The U.S. Food and Drug Administration (FDA) on Monday approved Farydak (panobinostat) for the treatment of multiple myeloma (see related Beacon news).

Since the FDA announced its decision, multiple myeloma patients, care­givers, and health care professionals have been asking a number of important questions about Farydak. This article compiles many of those questions and provides answers to them.

The information in this article is based primarily on the official, FDA-approved prescribing information for Farydak. In addition, The Beacon has received feedback in regard to several questions from representatives of Novartis, the pharmaceutical company that developed and will market Farydak.

What exactly did the FDA approve?

The FDA approved Farydak, to be given in combination with Velcade (bortezomib) and dexa­metha­sone (Decadron), for the treatment of multiple myeloma patients who have received at least two prior treatment regimens.

The two prior therapies must include Velcade and at least one treatment from the immuno­mod­u­la­tory class of drugs, which includes Revlimid (lenalidomide), thalidomide (Thalomid), and Pomalyst (pomalidomide, Imnovid).

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

Prior to the FDA decision, treatment with Farydak was only available through participation in a clinical trial.  Now that the drug is approved by the FDA, physicians will be able to prescribe Farydak to myeloma patients throughout the U.S. without any clinical trial participation requirement.

Although Farydak 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 plans, Medicaid, private insurance companies, and other health care payers may decide to restrict reimbursement of Farydak to patients meeting the FDA criteria described above (or, for that matter, other criteria).

How does Farydak work?

Farydak belongs to a class of drugs known as histone deacetylase (HDAC) inhibitors.

Drugs in this class previously were thought to be active against cancer through their effect on cell proteins known as histones. Currently, however, research indicates that the drugs broadly affect many proteins within cells, not just histones. In fact, drugs in the class are sometimes now called deacetylase (DAC) inhibitors, rather than histone deacetylase inhibitors.

Deacetylases are a group of enzymes within cells that remove a small molecule known as acetyl from cell proteins. Deacetylation, as this process is known, is important for the health of a cell. It enables successful protein production within the cell and the ability of the cell to reproduce. In addition, it assists in the elimination of waste proteins from the cell.

Deacetylase inhibitors, as their name suggests, interfere with the ability of deacetylases to do their job. This can disrupt the ability of cells to reproduce, and it also can kill cells by causing waste proteins to build up to lethal levels.

Although deacetylase inhibitors such as Farydak worked well against myeloma cells in laboratory testing, they have not shown much activity on their own when tested in clinical trials with myeloma patients.

Further laboratory research, however, found that deacetylase inhibitors were particularly effective as anti-myeloma agents when combined with proteasome inhibitors, the class of drugs that includes Velcade and Kyprolis (carfilzomib). The combination of the two classes of drugs seems to be particularly good at disrupting the processing of waste proteins within myeloma cells. In addition, pairing the two drug classes seems to reduce the ability of myeloma cells to nourish and protect themselves through their interaction with the surrounding bone environment.

How is Farydak pronounced?

According to a Novartis representative, the recommended pronunciation of Farydak is: Fayr-ah-dak .

When and where will Farydak be available?

Novartis expects Farydak to be available “within a few weeks” through the following specialty pharmacies:  Accredo Specialty Pharmacy, Advanced Care Scripts, Avella Specialty Pharmacy, Biologics Inc., CVS Caremark Specialty, Diplomat Specialty Pharmacy, US Bioservices, and Walgreens Specialty Pharmacy.

Farydak also will be available outside the above network of specialty pharmacies for either health care practices with in-house pharmacies or institutions with out-patient services. If a health care provider meets one of these two criteria, Farydak can be ordered by contacting McKesson Specialty Health.

How is Farydak administered?

Farydak is administered orally (by mouth) in the form of a capsule.

Capsules will be available with the following three different Farydak doses per capsule: 10 mg, 15 mg, and 20 mg.

What is the recommended dosing of Farydak?

The FDA recommends a three-week (21-day) treatment cycle for Farydak.  The drug is to be given in combination with Velcade and dexamethasone during Weeks 1 and 2 of each cycle, with no treatment during Week 3.

Farydaks’s recommended starting dose is 20 mg, and the approved dosing schedule calls for the drug to be taken on Days 1, 3, 5, 8, 10, and 12 of each cycle. Farydak should be taken at about the same time each day it is administered, with a cup of water, and either with or without food. The capsules should be swallowed whole, not chewed, opened, or crushed.

Velcade’s recommended starting dose for the combination regimen is 1.3 mg/m², and it is to be given as an injection on Days 1, 4, 8, and 11 of each cycle.

Dexamethasone’s recommended starting dose is 20 mg, to be taken on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle. The FDA recommends taking the dexamethasone on a full stomach.

The three-drug regimen can be administered for up to eight cycles.  If, after eight cycles, the patient continues to benefit from treatment with the Farydak therapy, and is not experiencing significant side effects, physicians may consider continuing treatment for an additional eight cycles.

During the second set of eight cycles, however, the FDA recommends reducing the frequency of Velcade and dexamethasone dosings to once per week (two times total per cycle) for Velcade, and twice per week (four times total per cycle) for dexamethasone.

The official prescribing information for Farydak also includes a set of recommended adjustments to the Farydak starting dose in cases where a patient has impaired liver function, or if the patient is taking certain medications – known as CYP3A inhibitors – which can interfere with the way the body metabolizes Farydak.

There also are recommended adjustments to Farydak’s dosing during treatment if a patient experiences low platelet counts, low neutrophil counts, low hemoglobin levels, or diarrhea.

How effective is Farydak?

The FDA’s approval of Farydak is based on data from the Phase 3 clinical trial known as PANORAMA-1. The trial tested Farydak in combination with Velcade and dexamethasone in 768 relapsed/refractory multiple myeloma patients who had received 1 to 3 prior therapies.

Patients in the trial were randomly assigned to one of two treatment regimens: Farydak, Velcade, and dexamethasone; or a placebo (sugar pill) combined with Velcade and dexamethasone.

Based on data from all the patients in the trial, the median progression-free survival was 12 months in patients treated with Farydak, Velcade, and dexamethasone, versus 8.1 months in patients treated with just Velcade and dexamethasone.

Although there is a trend to higher overall survival in the Farydak-treated patients in the trial – overall survival was 33.6 months for the Farydak-treated patients, versus 31.3 months for the placebo group – this difference is not statistically significant.

Out of the 768 patients in the PANORAMA-1 trial, 193 met the criteria for the FDA’s approved patient population for Farydak – that is, they had received at least two prior treatments, including Velcade and an immuno­mod­ula­tory agent such as thalidomide or Revlimid.

Among this subgroup of patients in the trial, the median progression-free survival was 10.6 months in the Farydak-treated patients, and 5.8 months in the placebo group.

The overall response rate in the Farydak-treated patients in the subgroup was 58.5 percent, with 22.3 percent of the patients achieving a complete, or near-complete, response.

In the placebo patients in the subgroup, the overall response rate was 41.4 percent, with 9.1 percent of the patients in that group achieving a complete, or near-complete, response.

What are the side effects of Farydak?

In the PANORAMA-1 trial mentioned above, severe side effects occurred in 60 percent of the patients treated with Farydak, compared to 42 percent of the patients in the placebo group.

The most common severe side effects that occurred in more than 5 percent of the Farydak-treated patients were pneumonia (18 percent), diarrhea (11 percent), low platelet levels (7 percent), fatigue (6 percent), and sepsis (6 percent).

Patients taking Farydak generally seemed to have issues with gastrointestinal side effects. Almost 70 percent of the patients treated with the drug experienced some degree of diarrhea, 36 percent reported becoming nauseous, and about a quarter reported that they had to vomit as a result of treatment.

Fatigue was the other common side effect of Farydak treatment, reported by 60 percent of the patients treated with the drug. Other side effects that occurred often included fever (30 percent) and swelling in the extremities (26 percent).

More than a third of the patients in the Farydak arm of the trial discontinued their treatment due to side effects.

What is the FDA doing to avoid serious side effects in patients treated with Farydak?

The FDA has taken three steps to ensure that patients who are treated with Farydak do not experience serious side effects.

First, Farydak’s official prescribing information includes a so-called “black box” warning regarding potentially serious side effects. This warning, which is featured prominently at the beginning of the prescribing information, states:

• Severe diarrhea occurred in 25% of Farydak-treated patients. Monitor for symptoms, institute anti-diarrheal treatment, interrupt Farydak, and then reduce dose or discontinue Farydak.
• Severe and fatal cardiac ischemic events, severe arrhythmias, and ECG changes have occurred in patients receiving Farydak. Arrhythmias may be exacerbated by electrolyte abnormalities. Obtain ECG and electrolytes at baseline and periodically during treatment as clinically indicated.

Second, as mentioned in the black-box warning, the Farydak prescribing information recommends that physicians conduct regular tests to monitor for the development of certain serious side effects.

In particular, physicians are advised to test a patient’s complete blood count and blood electrolyte levels, including potassium and magnesium, prior to and during treatment with Farydak.  Patients also should receive an electrocardiogram before, and regularly during, treatment with Farydak.

Third, the FDA is requiring Novartis to implement a program to communicate to health care professionals the serious side effects that can occur during treatment with Farydak and how to minimize them.

This kind of “Risk Evaluation and Mitigation Strategy” (REMS) program, as the FDA calls it, sometimes includes a requirement for physician certification, or it may require patients to complete a survey before they can be treated with a medication.

In the case of Farydak, however, a Novartis representative has informed The Beacon that the drug’s REMS program will not include a physician certification require­ment, nor will patients be required to complete a survey before they can be treated with Farydak.

It should be noted that, although a “black-box” warning is a clear sign that the FDA has concerns about a drug’s safety, such a warning is not unprecedented among myeloma therapies. Several myeloma treatments, including thalidomide, Revlimid, Doxil (doxorubicin liposomal), and Pomalyst, have black box warnings related to potentially serious side effects they can have.

How much will Farydak cost?

Farydak’s U.S. wholesale price will be $6,860 for a 21-day cycle of either the 20 mg, 15 mg, or 10 mg capsules, according to a Novartis representative.

This is equivalent to an average cost of $9,147 per 28 days of treatment with the drug.  (Oncology drug costs often are compared based on their cost for 28 days of treatment.)

In comparison, Kyprolis’ current U.S. wholesale price amounts to $10,386 per 28 days of treatment, based on the dosing recommended in the drug’s prescribing information (six infusions per 28-day cycle; 20 mg/m² per infusion during the first cycle of therapy, and 27 mg/m² per infusion in subsequent cycles).

Similarly, Pomalyst currently costs $11,414 per 28 days of treatment at its recommended dosing of once daily for 21 out of the 28 days of a cycle.

Kyprolis and Pomalyst price information is courtesy of the market analytics firm IHS and, in the case of Kyprolis, has been con­firmed with Onyx Pharmaceuticals

Will Novartis offer a patient assistance program for Farydak?

Novartis will offer a patient co-pay assistance program and a patient access program to help eligible patients with the cost of Farydak treatment. The company also will offer health care providers assistance arranging for reimbursement of Farydak. For more information, please see the Novartis “Patient Assistance Now Oncology” website.

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

Farydak is not currently approved outside of the U.S. and is therefore not available to myeloma patients in other countries except through clinical trials.  There are, however, a number of Farydak clinical trials in myeloma ongoing, in both newly diagnosed and relapsed patients.  A complete list of currently recruiting Farydak clinical trials, in locations overseas and in the U.S., can be viewed at clinicaltrials.gov.

Novartis has filed for the approval of Farydak in Europe and in Japan, and is pursuing additional approvals in other countries. A marketing authorization application for Farydak in Europe was submitted last May, and an application for approval in Japan was submitted last September.

Given approval timelines common for drugs such as Farydak, The Beacon expects decisions on the Farydak European approval application by sometime this summer and the Japanese approval application by the fourth quarter of this year.