After ASH, Amgen Assuages Wall Street Over Kyprolis CV Concerns

The biotech took time to address the recent suspicion that there are more cardiovascular events than previously expected with Kyprolis. But the bottom line is that head-to-head efficacy and safety data against Velcade, another multiple myeloma proteasome inhibitor, simply aren’t available yet.

Wall Street is worried about Amgen Inc.’s acquisition of Onyx Pharmaceuticals. Specifically, concerns have been circulating for weeks that the rate of cardiovascular events for Kyprolis (carfilzomib) could prevent the drug from advancing into earlier lines of treatment for multiple myeloma.

Without the ability to move gradually from third-line all the way to first-line treatment, Kyprolis’ revenue potential would be vastly diminished, thereby making Amgen’s $10.4 billion purchase of Onyx in August look like it wasn’t such a good deal after all (Also see "Amgen Wins Onyx, But Will The Deal Pave The Road To Transformation?" - Pink Sheet, 2 Sep, 2013.).

There were nearly 100 Kyprolis presentations at the American Society of Hematology conference, most of them investigator-sponsored trials of various drug combinations. Amgen officials held a conference call Dec. 11 to highlight some of the data and to try to assuage Wall Street concerns about CV safety for Kyprolis. (Officials also addressed questions about the gastrointestinal tolerability of its oral counterpart, oprozomib.)

But there aren’t sufficient data available yet to evaluate clearly the rate of cardiovascular events for Kyprolis versus the long-established Velcade (bortezomib), which is also a proteasome inhibitor. While Kyprolis is dosed intravenously twice a week, Velcade is primarily used subcutaneously, a method typically associated with lower rates of peripheral neuropathy, thrombocytopenia and neuralgia than intravenous usage.

Amgen shares pulled back a bit in November, partly due to investor concerns about this CV issue. Amgen remains up 28% this year, closing at $113.05 on Dec. 11. That’s not far below the 52-week daily high of $118.69.

Gaining More Clarity

Ongoing trials could shed more light on the issue, but results are several years away. Amgen has two ongoing randomized head-to-head trials of Kyprolis vs. Velcade: ENDEAVOR (relapsed) and CLARION (newly diagnosed, transplant ineligible). Data from these trials are intended to support earlier-line filings (Also see "Onyx’s Transformative Year: From Productive Partner To Big Cap Contender?" - In Vivo, 19 Mar, 2013.).

The data would need to be exceptional to make Kyprolis a viable first-line option; Velcade is going generic in 2017, likely making it a tempting, inexpensive, first-line, proteasome inhibitor option for payers. Velcade is approved in all multiple myeloma (MM) patients. But these trials should also give a clear picture of the comparative safety of the two drugs.

The company declined to comment on the timing of interim analyses for ENDEAVOR and CLARION. According to clinicaltrials.gov, final data collection to measure ENDEAVOR’s primary endpoint will be complete by January 2015, with the study itself ending in July 2018. The final data collection date for CLARION is listed as April 2016.

Pablo Cagnoni, the President of Onyx, said on the conference call that the data monitoring safety board met recently regarding ENDEAVOR. He noted that the DSMB did not feel the need to make any safety recommendations and that the trial is “accruing very, very well.”

“They looked at the overall safety profile for the two arms, as well as the overall emerging efficacy, although there is no formal efficacy analysis, of course,” Cagnoni said. “And based on that, if there is a need for a recommendation based on anything that is emerging on the safety profile of the drug, they would let us know. That has not happened at this point.”

Both Kyprolis and Velcade have cardiovascular event warnings listed on their labels.

According to the Kyprolis label, 7% of patients had cardiac failure events, including congestive heart failure and pulmonary edema. Physicians are advised to withdraw Kyprolis if a serious event occurs and to conduct a benefit/risk assessment to determine if Kyprolis treatment should resume. But patients at greatest risk for cardiac complications, those who previously have had serious cardiac events, were excluded from clinical testing.

The Velcade label also cites cardiac toxicity and advises that patients with heart disease or its risk factors be closely monitored. It cites a relapsed MM study in which the rate of treatment-related cardiac disorders was 8%.

Off-Target Effects

Several potential triggers for cardiovascular events in Kyprolis patients came up during the call. When queried about off-target effects in the heart that could increase with the greater efficacy for Kyprolis versus Velcade, Cagnoni said, “Yes, there are proteasomes in the heart, and there seems to be proteasome inhibition on level of the heart.” He did not elaborate further.

He concluded, “I think, overall, in the broad clinical experience that I described with Kyprolis, we have observed a low instance of cardiovascular events. This is consistent with the label, and they have not changed, in our opinion, the DSMB's opinion or KOL's opinion, the benefit/risk profile the drug at this point.”

Cagnoni also noted the high-dose Phase I/II CHAMPION study, which employs Kyprolis doses that are double, or even triple the FDA approved dosage as part of a weekly, rather than the approved bi-weekly regimen. Investigators reported positive interim results at ASH with 18 patients, which did not include cardiovascular problems among the adverse events.

He offered some suggestions for what could be triggering cardiac events in Kyprolis patients, citing the co-morbidities in the patients as well as possible fluid overload. On the latter point, Cagnoni noted that the label outlines necessary hydration before and after the first cycle of Kyprolis. Physicians make their own determinations on additional fluids in subsequent cycles. But patients may be getting too much fluid, which could trigger a CV event.

“We are convinced that there is a component of some of these low-frequency cardiovascular events that is related to the fluid overload, when you take into consideration that these are patients with multiple myeloma, many of whom are elderly. They have co-morbidities and some of them are quite heavily pre-treated. So, it is a combination of both factors,” he said.

Beyond Kyprolis, officials addressed the gastrointestinal issues that have plagued oprozomib, an oral proteasome inhibitor. Orals and monoclonal antibodies are coming along rapidly and are likely to be added soon to treatment regimens. Takeda Pharmaceutical Co. Ltd., which markets Velcade along with Johnson & Johnson, is conducting Phase III testing of a triple combination oral regimen that includes its oral proteasome inhibitor MLN9708 (ixazomib citrate) (Also see "Takeda Touts Oral Triplet Regimen With Velcade Follow-On MLN9708" - Scrip, 11 Dec, 2013.).

That could prove problematic for oprozomib, which is still in Phase I/II. Cagnoni said Amgen is introducing proactive management of GI issues by its investigators in new oprozomib trials.

While the sparring, for now, is between Kyprolis and Velcade, the approved ranks of MM treatment and combinations in use are likely to expand rapidly in the coming years as oral proteasome inhibitors and monoclonal antibodies enter the market. That could render the duel between these injectable proteasome inhibitors largely moot, particularly as generic Velcade further complicates the picture (Also see "Multiple Myeloma Market Snapshot: New Combos Offer Greater Longevity, But Payers May Push Back" - Pink Sheet, 13 May, 2013.).