Last week, the U.S. Food and Drug Administration (FDA) approved Kyprolis ^[1] (car­filz­o­mib) for the treat­ment of multiple myeloma patients who have received at least two prior ther­a­pies (see related Beacon ^[2] 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 ^[3] (bor­tez­o­mib) and an immuno­modu­la­tory agent, meaning either Revlimid ^[4] (lena­lido­mide), thalidomide ^[5] (Thalomid), or pomalidomide ^[6].  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 ^[3] (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 ^[7] 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 ^[8].  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 ^[9], 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 ^[10], 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 ^[11], comparing treat­ment with Kyprolis versus best supportive care.  In addi­tion, patients in Japan are being recruited for a Phase 1/2 study ^[12] (description in Japanese ^[13]) 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 ^[14] (pdf).