Amgen has given a first glimpse of key results from its FOCUS Phase 3 clinical trial testing Kyprolis in re­lapsed and refractory multiple myeloma patients.

The com­pany reported this past Wednesday that Kyprolis did not provide an over­all survival advantage in the trial, which is being con­ducted out­side the United States.

In addi­tion, the com­pany noted that patients treated with Kyprolis during the trial experienced more kidney-related side effects than patients who were not treated with the drug.

Up until recently, the primary significance of the FOCUS trial would have been its impact on Amgen’s plans to seek regulatory approval for Kyprolis in Europe and other parts of the world besides the United States.

The U.S. is cur­rently the only country where the drug is approved for use outside of clinical trials.

However, earlier this month, Amgen announced initial results of another Kyprolis Phase 3 trial, known as the ASPIRE study, and at the same time said that it would use the results of that study as the basis for its Kyprolis approval submissions in Europe and elsewhere (see related Beacon news).

Thus, oddly enough, the key question in regard to this week’s FOCUS results is whether or not they will im­pact Kyprolis in the United States.

For the im­medi­ate term, the answer to that question seems to be no. The trial has no bearing on the drug's existing approval from the U.S. Food and Drug Administration, and the trial's survival out­come was not un­ex­pected.

There could be, however, a longer-term impact of the trial on Kyprolis in the U.S. as a result of the kidney-related side effects seen in the trial. Whether or not this occurs will depend on what is learned when more data about those side effects are made public.

Study Design

The FOCUS trial enrolled 315 re­lapsed and refractory patients at treat­ment centers across Europe, Israel, and Australia. Trial participants were heavily pretreated, having received a median of five pre­vi­ous treat­ment regi­mens.

Patients in the Phase 3 trial were randomly selected to receive one of two treat­ment regi­mens.

The first regi­men consisted of single-agent Kyprolis (car­filz­o­mib).

The second regi­men consisted of a steroid, such as pred­ni­sone or dexa­meth­a­sone (Decadron), optionally com­bined with oral cyclo­phos­pha­mide (Cytoxan). Most of the patients receiving the second treat­ment reg­i­men did in fact receive cyclo­phos­pha­mide.

The dosing of Kyprolis in the trial was similar to what is recommended in the official U.S. prescribing in­for­ma­tion for the drug, with an upward adjustment in the trial to dosing in the first cycle, and a downward ad­just­ment in cycles 10 and beyond.

All patients in the trial con­tinued on their assigned treat­ment regi­men until disease pro­gres­sion or until they could no longer tolerate the treat­ment.

Top-Line Study Results

In Wednesday’s announcement, Amgen (NASDAQ:AMGN) reported that there was no statistically significant difference in over­all survival between the two treat­ment regi­mens. The com­pany did not report actual over­all survival times for the two regi­mens, nor did it report any pro­gres­sion-free survival or response rate results.

Amgen also reported that there was no significant difference between the two treat­ment regi­mens in terms of the per­cent of patients who dis­con­tinued treat­ment due to severe side effects or death.

In addi­tion, the rate of heart-related severe side effects in FOCUS trial participants treated with Kyprolis was similar to what is reported in the drug's U.S. pre­scrib­ing in­­for­ma­tion.

There were, however, a higher number of kidney-related side effects seen among Kyprolis-treated patients in the FOCUS trial than in patients in the trial who were not treated with the drug, and as compared to what is in the drug's U.S. pre­scrib­ing in­­for­ma­tion.

Amgen intends to provide addi­tional details about the FOCUS trial results at an upcoming scientific meeting.

Financial Market Reaction To The FOCUS Results

The stock market initially reacted negatively to Wednesday’s news of the FOCUS trial results. Amgen re­ported the results im­medi­ately after the close of U.S. financial markets that day, and the com­pany’s stock declined by up to 2 per­cent in after hours trading that evening.

Since Wednesday, however, financial markets appear to have reassessed the implications of the trial re­sults. Amgen’s stock closed Friday afternoon up more than 4 per­cent from its Wednesday close. The stock market as a whole was up about half a per­cent over that same period of time.

Impact Of The Study Results On Perceptions Of Kyprolis’s Effectiveness

One potential way the results of the FOCUS trial could affect the use of Kyprolis in the United States is by changing physician perceptions of how effective the drug is.

Myeloma specialists contacted by The Beacon, however, were not concerned by the FOCUS trial's survival out­come and do not believe the results will negatively affect impressions of the drug's effectiveness.

"I am not surprised" by the trial's survival out­come, said Dr. Jatin Shah of the MD Anderson Cancer Center in Houston, "and most doctors in the multiple myeloma community are not surprised."  He added that the trial "does not change the view that Kyprolis is very active."

The key factor to bear in mind when interpreting the survival out­come, The Beacon was told several times, is that patients in the trial who were not treated with Kyprolis typically received a two-drug regi­men – a steroid com­bined with cyclo­phos­pha­mide – that can be active even in heavily pretreated patients.

Dr. Prashant Kapoor of the Mayo Clinic, for example, noted that pre­vi­ous research has shown that pred­ni­sone com­bined with cyclo­phos­pha­mide can be quite active in advanced myeloma. In addi­tion, pred­ni­sone is often the steroid that myeloma specialists prefer to combine with cyclo­phos­pha­mide in patients such as those in the FOCUS trial.

Impact Of The Study Results On Perceptions Of Kyprolis’s Safety

Another potential way the FOCUS trial could affect the use of Kyprolis in the U.S. is by changing physician perceptions of how safe the drug is.

The good news for Kyprolis in this regard is that patients in the FOCUS trial who were treated with the drug did not experience heart-related side effects to a greater degree than was seen in other key Kyprolis trials. Some U.S. physicians have had concerns about Kyprolis’s potential for heart-related side effects.

The not-so-good news on the safety front, however, is that Kyprolis-treated patients in the FOCUS trial ex­per­i­enced more kidney-related side effects than the other patients in the trial.

Some industry analysts have downplayed the significance of this result by noting (correctly) that patients admitted to the FOCUS trial were allowed to have much more kidney damage than was permitted in other key Kyprolis trials, such as the ASPIRE trial and the Phase 2 trial for U.S. approval.

This difference in trial design may explain why the Kyprolis-treated patients were more likely in the FOCUS trial to have kidney-related side effects than was the case in the other two trials.

It does not explain, however, why the Kyprolis-treated patients in the FOCUS trial had kidney-related side effects more often than patients in the same trial who were not treated with Kyprolis. All patients in the FOCUS trial, regardless of the treat­ment regi­men they received, were admitted to the trial using exactly the same screening criteria.

That said, it is also true that, in its announcement of the ASPIRE trial results earlier this month, Amgen did not indicate that the Kyprolis-treated patients in that trial experienced higher kidney-related side effects than the patients in the trial who were not treated with Kyprolis.

Thus, the FOCUS trial is the only Kyprolis trial thus far in which a kidney-related safety issue has been flagged. This will likely limit the impact of that issue in the im­medi­ate term.

The Relevance Of Kidney-Related Side Effects To Kyprolis

Yet, if more detailed data from the trial indicate that the side effects were not just a sta­tis­ti­cal fluke, the potential longer-term significance of the kidney-related side effects in the FOCUS trial should not be overlooked.

Many physicians and myeloma patients today consider Kyprolis to be primarily a treat­ment option for re­lapsed myeloma patients, with Pomalyst (poma­lido­mide, Imnovid) being perhaps the key alter­na­tive to Kyprolis.

However, in the longer term, it is likely that Kyprolis will compete more and more with Velcade (bor­tez­o­mib) for use in newly diagnosed as well as re­lapsed myeloma patients. Kyprolis and Velcade are both in the same class of drugs, and Amgen has conducted – and is conducting – numerous clinical trials testing Kyprolis in newly diagnosed myeloma patients.

One key reason physicians turn to Velcade when treating myeloma patients, however, is that it is considered safe to use in patients with damaged kidneys. Moreover, kidney damage is quite common in myeloma patients.

Thus, any credible finding that Kyprolis may have kidney-related safety issues, while it may not have an im­me­di­ate effect on the drug’s use, could have longer-term implications for how often the drug is pre­scribed.

For further in­­for­ma­tion about the FOCUS trial results announced Wednesday, see the Amgen press release. See the in­­for­ma­tion at clinicaltrials.gov for further details of the FOCUS and the ASPIRE clinical trials.