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In this case, your assumption is correct - only about 25-30% are symptomatic after acute infection but asymptomatic cases almost never require treatment and can remain asymptomatic for up to three decades, so we can count them as "sitting in the warehouse" regardless of future all oral cocktail.
The promise of interferon-free treatment should keep the majority of HCV patients "sitting in the warehouse".
It will much depend on Teva's attempt for a patent term restoration of its two rasagaline COM patents.
Looks like you were right about Lucentis PRN
Bimonthly dosing (after the initial loading period) is already the de facto SoC for Lucentis in AMD, and the CATT study produced no data to change this. So, like it or not, bimonthly dosing of Lucentis is what Trap will have to compete against in the real world.
There's an ongoing patent litigation on Teva’s Azilect - there's a Paragraph IV challenge and a 30 month stay on approval till Nov 2013 (or a district court decision).
Note that NEJM ORIGINAL ARTICLES like the one you've posted are peer-reviewed while CORRESPONDENCES like Peter posted, usually aren't.
Andromeda/Teva/Clal DiaPep277
Data from the first phase III trial are expected next month. A free full text review on the area:
http://www.discoverymedicine.com/Dequina-Nicholas/2011/04/07/autoantigen-based-vaccines-for-type-1-diabetes/
Higher Lucentis dose (2mg) is dead but monthly vs. an As-Needed Basis (PRN) perhaps not:
Here not so good news is that the HARBOR study is clearly showing us that high-dose approach with Lucentis will not be an option. We were not able to show the superiority of this high-dose approach and we are still analyzing the data as far as the PRN versus monthly comparison.
I think AEZS still holds all perifosine rights outside of North America, other than Japan and Korea.
One case that comes to mind of generic-drug litigation of process patents is Pfizer vs. Ranbaxy's over two Lipitor patents #6,087,511 and #6,274,740 that expire in 2016.
Another case that was settled with several generics is Sepracor's Xopenex nebules which is protected by few method of use patents expiring until 2013 and one process patent #6,451,289 that expire in 2021.
[Semi OT]
Thanks for the reply and links, Jim. Did a bit of reading and seems the story is a bit more involved for the "common" addiction as well. Although DA is thought to be involved in the rewarding/reinforcing effects (a whole separate discussion on the difference between the two) of all drugs and "natural" rewards, this is sometimes not a direct activation of the system as in psychostimulants (cocaine, amphetamine). Opiates, e.g., heroin, are thought to activate the DA system by acting on GABA terminals (inhibiting release of GABA), as well as having a DA-independent reward mechanism.
Although GABA agonists, like benzodiazepines, certainly have abuse potential, it is not considered particularly high (it is only Schedule IV in the controlled drugs scale). The addiction potential is indeed not well understood, including the fact that it is not easy to have animals self-administer GABA agonists (although physical dependence readily develops), but DA might be involved, as usual. BTW, alcohol rewarding effects are thought to be mediated by its effects on GABA(A1) receptors, and alcohol is most definitely addictive...
Lunesta does seem less addictive with stronger clinical data plus it could go generic by mid 2012 (the 30-month stay expiration).
I think the royalty rate to AEZS starts from a high single digit and is progressing to
low double digit rate at higher sales.
If there were anaphylactic reactions, I imagine we would have known from Dupuytren’s studies and clinical practice.
I'm afraid I know very little about sleeping pills and their addictive properties and I'd be happy if you can elaborate a bit on the addiction aspect. GABA mechanisms are very different from the ones thought to underlie "common" addiction so my understanding was that it is a different "kind" of addiction, i.e., it's not the clinical symptoms you would observe with opiates or psychostimulants, but an inability to fall asleep without them.
BSTC / AUXL / Xiaflex
On the safety concerns with Collagenase - ruptures being the most scary, as nicely put by rkrw #msg-65958671 It would of course depend on incidence plus consider that surgical treatment also comes with its own risks.
There's no FDA approved drug for Peyronie's but I've found this review: http://www.nature.com/ijir/journal/v14/n5/full/3900917a.html that makes me wonder if Xiaflex' risk/reward/price profile can be better than verapimil's. Also, I'm quite sure Collagenase has no COM patents and the IP protection beyond orphan exclusivity period might not be very strong, but I haven't looked into this.
Phase III trial is allowing Modeling and a fourth treatment
[Way OT]
In other words, if there's nothing new to be done or thought, why bother?
Given the difficulty of producing a uniform product without carefully controlling the feed-stock, the "testing" that needs to be done is inherently part of the manufacturing process
Basically, Section 271(e)(1) provides an exemption so a generic manufacturer can carry out activities such as bioequivalency testing to satisfy requirements by the FDA for obtaining an approval. Activities for new drug discovery or during commercialization of the product certainly are not within the scope of this Section. The language “reasonably related" leaves quite a few activities that fall in a gray area.
I certainly agree with your view that exaggerating Section 271(e)(1) beyond the intent of the law would make the value of patents like Momenta's worth a lot less (using iwfal's words #msg-67816773). Still, from previous cases where utilizing patented techniques was allowed so long as it was related to gaining data for FDA approval for an ANDA, seems to me it is within the scope of Section 271(e)(1). Btw, Momenta will probably use the Bolar Provision in the Copaxone case (#msg-59195596).
Smells like the Bolar Exception again
Perifosine in phase I with different dosing regimens as single agent, found no response in CRC. Thus this could be the drug finally found the right combination for right disease setting, or the drug worked in a trial for patients that have certain hidden characteristics/inbalance that cannot be repeated in large trial. I don't think anyone knows at this point.
But the recently published data doesn't meaningfully expand the number of patients - what happened to the invited patients, or was it only 3 invitees (the latest paper, pointed to by genisi, had 38 patients)?
No sweat, RC2. I didn't really track the review down, it was mentioned (ref. no. 4 at the bottom) in Lilly's PR
https://investor.lilly.com/releasedetail2.cfm?ReleaseID=611956
It would be interesting if there turned out to be more than an age-related basis for BPH/ED association
[OT] Shame on you Dubi, the email I've sent you with this joke contained a photo, which you neglected posting
Hope fasting isn't too hard for you this year
PKI dependence on US research funding is a lot lower than that of ILMN and AFFX, so at least for this segment PKI should do better.
Here's a very recent review:
Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia
http://www.ncbi.nlm.nih.gov/pubmed/21726934
I think that about one third of men with BPH also suffer from ED and I'm sure LLY will target this segment.
First, it's a highly ranked journal, so good impact. Also, note the JCO authors analysis is on an ITT basis and OS difference is higher than of the ASCO abs.:
ASCO - Median TTP: 28 vs. 11 wks (p=0.012) and OS: 18 vs. 11 mos (p=0.0136).
JCO - Median TTP: 27.5 vs. 10.1 wks (P< .001) and OS: 17.7 vs. 7.6 mos (p= .0052)
Patients who failed 5FU have usually poor RR to later treatment line, there were 25 of them in this trial and the stat-sig increase in OS and TTP in this subgroup is important, imo.
I guess there's the question if the perifosine arm got mostly 2nd-line patients whereas the control arm got mostly 3rd-line patients
Have you seen the 23andme offer of a $999 genome?
9. Novel Diabetes Therapy: SGLT2 Inhibitors [e.g. BMY/AZN’s dapagliflozin]
So, you're one of them too ha? the PDP-11s lovers that is
But seems like some folks loved them just the same...
With regards to perifosine and colorectal cancer, it's a shame that the phase II trial results have not been published.
They've also got another new product called Stelara, an interleukin-12 and -23 inhibitor used to treat psoriasis. That's on track to become a billion-dollar product by 2012. [I question this sales projection.]
Seems I'm no less clueless than the Wall St. Cheat Sheet writer
They didn't "Swing to a Loss After Two Straight Profit Quarters" rather MON lost $122M on sales of $2.2B in the Q4 (better than Q3 were it was a loss of $143M on sales of $1.95B). They reported a $1.6B profit on sales of $11.8B in 2011!
Here's a basic read from Nature Reviews (January 2010) on the market. A bit out of date as development of motavizumab, the 2nd gen anti-RSV mAb derived from Synagis, was discontinued. Not sure how viable RSV604 is.
Respiratory syncytial virus market
By Shane Storey
See link for tables, figures, and ref. http://www.nature.com/nrd/journal/v9/n1/full/nrd3075.html
Respiratory syncytial virus (RSV) infections are the leading cause of viral death in infants, although RSV-related mortality has decreased since the development and approval of prophylactic antibodies. RSV also causes bronchiolitis, pneumonia and chronic obstructive pulmonary disease (COPD) exacerbations in the elderly, which lead to substantial rates of hospitalization and death1. RSV infection does not provoke lasting immunity, so human hosts experience lifelong cycles of infection and re-infection. Fortunately, RSV illness is mild in otherwise healthy people. The market for RSV treatments currently has only one, narrowly defined patient group: prematurely born infants at high risk of infection, who can be treated with immunoprophylactic antibodies. Over the next decade, the market could expand to reach at-risk adults and children suffering acute infections, probably through the availability of small-molecule and small interfering RNA (siRNA) agents (see Table 1 for selected RSV vaccine and antiviral development programmes). The development of RSV vaccines presents specific challenges, and their clinical use is currently a distant prospect.
Immunoprophylactic antibodies
Palivizumab (Synagis; MedImmune/Abbott) is a humanized murine monoclonal antibody against the RSV fusion protein that prevents the spread of virus to the lower respiratory tract2. It was approved by the FDA in 1998 and is licensed as a prophylactic agent for babies born prematurely at 35 weeks or less, and/or with congenital heart or lung disease. Palivizumab achieved blockbuster status (sales over US$1.2 billion in 2008), and MedImmune is likely to dominate this market for the next decade or more with second- and third-generation antibodies progressing through clinical trials. Motavizumab is an affinity-matured variant, which gives additional protection to the upper respiratory tract. In November 2008, MedImmune received a complete response letter to its biologics licence application (BLA) for motavizumab from the FDA and was expected to resubmit the BLA before the end of 2009. Further potency and lung bioavailability advances seem to have been achieved through directed molecular evolution, creating MEDI-557, which is now in Phase I testing3.
RSV vaccines
The approval of the first RSV vaccine is not expected before 2020. RSV vaccines require heightened safety evaluation by both sponsors and regulators because of the risk of enhanced disease. In the mid-1960s, a formalin-inactivated vaccine candidate caused the deaths of two infants who were enrolled in a clinical trial4.
To be cost-effective and gain reimbursement, RSV vaccines will probably need to be administered before the second month of life, because the population most at risk are babies aged 6 months or less. Candidate vaccines must also not reduce the safety or efficacy of the eight vaccines that are currently scheduled for routine administration in infants. MedImmune has the most advanced vaccine candidates: two formulations are now entering Phase I–IIa trials. MEDI-559 is a cold-passaged, live attenuated RSV that is being tested in 320 children aged 1 to <24 months. MEDI-534 is a human–bovine chimeric parainfluenza virus construct expressing the RSV fusion protein. Both candidates show promising safety profiles in Phase I testing and are expected to report efficacy data in 2012 (Ref. 5).
RSV antivirals
The availability of rapid (15-minute) RSV detection kits has opened a large market opportunity for RSV-specific antiviral drugs, which could be prescribed or administered in the general practice and emergency settings to treat acute RSV infections. The potential pool of patients (hospitalized or otherwise) who may seek RSV antiviral therapies is considerably larger than the group that is currently accessing palivizumab (Fig. 1).
RSV particles offer several targets to developers of small-molecule drugs. Many of the initial programmes targeted the fusion protein, perhaps because studies on palivizumab had provided such powerful molecular validation of that target. The attrition rate has been surprisingly high — several promising programmes have been discontinued after Phase I testing6 over the past 12–18 months, and there are now no fusion protein inhibitors beyond preclinical development. There are two reasons for this: the stringent requirements of the paediatric safety margin and the need to achieve a favourable pharmacokinetic–potency balance.
The two agents that have survived Phase I testing and are now undergoing Phase II trials have involved a different approach: both target the RSV nucleoprotein, but in different ways. RSV604 (Novartis/Arrow Therapeutics) is a benzodiazepine with oral availability, an excellent pharmacokinetic profile and potent activity7. Novartis is sponsoring Phase II trials of this compound in immunocompromised adults and has paediatric formulations in development. ALN-RSV01 is an siRNA compound that is designed to interrupt nucleoprotein synthesis and thereby inhibit viral replication8. Alnylam and Cubist Pharmaceuticals have conducted a randomized, placebo-controlled Phase II study of inhaled ALN-RSV01 in 24 lung transplant recipients with confirmed RSV infections. Only 7% of treated patients showed new or progressive bronchiolitis symptoms at 90 days post-treatment, compared with 50% in the placebo group. Although not designed to show efficacy, these results are encouraging, and ALN-RSV01 has the potential to become the first drug to be approved for RSV that is not restricted to prophylaxis in infants.
Future perspectives
The palivizumab market is large enough to attract interest from biogeneric developers, who may seek to enter the market from 2015, when the cornerstone palivizumab patents begin to expire. MedImmune aims to protect its market share with motavizumab, which shows superior efficacy to palivizumab in head to head Phase III studies9. The expansion of the RSV market will be enabled by products that satisfy specific needs in well-defined patient groups, as was achieved by palivizumab.
In the medium term, it will be interesting to see whether ALN-RSV01 can secure marketing approval for immunocompromised adults. The most lucrative target market is children under 2 years of age presenting with respiratory symptoms and confirmed RSV infections, for which the market demands an oral formulation.
Market indicators
Palivizumab is the only RSV-specific treatment on the market, and record sales of ~$1.35 billion are estimated for 2009 (Fig. 2). Motavizumab, an enhanced version of the product, is expected to receive approval in 2010 and eventually replace palivizumab in the market. MedImmune's antibody franchise is expected to expand if motavizumab confers an additional benefit and if the investigational product MEDI-557 can offer less frequent dosing. Motavizumab and ALN-RSV01 are the only compounds in development that have the potential to be approved before 2015, possibly followed by RSV604 in 2015. If approved, they will extend the RSV market to include elderly and/or immunocompromised patients and will increase market sales to more than $2 billion by 2015. Palivizumab is an expensive treatment, and it took several years before reimbursement support was granted outside the United States. Although the cost of acquiring palivizumab is the dominant expense in managing RSV, it has an attractive incremental cost effectiveness ratio, estimated at 11,000–21,000 per quality-adjusted life year gained10.
References...snip
Rate is not that high. Besides, it's easier when one can read the quizzer's mind
BMRN/Pompe in adults - could have been a good quiz
Thanks for the info and link. Didn't listen to the webinar yet, but always thought that the reason for going in Adults is because they are the majority of patients.