Concerns about life-threatening cardiac, pulmonary and hepatic toxicities for Onyx Pharmaceuticals Inc.’s second-generation proteasome inhibitor Kyprolis (carfilzomib) were ultimately dealt with in specific instructions for adverse event management in product labeling and post-marketing requirements attached to the drug’s accelerated approval.

The next-generation proteasome inhibitor was cleared July 20 for use as up to a 10-minute intravenous infusion for multiple myeloma patients who have received at least two prior therapies, including Takeda Oncology’s pioneering proteasome inhibitor Velcade (bortezomib) and an immunomodulatory agent, such as Celgene Corp.’s Revlimid (lenalidomide), and who have disease progression on or within 60 days of completing the last therapy. FDA’s Oncologic Drugs Advisory Committee had overwhelmingly endorsed the second-generation proteasome inhibitor for accelerated approval in the relapsed/refractory population in June Also see "Onyx’s Myeloma Drug Kyprolis Fits ODAC’s View On Accelerated Approval" - Pink Sheet, 25 June, 2012..

The company estimates some 10,000 to 15,000 patients annually in the U.S. will be eligible for treatment based on the labeled indication. Patients who are intolerant to Velcade are eligible, according to the label, as long as they have progressed within 60 days of their last treatment, company execs confirmed during a July 20 investor call. Onyx is pricing the drug at a significant premium to Velcade and plans to begin fulfilling orders August 1 Also see "Onyx Kyprolis Launch Strategy Includes Speedy Delivery, Premium Price" - Pink Sheet, 20 July, 2012..

Label notes cases of death due to cardiac arrest, but does not include a boxed warning.

The filing was supported by a single-arm pivotal Phase II trial of 266 relapsed/refractory patients, called PX-171-003, which showed about a 22.9% overall response rate and a median duration of response of 7.8 months in a relapsed, heavily pretreated patient population. At the time of the vote, Onyx had fully enrolled the Phase III ASPIRE trial of close to 800 patients, a factor that greatly helped pave the way for approval, despite some significant safety risks.

Labeling reflects the company’s analysis of duration of response, listing the 7.8 month figure; at the advisory committee, the agency used a different definition of response, coming up with a median of 6.5 months.

The label is “very much along the lines of what was required in the protocol” of the study supporting approval, with no new requirements other than what was done in the clinical trial, said Barbara Klencke, senior vice president of clinical development at Onyx during the investor call.

FDA briefing documents for the advisory committee meeting had highlighted serious cardiac, pulmonary and hepatic toxicities Also see "Safety Concerns Weigh On Onyx’s Carfilzomib In Multiple Myeloma" - Pink Sheet, 18 June, 2012.. But in the end, labeling did not include a boxed warning or contraindications.

Getting To The Bottom Of Adverse Events

At the advisory committee, FDA noted that across the 526 patients enrolled in Phase II studies, 8% experienced a serious cardiac event and 7% had pulmonary toxicities – and most of these were Grade 3 or Grade 4. The assessment of whether or not these are drug-related is complicated, but due to the single-arm study design, they must be considered attributable to the study drug, the agency explained. Labeling notes the rates of adverse events and provides advice on how to avoid them.

Onyx had argued that serious adverse event rates were consistent with prior reported outcomes in this end-stage patient population and that they could be managed through patient selection, dose reduction algorithms and other supportive measures.

The label’s warning and precautions section advises monitoring for cardiac reactions including heart failure and ischemia, pulmonary hypertension and pulmonary complications, and liver toxicity and failure.

A table in the label includes very detailed directions for how to modify dose in case of a range of side effects, such as neutropenia, congestive heart failure, pulmonary hypertension, liver abnormalities and peripheral neuropathy.

For example, in cases of Grade 3 or Grade 4 neutropenia or Grade 4 thrombocytopenia, the table advises withholding the dose and then resuming based on the patient’s recovery. If the patient fully recovers before the next scheduled dose, it recommends continuing at the same dose level. If they recover to Grade 2 neutropenia or Grade 3 thrombocytopenia, the dose should be reduced by one level – if that is well-tolerated, the reduced dose can be escalated to the previous dose.

On the cardiac front, labeling advises that cardiac failure events were reported in 7% of patients. And death due to cardiac arrest has occurred within a day of administration of Kyprolis. While there are no contraindications, the label suggests that patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding six months, and conduction abnormalities uncontrolled by medications were not eligible for clinical trials and may be at greater risk for complications. If Grade 3 or 4 events occur, prescribers should stop treatment and consider the benefits versus risks of continuing.

A section on hepatic toxicity notes that some fatal cases of liver failure had been reported.

During the advisory committee meeting, there was extensive discussion about co-morbid cardiac conditions in advanced myeloma patients, CEO Tony Coles noted during the investor call. “We think it is appropriate to take all precautions necessary to understand interactions of Kyprolis with these advanced co-morbid conditions and we will learn more as we proceed,” he said.

Looking To Phase IV For Greater Clarity

As part of post-marketing commitments, FDA is requiring Onyx to take baseline electrocardiograms and transthoracic echocardiograms to assess left ventricular function in all patients enrolled in the company’s Phase III ENDEAVOR study, which tests Kyprolis/dexamethasone head-to-head against Velcade/dexamethasone in 888 relapsed patients who had received one to three prior treatments. The trial began enrolling on July 2.

Ongoing Phase III Trials Of Kyprolis Enrollment in the Phase IIII ASPIRE confirmatory study helped pave the way for accelerated approval of Onyx’s proteasome inhibitor Kyprolis on July 20. Two other Phase III trials are under way. As part of post-marketing commitments, FDA is requiring Onyx to assess cardiac and pulmonary toxicity in a sub-study of the ENDEAVOR trial.
Study	Description	Status
ASPIRE	Randomized, open label study of 780 relapsed myeloma patients, testing Kyprolis/Revlimid/dexamethasone vs. Revlimid/dexamethasone	Fully enrolled
FOCUS	Randomized, open label study of 302 patients with relapsed and refractory myeloma, testing Kyprolis vs. best supportive care	Recruiting
ENDEAVOR	Randomized, open label study of 888 relapsed myeloma patients, testing Kyprolis/dexamethasone vs. Velcade/dexamethasone	Recruiting

FDA also is asking for a sub-study of ENDEAVOR including between 100 and 300 patients (50 to 150 per treatment arm) to fully evaluate cardiac and pulmonary effects. These patients will be checked periodically with echocardiograms during the trial and at the end of treatment.

Furthermore, the agency’s approval letter states, “any patient in the main trial who has a cardiac adverse event that is considered a clinically significant cardiac adverse event (AE) must have an ECHO performed to assess LV and RV function as part of the evaluation of that AE.”

Pulmonary toxicities in the main study need to be fully characterized, including, for example, time course of onset and resolution, according to the approval letter.

FDA is also requiring Onyx to run a separate study in patients with hepatic impairment to assess safety and pharmacokinetic characteristics of the drug given as a 30-minute infusion. The agency did not specify the size of this trial; rather the approval letter says that the number of patients “should be sufficient to detect PK differences that would warrant dosage adjustment recommendations in labeling.”

The post-marketing requirements are “routine with accelerated approval” and the company has “worked collaboratively with the FDA to address their areas of interest,” Klencke said.

Coles pointed out that the ASPIRE study continues despite several reviews by a data safety monitoring board and is providing the company with a good understanding of safety, but the ENDEAVOR sub-studies will provide the information FDA needs.

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