Re: PPHM -"The best summary of the research that I know of is found on the PPHM website."

When that summary of the research includes data from a randomized, placebo controlled trial I'll start to take PPHM seriously.

In the meantime, the repetitive release of clinical data using historical controls year after year after year leads me to one of two conclusions:

1) management is incompetent in moving a drug candidate expeditiously down the development pipeline.

2) management is trying to avoid the reality that the actual implementation of the drug isn't sufficiently efficacious to lead to a commercial product, despite the intriguing mechanistic story. so they drag their feet on the clinical development and keep selling the story.

Give us some well done, randomized, blinded, placebo controlled studies with meaningful clinical endpoints and we can start to determine to what extent the pathway of bavituximab has been influenced by #1 and/or #2.

If it's mostly #1, you might be justified in being interested.

If it's #2...

Hopefully Dr. Chabner's expertise in clinical trial design will lead him to convince peregrine that it's finally time to actually try a study with a placebo group. No more hiding behind small single arm studies with historical controls.

MNTA: "Craig stated unequivocally that the Top Line data alone will not be the highlight, rather, the bottom-line patient outcomes."

I didn't listen yet, so I have no context for the above summary, but to what extent is this meaning "We missed the primary endpoint (top line data), but look at how good some of these post-hoc analyses (i.e patient outcomes) are."

I don't take Craig Wheeler to be that kind of CEO, but it is par for the course for small biotech. Interested in more color on the statement (or i could just listen myself, but won't have time till monday).

"Dr. Gupta will present interim data for 10 recurrent GBM patients at first relapse treated at AIIMS as part of an ongoing 40 patient Phase II clinical trial."

Which 10 subjects? Nothing in the press release precludes them having cherry picked these for presentation, which they then compared to historical controls. And as per Standard of Trial at PPHM, there is no placebo group in this open label single arm study, and who knows what sub-set of patients they are reporting on.

PPHM might have drugs that work, but if they do, it is unfathomable how they have yet to run even one human randomized study with a control group on any of the drugs in their pipeline.

Makes you wonder.

financing is going to be interesting coming up, although off the top of my head i'm not sure of the timing. i'm sure hp can remind us how much cash they have left.

I assume that MM-093 doesn't work (or at least not well), which is why Merrimack is essentially giving it to GTCB, who accepts it as another premises described by Zebra's Law.

if HP is correct and they only have 2 months of cash left, it's probably going to take a financing to put in a real floor.

i'm sure there will be a nice bounce for somebody that can call the bottom in the next day or two, but this will be under pressure until a financing (assuming 2-months is correct...this is a horrible time to releasing bad news)

OT: Healthcare and the Obama Emergency

Bob Dole was recently on NPR advocating for an aggressive timeline.

The former Senate leaders will try to give today's lawmakers a push by reminding them that the effort goes back to Harry Truman's presidency 60 years ago and that its prospects seem brighter today than ever. And last, that if it isn't done this year, electoral politics may block chances of passage for years to come.

"If we don't do it this year, next year's (a congressional) election year, the next year is the year before the presidential election, and then the next year is the presidential election," Dole said.

"So you're looking at five years, that's the way I calculate it, it may be off a year or two. So let's do it now. We're probably not going to get everything. It's an enormous package."

http://news.yahoo.com/s/mcclatchy/20090617/pl_mcclatchy/3254601

Is your question what happens if they meet overall survival endpoint on maturity in the entire study population, or what i assume is the post-hoc subgroup analysis of the "intermediate-risk" they talk up in the press release, except at the bottom when they mention overall survival in the full eligible population.

Still, the HR for the total population of .81 isn't horrible if it runs through at stat sig on maturity.

Don't know anything about the drug or the company otherwise...it is just the subgroup hype that stood out.

Has PPHM ever compared BAVI to anything besides historical controls in any human trials, either viral or oncological? I might be wrong, but I think the answer is "no". Correct me if I'm wrong.

It's still hard for me to get excited about a series of single arm studies looking at tumor response rates. And these only based on the "evaluable" patients.

They might have something, but let's see complete results from a PII randomized trial. Still in "wait and see" mode, and will be until I see randomized results with a meaningful endpoint or a partnership. The ship may have set sail by that point, but the risk/reward is more tolerable.

"The CE analysis adds another layer of mythology to the (necessary) mythology of the FDA and drug trials. But this second layer is neither necessary nor will it ever be in any conclusive (as opposed to the first layer)."

No question that poorly done/biased science isn't going to help. But in the case of well done studies, I would argue the opposite from your assertion above. Namely that that objective independent population based CE studies will remove a layer of mythology from the industry sponsored registrational drug trials from which one has to make a number of assumptions to guess which drugs are best for a certain indication/person.

CE

"But don't try this comparative analysis crap in rheumatology, pain management or psychiatry. The claims made for objective analysis there are pure sophistry."

Then on what basis were these drugs/devises approved in the first place? There may not be as hard of endpoints as in cardiology, but "they" no doubt embraced some endpoints/designs with fervor when they submitted products to the agency for marketing approval.

OGXI-011 OS stat sig

Don't forget that the p=0.07 is based on 49 events (out of 82 patients) as of november. the asco data will update through April. The Co pointed out several times that they have new data to present at the conference that was not available at the time of the abstract submission, and plan a conference call to discuss the data after the release.

My guess is it goes stat sig or they wouldn't be falling all over themselves to remind everybody they have new data and announce a conference call to talk about it. Clark and Dew seem to handicap survival analysis pretty well...would be interested on their take.

Still, caution is warranted on a number of other points. They need financing or a partner. they missed on their primary endpoints of PSA declines. PFS was a miss. stock has run 400% in the last few months. Valuation obviously less compelling at 110M than 25M just weeks ago. and as somebody pointed out re ISIS, antisense hasn't lived up to it's billing.

OGXI-011 ASCO Abstract

[This abstract is based on the same analysis released in December which I think included events through November, but includes additional data. An update as of April 2009 will be presented at ASCO on May 30.]

Mature results of a randomized phase II study of OGX-011 in combination with docetaxel/prednisone versus docetaxel/prednisone in patients with metastatic castration-resistant prostate cancer.

Background: Clusterin is a cytoprotective chaperone protein associated with CRPC progression. OGX is a 2&cjs1227;-methoxyethyl antisense that potentiates chemotherapy in xenografts and inhibits clusterin expression at doses of <640 mg. Methods: Pts with CRPC and chemo-naive received docetaxel (DOC) 75mg/m2 q3w + OGX 640mg IV weekly + prednisone (Arm A) or DOC + prednisone (Arm B) in a single stage randomized phase II design. Primary endpoint was PSA response rate (RR). Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Planned sample size was 40/arm: Arm A the hypotheses (PSA RR<40% vs. >60%) could be tested at 10% β and 10% α, Arm B the true PSA RR could be estimated with half-width of the 90% CI<13% if PSA RR=40%. Results: 82 pts (41 Arm A, 41 Arm B) were randomized from 09/05-12/06. At this analysis time, all pts are off therapy and 49 have died. One pt was ineligible but included in ITT survival analysis. Baseline characteristics were similar: median age 69 (49-87), PSA >100 µg/L in 51%, Hgb ≥100 g/L in 98%, alk phos >ULN in 44%, LDH >ULN in 36%, ECOG performance status (PS) 0:1 in 51%:49%, bone/lymph node/visceral metastases in 69%/50%/28%. Median cycles for Arm A and B was 9 and 7.[This is interesting as those in the OGX-011 endured more treatment cycles, which could account for some of the survival advantage]. Adverse events associated with OGX included fatigue, fever, rigors, diarrhea and rash. Mean serum clusterin change on day 1 cycle 2 was -18% in Arm A and +8% in Arm B (p = 0.0005). PSA RR was 58% (Arm A) and 54% (Arm B).[This was the primary endpoint, and is presumably not stat sig...] PSA declines at 12 weeks of any/>30%/>50% was observed in 87%/65%/45% (Arm A) and 68%/58%/34% (Arm B)[probably data mining on this analysis, but there does seem to be a trend, although again not stat sig]. PSA/objective disease progression as best response occurred in 0%/4% (Arm A), and 3%/17% (Arm B). PFS for Arms A and B was 7.3 (5.3-8.8) and 6.1 months (3.7-8.6).[PFS not stat sig] Median OS for Arms A and B was 27.5 (19.2-infinity) and 16.9 months (12.7-26.0) (unadjusted HR = 0.60 [0.34-1.06], p = 0.07). Variables predictive of OS on multivariate analysis: PS 0 vs 1 (p = 0.0002), presence of visceral metastasis (p = 0.006) and treatment assignment (HR = 0.54 [0.29-0.97], p = 0.04). [This is new information] Conclusions: The PSA RR in both arms met criterion for further study. OGX reduced serum clusterin and OS appears superior with DOC/OGX. This combination warrants further evaluation. Supported by a grant from the NCI-Canada/Canadian Cancer Society.

OGXI Update

[Here's the update PR announcing the ASCO abstract. They explicitly stated the HR=.60 in this analysis. As iwfal surmised, the p-value was >0.05 (p=0.07 for this interim analysis), which isn't disclosed here but is in the abstract, which I'll post.]

-- OncoGenex Pharmaceuticals, Inc. (NASDAQ: OGXI) today announced the release of two abstracts to be presented during oral presentations at the upcoming American Society of Clinical Oncology (ASCO) Annual Meeting. Abstracts are now available to the public online on the OncoGenex Web site at www.oncogenex.com in addition to the ASCO Web site, www.abstract.asco.org.

Highlights from the OGX-011 Abstract

At the time data was submitted to ASCO and as previously disclosed in December 2008, the preliminary median overall survival in patients with advanced prostate cancer who were treated with OGX-011 plus docetaxel in a randomized Phase 2 trial was 27.5 months compared to 16.9 months for patients treated with docetaxel alone. The hazard ratio (HR), a measure used to determine the difference in survival between treatment groups, was 0.60, representing a 40% reduction in the rate of death for patients treated with OGX-011. New data disclosed today include a prospectively defined multivariate analysis evaluating variables predictive of overall survival. The analysis defined only three variables predictive of overall survival: performance status, presence of visceral metastasis and assignment to the OGX-011 treatment arm. Based on the multivariate analysis, patients treated with OGX-011 had a rate of death 46% lower than patients treated with docetaxel alone (HR=0.54; p=0.04).

The abstract represents survival data as of November 2008. Final survival data as of April 2009 for this trial will be presented during an oral presentation at ASCO. [ They made a relatively big deal about this in the last quarterly conference call...namely that the oral presentation at ASCO would have additional data, and they'd have a conference call after ASCO to discuss the data. ]

I'll listen a bit later today.

Anything there to suggest why they are off 15%?

looks like they plan to launch in 2009.

what's the potential for off-label use for fibroids if approved?

interesting that NIH ran the trial for them. I wonder hcr owns all the indications, and how much this type of competition is affecting partnership negotiations.

NIH Fibroids Trial

Has this been discussed on the board?

I listened to NIH radio last week (podcast from iTunes) and they highlighted the problem of uterine fibroids, and discussed an ongoing trial sponsored by the NIH. They didn't discuss the drug on trial, but the discussant was very positive from an efficacy/safety standpoint. They refer to this website for additional info:

http://fibroids.nichd.nih.gov/
or
http://fibroids.nichd.nih.gov/study.html for info about the current study:

" This study evaluates a new medical treatment for fibroids using the progesterone receptor modulator CDB-2914. A similar compound, mifepristone®, [which i think is the emergency contraception RU486] reduced fibroid size when given for twelve weeks."

I found this part really strange:
To do this, women will undergo MRI and a saline hysterosonogram (ultrasound with fluid) of the uterus before and at the end of the treatment; they will have blood drawn every 7 – 14 days, and will fill out a symptom calendar at home. Hysterectomy will be performed at the end of the treatment to evaluate the effects of the medication on the uterine and fibroid tissues, and to provide treatment for the study participant.

Comments?

The high new Rx% might be an aberration, but it could also likely be a result of the NEJM article that came out December 20th that put tyzeka in the front of some people's minds and the affect is starting to trickle down to new Rx.

Will be interesting to look for follow though in the next couple of weeks.

It takes journals a long time to get around to publishing these kinds of papers!

and yet the stock still spikes the next morning!

As long as we're being negative ;)

(of some relevance...delete if repost)
http://www.bmj.com/cgi/content/full/335/7632/1248

BMJ 2007;335:1248-1251 (15 December)


Objective To evaluate the benefits and harms of antithrombin III in critically ill patients.

Design Systematic review and meta-analysis of randomised trials.

Data sources CENTRAL, Medline, Embase, International Web of Science, LILACS, the Chinese Biomedical Literature Database, and CINHAL (to November 2006); hand search of reference lists, contact with authors and experts, and search of registers of ongoing trials.

Review methods Two reviewers independently selected parallel group randomised clinical trials comparing antithrombin with placebo or no intervention and extracted data related to study methods, interventions, outcomes, bias risk, and adverse events. Disagreements were resolved by discussion. Trials in any type of critically ill patients in intensive care were eligible. All trials, irrespective of blinding or language status, that compared any antithrombin III regimen with no intervention or placebo were included. Trials were considered to be at low risk of bias if they had adequate randomisation procedure, blinding, and used intention to treat analysis. Risk ratios with 95% confidence intervals were estimated with fixed and random effects models according to heterogeneity.

Main outcome measures Mortality, length of stay in intensive care or hospital, quality of life, severity of sepsis, respiratory failure, duration of mechanical ventilation, incidence of surgical intervention, intervention effect among various populations, and adverse events (such as bleeding).

Results 20 trials randomly assigning 3458 patients met inclusion criteria. Eight trials had low risk of bias. Compared with placebo or no intervention, antithrombin III did not reduce overall mortality (relative risk 0.96, 95% confidence interval 0.89 to 1.03). No subgroup analyses on risk of bias, populations of patients, or with and without adjuvant heparin yielded significant results. Antithrombin III increased the risk of bleeding events (1.52, 1.30 to 1.78). Heterogeneity was observed in only a few analyses.

Conclusion Antithrombin III cannot be recommended for critically ill patients based on the available evidence.

Telbivudine versus Lamivudine in Patients with Chronic Hepatitis B

New England Journal Volume 357:2576-2588 December 20, 2007 Number 25

has this not been posted?
ABSTRACT

Background Reducing hepatitis B virus (HBV) replication to minimal levels is emerging as a key therapeutic goal for chronic hepatitis B.

Methods In this double-blind, phase 3 trial, 1370 patients with chronic hepatitis B were randomly assigned to receive 600 mg of telbivudine or 100 mg of lamivudine once daily. The primary efficacy end point was noninferiority of telbivudine to lamivudine for therapeutic response (i.e., a reduction in serum HBV DNA levels to fewer than 5 log10 copies per milliliter, along with loss of hepatitis B e antigen [HBeAg] or normalization of alanine aminotransferase levels). Secondary efficacy measures included histologic response, changes in serum HBV DNA levels, and HBeAg responses.

Results At week 52, a significantly higher proportion of HBeAg-positive patients receiving telbivudine than of those receiving lamivudine had a therapeutic response (75.3% vs. 67.0%, P=0.005) or a histologic response (64.7% vs. 56.3%, P=0.01); telbivudine also was not inferior to lamivudine for these end points in HBeAg-negative patients. In HBeAg-positive and HBeAg-negative patients, telbivudine was superior to lamivudine with respect to the mean reduction in the number of copies of HBV DNA from baseline, the proportion of patients with a reduction in HBV DNA to levels undetectable by polymerase-chain-reaction assay, and development of resistance to the drug. Elevated creatine kinase levels were more common in patients who received telbivudine, whereas elevated alanine aminotransferase and aspartate aminotransferase levels were more common in those who received lamivudine.

Conclusions Among patients with HBeAg-positive chronic hepatitis B, the rates of therapeutic and histologic response at 1 year were significantly higher in patients treated with telbivudine than in patients treated with lamivudine. In both the HBeAg-negative and the HBeAg-positive groups, telbivudine demonstrated greater HBV DNA suppression with less resistance than did lamivudine. (ClinicalTrials.gov number, NCT00057265 [ClinicalTrials.gov] .)

Nature: 2007 in review. An eventful year for the FDA

(I don't think this has been posted yet)
2007 in review
Nature Medicine 13, 1400 (2007)
doi:10.1038/nm1207-1400

An eventful year for the FDA


With a seemingly endless string of scandals, 2007 turned out to be a tough year for the US Food and Drug Administration (FDA). Things turned around in September, when Congress gave the FDA new powers to monitor drug safety, but here's a quick sampling of the beleaguered agency's many troubles:

Dec 23

Only 24% of drugs approved by the FDA between 2000 and 2006 were evaluated by an advisory panel, the Washington, DC–based group Public Citizen reports (Lancet 368, 2210).

Jan 4

The FDA approved only 17 drugs in 2006, the lowest number in a decade, and each drug cost an average of $1.5 billion to develop, according to a Tufts University study.

Jan 30

The agency unveils a 38-page proposal to enhance drug safety, including a pilot project to assess the safety of approved drugs.

Feb 12

The FDA slaps a 'black-box' warning on the antibiotic Ketek, linked to liver failure and death, and restricts its use to cases of pneumonia one day before a congressional hearing on drug safety.

Mar 9

The FDA issues strict warnings for three anemia drugs linked to heart attack and blood clots in individuals with chronic kidney failure and to rapid tumor growth in those with cancer.

Mar 16

The FDA decides to fully fund its Office of Women's Health less than a month after intense criticism over its plans to cut $1.2 million from the office's $4 million budget.

May 21

A meta-analysis of 42 clinical trials, based in part on data reported to the FDA in 2006, finds that individuals taking GlaxoSmithKline's diabetes drug Avandia have a 43% increased risk of heart attack (N. Engl. J. Med. 356, 2457–2471).

June 4

The FDA announces plans to appoint a 15-member advisory committee of ethicists, journalists, marketing specialists and other experts to help communicate drug safety information to consumers.

June 14

The makers of Avandia and Actos agree to issue black-box warnings about the drugs' association with heart failure two months after a House committee chastises the FDA on the matter.

Aug 15

The FDA warns parents that cough and cold medicines can be dangerous for young children, seven months after a report says that the drugs sent more than 1,500 children to the emergency room over two years.

Aug 27

Two members of Congress rebuke the FDA for considering a plan to outsource more than 300 jobs.

Sept 11

Reports of deaths and serious injuries caused by prescription and over-the-counter medicines nearly tripled between 1998 and 2005, researchers report (Arch. Intern. Med. 167, 1752–1759).

Sept 18

The FDA launches a drug safety newsletter for healthcare professionals, fulfilling an Institute of Medicine recommendation to improve communication released a year earlier.

Sept 27

President Bush signs a law directing drug makers to post the results of their clinical trials in a public database and giving the FDA more power to demand post-marketing safety studies.

Nov 1

The FDA cannot guarantee the safety of the nation's drug supply because the agency inspects few foreign drug manufacturing facilities and lacks an accurate list of which facilities are subject to inspection, according to the US Government Accountability Office.

I attended a presentation on this from Steve Hoffman at the emerging infectious disease conference a couple of years ago. There was an overwhelming amount of skepticism among attendees that even if this does turn out to be efficacious, it wouldn't be relevant beyond the military and travelers from the developed world due to the labor intensive process. A big issue is how often you'd need to get a booster shot. Hoffman is (or at least was) banking on natural exposures to keep up immunity and reduce the need for a booster, but one well positioned malaria vaccine guy i talked to didn't think natural exposure would be nearly enough to avoid the need for a booster.

Hoffman is convinced otherwise though, as he states in the article.

My bet is that DORB did a poor job in the preparation of their NDA. If the ODAC is any indication, they didn't make a good presentation of the 10-day (post hoc) guarantee period, and the probably didn't have any answer for the differential (and inconsistent between trials) effect in myelos vs. non-myelos.

When you're talking about failing a primary endpoint these unexplained effects give one less confidence that there isn't type1 error in the DORB analysis.

IMO approval/approvable will hinge on how well DORB can defend their data on these two points. In the ODAC they were inadequate.

"The right chart did not emerge until post-voting."

This is a key point that shouldn't have been overlooked and inexplicably was. They also should have had a good answer for the myleo-vs non-myleos, which they didn't. You can't go into a meeting like that and expect to come out convincing people.

"Did they come of as "Reaching"?

Don't forget one of the craziest moments anybody has seen at one of those meetings in a while, when an apparently drunk member of the board went ape about apparent conflict of interest. I don't lay that on the company at all, but it didn't help.

"Based on these discussions, the FDA requested that DOR review its existing clinical data from both its randomized, double-blind, placebo-controlled trials and highlight pertinent additional data that could provide a more comprehensive picture of orBec®'s clinical effect in treating acute GI GVHD. This new presentation of data formed the basis for the recently filed supplemental submission to the orBec® NDA."

"We appreciate the FDA's willingness to allow us to provide supplemental data"

Not sure who's idea it was to provide the additional data, but my guess is that the DORB folks aren't all the sophisticated when it comes to regulatory affairs. That's ok, small Bios generally aren't, and it showed in the ODAC meeting.

Good luck to the longs, but I can't get a good sense for how this is going to go.

"While she basically hides behind the fatal-flaw=primary-endpoint-failure axiom she does ask why the 80 day endpoint isn't just as important. Overall she does seem to have some positive inclination but can't get beyond the headline failure."

IMO it was more that the FDA couldn't get behind the primary endpoint failure. Read the two FDA reps response when the question was raised about whether 80 days is just a more mature version of 50 days. They wouldn't answer. They just said there was no alpha left, and there concerns were broad, not just about the 50 day failure. That was the non-objectivity that disappointed me, and IMO was a reflection of the way the agency intended to handle the drug.

"Remember, if he likes the drug and asks for another trial it will never be approved."


This is the drug's best chance IMO. It already took a LONG time to get these trials done, and DORB doesn't have a lot of resources.

"The fred Hutchinson center supplied 47 percent of the patients. since they use the corn oil they would not be able to do a placebo trial so a new trial would never recruit patients.""

One could almost make an argument then that the corn oil should be the placebo.

What hasn't been mentioned recently, and what I think is the biggest sticking point frankly in the data package, is the huge differential in the myelo's and the non-myelos. That has yet to be even plausibly explained, and adds to the concern that the observed survival data is an artifact.

OT: AVNR

I'm not sure what you're trying to say.

The FDA raised serious safety and possibly efficacy concerns about AVNR's drug, demanded new trials with different formulations, saying that all the trials that had been done were with a does of quinidine that was unapprobable. It's been a year, they've lost every major officer, have a sub $90M market cap, and haven't even started new trials yet.

They were destroyed.

I"m not comparing the drugs, only the process. The only point i was making was that the extension in and of itself is not a positive sign. They grant an extension if the company significantly ammends the data package. Period. It isn't tipping their hand.

On the other hand, one has to ask WHY the company didn't include that data in the original package? You know as well as i do that they did a terrible job at the Advisory Committee presenting data, and the Committee even noted that.

BTW, AVNR eventually got priority review, but they screwed up their application twice and so all told from the first submission it was more like 16 months!!!

"We then take into account that the data given in June deemed important enough to take further consideration leads me to believe that the chances are very high for approval."

The fact that the FDA delayed the decision shouldn't be interpreted as either positive or negative. If applicant submits substantial additional information, the FDA delays a decision by 60 days. Substantial is not meant to imply whether the data are good or not, just whether they will take additional time to assimilate for analysis.

Off the top of my head, AVNR made a similar addition to their data package, got a 60 day extension, and was bludgeoned when the agency finally issued an approvable letter questioning the entire data package and demanding more trials. It wasn't even close.

The point is that the way the FDA presented their case (which IMO displayed a surprising lack of objectivity) and the narrow definition of "substantial efficacy" left no room for a "yes" vote from the panel.

Hussain was reflecting this back to Pazdur with a question which was basically "why are you wasting our time when you know the answer you want and set it up to get that answer...and you people refuse to look past .05 on a primary endpoint? Why does it take a panel to say >.05 or <.05?"

Remember the FDA response to the 80 day treatment failure? It was (paraphrased) "Well 50 days was the primary endpoint and it was p>.05 so you don't have any alpha left to look at anything else. Everything else is exploratory."

Pazdur was left to defend the entire proceeding in his response.

I don't know which way the FDA decision will go, this is a fairly strange case, but I wouldn't take Pazdur's response to Hussain as necessarily encouraging given the tone of the question.

You recall the context of this quote?

It was in response to the Chair's question to him:

It's clear that a miss on the primary endpoint is a fatal flaw, so why do you keep calling us all here for these meetings?

How else was Pazdur supposed to respond? It's just a show for the public to deflect blame away from the FDA when we reject drugs?

<<<<<<<<<<"We haven't proof that Proellex shrinks Fibroids either.">>>>>>>>>

I'm not sure shrinking of fibroids for Proellex and QOL for Androxal are analogous.

There isn't a meeting pending with the FDA in which they could require that Proellex shrink fibroids in order to be approved.

Also, we have other proof on improved QOL issues with Proellex in fibroids, even if it doesn't shrink them.

Re: QOL

I see two reasons why QOL is a problem. One is that they haven't yet shown that Androxal improves QOL, so there is some uncertainty as to whether they can design the right trial to show the effect (it is logical that there should be one). It introduces additional uncertainty.

The second (and related) reason is highlighted by docbanker...i.e. they may need to do another pII/III study with the patient population they plan to enroll for the pivotal study, to get estimates of effect, to further define the patient pop etc.

When they measured QOL in the recent trial, here's what they got:

Although the syndrome of secondary hypogonadism is characterized by the objective measurements of low testosterone and gonadotrophic hormone levels it is recognized that in some men testosterone deficiency may be accompanied by a variety of symptoms related to decreased sexual function. This study did not require that any of those symptoms be present at enrollment as the primary inclusion criterion was low testosterone and low to normal LH. Nonetheless, as an exploratory exercise, three different patient questionnaires were included in the study to explore the relationship of these symptoms to low testosterone and the effects on these symptoms exhibited by increasing testosterone. The questionnaires that the subjects completed at monthly intervals were the “International Index of Erectile Dysfunction”, “Sexual Desire Survey form, DISF-SR II” and the “Male Sexual Distress Scale” developed by Len Derogatis, PhD, Director, Center for Sexual Medicine at Sheppard Pratt Health Systems in Baltimore. Analysis of the MITT subjects indicate that in none of the symptom domains was there a difference in response from placebo although many of the treatment groups improved in comparison to baseline values. Although neither men treated with Androxal nor those treated with Androgel reported a significant increase in libido as determined using the DISF-SRII, both doses of Androxal performed comparably to Androgel. Likewise, although no statistically significant differences in distress, as measured by the MSDS scale, were recorded for men receiving Androxal or Androgel, both doses of Androxal performed in similar fashion to Androgel.

If the results translate from rats to humans, it may ultimately help androxal relative to competitors, but will it have a negative impact on the overall size of the the T market?

The more immediate question is what effect would such concerns (note not from this report specifically, as a single unpublished animal study doesn't carry much weight) be on the FDA's direction on the clinical development program???

Study: Testosterone pills could damage kidneys
It's only a study in rats, but it makes one wonder if such concerns would play any part in the FDA's decision on study design for androxal.
http://www.cnn.com/2007/HEALTH/conditions/08/27/hm.testosterone.pills.reut/index.html

NEW YORK (Reuters) -- Testosterone supplements may make aging men feel and look better, but the results of a study conducted in rats suggest that it could lead to kidney damage and worsen high blood pressure (hypertension).

Testosterone levels gradually decrease with age in healthy men, a condition some doctors refer to as "andropause," which is analogous to menopause in women.

A growing number of healthy older American men take testosterone replacement therapy to improve their feelings of well being, sex drive, and muscle mass.

"Because chronic cardiovascular disease, like hypertension or kidney disease, is related to a sharp decrease in testosterone, a lot of doctors also prescribe testosterone to men who suffer from heart disease," Dr. Radu Iliescu, of University of Mississippi Medical Center, Jackson, noted in a telephone interview with Reuters.

However, "no well-controlled clinical studies have addressed the effects of testosterone on the cardiovascular system," Iliescu warned, "and our research actually showed that testosterone contributes to hypertension and end-stage renal disease in various rodent experimental models."

Iliescu and colleagues found that testosterone supplements caused about a two-fold increase in testosterone levels in the blood of male rats. They also found that blood pressure was significantly higher in testosterone-supplemented rats compared with normal "control" rats. Castration did not alter blood pressure levels.[I'm not sure if this means among rats who were already supplemented or among rats who weren't]

Compared with normal rats, testosterone-supplemented rats also had higher concentrations of protein in the urine, a sign of possible kidney trouble, whereas castration reduced protein in the urine.

These results were reported by Iliescu and co-researchers at a recent meeting of the American Physiological Society in Austin, Texas.

Supplementing testosterone or preventing the testosterone loss that occurs with age or chronic disease [i.e. androxal, but it doesn't appear from the article that their experimental model included anything other than supplementation] may actually worsen preexisting heart or kidney disease, the researchers conclude. [note "preexisting" all of a sudden appears on the conclusion, but it wasn't in the write up before, so i'm not sure what to make of it]

"We are trying to bring to the attention of the clinician of using care when prescribing testosterone supplements and to address cardiovascular risk," Iliescu told Reuters.

I'm in at an average of 5.5, so same boat as well.

I keep waiting to average down, but at some point you have to wonder why people are selling with such voracity. Some combination of shorts selling with impunity and longs wanting out badly enough that they don't care what kind of discount it takes to exit.

One can construct explanations that don't challenge the fundamental reasons most of us bought JAV, but the further it goes down the harder you have to consider the alternative that all isn't as it seems to be.

I find the minutes to be strange.

Why would they propose that DORB do a prophylaxis trial?

Either the drug hasn't proved its efficacy and it is therefore ethical to conduct a randomized treatment trial, or it has proved its efficacy and a should be approved.

What is particularly strange is that right before they "suggest" a prophylaxis trial they hash through all their problems with combining trials of different designs etc in a meta-analysis. What does a prophylaxis trial have to do with the current indication/nda?

If an approval was coming down this week, they would have massaged the minutes of the meeting to be less dismissive.