiting for it to be used as medicine , the cost seems high though and side effects severe too.

  • Elizabeth Wallace said:

    My sister, who is suffering from multiple myeloma, is currently in the ICU on dialysis, hallucinating, near death–all her medical indicators are the worst they have ever been after only TWO infusions with this new wonder drug (poison) approved recently by the FDA.

    Her doctor obviously didn’t think this one through–her kidneys were already marginal and compromised before treatment with Kyprolis, and her hemoglobin levels were also quite low. I think this new “treatment” is very, very dangerous and only the strongest MM patients treated with this. My sisters kidney doctor is livid that they went ahead and gave her Kyprolis given the condition of her kidneys.

  • Myeloma Beacon Staff said:

    Hello Elizabeth,

    We are very sorry to hear about what has happened with your sister. We sincerely hope that she is able to make it through this crisis successfully.

    Please make certain that your sister’s physicians include myeloma specialists working together with your sister’s kidney doctor to determine what treatments will be the best option for her going forward — both immediately and in the longer run.

    Kidney issues are — unfortunately — all too common among myeloma patients. So most myeloma specialists who might help with your sister’s case should have experience dealing with situations like the one she is currently facing.

  • suzierose said:

    “Kyprolis’s recommended dosing is 20 mg/m2 six times per 28-day cycle for the first cycle and 27 mg/m2 six times per cycle thereafter for all patients able to tolerate the higher dose.”

    Beacon Staff,

    Was Kyprolis was approved for only the lower 20-28mg/m2 dosing?

    Based on Phase I studies carfilzomib did not have a maximum tolerated dose(MTD)
    In NDMM clinical trials carfilzomib was used at doses up to 36mg/m2

    Do you have data, or will you please send a query to Dr.Jakubowiak and ask how many patients that achieved sCR were on 36mg/m2?
    http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=114&abstractID=100344

    Does Onyx make/distribute higher dose solutions?

    Thanks for your help.

  • Beacon Staff said:

    Suzierose,

    Kyprolis was only approved for the 20/27 mg/m2 dosing described in the above article.

    Specifically, Kyprolis’ prescribing information states:
    “In Cycle 1, Kyprolis is administered at a dose of 20 mg/2. If tolerated in Cycle 1, the dose should be escalated to 27 2 beginning in Cycle 2 and continued at 27 2 in subsequent cycles.”

    Kyprolis is sold in vials of 60 mg of powder that is then reconstituted in a specific amount of water. Then the appropriate volume, based on the desired dose and the patient’s weight, is added to an IV bag of solution for infusion.

    Dr. Jakubowiak’s CRD study included 53 newly diagnosed patients. Among those, 22 patients (42) percent achieved a sCR; 14 of those patients were treated with 36 mg/2. Another way of looking at the data: 36 patients were treated with 36 mg/2; 14 of those patients (39 percent) achieved a sCR.

    Here’s a link to Dr. Jakubowiak’s study as published in the journal Blood:
    http://bloodjournal.hematologylibrary.org/content/120/9/1801.long

    Here’s a table with the response rates broken out by Kyprolis dosing:
    http://bloodjournal.hematologylibrary.org/content/120/9/1801/T4.expansion.html

  • Nina said:

    I am a registered nurse and I have a question to Beacon Staff about the administration of this drug. I recently had a patient given this drug who was on dialysis. The patient was in cycle 1 of treatment and received their second dose of drug the evening prior to dialysis via IV push with a concurrent normal saline piggyback running at gravity. Do you have any recommendations as to whether this drug should be given IV piggyback versus IV push and what is the rationale behind receiving the drug after dialysis? Also, I can confirm from firsthand experience of administering this drug, respiratory compromise and dyspnea are major side effects I witnessed within 24 hours post administration.

  • Beacon Staff said:

    Hi Nina,

    The prescribing information for Kyprolis says:

    Administer intravenously over 2 to 10 minutes, on two consecutive days each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28).

    Saline is also supposed to be given prior to and following Kyprolis administration:

    Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome…Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline…Give an additional 250 mL to 500 mL of intravenous fluids as needed following Kyprolis administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload.

    In regard to the timing of Kyprolis treatment and dialysis:

    Since dialysis clearance of Kyprolis concentrations has not been studied, the drug should be administered after the dialysis procedure.

  • suzierose said:

    Nina,

    Wow. IVpush? Really…can’t say I’ve heard of that route of administration. I would anticipate respiratory compromise and dyspnea if it is used IVpush.

    geez

  • suzierose said:

    Thanks Beacon staff!!