Hi $heff, AMRN has seen huge volume and positive price movement due to the speculation on their patent. What are your thoughts on the patent approval chances? Also, the FDA decision on AMRN 101 is in July. Do you think this is a good catalyst for AMRN in the coming months? TIA
TLON..$.87 Will be doing a brief write-up from the documents here shortly. I don't think that after reading the documents in their entirety that these documents really helped Talon in achieving accelerated approval for Marqibo for Wednesdays panel meeting. The FDA will need to consider special circumstances outside of the briefing documents for consideration. Situations like last ditch therapy for patients where there are no other options after the 2nd line. This will be key for the panel.
Panel needs to view these situations favorable for Marqibo:
1) Better than Vincristine though not much better. 2) Severe patient population for which no other therapies exist. 3) If they see an Overall survival benefit they they could get at least conditional approval. That was the 4.7m that Marqibo showed even though FDA said OS cannot be reliable.
TLON..$.85 The meat of the briefing document has been a surprise to me. It's not the fact that the FDA would question non-randomized trials because TLON has one in the HALLMARQ study. I would have been completely happy if the FDA just questioned study design, OS, as well as RR. I expected them to do that and I figured that a Ph III randomized study would be suffice to answer those questions. I was convinced that the safety was strong from the data that was reported at ASCO.
There are different issues & surprises that have thrown me off in the documents. That is the issue of safety from the Marqibo Phase II RALLY. Safety & efficacy have been the premise for having a liposomal vincristine (Marqibo). According to the FDA you can have similar efficacy but if you show that you are safer than that can be suffice. The briefing documents show that that Marqibo has failed to do that. It is something I did not expect from their Phase II data. As the FDA has intervened, they are seeing gaps in their abstract regarding efficacy and safety.
I let everyone know last week that I had a small position last week prior to the Ad note release. Also discussed folks who had been in since $.60 as well since stock was at $1.23 at time of post. http://bit.ly/zUAWgU I stated I would add if the documents were good and their was a positive ad panel. http://bit.ly/yRCTss
I will not be adding position in Talon and will wait until after I know whether there is a positive or negative panel meeting. I was definitely wrong here in that I expected the data that I saw from the Phase II abstract (RALLY) to be the same in the briefing document & it is not..both in terms of efficacy & safety. FDA is seeing different data pts on key efficacy & safety parameters. This does not mean that the FDA will not conditionally approve Marqibo as there are many factors that come into play as I mentioned. Talon will be looked at closely especially since there are no options available for pts into later lines of therapy.
Panel needs to view these situations favorable for Marqibo:
1) Better than Vincristine in terms of benefit/risk. 2) Severe patient population for which no other therapies exist. 3) If they see an Overall survival benefit they they could get at least conditional approval. That was the 4.7m that Marqibo showed even though FDA said OS cannot be reliable. ________________________________________________________________
Issues with the submission: 1. Available Therapy 2. Benefit/Risk The voting question & one that matters most!
Given the magnitude of CR and CRi rates and the safety profile observed, we ask the Oncologic Drugs Advisory Committee to discuss the risks and benefits of Marqibo for the treatment of adult (age >18 years) patients with Philadelphia Chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more treatment lines of anti-leukemia therapy.
Throughout Marqibo’s drug development program, FDA recommended randomized clinical trials to demonstrate the potential clinical benefit of Marqibo. We knew this and this is why a Ph III study was convened
There is no FDA approved drug for the current proposed indication for the treatment of adult patients with Ph- ALL in second or greater relapse or whose disease has progressed following two or more treatment lines of anti-leukemia therapy.
Previously Received Advice from the ODAC On February 8, 2011, the Office of Oncology Drug Products convened a meeting of the Oncologic Drugs Advisory Committee (ODAC) to discuss the status of drugs approved under the accelerated approval regulations; the following advice was offered from the committee:
Overall, ODAC members agreed that randomized controlled trials should be the standard and that single arm trials should be the exception. Committee members commented that single arm trials may be used in the following situations: 1) rare diseases and 2) high level of activity of the agent or pronounced treatment effect. It was also mentioned that the toxicity of the agent must be taken into account in a risk/benefit analysis in the situations in which single arm trials may be used. Key that single-arm trials would be considered if benefit/risk analysis was favorable. Committee members noted that it would be helpful to have a definition of rare diseases. Members also noted that the bar for accelerated approvals should not be lowered to move products on to the market faster through single arm trials, but rather single arm trials should only be used in certain situations and randomized controlled trials should be the standard. Overall, members agreed that at least two controlled trials should be needed for accelerated approval commitments. Most members agreed with this statement with the caveat that in rare diseases and pediatrics this may not be feasible. Overall, members felt that a well designed development plan is needed prior to the application being filed. Most also preferred that the sponsor have studies already ongoing at the time of application.
ODAC discussed the results of this trial on December 1, 2004. The committee unanimously agreed that these results were not predictive of clinical benefit and should not be the basis of approval under Subpart H. For a drug to be approved under subpart H, the drug must demonstrate an improvement over available therapy. Per ODAC discussion and committee voting, Marqibo did not demonstrate an improvement over available therapy. The committee recommended a randomized clinical trial to demonstrate the clinical benefit of Marqibo for the treatment of patients with aggressive non-Hodgkin’s Lymphoma. This did not apply to ALL so Marqibo was getting clean slate IMO w/ new disease
The FDA response assessment that included all patients who received at least one dose of study drug was not in complete agreement with the applicant’s. FDA’s assessment found that 10 patients’ disease status was a CR or CRi with treatment. FDA review of the CRFs provided in the initial submission suggested that one patient’s BM persistently contained >5% blasts, hence could not be considered as CR or CRi. The review team queried the Applicant regarding this one case. The Applicant stated that “Course 1 Day 28 and Course 3 Day 28 case report forms appear to have been misfiled in a manner that could lead one to conclude that there was reviewer discordance where there was actually none”. Table 7 summarizes the bone marrow assessments for this patient. Compared to the initial submission, in the amended submission the central pathology reviews were switched between course 1 and course 3. The dates on which bone marrow examinations were performed are not indicated on the central pathology review forms and this case may need additional documentation to determine final status.
Duration of CR or CRi: FDA assessment of duration of remission was based on the first date of CR+CRi to the date of the last available assessment of the same response. The Applicant’s, duration of response used time, in days, from first CR or CRi until recorded (or inferred) relapse which included the period after transplant or other subsequent chemotherapies. By FDA assessment, five out of 8 confirmed CR+CRi patients had duration of response less than one month. The median duration of response for these 8 confirmed CR+CRis was 28 days. Table 9 demonstrates the duration of CR/CRp/CRi by both IRRC and FDA assessments. This is lower than what TLON reported.
Approximately one-half of the 83 patients (53%) who began treatment with 2.25 mg/m2 VSLI actually received the intended prescribed dose and dosing schedule. Of the remaining patients, 17 (20.5%) missed doses, 18 (21.7%) had reduced doses, and 5 (6.0%) had delayed doses. The majority of missed doses occurred in the presence of a new AE. More than one third of patients (6 of 17 patients, 35%) missed doses due to AEs associated with neuropathy including peripheral neuropathy, pain in extremities, facial neuralgia, and ileus. Neuropathies are the most notable adverse events associated with vincristine. The number of patients who required neuropathy-related dose reduction, dose delay and missed doses do not suggest a better toxicity profile for Marqibo than vincristine. Concern regarding neurotoxicity not being better for Marqibo over standard vincristine. This is where benefit vs. risk come in. If it's not safer than that poses a challenge. Needs to be looked at as better tolerated by panel.
Deaths: All patients in Study HBS407 were to be followed for survival, while no long-term follow-up was conducted for Study VSLI-06, hence the number of deaths in Study VSLI-06 is underreported. # of deaths are underreported? That is a surprise. Also need to look at sick patient population on multiple lines of therapy prior to Marqibo Sixty out of 65 patients in study HBS407 died during the follow up period. In study HBS407, 15 (23.1%) patients died during the treatment period (i.e. deaths that occurred after the first dose infusion date through last dose date plus 30 days), Table 13.
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