Please take good care of yourselves and practice these guidelines. More information will be posted here as it comes in.

The CGRP Receptor and Migraines. 

A video review from Eli Lilly. Venture 17 has no economic relationship with Eli Lilly. This video is for educational purposes only.

Click this image to view the video.

Venetoclax monotherapy appears to improve outcomes in some patients with acute myelogenous leukemia (AML), according to a phase 2, single-arm study.

"This study included patients that were in categories that are difficult to treat - relapsed, refractory, and/or elderly and deemed medically unfit to receive induction therapy," Dr. Anthony Letai from Dana-Farber Cancer Institute in Boston told Reuters Health by email.

"The fact that some of these patients had leukemias that were relapsed or refractory to very tough regimens, including regimens that require multi-week inpatient hospital stays, but nonetheless responded to an oral outpatient therapy taken once a day was a very interesting result," he said.

Venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor, received FDA approval for chronic lymphocytic leukemia (CLL) earlier this year.

Dr. Letai and colleagues investigated the efficacy and biological correlates of response in the first clinical study of venetoclax monotherapy in 32 patients with relapsed/refractory AML or untreated AML unfit for intensive therapy.

The objective response rate was 19% (six of 32), with two patients achieving a complete response and four achieving a complete response with incomplete blood count recovery. All objective responses were achieved by the week-4 assessment.

An additional 19% had antileukemic activity demonstrated by partial bone marrow response and incomplete hematologic recovery.

The six-month leukemia-free survival rate was 10% (median leukemia-free survival, 2.3 months), and the six-month overall survival estimate was 36% (median overall survival, 4.7 months), the researchers report in Cancer Discovery, online August 12.

At the time of this report, all patients had discontinued venetoclax: 29 due to progressive disease, one due to adverse event, one withdrew consent, and one proceeded to allogeneic hematopoietic stem cell transplant after achieving stable disease.

"Our data provide evidence that AML with IDH1/2 mutations exhibits BCL2 dependence and validates preclinical data that suggest suppression of cytochrome c oxidase activity in IDH1/2 mutant AML lowers the mitochondrial threshold to trigger apoptosis upon BCL2 inhibition," the researchers note. "However, activity observed in patients with wild-type IDH1/2 suggests targeting BCL2 with venetoclax should not be restricted to patients with mutations in IDH1/2."

Venetoclax monotherapy was generally well tolerated, although treatment-emergent adverse events were reported for all patients. Nausea, diarrhea, hypokalemia, vomiting, and headache were the most commonly reported adverse events.

"This study was the first report of venetoclax in AML, and as such was a single-agent study," Dr. Letai said. "However, I do not think single-agent use will be common in AML for this drug. I think that venetoclax will be incorporated into combinations with many other agents active in AML."

"Right now, in the elderly setting, it is being combined with either hypomethylating agents (vidaza or decitabine) or low-dose cytarabine, both commonly used in the elderly in AML," he said. "The response rates have been fantastic, around 70%, as reported in abstracts at ASH and ASCO. There will likely be clinical testing of combinations including venetoclax at all stages of AML therapy, including induction, consolidation, salvage. Indeed, some of these trials are already starting. Who knows, perhaps even maintenance? It is well tolerated, so lends itself to combination."

"Genomics and genetics are often equated with personalized medicine, the job of which is to match the right patient with the right drugs," Dr. Letai added. "Venetoclax has so far demonstrated activity in CLL, mantle cell lymphoma, AML. There are no genetic abnormalities related to BCL-2 that would indicate activity in these cancers. If we relied on genetics alone, these would have missed."

"Instead, we and others took a functional approach to identifying BCL-2 dependence in cancers, and thus identifying good targets for venetoclax," he said. "I think that these functional precision-medicine approaches are going to be vital to taking advantage of all the new drugs that are appearing in cancer. If we rely on genomics alone, we will probably miss most of our therapeutic opportunities."

Dr. Fernando Ramos from the University of Leon in Spain, who recently reviewed AML in older adults, told Reuters Health by email, "Venetoclax may be an interesting option for rescue therapy in this patient subset."

"Precision medicine has come a long way," added Dr. Ramos, who was not involved in the study. "Venetoclax may be an interesting partner to azanucleosides in unfit AML patients."

Currently, venetoclax is in phase 2 testing for AML, diffuse large B-cell lymphoma, and non-Hodgkin lymphoma and in phase 3 testing for multiple myeloma.

AbbVie and Genentech funded the study, employed 13 of the 22 authors, and had various relationships with four other authors, including Dr. Letai.

Von Willebrand disease (VWD) is an inherited, genetically and clinically heterogeneous hemorrhagic disorder caused by a deficiency or dysfunction of the protein called Von Willebrand factor (VWF). This protein is a necessary step in the coagulation cascade, but also involved in the initiation of platelet aggregation for proper blood clotting.

Consequently, defective VWF interaction between platelets and the vessel wall impairs primary hemostasis. Von Willibrand factor circulates in blood plasma at concentrations of approximately 10 mg/mL. In response to numerous stimuli, VWF is released from storage granules in platelets and vascular bed endothelial cells.

VWF performs two major roles in hemostasis, wether intrinsic or extrinsic. First, it mediates the adhesion of platelets to sites of vascular injury. Second, it binds and stabilizes the procoagulant protein factor VIII (FVIII).

The disease is divided into three major categories: Partial Quantitative Deficiency (type I), Qualitative Deficiency (type II), and Total Deficiency (type III). VWD type II is further divided into four variant conditions (IIA, IIB, IIN, IIM), based on characteristics of dysfunctional VWF.

According to data pre-published online August 3rd, 2015, in Blood, successful management of bleeding episodes were observed in 100% of subjects treated with BAX 111 for von Willebrand disease (VWD) during a recently completed Phase 3 clinical trial.

Bleeding-episode-management success was the primary endpoint of the clinical trial.

BAX 111 is a highly purified recombinant von Willebrand factor (VWF) analog manufactured by Baxalta, Inc.

VWD is a rare, inherited, incurable, gene-based bleeding disorder in which a missing or defective clotting protein (VWF) fails to bind with platelets in blood vessel walls.

Normally, a blood-vessel tear initiates bleeding and  VWF assists in the repair. When VWF is absent or under-represented, the formation of platelet plugs are inhibited during the clotting process, resulting in excessive bleeding and easy bruising.

In more severe forms of VWD, the bleeding can be life-threatening and require emergency treatment.

Gill et al derived their findings from a Phase 3, multicenter, international, open-label study which evaluated the safety, efficacy and pharmacokinetics of BAX 111 in 37 patients with severe VWD.

Study participants evidenced a mean efficacy rating of < 2.5 on a 4-point scale wherein lower numbers correlated with a higher degree of bleed control (see sidebar below). Bleed control for all treated bleeding events (N=192 bleeds in 22 subjects) was rated as good or excellent (96.9% excellent; 119/122 minor, 59/61 moderate, and 6/7 major bleeds). In 81.8% of bleeds, 1 infusion was sufficient to attain control. For major bleeds, the infusion median was

 
• Minor and Moderate Bleeding Events

o Actual number of infusion less than or equal to estimated number of infusion required to treat that bleeding episode. No additional VWF-containing/coagulation factor containing product required.

• Major Bleeding Events

o Actual number of infusion less than or equal to estimated number of infusion required to treat that bleeding episode. No additional VWF-containing/coagulation factor containing product required.

• Minor and Moderate Bleeding Events

o 1 to 2 infusions greater than estimated required to control that bleeding episode. No additional VWF-containing/coagulation factor containing product required.

• Major Bleeding Events

o Less than 1.5x greater than estimated required to control that bleeding episode. No additional VWF-containing/coagulation factor containing product required.

• Minor and Moderate Bleeding Events

o 3 or more infusions greater than estimated used to control that bleeding event. No additional VWF-containing/coagulation factor containing product required.

• Major Bleeding Events

o Greater than or equal to 1.5x greater than estimated used to control that bleeding event. No additional VWF-containing/coagulation factor containing product required.

• Minor and Moderate Bleeding Events

o Severe uncontrolled bleeding or intensity of bleeding not changed. Additional VWF-containing/coagulation factor containing product required.

• Major Bleeding Events

o Severe uncontrolled bleeding or intensity of bleeding not changed. Additional VWF-containing/coagulation factor containing product required.References:
 

Safety and tolerability outcomes - evaluated via clinical assessments of adverse events, hematology panels, coagulation panels, serum chemistry, urinalysis, viral serology and immunological assessments - were also encouraging. With the exception of 1 patient, adverse events were minor or unrelated to treatment. No thrombotic events or severe allergic reactions occurred, and none of the participants developed anti-VWF binding or neutralizing antibodies to VWF.

Researchers concluded that the data offer evidence that BAX 111 is “safe and hemostatically effective in severe VWD patients in a variety of clinical bleeding presentations.”

“Von Willebrand disease is the most common hereditary bleeding disorder, yet few treatment options exist,” noted John Orloff, MD, Head of Research & Development and Chief Scientific Officer, Baxalta. BAX 111, Dr. Orloff asserted, “has the potential to transform the standard of care for patients with severe von Willebrand disease by offering an effective, individualized treatment option.”

Both the FDA and the European Medicines Agency granted orphan drug designation to BAX 111 back in November 2010.2 Currently, BAX 111 remains under FDA review, a pending Biologics License Application having been filed in December 2014.5 While no official Prescription Drug User Fee Act (PDUFA) date has been set, December 22, 2015, has been cited by industry insiders as a speculative estimation.

The PDUFA date is an FDA approval deadline for new drugs. If approved, BAX 111 would become the first recombinant replacement treatment indicated for the management of VWD-related bleeding episodes.

 

On February 3, 2015, many physicians received a surprising email from Richard Baron, MD, MACP, president and chief executive officer of the American Board of Internal Medicine (ABIM). Referring to the board’s controversial maintenance of certification (MOC) program, Baron wrote, “ABIM clearly got it wrong. We launched programs that weren’t ready and we didn’t deliver a MOC program that physicians found meaningful…We got it wrong and sincerely apologize. We are sorry. ”

Baron’s email— which went to the approximately 200,000 internists and practitioners of 20 sub-specialties who have obtained their board certifications from the ABIM—followed by a few weeks (and many believe was at least partially in response to) the announcement a new organization, the National Board of Physicians and Surgeons (NBPAS), with the announced goal of giving doctors “an alternative route for continued board certification.” It is led by Paul Teirstein, MD, chief of cardiology at the Scripps Clinic in La Jolla, California, and an outspoken MOC critic.

While the controversy surrounding MOC remains far from settled, it seems clear that critics of the process and of ABIM have scored some significant gains, by forcing ABIM to review or scrap some elements of MOC, and by possibly opening new paths to maintaining certification.

The creation of NBPAS and the ABIM’s apology are but the latest developments in a long-simmering dispute over how doctors should best keep their skills and knowledge up-to-date—and prove that they are doing so. The controversy dates to the 1990s, when the ABIM instituted a policy whereby, beginning in 2000, physicians who certified after 1990 would have to recertify every 10 years. (Until then certification had been life-long.) The change was subsequently adopted by the other 24 boards comprising the American Board of Medical Specialties (ABMS).

The 10-year maintenance requirement produced some grumbling among doctors, but no organized resistance. That changed at the start of 2014 when ABIM announced that doctors would need to earn accreditation points on a continual basis over the 10 years between taking the recertifying examination. Moreover, doctors who had board certified before 1990 would be listed as “certified, not meeting MOC requirements” on the ABIM’s web site.

For Teirstein and many of the physicians boarded by the ABIM, these latest changes were the final straw. They were further incensed by what they regarded as the excessive growth of the nonprofit ABIM—whose budget exceeded $59 million—and the nearly $29 million spent on salaries, benefits and “other expenses” during the ABIM’s 2014 fiscal year. A few months later Teirstein launched an online petition opposing the MOC requirements that to-date has garnered more than 23,000 signatures, he says.

In addition, he says, “I began getting comments like, ‘it’s great we have all these signatures, but what do we have to show for it? Have they [the ABIM] actually changed anything?’ And they had not.”

 

Teirstein’s response was to found the NBPAS, a nonprofit organization with what he describes as “a much less expensive, much simpler approach to life-long learning.” In the news release announcing its formation, the organization says it is “committed to providing certification that ensures physician compliance with national standards and promotes lifelong learning.” Among the requirements for continued certification are that a candidate be previously certified by an ABMS-member board and have completed 50 hours of CME in the past two years.

Teirstein describes NBPAS as a “grass- roots organization,” one that is funded entirely by its members. Membership fees are $85 per year or $169 for two years, and cover all specialties and sub-specialties covered by the ABMS. “Right now we’ve got about a thousand members and we’re making ends meet doing that,” he says. Teirstein is taking no salary.

As of mid-April none of the nation’s hospitals were accepting NBPAS certification as a basis for admitting privileges, but Teirstein notes that the process usually involves approval from numerous boards and committees and thus will take some time. “I’m of the firm belief that the as long as the medical community is willing to stand up and say this is what they want we’ll figure out a way to make it happen, but it won’t be overnight,” he says.

Teirstein and other NBPAS board members say they support the notion of physicians keeping their knowledge and skills up to date, but think CME offers the best method for accomplishing that. Teirstein notes that CME courses must be accredited by the American Council for Continuing Medical Education (ACCME) to count towards license renewal. “We’ve decided the best compromise is where you can have lifelong learning which doctors don’t consider onerous,” he says. “The doctors can choose which offerings to attend. They’re not going to pay and take time to go to something that’s not relevant.”

Harry Sarles, MD, FACG, an NBPAS board member and past president of the American College of Gastroenterology objects to what he calls the “esoterica” on the certification examinations. “It’s not good learning. It’s learning for the test,” he says.

“ABIM should not be allowed to set the bar, make the rules, and then provide all the CME that can only be accepted to meet their rules,” he adds. “I’m answering to my hospital, my state, my patients, the health plans, in terms of my quality being measured and monitored. And now ABIM steps in and says you should be doing something for us too. I felt like I was in the middle of a shakedown.”

“When I took my certification I felt proud and driven to continuously improve myself,,” he says. “But everything ABIM has instituted since then, to my way of thinking, has really been about themselves and not what’s best for physicians.”

Sarles endorses the idea of physicians demonstrating quality and a commitment to ongoing education, but wants to see “multiple pathways” for doing so. “I’m all for competition, because it will make us all better,” he says. “If we only had one kind of car to buy it would probably be a crappy car. Whatever your criteria are, competition is very healthy and I believe in it.”

 

ABIM’s February 3 statement, while not directly acknowledging NBPAS, did appear to address some of its complaints and those of others who have been critical of the MOC process. It said that the board will:

In addition, according to the statement, “ABIM will work with medical societies and directly with diplomates to seek input regarding the MOC program” via meetings, webinars, forums, and other venues. “We are embarked on a whole new way of doing business and much more engagement with our community,” Baron said in a phone interview with Medical Economics.

As evidence, he cites implementation of “a sub-specialty board structure that involves depth in each of the disciplines in internal medicine,” and that includes physicians in community practice as well as patients and other public stakeholders.

“Those groups have been reaching out to colleagues and members of their societies,” Baron says. “And what we’re hearing is that lots of the activities we had either as board products or expectations maybe are being done by other people in the [healthcare] delivery system better than we’re doing them. And in that case we want to learn more about those and figure out how to give people credit for the work that they’re doing during their day jobs and avoid redundancy and wasting members’ time.”

Responding to the complaint that MOC tests doctors on knowledge and skills they don’t encounter in their practice, Baron says he took the exam a year ago and acknowledges that it included topics he’d not seen in his general internist/geriatrics practice. On the other hand, he says, “I think all of us in practice confront that there’s a difference between what we use every day and what we might need to use some time.”

Baron recalls joining the ABIM’s test-writing committee in the summer of 2001 and being surprised to find the test included a question on anthrax. But several months later it was a board-certified internist in Miami, Florida (Larry Bush, MD) who first identified anthrax as the mysterious substance being sent through the mail that was sickening—and in the case of Bush’s patient, killing—recipients was anthrax.

”That’s a doctor who had a piece of knowledge that he didn’t use every day, but fact that he had it made a huge difference for a patient,” Baron says. (Bush subsequently coauthored an article about the incident in The New England Journal of Medicine.)

Regarding the fees associated with MOC, Baron says, “Nobody likes to write checks, and when I was in practice there were a lot of things I wished I didn’t have to pay for. But I want to acknowledge that it’s really hard for doctors in practice now and every check is a painful check. We are looking at ways to reduce the cost.”

As evidence, he points to the February 3 announcement regarding enrollment fees. “We are taking time to listening to physician feedback about all aspects of our program before announcing any additional changes,” he says.

“We know that doctors need to experience more value in the program, and the areas we pulled back on were those that doctors were in effect saying, ‘I’m not getting much out of this,’” he says.

 

Underlying much of the controversy surrounding MOC is the question of how much—or even whether—the process as currently structured actually improves physician performance and/or patient outcomes. A great many internists clearly believe it does not, according to a study published in the January 2015 issue of JAMA Internal Medicine.

The authors assembled a focus group consisting of 50 board-certified primary care and subspecialist internal medicine and family medicine physicians in an academic medical center and community sites. They found that “at present, MOC is perceived by physicians as an inefficient and logistically difficult activity for learning or assessment, often irrelevant to practice, and of little benefit to physicians, patients, or society.”

Data on the effectiveness of certification since the institution of time limitations is sparse, consisting largely of a handful of studies published over the past 15 years in Academic Medicine, the Journal of the American College of Cardiology and JAMA, among others. And while MOC supporters say the studies support MOC’s effectiveness, in a debate earlier this year with Baron and Lois M. Nora, president and chief executive officer of the ABMS, Teirstein maintained that the studies’ results are, at best, ambiguous.

He cited, for example, the results of a 2014 investigation published in JAMA comparing clinical outcomes among patients at four Veterans Administration hospitals treated by internists with time-limited and time-unlimited certifications (i.e. those who were grandfathered out of the ABIM’s 10-year certification requirements and those who were not.) The authors found “no significant differences” between the two groups on 10 primary care performance measures.

“If you say we have data that supports our MOC process, you’d better have the data,” Teirstein said in his interview with Medical Economics. “And if you look at the papers they cite, they’re very unconvincing.”

Baron acknowledges that the evidence in support of MOC “could be stronger,” but also notes “at least one of the studies he (Teirstein) criticized met rigorous methodological standards.”

“I don’t think it’s unusual to have good faith people arguing about whether the evidence shows ‘x’ or ‘y,” Baron says. “Every clinician operates all the time in an environment where the patient didn’t walk out of an article in a journal. You have to navigate between what you know you know and how close the patient before you gets to that.”

Teirstein says NBPAS has no plans to try and link ongoing education and training to quality and patient outcomes. “I just don’t think you can measure this adequately,” he says. “Would randomizing really work? A doctor might be more inspired to do a good job because he wants to prove you don’t have to do this [maintain certification.] It’s just not the kind of thing that lends itself to scientific study.”

Looking ahead, Teirstein envisions the NBPAS playing a watchdog role for the ABMS and its member boards, in addition to providing certification. “We’ll be keeping an eye on things and making sure everyone knows physicians are not just going to take whatever they’re given. We’re going to react and try to make our voices heard.”