ASH Data Give Millennium’s Velcade A Boost, Raise Bar For Competitors

Myeloma trial data released at the American Society of Hematology meeting promises to further lift utilization for Takeda/Millennium's proteasome inhibitor Velcade , which just passed $1 billion in sales.

News that global sales for Millennium's only marketed product, Velcade (bortezomib), passed the $1 billion sales mark in November surfaced during the ASH meeting in San Francisco Dec. 6-9. Sales of the drug have increased 25 percent over last year, due partly to a new indication granted mid-year in frontline myeloma (¹ (Also see "Velcade Wins FDA Clearance In First-Line MM" - Pink Sheet, 20 Jun, 2008.)).

"What we have seen from the time of approval is an increase in utilization of Velcade in the frontline setting," said Nancy Simonian, Chief Medical Officer, in an interview.

The ASH meeting featured updates of three major Phase III studies, showing frontline treatment with Velcade yields a long-lasting impact on survival in multiple myeloma patients.

In the VISTA study of 682 transplant-ineligible multiple myeloma patients, bortezomib plus melphalan and prednisone resulted in a 72 percent three-year survival rate, compared with 59 percent for melphalan-prednisone alone, researchers reported Dec. 8.

VMP reduced the death rate by 36 percent, a statistically significant finding despite the fact that 43 percent of the MP arm ultimately received Velcade later on. Results applied across prognostic subgroups, including those with impaired kidney function.

Grade 3 to 4 peripheral neuropathy has been a dose-limiting side effect for Velcade in past trials and continues to be a problem, occurring in 30 percent of patients on the VMP regimen, versus 0 percent for the MP arm. It is not necessarily permanent, however. In 79 percent of patients, symptoms gradually abated and 60 percent completely recovered.

The results confirm the original VISTA findings, presented a year ago in September and used as the basis for the frontline approval (² (Also see "Velcade As Front-Line Multiple Myeloma Treatment Solidified By Phase III Data" - Pink Sheet, 18 Sep, 2007.)).

"Now we have real evidence that higher response rates with Velcade turn into prolonged progression-free survival," said Simonian.

In a post-ASH research report, Leerink Swann analyst Howard Liang described the emerging data for Velcade in high-risk multiple myeloma patients as "notable." Many physicians "appear to have the impression" that Velcade is equally effective in patients with normal or poor cytogenetics, even though data has only been available for a small number of patients, Liang wrote.

"Updated VISTA data at ASH show that this trend is holding up. This may help reinforce physicians' perception and help Velcade's position in this important group (~25 percent of MM patients)."

In the past, a lot of regimens worked well in low-risk patients but fell short for those at high risk, Simonian commented. "What is remarkable today is that the Velcade-based regimen works just as well in people that have poor prognostic features," she said.

Additional Clinical Trials Bolster VISTA

Millennium is also gaining additional evidence to support initial use of Velcade. Another Phase III study found a superior complete response rate and progression-free survival for upfront therapy with Velcade/thalidomide/dexamethasone, compared to the standard thalidomide/dexamethasone combination in newly-diagnosed MM patients prior to melphalan-based autologous stem cell transplantation.

"Superior rates of response to VTD as an induction therapy translated into an even higher frequency of high-quality responses after the first autologous transplantation," University of Bologna's Michele Cavo commented in presenting results.

The frequency of adverse events was comparable in the two treatment groups, but those with VTD had more cases of peripheral neuropathy and skin rash. More TD patients discontinued therapy due to higher rates of disease progression.

In a third ASH update, researchers presented the latest data for 482 patients in the Phase III IFM 2005/01 trial pitting Velcade/dexamethasone against vincristine/adriamycin(doxorubicin)/dexamethasone as induction treatment prior to ASCT in untreated myeloma.

At two-year follow-up, progression-free survival reached 69 percent in the VcD arm, versus 60 percent for VAD, researchers reported during a joint ASCO/ASH symposium Dec. 7.

Revlimid Adds Evidence Too

In an ASH preview report, Baird analyst Christopher Raymond had noted that "impressive" longer-term VISTA results "raise the bar" for potential competitors.

During the joint ASH/ASCO symposium, Celgene presented updated data on its immunomodulatory agent Revlimid (lenalidomide) in newly-diagnosed multiple myeloma patients. Revlimid is currently FDA-approved for use with dexamethasone in relapsed patients who have already tried one therapy.

Researchers reported a three-year survival rate of 75 percent for patients taking Revlimid with a standard dose of dexamethasone and 74 percent survival for those on Revlimid with low-dose dexamethasone.

"These survival rates are among the highest seen in the disease thus far. It remains a formal possibility of filing for a first-line label in MM based on these data," JP Morgan's Geoffrey Meacham said in a Dec. 8 note.

A number of small studies reported at ASH support the potential value of the triple combination therapy with Velcade/Revlimid/dexamethasone in the frontline setting and for relapsed patients, suggesting a new standard of care is emerging (³ (Also see "ASH Preview: Researchers Chase Winning Combination In Frontline Myeloma" - Pink Sheet, 1 Dec, 2008.), p. 16).

The frontline Revlimid/Velcade/dexamethasone combination proved to be well-tolerated in a Phase I/II study and showed a response rate of 100 percent in both the Phase I and Phase II parts of the study. Meacham observed that physicians they spoke to were impressed with the response rate data.

Another study showed that the same triple combination is effective in the relapsed/refectory MM setting regardless of whether a patient had received prior treatment with Revlimid, thalidomide or Velcade. Results were good for those with abnormal cytogenetics and side effects were manageable.

"This is important because it supports our view that patients currently receiving only Revlimid or Velcade in front-line therapy are likely to be treated with the triple combination when they progress," wrote Bernstein Research's Geoffrey Porges in a Dec. 8 note.

Though researchers are enthusiastic about the possibilities for combination of Revlimid with Velcade, some say news from ASH was on the whole not good for Celgene in the frontline myeloma space.

"Session after session on multiple myeloma was dominated by European investigators presenting data for a variety of different regimens, all based on Millennium's Velcade. This array of presentations highlights the handicap Celgene must overcome entering the market in Europe well behind their arch competitor without a pivotal trial in frontline myeloma," Porges wrote.

"It is clear that in Europe at least, Velcade-based regimens are likely to emerge as dominant, with Revlimid now chasing either combination use with Velcade, or maintenance use after Velcade, or second or third line use after failure of Velcade-based regimens," he wrote.

- Emily Hayes ([email protected])