Post Hoc Q: Did IMPROVE-IT Only Show Meaningful CV Benefits — For Diabetics?

September 2, 2015 - Leave a Response

As ever, CardioBrief — with Larry Husten on the keyboard — does an excellent job of pointing out just how “fuzzy” the ultimate learnings may be — from even large studies (with 18,000 patients) — upon careful, closer (post hoc) data analysis.

In a sub-set post-hoc study, it would seem that the vast bulk of the CV outcomes benefit appeared in about only one quarter of the study’s population: those who already had diabetes. Of course, correlation is not causation, and perhaps the diabetics were sicker, as a group, but it is. . . intriguing, nonetheless. Can we (as a finite resource/constrained payer-based system) justify these premium prices, for any non-diabetic cholesterol management patient in the US, where the outcome benefit seen in a very large group, over several years, was almost. . . non-existent? This is a very fair question — and do go read it all, for some other competing theories to explain the subset data — but here’s a bit:

. . . .The beneficial effects of ezetimibe are found almost exclusively in patients with diabetes. . . .

The main IMPROVE-IT trial randomized 18,144 patients with acute coronary syndrome to the combination of ezetimibe and simvastatin or simvastatin alone. The primary endpoint of the trial– CV death, MI, documented unstable angina requiring rehospitalization, coronary revascularization after one month of treatment, or stroke– was significantly reduced in the ezetimibe group (32.7% vs. 34.7%, p = 0.016).

The ESC presentation focused on the 27% of patients in the trial (n= 4,933) who had diabetes. “We did see a quantitative, statistically significant interaction between diabetics and non diabetics,” said Giugliano. . . .

Giugliano concluded that diabetic patients were at higher risk than non-diabetic patients and that they had a greater relative and absolute benefit from the addition of ezetimibe. The greater benefit in diabetics was driven by reductions of MI and ischemic stroke. . . .

Almost a year ago, we had asked whether one fewer CV event, in 50 patients, over seven years, was worth almost an additional $750,000 in spending. [That’s what the legacy Schering-Plough combo-pill Vytorin® costs, compared to a generic statin.] I think the answer now will be. . . no, unless the patient is ALSO diabetic. Harlan Krumholz (the world renown expert, at Yale University) has all but said as much, previously. And so. . . onward. . . with a lovely end to a short week approaching. . . .

Propecia® MDL Status Call Tomorrow — Here’s The Agreed Agenda

September 1, 2015 - Leave a Response

To be clear, this status hearing tomorrow in Brooklyn will not touch on the Cornell-Weill/Dr. Imperato-McGinley boxes of putatively “missing” clinical trial/study documents.

That discussion is slated for September 10. I thought this hearing would happen on the 10th as well — but apparently it will go forward tomorrow. I’ll keep an eye on the PACER filings, and offer any update — as events warrants. Here’s the agenda, in pertinent part:

. . . .The parties jointly submit the following agenda for this Court’s September 2, 2015 Status Conference.

1. Argument on the parties’ separate proposed Discovery Plan submissions.

2. Argument regarding the parties’ submissions related to Defense Fact Sheet/Merck Profile Form.

3. Merck’s administrative Motion to Dismiss (Doc. 233) 16 cases for failure to serve a PPF, filed April 29, 2015. Responses were due May 11, 2015, and no Responses have been filed.

4. Further discussion on Merck’s privilege log and the Court’s order of July 22, 2015. . . .

I’ll let you all know — right here — if anything more interesting comes of this ongoing privilege log dispute, tomorrow.

Ebola Setback In Sierra Leone — One New Fatality; Restarts The Clock

September 1, 2015 - Leave a Response

An international team of doctors and epidemiologists, with experts from The University of Bern, the University of Florida, the London School of Hygiene and Tropical Medicine, Public Health England, the European Mobile Laboratories (among others) has arrived in Guinea. This is the same team that just finished a ring-vaccination in Guinea — vaccinating people against the latest re-appearance of a node of Ebola cases/contacts. The team drove overnight Sunday — to Kambia District, Sierra Leone, to meet and confer with local health officials and WHO officers.

Later today, in all probability, a new ring vaccination — once again, deploying Merck/NewLink’s single course vaccine candidate will get underway, covering all known/traceable contacts of the 60 year old woman who just passed away. Here’s a bit from the local news outlets:

. . . .Detection of a new case of Ebola Virus Disease in Kambia, Sierra Leone after the country had marked almost three weeks of zero cases has set in motion the first ‘ring vaccination’ use of the experimental Ebola vaccine in Sierra Leone.

A team of experts in ring vaccination has travelled from Conakry, Guinea to join a large WHO and Ministry of Health team already in Kambia District. The source of the Ebola virus transmission is being investigated and all the people who may have been in contact with the infected person are being traced.

“Although no one wanted to see more cases of Ebola virus disease in Sierra Leone, we kept all our teams on alert and ready to respond and close down any new transmission” said Dr Anders Nordstrom, WHO Representative in Sierra Leone.

Heightened surveillance for Ebola Virus Disease in Sierra Leone includes swabbing all people who have died at home and testing those swabs for Ebola virus. On Saturday 29th August 2015, a swab taken from a woman who died aged around 60, in the village of Sella, Tonko Limba, Kambia District, tested positive for Ebola virus.

Members of the team currently conducting the ring vaccination trial in Guinea drove from Conakry in Guinea to Kambia on Sunday to begin work. . . .

So it is with all of life, it would seem — two steps ahead; one back. Ebola has the same Darwinian proclivities as we see in all other life on the planet — it will mutate, adapt and attempt to survive. Even so — Onward — and keep your chin up. . . we (i.e., the collective human race “we“) are beating it, bit by bit — no doubt, now.

ENHANCE-Era Institutional Investors’ Opt Out Claims May Proceed Against Merck: USDC, NJ

August 31, 2015 - Leave a Response

It has been over a year since last we looked in on this narrative. [And yes, it is — in the main (in my opinion) — yet another bounced check left behind, by one “Fast” Fred Hassan.] Back in April of 2014, we noted that this litigation — by large investors like GIC, North Sound Capital and Colonial First State — each of which declined the agreed $668 million class settlement, choosing to “opt-out“, and sue on their own behalf, would have to wait for a US Supreme Court ruling on whether the claims were now time-barred. Then, in November 2014, the reference case that the Supremes had selected to review (IndyMac, on so-called American Pipe tolling) was largely settled, by an agreement of the parties. So the Supremes removed that case from the docket. And this opt out case went. . . quiet, for a bit.

In the nearly full year since then, though, the very able federal District Court Judge Freda L. Wolfson has been busy — reviewing whether the relevant law would allow these investors’ individual opt-out cases to proceed. She has now ruled (as of last week) that they indeed may. So Merck will presumably have to offer the same defenses, and presumably, end up settling with these investors — as well, for additional sums — due to the alleged acts and ommissions of Fast Fred Hassan, and his band of skallywags, from legacy Schering-Plough. [Background here.] Here is a bit of her opinion (and a PDF file of the whole affiar):

. . . .The tolling doctrine established in American Pipe is legal tolling and applies to the statutes of repose here. Further, the common-law fraud claim sets out sufficient allegations of actual reliance to survive a 12(b)(6) motion to dismiss. For the reasons given above, Defendants’ Motions to Dismiss is DENIED. . . .

As I say — I’d expect a settlement here, eventually. And it will involve Merck paying more money to these three investors. Do recall here that the $668 million earlier settlement exhausted all of Merck’s insurance related to these claims — and Kenilworth keeps no reserve, for these legacy matters, as the SEC filings have long stated. So this will be a hit to quarterly earnings, when the settlement is announced — in my estimation. However, the amount won’t likely be material to Mother Merck (as she’s just too. . . big).

So. . . Onward — on an approaching long holiday weekend. . . with family nuptials in the offing! Big smile, and. . . a gathering of all!

Class-Wide DPP-4 Diabetes Med Effect: Joint Pain — FDA Warns, On Friday

August 29, 2015 - Leave a Response

I’ll note this almost solely to complete the record, here — since we try to run down all material items related to Merck.

As we’ve previously indicated, in fairly short order, the SGLT-2 class will be supplanting the DPP-4 class as the oral diabetes med of first choice (beyond metformin — a Merck drug, but now long generic). This FDA revision will likely hasten that coming switch-over, at least for prescribers with patients complaining of recurrent joint pains, along with their diabetes. Not good news, here in the US — for Kenilworth — but only a minor headwind near term, overall, for the behemoth that is Merck’s annual revenue tide, rolling in. Here’s the FDA press alert — and the list of covered products:

. . . .The U.S. Food and Drug Administration (FDA) is warning that the type 2 diabetes medicines sitagliptin, saxagliptin, linagliptin, and alogliptin may cause joint pain that can be severe and disabling. We have added a new Warning and Precaution about this risk to the labels of all medicines in this drug class, called dipeptidyl peptidase-4 (DPP-4) inhibitors.

Patients should not stop taking their DPP-4 inhibitor medicine, but should contact their health care professional right away if they experience severe and persistent joint pain. . . . [Affected DPP-4 class products]:

Januvia (sitagliptin), Janumet (sitagliptin and metformin), Janumet XR (sitagliptin and metformin extended release), Onglyza (saxagliptin), Kombiglyze XR (saxagliptin and metformin extended release), Tradjenta (linagliptin), Glyxambi (linagliptin and empagliflozin
Jentadueto (linagliptin and metformin), Nesina (alogliptin), Kazano (alogliptin and metformin), Oseni (alogliptin and pioglitazone). . . .

So it goes. . . . Meanwhile, our eyes will be on the night skies for a few evenings now. . . smilingly so, immortal and beloved. . . .

O/T: The Dream — Set On Wings — 52 Years On. . .

August 28, 2015 - Leave a Response

This turns out to be a Friday afternoon for. . . reflections. And reflect we shall — on the eve of my long-gone father’s own birthday. For today is the day that Dr. King spoke — at the March on Washington. Today he set his version of the dream. . . on wing. So do take a moment and express gratitude, for all this moment did to advance our nation — to this very day.

Below is — of course — from his letter inside the Birmingham Jail. . . and the YouTube below that, is “the dream” proper.

. . . .My friends, I must say to you. . . . it is an historical fact that privileged groups seldom give up their privileges voluntarily. Individuals may see the moral light and voluntarily give up their unjust posture. . . .

Frankly, I have yet to engage in a direct action campaign that was “well timed” in the view of those who have not suffered unduly from the disease of segregation. For years now I have heard the word “Wait!” It rings in the ear of every Negro with piercing familiarity. This “Wait” has almost always meant “Never.” We must come to see, with one of our distinguished jurists, that “justice too long delayed is justice denied.”

We have waited for more than 340 years for our constitutional and God given rights. The nations of Asia and Africa are moving with jetlike speed toward gaining political independence, but we still creep at horse and buggy pace toward gaining a cup of coffee at a lunch counter. Perhaps it is easy for those who have never felt the stinging darts of segregation to say, “Wait.” But when you have seen vicious mobs lynch your mothers and fathers at will and drown your sisters and brothers at whim; when you have seen hate filled policemen curse, kick and even kill your black brothers and sisters; when you see the vast majority of your twenty million Negro brothers smothering in an airtight cage of poverty in the midst of an affluent society; when you suddenly find your tongue twisted and your speech stammering as you seek to explain to your six year old daughter why she can’t go to the public amusement park that has just been advertised on television, and see tears welling up in her eyes when she is told that Funtown is closed to colored children. . . .

[W]hen you take a cross county drive and find it necessary to sleep night after night in the uncomfortable corners of your automobile because no motel will accept you; when you are humiliated day in and day out by nagging signs reading “white” and “colored”. . . .

[It is also the 60th passing of the murder of young Emmett Till.] Travel light, but travel well, Dad (and Ter — 30 years on) — you both had to leave our party far too soon.

Of The Persistence Of Communicable Diseases: Three New Ebola Cases, In Guinea Last Week

August 26, 2015 - Leave a Response

The good news tonight is that Sierra Leone is approaching the 42 day marker again — on being Ebola free. However, Guinea has seen new cases — one of them a cabbie, in an urban area — so we might expect several more cases, unless all his contacts are found, and vaccinated in an immediate ring fashion. And that is exactly what the Guinea health authorities are now undertaking. [The last re-emergence in Guinea was June 2015, as we had previously reported.]

Again, it is the single course (as opposed to a “prime plus booster” approach — needed in the GSK candidate), and rVSV-ZEBOV’s extremely robust near-term efficacy, that have handed the Merck/NewLink vaccine the wheel, in Africa. Here’s the operative bit — from the online CIRAP center, on the campus of the University of Minnesota:

. . . .With three new cases, Guinea was the only country in West Africa’s outbreak region to report Ebola infections last week, and responders are on high alert because all of the confirmed case-patients, one of them a taxi driver, pose a high risk of transmission.

The World Health Organization (WHO) said in its weekly snapshot of the outbreak that Sierra Leone has gone two weeks without a new case and that the outbreak region’s weekly total has remained at three for four weeks in a row. . . .

Now, sleep well, all you young buckaroos. . . and do say your prayers — that this latest Ebola ring-outbreak is snuffed out soon. G’night!

New! With Now Daily Propecia® MDL Documents Updates: The Good Doctor Must Appear — At High Noon, On September 10, 2015, Sez US Magistrate Judge

August 26, 2015 - One Response

The emminently capable Magistrate Judge Pohorelsky, sitting in Brooklyn’s federal District courthouse has ruled that the doctor will be given one additionnal week to prepare, but that both she — and her Weill-Cornell Medical Center lawyer — WILL in fact have to appear personally, to answer his questions about the state of the play, on these supposed 16 to 40 boxes of study documents. Now that is. . . fascinating.

So — if anyone were to wander by (and bring a picture ID, to be granted admission to the gallery) they could sit in that day, in Brooklyn. It could turn out to be a pretty darn interesting show cause hearing, given the interplay between what has been reported to be the doctor’s earlier position — per her lawyer — and what we all understand the federal rules governing national clinical trials for FDA approval of new drug candidates might have required of her. Do stay tuned, but I have no plans to be in New York that day, at this point. Here is the full text of today’s order — just entered, below:

. . . .Order on Motion for Discovery: the Hearing on the Order to Show Cause is adjourned to September 10, 2015 at 12:00 noon. Dr. Julianne Imperato-McGinley and her counsel are both required to attend in person. Ordered by Magistrate Judge Viktor V. Pohorelsky on 8/25/2015. . . .

The delay from September 2 — to September 10 — was designed to accommodate the doctor’s availabilty — to appear in person. Pop the popcorn folks! [And, in answer to Mr. E (below), there was no status hearing scheduled for today, given yesterdaty’s developments — it was superceded/deleted.] Onward.

August 25, 2015 Propecia® MDL Document Discovery Update — Small Delivery Of Documents Made; And An Assertion That Many More Are. . . “Missing”

August 25, 2015 - Leave a Response

Again, I must emphasize that we should not infer too terribly much from the plaintiffs’ lawyers’ claims that the vast bulk of the historical Propecia® study documents have gone “missing“. But the surprising news here (to my eye) is that only some 630 or so pages were turned over by the University hospital, as of yesterday afternoon.

And so, with that said, I do think the plaintiffs make a generally very solid point — when they ask where the doctor’s study files — as PI of the clinical trials (some of which were submitted to, or filed with federal agencies) — now reside. [There is a passing and rather vague reference, to the Dominican Republic here, as well — and it may well turn out that some records need to be culled from storage, on the island.] As I’ve indicated before, the federal rules contemplate that those documents should remain under the control, directly or indirectly, of the principal investigator — precisely in the event that questions like those raised in the present mass-tort litigation arise. The rules contemplate having a repository (under the direct supervision of a particular person — the doctor) for exactly this sort of eventuality. Here is the Response filed today (a six page PDF file), by the plaintiffs’ lawyers — and a bit of it:

. . . .On August 24, 2015, in response to the Second Subpoena, Weill Cornell Medical College produced a mere 631 pages of documents, constituting less than half a box [of a purported 40 boxes]. . . .

The documents appear to contain nothing from Dr. Imperato-McGinley’s days researching in the Dominican Republic, nothing about her discovery, and just a handful of documents related to Merck. The paltry production by Weill Cornell Medical College emphasizes, as opposed to eliminates, the continued need for a “show cause” hearing with regard to the issue of Dr. Imperato-McGinley’s documents, and where these highly relevant and probative documents went. . . .

Though Ms. Orwel repeatedly affirms that Dr. Imperato-McGinley has no documents in her possession, custody, or control, these statements must be disregarded under Second Circuit precedent, as Ms. Orwel does not claim to have personal knowledge, or even any “knowledge,” regarding the factual question of what documents Dr. Imperato-McGinley has or had in her possession, custody, or control. . . .

Dr. Imperato-McGinley should appear in Court and explain to this Court why she has produced in effect absolutely nothing in response to the Subpoena served upon her. This Court should direct Dr. Imperato-McGinley to appear before this Court and show cause why she should not have to produce all responsive documents, to provide an explanation as to what if any documents were destroyed and when they were destroyed, advise what prompted counsel to initially believe there were between sixteen and forty boxes, and what those boxes contain, and find Dr. Imperato-McGinley in contempt of Court if she continues to refuse to comply with the Subpoena. . . .

The conclusion of the just filed Response renews the plaintiffs’ request that the doctor be required to appear personally, and explain the whereabouts of the clinical trial documents. I remain skeptical that the Court is ready to order that appearance. I do think the Court will ask the counsel for Weill-Cornell to make an accounting of what was in the 40 boxes — and which parts of it might not be discoverable. So — do stay tuned for September 2, 2015. Onward — and be excellent to one another!

BioPharma Dive: On An Apparently Cardio-Protective Side-Effect Of Lilly’s Jardiance® — Longer Term Effect On Merck’s Januvia® Sales

August 24, 2015 - Leave a Response

While the markets gyrate rather wildly on concerns about emerging market growth — or the lack thereof, more precisely — we will take a moment to look forward, into 2016-2017, and predict that (if this preliminary study result holds up, upon peer review) Jardiance® may eat into Merck’s more than $5 billion franchise, here. The Boehringer Ingelheim/Lilly drug is an SGLT2 inhibitor, and Merck’s only current bet in this space is in a venture shared with Pfizer. That venture effort is not likely to reach market before 2018, in my estimation.

All of which is to say I think Merck would be quite vulnerable to product switching — away from Januvia® — should Jardiance turn out to provide a reduced cardio-vascular risk to most diabetes patients. [As we’ve reported before, repeatedly, Merck’s presently-available study data shows only that there is no increased cardiovascular risk with Januvia.] Speaking broadly, and oversimplifying, here — longer term cardio-vascular events are generally the proximate cause of disability/death for people with advanced diabetes. So it stands to reason that a drug able to mitigate that risk would be welcomed with open arms, by prescribing doctors. Here is BioPharma Dive‘s quite cogent take on it all:

. . . .Merck’s Januvia is often used as treatment for diabetes when metformin is not enough to control blood glucose. Diabetes is treated in a stepwise fashion, generally starting with metformin and adding on various classes of drugs over time. Given the new data published about Jardiance, Jardiance could become the go-to drug after metformin.

As mentioned in BioPharma Dive’s coverage last week, the positive news about Jardiance, which is an SGLT-2 inhibitor could bode well for the entire class, including Johnson & Johnsons Invokana and Bristol-Myers Squibb’s Farxiga. . . .

And so (from a larger, macro- perspective) — in the longer run, the emerging markets will be a net positive for the solid counter cyclicals, like pharma and biotech. There may — as ever — be bumps along the way (as today is no doubt proving). . . Enjoy, one and all!

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