The Oncologic Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) met today to discuss and vote on the new drug application for carfilzomib (Kyprolis).

The committee, often referred to as the ODAC, reviewed data on the efficacy and safety of car­filz­o­mib that the FDA released for the committee members on Monday (see related Beacon news) and then voted on whether car­filz­o­mib’s benefit risk profile was favorable for the treat­ment of multiple myeloma.

Myeloma Beacon staff members provided live updates below as the ODAC meeting progressed.

1 p.m.: The car­filz­o­mib portion of the meeting gets underway.  The committee members introduce themselves.

1:08 p.m.: Onyx begins their presentation about car­filz­o­mib.

Dr. Ted Love, Executive VP, R&D and Technical Operations at Onyx, introduces car­filz­o­mib.  He stresses that car­filz­o­mib does not cause neurotoxicity, unlike Velcade (bor­tez­o­mib).

He explains that despite advances in the treat­ment of multiple myeloma, there is still an unmet need for better treat­ments, particularly for patients who are re­lapsed and refractory (resistant) to current myeloma ther­a­pies.

1:13 p.m.: Dr. Ken Anderson from the Dana-Farber Cancer Institute presents the cur­rently available treat­ments for multiple myeloma.

He says there are many options for newly diagnosed patients, although the drugs all have side effects that limit their use.  Tragically, he says, all patients reach a point when they become refractory (resistant) or intolerant to current ther­a­pies, and there is an unmet need for these patients.

Dr. Anderson points out that survival is poor for patients who are refractory to both Velcade and Revlimid (lena­lido­mide).  These patients can par­tic­i­pate in clinical trials, but addi­tional novel agents are needed for myeloma.

1:22 p.m.: Dr. Barbara Klencke, Senior VP of Clinical Benefit at Onyx, begins presenting the Phase 2 “003-A1” car­filz­o­mib clinical trial, which studied single-agent car­filz­o­mib in re­lapsed and refractory multiple myeloma patients – those who exhausted cur­rently available treat­ment options, including Velcade and Revlimid.

Dr. Klencke reports that among the 266 patients included in the study, the over­all response rate was 22.9 per­cent, the median duration of response was 7.8 months, and the over­all survival was 15.4 months. She adds that these results were replicated in supportive Phase 2 clinical studies.

1:32 p.m.: Dr. Natalie Sacks, VP of Clinical Science and Biometrics at Onyx, is now going to discuss the safety profile of car­filz­o­mib.

She says that car­filz­o­mib was generally well tolerated, with the most common side effects being fatigue, low red blood cell counts, nausea, low platelet counts, shortness of breath, diarrhea, fever, upper res­pira­tory tract in­fec­tion, headache, and increased serum creatinine. There was not much periph­eral neu­rop­athy (pain, tingling, or loss of sensation in the extremities), unlike treat­ment with Velcade and thalidomide (Thalomid).

She also reports that the rates and types of serious side effects were consistent with pre­vi­ously reported out­comes for patients with very advanced myeloma.

Dr. Sacks is now specifically addressing the FDA’s concern about the heart-related side effects seen in the car­filz­o­mib study.  She shows data supporting that heart problems are common in elderly myeloma patients. She says that serious heart-related side effects and deaths were observed, but the rates are com­parable to those seen in the literature for other myeloma studies.

1:46 p.m.: Dr. Sagar Lonial from the Emory Winship Cancer Institute is now addressing the advisory committee.  He is presenting the benefit-risk profile for car­filz­o­mib.

Dr. Lonial is going to address several questions:

Does the agent have toxicity that precludes its efficacy?  He compares rates of periph­eral neu­rop­athy seen in car­filz­o­mib- and Velcade-treated patients, showing that rates with car­filz­o­mib are very low.

Are there unexpected toxicities?  He states that eight out of 526 patients in the Phase 2 car­filz­o­mib studies potentially had a heart-related side effect.  He points out that patients in the car­filz­o­mib studies are more heavily pre-treated that those included in historical clinical studies of myeloma patients.

He now addresses the clinical benefit of car­filz­o­mib.  He states that the over­all response rate is 23 per­cent, but an addi­tional 13 per­cent had a minimal response, which is clinically meaningful.

He also says that patients treated with car­filz­o­mib have a promising over­all survival.

2:00 p.m.: The FDA presentation about car­filz­o­mib begins.  It is presented by Dr. Thomas Herndon, Medical Officer for the FDA.

Dr. Herndon presents the FDA’s analysis of the 003-A1 study results.

He con­firms that 22.9 per­cent of the trial participants responded to car­filz­o­mib.  Results from a subgroup analysis show that the types and number of pre­vi­ous treat­ments do not have much impact on the response rate.  He also states that the duration of response was 7.8 months.

He then points out that patients received dexamethasone (Decadron) prior to some car­filz­o­mib injections to prevent injection site reactions.  However, he says that the doses used in the car­filz­o­mib study were much lower than those used alone or in com­bi­na­tion with other myeloma treat­ments.

2:05 p.m.: Dr. Herndon presents safety data for car­filz­o­mib.

Dr. Herndon notes although the most common cause of death on trial was disease pro­gres­sion, the next most common cause was heart-related issues.

The FDA attributed up to nine deaths to heart-related issues and two to liver.

Dr. Herndon said that life threatening heart, lung, and liver-related side effects were seen in a small per­cent­age of car­filz­o­mib-treated patients.  He explains that since 003-A1 is a single arm trial, these side effects must be attributed to car­filz­o­mib at this time.

2:12 p.m.: Dr. Herndon concludes his presentation with a question for the committee: Is the risk benefit assess­ment favorable for the use of car­filz­o­mib in the treat­ment of patients with re­lapsed and refractory multiple myeloma who have received at least 2 prior lines of ther­apy that included a proteasome inhibitor [such as Velcade] and an immuno­modu­la­tory agent [such as Revlimid or thalido­mide]?

2:13 p.m.: The floor is now open to the committee to ask questions.

A member of the committee asks: What is the response rate in patients who had Velcade in their last line of ther­apy and progressed on that ther­apy?  Dr. Klencke shows that 18.3 per­cent of these patients responded to car­filz­o­mib.

Dr. Sekeres asks for a clarification about the design of the Phase 3 car­filz­o­mib trial in re­lapsed myeloma patients.

Another committee member asks: How was neu­rop­athy monitored during the study? Dr. Sacks says that patients were assessed for neu­rop­athy at base­line as well as throughout the study.  She shows data showing neu­rop­athy out­comes of the patients who had neu­rop­athy versus no neu­rop­athy at base­line.

Onyx is now given a chance to address a letter from Dr. Singhal in which she points out differences in analyses of how patients responded to car­filz­o­mib in the 003-A1 study. Onyx’s conclusion is that although some of the patients were classified as having different responses, according to the different analyses, it does not change the over­all response rate.  All analyses found the response rate to be around 22 to 23 per­cent.

Another committee member asks: Did anthracyclines (e.g. doxorubicin) play a role in the cardiac deaths?  Onyx states that anthracycline exposure did not seem to affect cardiac deaths.

Were there patients who received main­te­nance ther­apy on this study, and was there any difference in their response rates?  Dr. Klencke says that Onyx is not aware that any of the patients in the car­filz­o­mib study pre­vi­ously had Revlimid main­te­nance.

Another member asks: Was the 23 per­cent response rate for initial response or best response?  Onyx states that it is the best response.

Was the frequency of response mea­sure­ment the same in this trial as it is in other trials?  Testing more frequently can cause a higher response rate.  Dr. Anderson says it is com­parable.

Dr. Wozniak asks: Were patients with amyloidosis allowed on the trial?  Onyx responds: No.

Among the two patients who had liver toxicity, did they have any other con­di­tions that could have led to their death?  Onyx explains that they both had other con­di­tions that could have led to their liver toxicity.

Another committee member asks: Can you explain which patients should be excluded from car­filz­o­mib treat­ment, in order to prevent heart-related com­pli­ca­tions, if car­filz­o­mib is given accelerated approval?  Onyx presents recommended guidance.

A panel member questions the comparisons between the survival data for car­filz­o­mib and the survival data in similar trials for Velcade and Revlimid.  The car­filz­o­mib patients have survived longer, so they may be a heartier patient population.  Dr. Anderson says he thinks that if those patients were retreated with Velcade that 0 to 10 per­cent would respond.

Another member states that there seems to be a dose response.  Onyx con­firms that there appears to be a dose response; 27 mg of car­filz­o­mib appears to have a higher response rate than 20 mg.

Dr. Sekeres asks Onyx to clarify what per­cent­age of patients were purely intolerant, not refractory to pre­vi­ous ther­apy.  Onyx says 16 per­cent were purely intolerant to pre­vi­ous ther­apy.  Onyx cannot provide what the response rate was for this subset of patients.

All patients in the 003-A1 study were pre­vi­ously treated with Velcade.  Dr. Sekeres asks: What is the range of duration of exposure to Velcade?  Onyx says that the patients had a median of two prior Velcade-containing regi­mens.  The com­pany does not have data about how long (e.g. how many cycles) the patients were treated with Velcade.

What is the response rate for patients retreated with Velcade?  Dr. Lonial says 20 to 25 per­cent will respond again; however, the duration of response is slightly shorter than duration of response to the original exposure.

Another panel member asks: For re­lapsed myeloma patients, do you con­tinue to treat until pro­gres­sion?  Dr. Anderson says yes.  What is the median time to response to Velcade?  Dr. Anderson says for re­lapsed patients, they usually see response within two months, other­wise you typically will not see a response.

If you measure survival from time of diag­nosis for this study, is there a survival benefit compared to other studies?  Onyx says they focused on response rates.

A member questions whether natural variation in disease mea­sure­ments can be mistaken as a response.  Another panel member clarifies that there cannot be that large of natural variation.

The trial excludes primary refractory myeloma patients, correct?  Dr. Anderson con­firms that the trial did not allow primary refractory patients because those patients have other treat­ment options.  The car­filz­o­mib data shows that response rates continuously decrease with more relapses.

Another member asks: Is car­filz­o­mib tolerability similar in patients who are younger (less than 65 years) versus older (more than 65 years)?  About half of the patients were above and half were below 65 years.  In the older patients we saw a bit more blood-related side effects, fatigue, diarrhea, and increased creatinine levels.  For each of these, there were at least an addi­tional 5 per­cent of older patients who experienced the side effect.

A committee member asks about preclinical safety studies.  Chris Kirkpatrick, VP of Research at Onyx, presents toxicity studies in rats and monkeys.  Heart-related toxicity was the main side effect for both Velcade as well as car­filz­o­mib.

3:15 p.m.: There will now be a 15 minute break.

Recap So Far – The presentations by Onyx per­son­nel as well as by Drs. Anderson and Lonial went smoothly and addressed a substantial number of key points.  The presentations came across as quite persuasive, although that was somewhat to be expected.  The presentation by the FDA staff representative was surprising.  From the tone of the briefing document prepared by the staff for the meeting, one would have expected a much more aggressive presentation, challenging car­filz­o­mib on a number of fronts.  Instead, the presentation almost entirely lacked the bluster and negative language of the briefing document.

After the FDA presentation, the momentum seemed clearly in car­filz­o­mib’s favor.  This con­tinued to be the case during many of the initial questions.  However, as the questions con­tinued, they became tougher, and there were signals that a few committee members are not ready to vote in car­filz­o­mib’s favor.

Thus, for perhaps five, 10, or maybe 15 minutes, it seemed like the momentum might have shifted against car­filz­o­mib.

That shift ended, however, during the last five or ten minutes right before the break.  Indeed, going into the break, there did not seem to be substantial momentum in one direction or the other.

That said, the committee seems to be heading toward a positive vote in car­filz­o­mib’s favor.  The vote may even end up being strongly in car­filz­o­mib’s favor.

3:30 p.m.: The meeting resumes with an Open Public Hearing.

The first speaker is Veena Agarwal, who was diagnosed with myeloma in 2007.  She never achieved remission and started to experience periph­eral neu­rop­athy, until she was treated with car­filz­o­mib.  She responded to car­filz­o­mib and thinks it is important for others to have car­filz­o­mib as a treat­ment option.  She believes that car­filz­o­mib has prolonged her life.

Robin Tuohy, Director of Support Groups for the Inter­na­tional Myeloma Foundation, is the next speaker.  Her husband was diagnosed with myeloma more than 12 years ago.  Thanks to new drug treat­ments, her husband has survived long past his initial prognosis.  However, she knows her husband’s myeloma will eventually return and the drugs that worked pre­vi­ously for him will no longer work.  She feels that car­filz­o­mib literally means life or death for myeloma patients who have run out of other options.

Michael Tuohy, as his wife just said, is a myeloma survivor.  He was diagnosed at the age of 36 years, when he had two young children.  He thanks research for making more treat­ment options available so that patients are able to live longer.  He says that each new drug approval extends patients’ lives.  He has been on Revlimid for seven years and is in complete remission.  He hopes the committee will recommend car­filz­o­mib so it will be an option for himself and any other myeloma patients who may relapse while on other treat­ments.

Benjamin (Doug) Rickert was diagnosed in 2001 and has received six lines of ther­apy, including car­filz­o­mib.  He says that his periph­eral neu­rop­athy has significantly decreased while he has been on car­filz­o­mib and that his quality of life has significantly improved.  He asks the FDA to please approve this drug.

Diane Moran, Senior VP Strategic Planning of the Inter­na­tional Myeloma Foundation, addresses the committee.  She says that car­filz­o­mib is a crucial option for myeloma patients for whom other drugs have failed.

The next speaker is Dr. Stephen Berrager, a 70 year old grandfather.  He was diagnosed in 2007.  Two and a half years ago, his myeloma was raging out of control.  A stem cell trans­plant was not an option.  His oncologist recommended a car­filz­o­mib trial.  After three months, his myeloma was under control.  He is now living a prod­uctive life again.  He urges the FDA to approve car­filz­o­mib im­medi­ately.

Walter Capone, Chief Operating Officer of the Multiple Myeloma Research Foundation, speaks next.  He says that patients with advanced myeloma typically survive six to ten months.  He explains that the car­filz­o­mib access pro­gram has allowed 500 patients to benefit from car­filz­o­mib.

The next speaker is Amy Wolverton, who was diagnosed with myeloma in her 30s.  After being treated with Revlimid for several years, her disease is progressing again.  Particularly given her young age, she wants to see myeloma become a man­ageable disease.  She says that the more treat­ment options that are out there, the better.  She says that given the option of letting myeloma take her life or taking on some side effects asso­ci­ated with a drug, she would take on the side effects.  She urges the committee to approve this medication.

Paul Westrick, a 15-year myeloma survivor, says his goal has always been to surpass the median.  He is cur­rently participating in the Phase 3 car­filz­o­mib trial, and he has achieved a near complete response.  He says he was out of commission for several months after his stem cell trans­plant, but he has not missed a beat while being on car­filz­o­mib.  He asks the panel to consider approval of the application.

The next speaker is Libby Mullin from the Cancer Support Community.  The mission of her organization is to help cancer patients regain a sense of control over their lives.  She says we have the opportunity right now to expand the chances that families have better treat­ment options.

4:00 p.m.: The panel begins to discuss the Question to the Advisory Committee.

In particular, the FDA has asked the committee: Is the risk benefit assess­ment favorable for the use of car­filz­o­mib in the treat­ment of patients with re­lapsed and refractory multiple myeloma who have received at least 2 prior lines of ther­apy that included a proteasome inhibitor [such as Velcade] and an immuno­modu­la­tory agent [such as Revlimid or thalido­mide]?

A panel member begins by reiterating the question: Is the benefit offset by the risks?  He says that the median duration of response is approx­i­mately 7.8 months.  He also points out the cardiac toxicity but says that animal studies show this risk is similar between car­filz­o­mib and Velcade.

Dr. Jim Omel, a 15 year myeloma survivor, says that patients are willing to take the side effect risks.  He points to patients taking Revlimid main­te­nance ther­apy, even though it is asso­ci­ated with second cancers.

He says that car­filz­o­mib will not cure myeloma, but it will buy patients valuable time.  He says it has done this for 22 per­cent of these patients who had no other options.

A panel member mentions that the FDA does not seem as concerned today about the toxicity of car­filz­o­mib as they did in the briefing documents released on Monday.  As FDA representative con­firms that they are not as concerned at this time.

Dr. Wilson highlights that 18 per­cent of patients refractory to Velcade responded to car­filz­o­mib, indicating that car­filz­o­mib works differently than Velcade.

Dr. Sekeres asks whether pro­gres­sion-free survival is an acceptable end­point for myeloma studies.  It is con­firmed that the FDA accepts pro­gres­sion-free survival as a surrogate for over­all survival.

4:19 p.m.: Voting begins.

The final vote is as follows:

Yes: 11
No: 0
Abstain: 1

Dr. Neaton abstained from voting.  He feels he is not knowledgeable enough about the field to determine whether the benefits outweigh the risks.

The rest of the committee members voted yes.  Some feel strongly that car­filz­o­mib offered a clinical benefit with an acceptable safety profile.  Others feel the risk benefit profile was more neutral, but not negative.  A few even are not confident about the risk benefit profile but voted yes.

Several members say they hope the con­firmatory studies will show acceptable responses and a pro­gres­sion-free survival at least as good as the current treat­ment options.

4:26 p.m.: The FDA thanks the presenters and the committee and adjourns the meeting.

Onyx Pharmaceuticals (NASDAQ:ONXX) completed its application to the Food and Drug Administration (FDA) last September to have car­filz­o­mib approved for the treat­ment of re­lapsed and refractory multiple myeloma patients who have had at least two prior ther­a­pies (see related Beacon news).

The FDA is required to make a decision about car­filz­o­mib’s application by July 27.  It also has the option, however, of extending this deadline if it feels it needs addi­tional time to complete its review.

The ODAC vote will generally be interpreted as a recommendation for, or against, the FDA approving car­filz­o­mib.

The FDA is not legally required to follow the recommendations of its advisory committees; however, it usually does.

In a Beacon survey of financial market analysts who follow Onyx, a majority of the survey participants said they expect the ODAC to cast a close vote in favor of the FDA approving car­filz­o­mib.  A larger survey of major Wall Street investors, however, revealed more pessimistic expectations about the out­come of the vote (see related Beacon news).

Both of the surveys just mentioned were carried out before the FDA released its internal review of car­filz­o­mib for today’s meeting.  The FDA review has been interpreted as critical of car­filz­o­mib, particularly its safety, and Onyx’s stock has declined almost 5 per­cent since the report was issued (see related Beacon news).

The Center for Drug Evaluation and Research is also providing a live webcast of the ODAC meeting (instructions available as a pdf).