When You Are Already A Terminal Case, What Would Three Years Of Cancer Free Living Be Worth?

September 5, 2014 - Leave a Response

This is — to be fair — all the data we have. It does seem possible — likely even perhaps — that many many of these formerly end-stage cancer patients will experience a decade or more of cancer-free life. The clinical trials just haven’t run their course yet.

I honestly don’t know that we (as a matter of public policy) should rush to complain about the price attached to that sort of an outcome, for potentially hundreds of thousands of cases. Biologics are extremely tricky to manufacture in quantity, and the R&D involved — in getting the anti PD-1 immuno-oncology candidates to this moment of first approvals — was vast, and is ongoing (and the expenditures are still accelerating — as more and more clinical trials, for other cancers, are launched).

And so, I (for one) won’t immediately complain about the $184,000/year cost for BMS’s Opdivo® — nor about the indicated $150,000/year cost of Keytruda®. [Similarly, I am pretty sure Sovaldi® is a reasonably fair price (all things considered), at $84,000 -- as a cure for Hep C.]

Back to the central point: do I wish that potential cures for many forms of high-burden cancers could be manufactured and sold nearly for free?

Of course I do. But we all know that is a near impossibility. The prices must reflect at least a recoupment of the cost of the effort, and in fairness ought to be measured against the societal cost of not having the new therapy available.

Now, the point of my little narrative: do I think this is some form of price gouging? Not at all. And this, from a deeply avowed skeptic — about the value of pharma’s marketing efforts.

FDA Grants Keytruda® (Pembrolizumab) Approval For A Very Narrow Class Of Melanoma Patients — Non-Responders To BMS’s Yervoy®

September 4, 2014 - Leave a Response

MRK-Keytruda-2014 This is good news for Merck, to be certain — but the first approval window is needle thin — in a very narrow class of patients.

FDA has granted Merck approval for MK-3475 in end stage melanoma patients — and only in those who are failing on other drugs, or have already failed to respond. The truth is that Merck probably is not ready to launch Keytruda® in very high lot/batch quantities, anyway — so this will make only a bit of difference, in the near term. And, longer term, Merck needs to complete the ongoing clinical trials to finally establish Keytruda’s place in treating other, higher burden, cancers.

The approval is great — but with BMS close behind, and perhaps ahead, in the higher burden cancers — the race remains wide open. In fact, BMS’s Nivolumab/Opdivo® is on market in Japan, and with a whopping price tag ($184,000 per year) — ever since mid August 2014. Here’s Pete Loftus (of the Wall Street Journal) on it all:

. . . .The drug, which Merck plans to sell under the brand name Keytruda, is part of a long-anticipated wave of medicines that could transform cancer treatment and forge a large new market for pharmaceutical companies.

The Food and Drug Administration cleared the drug, pembrolizumab, for the treatment of a deadly form of skin cancer, melanoma. The approval followed a swift review of data from a relatively early-stage human trial — an unusual move reflecting the medical community’s keen interest in pembrolizumab.

The infused drug is a new type of immunotherapy, a category of treatments that harness the immune system to fight cancer. It was approved for people who’ve failed to respond adequately to Yervoy, a Bristol-Myers Squibb Co. immunotherapy that works in a different fashion, and certain other drugs. . . .

Now it will get interesting — likely with news every few days — from both Whitehouse Station — and BMS. Stay tuned, but I still think Opdivo® (Nivolumab — BMS) will emerge as the overall winner. Most of Wall Street does, too.

Extremely Doubtful Arguments Dept.: Legacy Schering-Plough’s Integrilin® (Eptifibatide) Off-Label Promotions Trouble

September 4, 2014 - Leave a Response

The trade group PhRMA, on behalf of legacy Schering-Plough, has argued in a federal False Claims Act case brought by US DoJ against Millennium Pharmaceuticals and Schering-Plough (now Merck) — for off label promotion of Integrilin® (Eptifibatide) — that the first amendment should essentially allow defrauding the government. That is, PhRMA argues it should be okay to cause the government to reimburse for a medicine it has not approved reimbursement for, by touting study results for off-label uses for a drug, in contravention of FDA rules. That’s a specious argument (in my opinion), even after Sorrell v. IMS Health was decided by the Supremes.

Just because one accurately conveys study results, that should be no defense to causing a government payer to overpay — for uses the FDA has not sanctioned. If truthful speech is always immunized, then there would be no crime called aiding and abetting a criminal conspiracy — currently a felony. The idea is simply off the charts. . . silly. The founders would never have suggested the first amendment immunized what was otherwise a crime — an action. Conduct is wildly different that advocacy– that’s black letter law. And it is the conduct here, that makes the crime (in my opinion).

In any event, here’s a bit of the coverage, from the Law 360o article:

. . . .PhRMA’s logic, according to the government attorneys, would essentially create a constitutional right to intentionally cause others to defraud the government, so long as that’s achieved through speech.

“This radical position has never been endorsed by any court and is not supported by any precedent,” the DOJ said.

Further, by allowing companies to claim legal immunity for any truthful speech, courts would prevent the government from enforcing a wide range of laws, such as those prohibiting criminal conspiracies and anticompetitive collusion, according to Thursday’s brief.

“If a course of conduct were constitutionally protected as long as it was effectuated through the use of speech, vast areas of federal and state law would be invalidated,” the DOJ asserted.

Numerous FCA cases have been successfully waged against drugmakers accused of off-label marketing. Typically, there is some allegation that uses were not only unapproved but also lacking support in scientific literature. . . .

We should note that outright prohibitions on off-label marketing were curtailed in the wake of the U.S. Supreme Court’s 2011 ruling in Sorrell v. IMS Health, which now protects truthful and nonmisleading prescription drug marketing — but does not allow defrauding the government in the process.

Preliminary Discovery Battles — In Federal Incretin Mimetics MDL — Two Central Questions: Pre-Emption And General Causation

September 1, 2014 - Leave a Response

Incretin mimetics, like Merck’s Januvia® (sitagliptin phosphate), are suspected by some medical practicioners and researchers, of begin associated with increased risks of pancreatitis — and perhaps even certain cancer risks. But “suspected” is the key word, there. As of the moment, there appears to be no gold standard, independently rigorous study linking the increased risk of cancer claimed by some, to any incretin mimetic regimen of any particular drug manufacturer. [My earlier backgrounder here.]

But the plaintiffs, some of whom claim against Merck, are (under our legal system) entitled to try to establish that so called “general causation” — a tort of product liability, through reasonable document discovery efforts — against the drug companies involved (including Merck). That is what is playing out over the next few weeks, as the plaintiffs seek adverse event reports they claim Merck and others are withholding, wrongfully, from them. Perhaps most sensationally (if proved), the plaintiffs apparently also claim that one or more drug manufacturers “spiked” or withheld certain study results which (they claim) have since mysteriously gone “missing“. That claim could be decidedly. . . interesting, if it turns out to have a basis in fact. So — yes — we will watch this one.

Moreover, the second prong of the current discovery fight centers on whether the suits are pre-empted, under the Supremes’ Wyeth v. Levine reasoning of a few years back. On that prong, the question will be whether Merck and the others complied with FDA instructions regarding warnings and labeling — such that no tort claim can arise. That argument runs that if the warning was made to the limits of what FDA would allow the drug companies to assert, then they can’t be liable for a “defective” warning — insofar as FDA would not have permitted them to vary that “FDA mandated” warning. So — as ever — discovery will help the parties figure out whether this “FDA preemption” state of affairs in fact exists as to any (or many) of these would-be thousands of plaintiffs.

From the orders (PDF file) entered by the very able Judge Anthony J. Battaglia, in the federal trial level courthouse, sitting in the Southern District of California, last week then — a bit:

. . . .All discovery issues must be resolved without delay. Currently, there are ten (10) potential discovery disputes ( the “current” disputes) being discussed by counsel, as well as the prospect for additional issues as other responses and productions are completed ( the “future” disputes),timing for these will be as follows:

a. Counsel will continue to meet and confer on the matters listed below, and the court will review the status of these matters at the September 16, 2014 status conference. The matters are:

i. The recently received certification and production by Lilly;

ii. Amylin’s pending certification and production;

iii. EMA submissions;

iv. Health Canada and other foreign submissions;

v. Non-clinical trials;

vi. Histology slides;

vii. The addition of other custodians to the deposition list;

viii. “Ongoing” study results;

ix. Written discovery regarding “outside” source information re: causation;

x. The purportedly “missing” studies.

Regarding the EMA, Health Canada and other foreign submissions, counsel might want to discuss the prospect of narrowing this data to things submitted to other agencies that differ from the submissions to the FDA, to reduce duplication and the associated time and expense that goes with it. . . .

We will keep the readership informed here. I’ll happily pop the popcorn — should be good theater for a bit, into October 2014.

Advaxis’ Immune Oncology Program Candidate, In New Combo-Studies, With Merck’s Pemrolizumab: Prostate Cancers

August 30, 2014 - Leave a Response

Yet another class of cancers will now be studied in an immuno-building combination, along with MK-3475 — Merck’s single most promising drug candidate, across the entire company. [And this tidbit comes to us from a kindly anonymous commenter. My regular readers are. . . the best!]

Once again, this bit of news broke while I was traveling, last week. But here it is, from the Advaxis presser — Advaxis’ candidate is called ADXS-PSA:

. . . .Both ADXS-PSA and pembrolizumab are investigational members of a new class of cancer treatments known as immunotherapies that are designed to enhance the body’s own defenses in fighting cancer. Preclinical evidence suggests that Advaxis Lm-LLO immunotherapies in combination with a PD-1 inhibitor may lead to an enhanced anti-tumor immune response.

“We are excited to be working with Merck. Equally as exciting is the combination potential of our Lm-LLO immunotherapy with Merck’s anti-PD-1 immune checkpoint inhibitor,” commented Daniel J. O’Connor, President and Chief Executive Officer of Advaxis. “We believe the combination of Advaxis Lm-LLO cancer immunotherapies and checkpoint inhibitors holds significant promise for the treatment of prostate and other cancers.”

Under the terms of the agreement, Advaxis and Merck will collaborate to evaluate the ADXS-PSA/pembrolizumab combination as a treatment for prostate cancer. The Phase 1 part of the trial is designed to establish a recommended dose regimen for ADXS-PSA alone and combined with pembrolizumab, and the Phase 2 portion will assess the safety and efficacy of the combination. Advaxis will sponsor and fund the study and Merck will provide pembrolizumab. The companies will collaboratively oversee the conduct of the study, which is planned to begin in early 2015. Results from the study will be used to determine the path for further clinical development of the combination. . . .

[And just a bit more, from an Onc-Live interview:]

. . .[Advaxis' approach to attacking] immune tolerance involves cells that live inside tumors and send out clouds of biologic chemicals that also can shut down activated T cells in the area. Scientists know these as Tregs and MDSC cells. Even if the T cells get past the PD-1 [which MK-3475 is designed to address] they can still be shut down by Tregs and MDSCs in the tumors. ADXS-PSA has the ability to decrease the number and activity of Tregs and MDSCs inside the tumors in tumor models.

The point behind this combination is that ADXS-PSA stimulates the immune system to generate a new crop of cancer-fighting T-cells that recognize a key target on the tumor cells, PSA. Then the pembrolizumab PD-1 blockade masks PD-1, which the tumor may be hiding behind, and amplifies the number of cancer fighting cells that are produced. Once these cancer-fighting cells get inside the tumor tissue itself, past the PD-1 blockade, they find that the ADXS-PSA had disabled the Tregs and MDSCs inside the tumor, allowing the cancer-fighting cells to do their job and eliminate cancer cells. Therefore, the combination treatment provides a fresh crop of cancer-fighting cells, while at the same time, overcoming two different mechanisms of immune tolerance that could be protecting the prostate cancer inside patients. . . .

Financial terms were not disclosed — but the Advaxis oncology candidate has a nice pedigree. We will watch it closely. And, interestingly, a good portion of the management team (and board) had deep ties to the former ImClone — acquired by Lilly some years ago. Now you know. One to watch.

[Just as trivia, as I close out, and head off to bed -- the older Advaxis logo (circa 2011) was unabashedly a Trojan Horse (see small image at lower left, of the main image). That stark (and perhaps provocative) imagery has been softened, muted and stylized -- in the new logo (top left) -- and I can certainly see why. I suppose the company thinks of its cancer killer as using a "Trojan Horse" approach -- to re-ignite the body's own immune system. Still risky imagery (in my view), for a bioscience company. Smile. G'night, one and all of good will.]

Tiny Matters: Most MSM Outlets Misunderstand the UK Takeover Regs Timelines

August 30, 2014 - Leave a Response

I’ll not expend an undue flow of electrons on it here, but in my estimation, there is almost no chance of a September renewal of the foundered Pfizer hostile deal, for AstraZeneca. In short, AZ has no reason to invite Ian back. And that’s what the UK Takeover Code would require (at this moment, anyway). [Two of many backgrounders, here, and here.]

Here is one of the more confused reports — it has the three- and six- month re-engage dates exactly backwards. AZ must have voluntarily invited Pfizer back to the table — if talks are to resume this coming Tuesday. And there is not a snowball’s chance in August — in Dallas, Texas, of that (in my not so humble opinion). And so now, I’ve reordered and edited the above Bidnezz(!) story, to make it passingly accurate, as to UK law. November 26 Pfizer may ask AZ to re-engage. And AZ may (and likely will) decline.

. . . .The [UK Takeover Code] regulations allow would-be acquirers to make a one-time offer [if] the target [has] invite[d] [the acquirer] back to the table, [at three months]. In most cases, UK takeover regulations allow companies to re-engage with one another once a mandatory six-month cooling off period expires. . . .

AstraZeneca also has the option to reengage in talks with Pfizer with a proposed sale offer [by inviting Pfizer back as of August 26 -- which I say is unlikely]. The companies will not have any regulations applicable on them from November 26 onward, when the six-month cool off period ends. . . .

Um. . . pronouns matter.

AZ’s checkpoint inhibitor (oncology) program posted spectacular data, at ASCO in June 2014. A strong business case may now be made that Pfizer needs AZ far more than the other way around. And that will put the board of AZ in a very sound position to talk politely for a bit to Ian, then just say. . . no. That checkpoint inhibitor candidate — much like the BMS and Merck similar PD-1 receptor candidates — has the real potential to reshape the treatment of cancer, globally. And AZ could garner perhaps $10 billion a year in peak oncology sales from it. No need to share that with wee ole’ man Ian. Q.E.D.

A New Analyst Firm’s Coverage Of Merck: Deutsche Bank Starts At $65

August 30, 2014 - Leave a Response

Okay, during the week (while I was out, on Wednesday), Deutsche Bank began coverage — on Merck.

Deutsche Bank has a “hold” on the name, with a target of $65. That makes sense, given that Merck has now touched — and surpassed the $60 mark.

Two things that $60 event imply: One, Merck’s dividend yield is now just under three per cent. . . generally a good thing (Merck is both a growth stock, and yet a pretty fat dividend payer!) — and two, the Bank’s 12 month target is actually only like seven per cent above Friday’s close. Still a suggestion that Merck is pretty fully valued here. Just my $0.02. [I could wax cynical, and suggest that the bank would like to win some debt underwriting business from Merck (for the other side of its house), and so put a slightly outsized target on Merck's price -- I think $65 is the top quote at the moment. But I'll restrain my cynicism.]

Now At Least Two Pfizer Pembro-Collaboration Projects Are Known. . .

August 26, 2014 - Leave a Response

This from that erstwhile gent Ed Silverman, over at Pharmalot (see below, but do go read it all).

Longer term, the race will be won by the company that gets approval in the heaviest burden cancers. But both BMS and Merck are lead pipe cinches to win approval — and likely before year end 2014, for each.

. . . .The agreement comes days after Bristol-Myers Squibb Co. and Celgene Corp. said they agreed to collaborate on a clinical study for a treatment that would combine immunotherapy and chemotherapy to combat pancreatic, lung and breast cancers.

Pharmaceutical companies are jockeying for position in the rapidly growing cancer-treatment market. Immunotherapy, which uses immune systems to fight the disease, is driving much of the expansion.

Merck said in February that it had reached three separate agreements to collaborate on studies of pembrolizumab in in combination with therapies from Pfizer, Amgen Inc. and Incyte Corp. The company has sought to test the drug for effectiveness on a wide range of cancers.

The study announced Tuesday will test a combination of Merck’s investigational antibody pembrolizumab and Pfizer’s crizotinib, also known as the brand name Xalkori, which is indicated for the treatment of nonsmall-cell lung cancer. . . .

As ever, we will keep an eye on the BMS-generated nivolumab progression, which has been excellent — outstanding, in fact — as well. Most informed watchers grant the overall efficacy nod to BMS’s candidate, to be fair.

Pre-Arranged Stock Sales By Merck Executives — Pursuant To SEC Recognized Plans — Mean Very Little. Yawn.

August 25, 2014 - Leave a Response

Okay — like the others (most recently, two weeks ago — by the Chairman & CEO), this is an algorithm trade. Mr. Schechter had pre-set this trade, likely via formulae, in my experienced guestimation.

His trade executed today, August 25, 2014.

. . . .Adam Schechter Pres. Global Human Health | 22,000 shares @ $59.69. . .

This thus means. . . Nothing. And speaking of meaning nothing — today’s Reuters’ rumor piece — about the possibility of an earlier than October 28 FDA approval date for pembrolizumab, seems to be much ado about nearly nothing. When it happens, we will all know. Same way with nivolumab. I can say that no FDA Advisory Committee date has been set; and in the same breath, I can say that in this case (under applicable FDA rules) FDA could approve it without an Advisory Committee vote. Now, be safe out there.

Small PSA — These Nine Fosamax® ONJ Plaintiffs Should Call Their Lawyers

August 21, 2014 - Leave a Response

It seems that several plaintiffs have “opted in” — i.e., elected to accept — the global Fosamax® ONJ settlement, but their paperwork is — in various ways — deficient (or, at least Merck so alleges).

So Merck would like the very able Judge John F. Keenan, sitting in the federal trial-level courthouses in Manhattan, to give them a period of time to cure, and then if they do not — dismiss them without any payments, from the common settlement fund.

That process began in earnest, Tuesday. The affected plaintiffs are: (1) Claudette Williams, (2) Robin Swolley, (3) Susan Sloan, (4) Audrey Minzer, (5) Naheed Khan, (6) Lowell Howell, as Personal Representative for Mildred Robinson, Deceased, (7) Doris Hanke, (8) Susan Doyle, and (9) James Corbett, as Personal Representative for the Estate of Ivy Corbett. Do contact your counsel, one and all.

. . . .ORDER: On August 15, 2014, Merck served a motion for a new Lone Pine order, this one targeted at nine plaintiffs who initially opted into the global settlement but whose paperwork is allegedly deficient.

Counsel for the affected plaintiffs are directed to file a response indicating whether they oppose the motion by August 29, 2014.

Any reply by Merck must be filed by September 5, 2014.This Order should be entered on the docket of 06 MD 1789 as well as on the dockets of the individual cases listed in the attached table. (Responses due by 8/29/2014, Replies due by 9/5/2014.)

(Signed by Judge John F. Keenan on 8/19/2014). . . .

Separately (and perhaps immodestly — I’ll report that) overnight, the National Law Journal has picked up my scoop on the Incretin Mimetic MDL discovery/adverse event source documents spat. Safe travels all day, one and all, as well.

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