Cldx:

You note that rindo is effectively a mutated peptide, and therefore not a strict case of vaccinating with a self-antigen. In effect, this peptide then presents a foreign epitope that therefore has a chance of eliciting an immune response.

I won't necessarily disagree with that, but will add that blp25 is also proposed to present a typically unseen epitope rather than a plain vanilla self-antigen. If I recall correctly, the change in glycosylation of muc1 was supposed to alter the structure in this region so as to expose an area that would normally not be available for recognition. In effect, blp25 is meant to be this foreign epitope. That might mean the onty trials will provide a meaningful readout for cldx's strategy.

Never say never. But it's not a proposition that I would bet money on.

I've not really looked into this, so I don't have anything meaningful to add. I will note, however, that they're using additional methods to stimulate T cells. I think this highlights the difference in approach between companies who simply believe this pathway will take care of itself (a la rindo) versus companies that believe direct stimulation of this pathway is a necessary part of improving the success of immunotherapeutics (ipi, blinatimumab).

===

Not to belabour the point, but I think one important point of all these vaccine immunotherapeutics against self antigens is to pay attention to the immune response related side effects (if any). Since we've not had much success with vaccine-type immunotherapeutics, new approaches will most likely show outright failure (we see little to no immunological adverse events coupled with little efficacy - theratope and various other vaccine immunotherapeutics) or a degree of success that goes hand in hand with a serious immunological adverse event profile (ipilimumab; remember TGN1412?).

I don't think we're at the point technologically where we can manage to break self-tolerance with these vaccination strategies while demonstrating zero immunological adverse events. In my opinion, anyone currently selling this utopian view is selling a vaccine strategy that doesn't work.

My comments were directed towards rindopepimut, which I thought was the larger focus of the piece. So in regards to A, i would note that the mechanism of action of provenge and ipilimumab are very different that rindopepimut.

Rindopepimut is simply a 13 amino acid peptide attached to a carrier protein (KLH in this case). So the body has to ramp up an immune response against this peptide. This has historically been a relatively failing proposition in producing an adaptive immune response: you get low titre B-cell derived antigen specific antibodies and a weak T cell response. This is very similar to BLP25.

MAbs like ipilimumab skip the step of requiring the body to produce high affinity antibodies against the desired target. I think this is key. I do not debate ipilimumab's efficacy, but its mechanism is very different than what rindo asks of the immune system.

As for provenge, the earlier papers by Vuk-Pavlovic showed very weak T cell responses. And as we know, the response was largely against the fusion point of the constructed peptide cassette. I won't deny that provenge has demonstrated some efficacy, but I think we can agree that the mechanism through which that efficacy is manifest depends on a pathway very different than rindo.

Cldx:

As per usual, I do not believe that such peptide immunotherapeutics elicit a sufficient immune response. I would personally stay away from cldx even if that means I miss out on a phase iii success.

Given:

- the recent shenanigans of the banking industry in general

and

- the intentionally suggestive yet ambiguous ways that companies (especially biotech) describe what they have in hand,


then what assurance does a bidder have that the banker is being completely truthful about the intent and degree of seriousness of competing bidders? This area seems ripe for a little bit of abuse.

OT:

I'm on the record as being anti-quiz, so take these grumblings as those of a grumpy old man who wants the kids to get off his lawn, but...

... that answer doesn't even make sense. If you're to make a connection between pedal-ity (insert more appropriate word) and p-value threshold, then it would only make sense that hexapedals would look for a p value of 0.15 since we bipedal humans look for 0.05.

I have no special insight. Just speculating out of sheer, untempered ignorance

True, a PFS hit and no survival advantage would be considered ambiguous by the market. Especially in this case where the comparator arm is active. If they do hit PFS and not survival, it may be worth waiting to see what the FDA does with Aria's rida... I could see them acting similarly in both cases.

Obviously these predictions all depend on the magnitude of the PFS advantage. A 2-3 month PFS advantage over nexavar with less side effects would be an real improvement and grounds for approval in my book. A 1 month improvement in PFS, a milder side effect profile and no clear survival advantage would have me biting my nails.

But I've had a real hard time valuing and appraising AVEO myself so I've stayed out. Others undoubtedly will have a better perspective..

aveo:

bets?

I don't have a position in it, but do have one in ONXX.

I say PFS hits, survival does not.

I knew it! You're soft on pesticides.

All you people think we can just mutate away our problems.


(this line of bantering makes me realize how much I miss Gary Larson's work)

To be clear, I'm not commenting on whether the man is a distinguished scientist or not. By and large, I think the term is stupid and not very meaningful. As long as he's made a contribution to the scientific literature, then I'm happy.

I'm simply questioning whether someone of his background is ideal to design a clinical strategy to achieve FDA approval.

Anyways, it's clear that PPHM is an emotional issue and not a rational one. I'll let the topic rest.

I'll ask again: why do you think a guy with an organic chemistry PhD, no clinical training, and a history of being a QC / Compliance guy is a compelling candidate to design a clinical strategy for approval of a biologic drug?

gotcha... i hadn't read that post yet as I was labouring to craft my own

Unless the explanation is that the technology, resolution and analyses methods that MNTA mastered early on are slowly becoming commoditized through the advances made by equipment manufacturers and software programmers. Not so much yet that other companies will unhesitatingly develop the processes themselves, but enough to give MNTA pause regarding the amount of rent they feel they can extract from those seeking the service.

I know what you're saying, but I think it's important to distinguish the types of deals that MNTA will enter into versus those of companies like PCYC. One has a proprietary drug, whereas in most instances MNTA isn't offering a drug but rather analytical services.

The 8K even refers to this by noting that MNTA stands to gain if they can lessen the regulatory burden for approval of the molecules under consideration. As it stands, I think it's a fine deal for the type of company that MNTA is.

Sadly, Speedel's drug has been underwhelming.

In this respect, I guess I was lucky that Speedel was bought.

ONXX:

From the PR, it sure sounds to me that ONXX would have known the FDA's reluctance up front before submitting the NDA. I think it's going to take a very strong ODAC recommendation to get approval this time around.

PYMX:

Agreed. That's why I noted that the perspectives have understandably changed now that the data have come in.

PCYC:

Woot!

JNJ wouldn't enter this collaboration if the drug wasn't working! amiright?

I do wish they would have arranged for the inflammatory indications to be included as well. Arguably that path is longer and more torturous than oncology, so a collaborator would be more helpful.

PYMX:

Just to add to your notes, a couple of observations / curiosities from me:

- they say they're making assessment based on the latest (August 2010) FDA guidance, but then the speaker kept adding the "skin infection" qualifier. It almost made me feel like they're just using a subset of the guidance rather than making a comprehensive assessment based on the full guidance. I've not read the referenced FDA doc so I might be way off here.

- to drive biomaven nuts, they don't seem to be looking at increasing dosing but rather shortening duration and/or lowering total dose But obviously having the data in hand changes everyone's outlook.

- they're reporting "response" and not "cure." So I think we need to be a little careful with that. Response = # cured + # improved. They may be being a little coy with this.

- Russia is part of Europe now? The term "asian" has entirely lost all semblance of its original meaning.

- I'm not too concerned about them having grouped data and not sharing it. Given the tight range and the small patient numbers, there isn't too much wiggle room for the other two numbers that go with 87 and 100. Plus, if we don't know how many were MSSA vs MRSA in each arm then it really doesn't help. I presume they're balanced based on the randomization, but still.

- i thought the ending to the call was very amateurish. The speaker basically reiterated to everyone that "yes the drug is working and yes the drug is safe." I hope he got chewed out for that afterwards.

PYMX:

For those who like to parse meaning out of PRs, I'm wondering if this sentence is:

1) an indication of doom? Hey, this is the first ever trial using this thing, what did you guys expect???

or

2) an attempt to focus investors that the data are good and that you shouldn't look around to anyone with comparable tech: We're the sh*t!

I can't tell.


====

edit: well, at the least they note that they're presenting interim data from an "ongoing" trial. I guess that it isn't total nuclear winter if it's ongoing after the interim analysis.

Why do you think that someone who holds a Ph.D. in Organic Chemistry and spent his time at Genentech developing and validating assays and drug production would have a strong understanding in running clinical trials?

Well, even if it works out with ARIA, that strategy will guarantee that you eventually give those gains back to Mr. Market.

Once again I bid you all farewell.

I read it as he's going to put all his IRA funds into ARIA.

If that's not the intention, then my apologies and I'll go back to hiding.

If that was the intention, then there is no good buy point. It's a horrifying course of action.

I've tried to stop posting here for obvious reasons, but for the love of God do not do that.

This happened to CELG too with Revlimid. It's not unheard of.

ONXX

True enough.

The only comforting thought, at that point, would be that management knows it is in over its head and is going to bail out because it would be in the best interests of the company. Sometimes that's better than having people waste money trying to develop drugs when they really have no clue.

Since ONXX hasn't exactly been stellar in developing their own drug de novo, it might not be a bad idea to sell out.

Obviously it depends on the price.

I'm just wondering if ONXX is on the verge of a run similar to what CELG saw prior to revlimid approval. Granted they had better ownership terms of their drugs, but nonetheless earnings could accelerate appreciably with two more drugs on the market within 2 years.

I'll say anything less than the Pharmasset premium will be a bit of a disappointment. I know that makes me greedy, but that's my knee-jerk reaction.

I was going to guess Bayer as well.

ONXX has a good deal with Bayer, meaning that Bayer has a good deal to gain from regaining Sorafenib sales to themselves.

Carfilzomib appears to be a decent drug, and even if this initial application has a set-back, additional trials are ongoing, Bayer could easily scale up new trials, and (correct me if I'm wrong) but they're not major players in hematological cancers. I figure they could easily follow the Velcade route with Carfilzomib, and given similar efficacy and reduced neuropathy, make decent inroads.

Also, Bayer may have indications that there is more to fluo-sorafenib than CRC alone. They're in the best position to know.

I'm usually an advocate of take-the-money-and-run, but with ~1 billion in sorafenib sales, a good chance of carfilzomib reaching market in the next couple of years, and possible strong royalties from a fluoro-sorafenib approval, this could be a really crappy buyout for ONXX shareholders.

If true, I don't see why they wouldn't be advantages.

Unfortunately I don't have too great a handle on the side effects at this point. Only PFE has done a proper trial, so it's tough to put a lot of stock into the 24 patients Galapagos has tested and ponder whether it offers a meaningful advantage.

INCY's claim has been that avoiding JAK3 inhibition is desirable, but to my knowledge they've not made any claim that inhibition between JAK1 and 2 needs to be discriminated. I think it is generally believed that JAK1 and 2 function overlaps to a degree.

At least that's my guess

On the basis that conference calls are dangerous times when an executive could accidentally tell the truth about the company.

See, for example, Introgen: each of their ridiculously long conference calls were really just treacherous, extended opportunities to accidentally divulge the truth to investors. That truth would have certainly destroyed shareholder value.

Your MO on this topic has been pretty textbook.

INCY:

They gave the cMET to NVS, so I suspect that it won't be a big driver for revenues.

They sound somewhat excited about the IDO inhibitor, but they also sounded enthusiastic about the sheddase inhibitor and dropped that one after phase 2.

At the least, they do seem to be placing an emphasis on making stringent decision about what they will and won't develop. They have a couple of projects (a topical JAK inhibitor and a diabetes candidate, INCB13739) that they don't seem to be putting money into but rather waiting for someone else to work on.

For the next 3-4 years, it's really about PV/ET and RA.

Now you're being obtuse.

We all know about the enumerated reasons for an interim analysis.

But your claim re: 3* is that ONTY / Merck are being extra double super sure, without any hard evidence that they are.

When boiled down to it, you're simply supposing that the company is employing a modification to OBF because:

1) You have no hard evidence that they're NOT doing what you alone propose they might be doing (message 131319).

2) You can't make sense of the data otherwise.



* From 131319: Efficacy, don't keep the placebos on placebo if the drug REALLY works

But that's the whole point of the interim look...

Why? I don't follow this at all.

ONTY:

Not to be creepy, but this is also what happened with the Theratope Phase 3.