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Please continue this discussion here.
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I'm not a Dr. I happen to be long the CVR and think this is a fascinating drug that shows promise based on my limited research for a terrible disease. How crazy that an 'old' drug can be recycled for treatment of a new disease?
Chris, I'm on the free side of the paywall. Any thoughts on the valuation of the CVR with the new (small but unexpected) hurdle of the panel in November?
It may sound self-interested but it's a shame this drug is off the market one day longer than absolutely necessary. AT.
Seems some physicians are negative about the drug:
"Medical director at the Providence Multiple Sclerosis Center in Portland, Oregon, Stanley Cohan, MD, said, "I don't think this drug will be approved, but if it were available, I wouldn't use it." The authors of the study, Alasdair Coles, PhD, from Cambridge University in the United Kingdom acknowledged that many of his colleagues do not agree with the idea of using alemtuzumab in multiple sclerosis."
I read the story of David Sturt who has MS and has not suffered a relapse after being treated with Campath (Lemtrada) 10 years ago:
This was pulled from a forum of patient experiences with Lemtrada/Campath:
Are they saying these were all caused by the drug?
There are about 95,000 patients on Tysabri currently and 59 have died from PML (271 have PML). If we divide these two to get a crude risk of mortality measure we have 0.25%. Which is in the ballpark of reported PML risks (0.4%-2%) multiplied by PML mortality rate (20%). But note for PML: "all survivors had additional disability, often severe."
As far as I am aware, in Phase 2 and 3 trials, Alemtuzumab has had 1 death from ITP and 1 from sepsis, out of 334 (Phase 2), 581 (CARE MS-1), and 657 (CARE MS-II) patients, respectively, for a bit lower back-of-envelope mortality of 0.13%. It seems my math on risks agrees with your sentiment about Tysabri being worse, although not significantly worse.
My main concerns for approval are the FDA may not believe the safety procedures for early detection of ITP, or may not like the risks of abnormal thyroid function, or may consider the mortality risks as being too high. And of course approval could be delayed past the GCVRZ approval deadline of March 31, 2014. Actually delay is much better for us than the binary outcome of rejection since the other CVR payouts are still available. It is encouraging that you believe the FDA gives more latitude for RRMS drugs and can delay in the interests of safety if needed.
Some people were asking about the payout conditions of the CVR. They are available from the SEC. All investors should read them:
Finally, this situation was discussed by "longtermvalue" in 2011. His highest probability guess was estimating that the production milestone would be hit but it was missed. He estimated Lemtrada approval at 70%.
Secondarily, is this panel a "out of normal" activity prior to approval? Why does this pose additional risk? Or why does the market view it that way?
MS is a long, lousy disease. If you have MS, even when you think nothing is going on, the brain of a patient with MS is being systematically shredded slowly and silently and it progresses from the relapsing, remitting phase into the secondary progressive phase. We talk incessantly about the medications for RRMS but we never hear any mention of a medication to slow down secondary progressive MS. Why? Because there is nothing available. The patient who evolves into SPMS is more or less set adrift. The pharmaceutical companies collect their billions of dollars from patients who have RRMS but have nothing to offer them when they reach the secondary progressive phase of the disease. It takes about twenty years for this process to evolve. The end result is unemployment, divorce, loneliness, paralysis, numbness, loss of vision, incontinence, and severe dementia followed by death. I won't even talk about the patient who presents with primary progressive MS. That is a quicker path to death.
So when we say that there is no cure, we mean that there is no way for us to prevent progression from RRMS to SPMS. And if we have a medication that induces a remission, we won't know if it is actually a cure until twenty years from now. Nothing in life is one hundred percent other than death. But if a medication can result in a durable remission and/or cure for about fifty or sixty percent of the patients that take it, isn't the chance of developing hyperthyroidism worth the benefit of a possible durable remission (or cure)?
Should we wait twenty years to find out? Just let everybody with RRMS slowly progress into SPMS so that the pharmaceutical companies can collect their billions of dollars from patients that are on some form of maintenance therapy? Or can we find some way to offer alemtuzumab to patients, while managing the risk of developing hyperthyroidism (30%) and ITP (1%)?
The thirty member countries that make up CHMP thought about this question and said, yes. We can manage the risk and we want to offer alemtuzumab to the patients in Europe rather than wait twenty years to find out whether or not it is a cure. Even if it only cures ten percent of the patients that take the drug, but results in a durable remission in the other sixty or seventy percent of patients, that benefit of slowing down this deadly, relentless disease is worth the risk of developing hyperthyroidism (which is curable).
While we wait for the advisory committee meeting, a question has been raised regarding the three year history of neurologic drug approvals and rejections (complete response letter). The worry is that there is an overall negative trend in the approval of neurologic medications. I am willing to address this theory but, felt compelled to spell out the question that will be addressed by the advisory committee, one that has already been addressed by 30 member countries in CHMP, using the same data that is now up for review in the FDA.
To be continued...
- Andrew Berens and Thomas Smith, Bloomberg Biotech Team
Although I call myself Biological, I am no biologist. I have had exposure to biotech, both via funds and individual companies, in the past. I see a very remote parallel between investors in GCVRZ and what was then CRA (Celera Genomics, the folks in Maryland who decoded the human genome). I made much money on CRA only to lose it all back...I hung on to it out of emotion like, I think, people are hanging on to TSLA today, perhaps. At the time, CRA made a good scientific case for infinite returns.
GCVRZ is clearly different but I tell story just to highlight what emotions did to me, back then. Investing requires serious fortitude and clarity. I lacked it then but I believe I have learned.
I added to GCVRZ yesterday because the analysis and commentary to date seems to indicate a better proposition than initially highlighted by Chris. Way better and, in my case, at a better price. At that time, we were looking at a potential binary situation...yeah or nay. Fine, kind of unusual payout situation but - well - better understood than, say, I can understand longs in Z or TSLA. Today, we have approval in Europe to fall back on, do we not? We have greater knowledge, Europe approval and a fixed date for FDA review.
Now, I recognize that Lemtrada could be transformative but this is where emotions can run wilder than logic. I wish it be so transformative, surely, for those who suffer and for my own profit, but no one will really know what the future will hold. Don't let that drive your investment - you do not need to. I still think Chris' original proposition is the best guide. At that time, the security seemed undervalued in light of greater uncertainty and without the benefit of so much information (which now points to transformative type of upside). That original proposition, I think, is still indicating a 50%+ bargain (with all the caveats) regardless of the revenues that GCVRZ may yet produce.
- 5/22/2013: Suvorexant, complete response letter
Comment: people are not dying from insomnia. FDA, therefore, places higher emphasis on safety.
- 5/24/2012: Vyndaqel, complete response letter
Comment: for a trial endpoint (trial result) to be deemed clinically significant, it must have a P value < 0.05 or less than 5% probability that the results achieved, were simply due to chance. Drug was rejected due to lack of proven efficacy. I guess that Pfizer spent a ton of money on developing this drug and had nothing to lose by submitting it for approval. This was like trying to throw a ninety five yard touchdown pass from your own 5 yard line with 5 seconds remaining in the game.
- 10/17/2011: Azilect, complete response letter
Comment: TEVA markets Copaxone which has been responsible for about 50% of the company's profits. This drug comes off patent in 2014 and TEVA is apparently not averse to begging the FDA for label expansion of already approved drugs in order to maintain revenue.
- 3/10/2011: Lamicital XR (new indication), approved
- 1/21/2011: Gadobutrol, approved
- 1/20/2011: Florbetapir, complete response letter
Comment: A negative Amyvid scan is helpful in ruling out Alzheimer's Disease. A positive scan has overlap in patients with other dementias.
- 8/11/2010: Potiga, complete response letter
Comment: the recurring theme in the FDA is one of emphasizing safety when there are other alternative therapeutic options in non lethal diseases. Strict adherence to safety concerns resulted in a delay of approval but, not a rejection.
- 6/10/2010: Gilenia (Gilenya), approved
- 5/6/2010: Acthar, approved
I think that it is more instructive to look at the record of approvals and rejections for drugs used in RRMS. No proposed drug for RRMS has ever been rejected by the FDA in the last 10 years (that I am aware of).
Cladribine, a drug approved for use in Leukemia, owned by Merck, and tested in a phase III trial for RRMS, was withdrawn from consideration after feedback from the FDA. The FDA did not dispute efficacy. The FDA was concerned with the known toxic side effects (resulting in death) and wanted another phase III trial. The patent expiration would not have allowed Merck to recover the development costs and the drug was withdrawn from all marketing applications.
There is an unmet need as I have explained in prior posts. People are slowly succumbing to the disease even while on a disease modifying therapy such as the injectables, Tysabri, and the newer oral medications. In this situation, the safety concerns have to be muted in an attempt to offer patients some chance of slowing disease progression.
Regarding safety of Alemtuzumab, risk mitigating strategies have already been included in the NDA.
The FDA had previously approved alemtuzumab when it was marketed as Campath and used in CLL. Alemtuzumab resulted in one death due to brain hemorrhage due to development of ITP during the trials for MS. The risk mitigation strategy is to monitor the platelet count and initiate therapy for ITP if it develops. (The risk is only 1%.)
The reader is encouraged to search my prior posts regarding the risks of PML while on Tysabri for some perspective on how much latitude the FDA is willing to grant the pharmaceutical companies in approving drugs for RRMS.
3) Product Sales Milestone #2: CVR holders are entitled to receive $3 per CVR in the
It is also a mistake to think that the FDA will reject the medication based on efficacy and demand a new trial. Perhaps the discussion results in a request to change the label language, resulting in a delay but, the CHMP did not request this. To postulate that SNY receives a CRL, withdraws the request for marketing approval, and markets alemtuzumab in the rest of the world, holds no merit. This leaves US MS patients with no option, other than to travel to Europe if they want a chance at durable remission. And where does this situation leave patients with CLL? They no longer have access to a medication that is given in a dose up to 90 mg per week for approximately 12 consecutive weeks. SNY agreed to make the medication available for free to the European patients with CLL in exchange for the right to market the medication as Lemtrada, rather than Campath. I presume the same for the US. Outright rejection of the medication is a rejection for the MS patients and the patients with CLL since the medication has been withdrawn from the market. Not a tenable thesis and 3/31/14 has no real bearing on the CVR payments.
So rejection is still the main binary outcome to be concerned about at this stage, but delay isn't necessarily that bad.
@rootbeer, Be careful when judging odds as 100% in investment. Those are bet your life sort of odds. Always having some doubt prevents over-aggressive sizing mistakes.
These are the reason that I own the CVR.
4 people died in the Cladribine study so that is not so different in numbers than the people who died in Alemtuzumab phase 2 and 3 studies. If the FDA requires an additional Phase 3 trial, well, the last one took 2 years, so it might be January 2016 before that is complete. But the U.S. patents expire in September 2017. So it seems possible Sanofi might not want to pay for an additional Phase 3 trial (under that scenario). Then there might just be the E.U. sales until 2014 when the E.U. patents expire (I was not able to find when in 2014 they expire -- does anyone know?). With a pessimistic 60-70% chance of hitting that milestone the value would be $1.2-1.4.
But I have no particularly good insight in that scenario. In the event of delay what do you think is the most likely outcome?
Two doses of cladribine were compared against placebo. There were a total of four deaths in the two cladribine arms and two deaths in the placebo arm. The cladribine arms had a heart attack, cardiac arrest related to tuberculosis, a drowning, and death due to metastatic pancreatic carcinoma. The two deaths in the placebo arm were a suicide and a stroke.
Cladribine is an antineoplastic approved for use in Hairy Cell Leukemia. But in the MS population, it causes fairly frequent severe infections and had caused multiple neoplasms that were both benign and malignant. It did receive a complete response letter from the FDA in March of 2011, citing safety concerns. (Please accept my apology for a post made in the past in which I said that I was not aware of any FDA rejection of a MS medication in the past ten years.). This would have been an oral induction therapy if it had been approved. Merck could have done another trial at the lower dose. With the proper patient selection, and utilizing risk management strategies, this could have been a useful medication. Patent considerations apparently kept Merck from pursuing an additional phase III trial.
Phase II trial of alemtuzumab in comparison to Rebif:
This study compared two different doses of alemtuzumab to Rebif, was begun in 2002, and was suspended in 2005 after three cases of ITP were reported. Idiopathic thrombocytopenic purpura is a disease in which there is a severe deficiency of platelets. Platelets are necessary for clot formation. These patients are prone to severe bleeding anywhere in the body. One patient died after developing a hemorrhagic stroke. (He bled into the brain.) A risk management strategy consisting of monthly blood counts was implemented. The trial resumed and ultimately, there were a total of two deaths, one from pre existing cardiovascular disease and one from the stroke due to ITP in patients who were on alemtuzumab. No death from ITP occurred after implementation of the monthly blood count. (ITP is treatable. Platelets are administered along with IV steroids and gamma globulin.)
In this phase III trial, alemtuzumab was compared to Rebif. As a result of the phase II trial, Risk mitigation strategies were implememted for the phase III trial. Patients received acyclovir as prophylaxis for herpes skin infections. The risk of ITP was previously defined as 1%. Monthly blood counts were performed to detect developing ITP, and if detected, conventional therapy was instituted. The risk of hyperthyroidism was previously defined at about 15-20%. Blood samples were taken every three months to screen for developing hyperthyroidism and if detected, conventional therapy was instituted.
One patient died in the alemtuzumab group due to an automobile accident during the study. One additional alemtuzumab patient died after the study due to sepsis.
After 22 months, three patients developed ITP and all were successfully treated with conventional therapy.
Infections occurred in 45% of the Rebif patients and in 67% of the alemtuzumab patients. No infection led to discontinuation of treatment during the study and no infection was life threatening.
Regarding thyroid disorders, 6% of patients on Rebif developed a thyroid disorder and 18% of patients on alemtuzumab developed a thyroid disorder.
Regarding cancer, 2 out of 376 alemtuzumab patients developed thyroid cancer. None of the 187 Rebif patients developed cancer. (The vast majority of thyroid cancers can be treated with excellent long term results.)
Overall, and most importantly, adverse events (including relapse of disease) led to a discontinuation of therapy in 12 % of the Rebif patients and in 3.7% of the alemtuzumab patients.
Alemtuzumab is entitled to 12 years of data exclusivity from the date of FDA approval (similar in Europe). If FDA rejects alemtuzumab and requests a third phase III study, Sanofi could theoretically complete this and still have effective exclusive rights. I view this as extremely unlikely. FDA has already approved Tysabri knowing that it could cause a serious rare complication called PML. There are now 400 reported cases due to Tysabri. PML carries a mortality rate of 25% in the MS population. Please see my prior posts on Tysabri and PML for more detail.
There have been no lethal complications reported with alemtuzumab following adoption of the risk management strategies discussed above. Although any immunosupressive agent can theoretically induce PML, it has never been reported with alemtuzumab in the MS population.
Here is a link that discusses the ramifications of data exclusivity:
"I have about 20% of my (small) portfolio in GCVRZ rights. I'm quite comfortable with that... it amounts to half of the profits from a recent windfall from buying puts on LRN a few weeks before it plummeted by 36%, so if I suffer a loss I'm still way up for the year.
Since the LRN win I have kicked myself a few times for not putting more money on the table. It was almost certain they would miss earnings in October, and if I'd bought 10X more puts I still could have sold them the day after earnings if there had been no surprise.
I'm looking at GVCRZ as a similar situation: a near-certain win. The risk is higher in that if there is a delay past March, the rights will immediately decline by probably 50% or (much) more and will not recover for a couple of years at best, whereas LRN puts would have declined by only 20% (the bid-ask spread). If Lemtrada is approved by March, however, the combined market value of the rights and the reward payout immediately increase from my cost of $1.95 to about $5-6 for a 3X return.
The question is whether and to what degree we can expect a March approval? Dr. Robbins (rootbeer) is certain Lemtrada will be approved, and perhaps for that reason we can be equally confident that eventually at least a couple of the milestones will be reached and the $1 'approval reward' paid out eventually. If it is not approved by March, of course, it will take years and not months to see a profit on the investment... years during which I could take advantage of many other arb/special situations.
Needless to say, I'm not asking you what to do. I am trying to put a number on the probability of a March approval, however. I also want to discern what the likely downside would be in the case of a delay. Is this something you'd like to look into with me?
I'm sending this to you privately because my appetite for risk is quite high and I wouldn't suggest that anyone else contemplate some of the asymmetrical bets I make."
Chris's response, which I tend to agree with, is that there is a 90% probability of approval by March 31. Chris considers the rights to be worth zero in the case of a delay (for sizing purposes, not as a prediction); I assume they will drop to .25 or .50 at best and languish until sales show definite promise.
I'm very interested in others' perspectives on the probability of a delay.
Whenever I miss out on a good trade by selling too early or having too small a position, I am quick to remind myself of how greed can easily destroy my account. While I could quickly rattle off 10-15 names ($FB for instance) in which I would be MUCH farther ahead if I had held on.. I can also think of a handful of names that went bust and would have taken me down with them if I hadn't taken profits/cut losses ($PMI is one of my worst). Remember, at the end of the day, you need cash to play this game, which is why capital preservation is equally as important as capital appreciation.
My .02 on delay is that it seems unlikely. Rootbeer seemed to nail it on the head when he said that delay would only come from issues about safety. But, even that seems unlikely, as the safety concerns are well-known and don't seem to have changed through the trials. I suspect the Advisory Panel will want to hear about patient monitoring programs and will base its decision on their opinion of the effectiveness of this monitoring.
I try to remind myself that, in considering any drug for approval, the FDA is performing a risk-benefit test. Even a drug with significant risks (like Lemtrada) can be approved if it offers enough benefits to outweigh those risks. I think these benefits have been demonstrated in the various trials, and also with the CHMP recommendation:
"The CHMP, on the basis of quality, safety and efficacy data submitted, considers there to be a favourable benefit-to-risk balance for Lemtrada and therefore recommends the granting of the marketing authorisation."
If the first milestone is not met then there will be an opportunity. Then the market might price the CVR at 0.5 or so, but that's below the real value. As Rootbeer pointed out the value will then be at least the discount of 2, let's say 1.8 since the second milestone will still be met.
If the FDA rejects the drug completely then that's all, the other milestones won't be met. Extremely unlikely though.
If the approval is just delayed, let's say by 3 months, then the second sales milestone will still be met paying an extra dollar for the late approval, and the value will be around $5, at least.
Make sense?
I noted that the record was just posted on October 17th.
I discovered that Dr. Omar Kahn, the neurologist who performed the previously linked to survey, is the principal investigator for the Peripheral and Central Nervous System Drugs Advisory Committee (as of 2011, cannot confirm presently). There are several articles readily available on Google showing Dr. Kahn's praise for the drug.
http://bit.ly/1akjmqR - "Alemtuzumab could be the first definitive treatment that may eliminate active disease in MS patients, meaning no further relapses, no disease progression and no new lesions in the brain," he said. "While it may not cure the disease, it may give hope to millions of patients that early intervention with Alemtuzumab may prevent the fear and stigma of the disease in the form of crippling disability and being in a wheelchair. It has been a very rewarding 10-year effort to see this happen with WSU's participation and leadership."
http://bit.ly/1akjo26 - "The data from this second of two such studies, Dr. Khan said, are the "best ever efficacy data in any MS trial in the last 20 years." Alemtuzumab, he said, significantly reduced the rate of sustained accumulation of disability compared to treatment with interferon beta-1a. "With the completion of this study, we are now looking at FDA registration and approval in 2012," said Dr. Khan. "As we speculated, which is now substantiated by this study, Alemtuzumab presents with the best data and sets a new benchmark of efficacy. This is clearly a major breakthrough in the treatment of MS."
Obviously, here we are in late 2013 and the drug is still not approved, so maybe Kahn is a bit optimistic. I was able to find this article - http://bit.ly/1akjo28 - which is a bit more recent and talks about concerns regarding thyroid side effects (which has been discussed at length in this forum and Chris' original post). Here's the relevant quotes that from article:
"In an interview, Robert Lisak, MD, professor of neurology, Wayne State University School of Medicine, Detroit, Michigan, pointed out that side effects of the drug have encompassed potentially serious autoimmune diseases, including thyroid disorders and immune thrombocytopenia, both of which require careful monitoring and management...This drug, in phase 2 trials especially, and to some degree in phase 3, did look like a bit of a game changer," said Dr. Lisak. "But it doesn't look like it's that way for every patient anymore."
Hope that this is helpful.
1. The panel results/outcome will NOT be an official approval or rejection of Lemtrada, nor will any official date be announced for approval if sentiments at the meeting are positive. However we will have a high level of confidence aftewards as to whether it will be approved or not before the milestone date.
2. For brand new drugs, advisory panel recommendations for approval typically take about 2-3 months before the actual PDUFA date. However since Lemtrada is/was already on the market as Campath, this lag period will likely not be as log. Hence that is why numerous links point to the PDUFA date occurring before year-end.
3. Upon announcement of the advisory panel review last week, the 10% drop in GCVRZ price was likely attributed to an increased probability in the drug receiving a negative recommendation for no other reason besides the fact that a panel was convening, an not due to any recent negative press regarding the drug
My question is, do all drugs typically have advisory panels like this one between Phase III and FDA approval? Or is this a special situation for drugs that are 50:50?
Appreciate if anyone can confirm or clarify these thoughts and answer my questions at the end, thanks
Are you familiar with the way Tysabri is prescribed? Apparently it is administered only through the TOUCH program which allows FDA to monitor patients and outcomes. Only authorized prescribers/infusion centers and registered patients have access to Tysabri.
I am thinking perhaps FDA called the advisory committee seeking guidance re the potential need for a robust monitoring program similar to TOUCH.
One could argue that Alemtuzumab is not as dangerous as Tysabri, but it does have numerous side effects that need to be monitored.
I don't see how FDA could have significant questions re efficacy or safety.
"Some drugs would not be able to be approved, or be able to stay on the market, unless a REMS with ETASU was required to ensure that their benefits outweigh their risks."
ETASU - Elements To Assure Safe Use
At the end of the day, hyperthyroidism is just not a big deal. I have personally treated many patients with hyperthyroidism. You take a radioactive iodine pill with a glass of water and go on with your life like nothing ever really happened.
Lemtrada/hyperthyroidism vs Tysabri/PML :
Biogen Idec Total Revenues Increased 32% to $1.8 Billion in Third Quarter;
Biogen's new MS drug tops expectations; ups 2013 forecast
Sustained progression on the expanded disability status scale (EDSS) is a common outcome measure of disease progression in clinical studies of MS. It is a generally held belief that relapses result in sustained worsening of disability over time.
The majority of MS patients (80–90%) initially experience a relapsing−remitting disease course (RRMS), with alternating phases of clinical worsening, remission and stability. Over time, approximately half of MS patients convert from a relapsing−remitting to a secondary progressive disease course (SPMS), with continuous clinical worsening independent from relapses. In 10–20% of patients, the disorder presents with a primary progressive course (PPMS) with continuous clinical worsening, with and without additional relapses from the disease onset.
The overall rate of age related brain atrophy in normal adults is approximately 0.3% per year. In MS patients, the rate is 0.6% per year. So time is brain and the more time spent on a less efficacious drug, the higher the rate of relapses, and the higher the rate of acquiring sustained disability.
The benefit of long-term treatment with interferon beta (IFNB) preparations for RRMS remains unproven. Randomized controlled trials of these agents provide evidence of benefit only for the relatively short duration (generally two years) of the trials.
Copaxone (daily 20mg sc) the cumulative probability of disease progression was 22% and 40% for placebo at 35 months (1)
Avonex (30mg, injection) the cumulative probability of disease progression was 22% and 35% for placebo at 24 months (2)
Betaseron (250mcg, injection) the cumulative probability of disease progression was 35% and 46% for placebo in the 60 month follow up study (3)
Rebif (injection) cumulative probability of disease progression is not available due to the fact that the randomized clinical trials did not use sustained accumulation of disability as an endpoint.
Peginterferon (injection) cumulative probability of disease progression is not available
Gilenya (0.5mg oral) The cumulative probability of disease progression was 12.5% and 19.0% for placebo during the 24 month study. FREEDOMS Trial (4)
Tysabri (300mg IV) The cumulative probability of disease progression was 17% vs 29% in the placebo group after 24 months. (5)
Tecfidera (240 mg, oral, twice per day) CONFIRM (6) trial showed no significant difference in the probability of disease progression when compared to placebo. DEFINE (7) trial showed that after 24 months 16% of patients showed progression of disability compared to 27% for placebo.
From NEJM editorial after publishing CONFIRM and DEFINE trials:
Aubagio (7 mg, oral once per day) The cumulative probability of disease progression after two years was 21.7% for Aubagio and 27.3% for placebo. TEMSO trial (9).
Lemtrada (12 mg, IV, induction therapy given as 5 daily infusions in month one and 3 daily infusions in month twelve.) CARE MS II, a phase 3 trial, compared Lemtrada to Rebif. The cumulative probability of sustained disability was 13% for Lemtrada and 20% for Rebif. This was a risk reduction of 42% with a P value of .0084.
2. http://1.usa.gov/1cq0okq
3. http://1.usa.gov/1cq0oks
4. http://bit.ly/1cq0oku
5. http://bit.ly/1cq0oAI
6. http://bit.ly/1cq0nNe
7. http://bit.ly/1cq0oAK
8. http://bit.ly/1cq0nNf
9. http://bit.ly/1cq0oAM
10. http://bit.ly/1cq0nNg
It is relatively easy for a drug to look good when it is compared against...nothing.
But, for the sake of argument let us say that they ask for more data on safety. They want four years of follow up on the phase 3 patients to see if there is any further cases of hyperthyroidism, a treatable disease.
Is it really all or none in this investment? It is none if SNY decides to walk away from the US market. But not likely, since SNY needs this medication to help reinvigorate growth of revenue.
So, the downside is not zero. But, there would clearly have to be a reassessment of the value of the CVR. The value depends on the likelihood of reaching all the milestones. The delay would result in a possible competitive therapy appearing on the market just as sales are beginning to ramp up in 2017-2018. The drug is called ocrelizumab and is owned by Roche.
I think that there would be an eventual payout of $4 on reaching 1.8 billion in sales. It would probably not reach the other milestones of 2.3 billion and 2.8 billion in sales unless there is a breakthrough in predicting who will develop autoimmune thyroid disease.
Has any phase 3 trial started for ocrelizumab on MS patients? And how long would such a trial take? I think at least 2 years. If this trial starts next year and it takes a year to approve it then ocrelizumab could be on the market in 2017.
Note that ocrelizumab requires an injection twice a year, so more often than Lemtrada.
I was, more or less, asked to come up with a worst case scenario. And I pointed out that the worst case scenario is not all or nothing. It is all or something. Alemtuzumab has already been approved in Europe and will be approved very shortly in the US because it is a step change. It is a step change because it is an induction therapy that induces a durable response and possibly, a cure in some people.
Regarding monoclonal antibodies, I expect that Tysabri will fall hard due to the risk of PML. Alemtuzumab will compete with Ocrelizumab if the latter makes it through the phase 3 trials.
For now, I am confident that the $2 that I invested will be returned to me.
I think this is highly unlikely.
1. GVCRZ rights were issued to Genzyme shareholders upon the merger with SNY.
2. Genzyme is running the Lemtrada show, so incentive lies with the major actors (Genzyme employees=GVCRZ shareholders) to get the approval in time.
3. Any attempt by Sanofi to delay approval would cause severe discontent within the organization.
4. Sanofi up this point gets Lemtrada for free, don't they? Broadly speaking that is. Making the payouts is just a way of compensating Genzyme for R&D. It shouldn't be met by any resistance by Sanofi since it represents a normal cost of doing business.
One reason that the treating-to-target or "zero tolerance" approach to MS disease activity is gaining acceptance is that "we're realizing that almost any ongoing disease activity has some potential ramifications, in terms of causing additional tissue damage," said Dr. Cohen. The emergence of an increasing number of new and more effective disease-modifying therapies also has decreased tolerance for disease activity.
"Increasingly, we strive for a completely stable disease if we can attain it with reasonable safety and tolerability," said Dr. Cohen. "Because none of our assessment tools is 100% sensitive, repeated re-evaluation of individual patients over time is needed. In addition, no particular treatment is going to work for all patients."
Full disease remission is not possible in patients with high levels of disability, but it may be possible in patients with early-onset MS. A disease activity–free state appears to be achievable in at least some patients who are JCV antibody negative (ie, approximately 45% of the overall patient population) and are in the earlier relapsing-remitting phase of the disease, said Dr. Vollmer.
"On natalizumab and, we think, also on rituxumab, and probably on alemtuzumab, … in that patient population, a majority of patients … will not only have cessation of disease activity, they'll actually get better over time," he added. "About 30% continue to have relapses and will continue to develop ongoing disability." Symptom stability or improvement may also be achievable in some patients with newer drugs such as fingolimod and dimethyl fumarate, "but we just haven't treated enough patients and haven't had them out long enough to be sure yet," said Dr. Vollmer.
"In our clinic, we're now trying to actually improve patient function over time," noted Dr. Vollmer. "We expect them to get better, particularly if they exercise and take some of the more highly effective therapies. Particularly for patients with the earlier phase disease, we're looking for full disease remission, including remission of fatigue and depression symptoms." (1)
1. 2013;21(2):9 Neurology Reviews
The aim of this study was to examine treatment decisions regarding whether or not patients were willing to stay on Tysabri and whether or not the patients were willing to use levels of antibody titers to guide this decision. If your level of antibody titers to the JC virus (JCV) is low, you presumably have a relatively low risk of developing PML which is about 1 in 1000. But there is no real legitimate way to detect the development of PML until it is in full swing, wreaking havoc on the brain.
RESULTS:JCv antibody status was available in 112 Tysabri patients. Mean Tysabri duration was 27.4 months (2-72). Antibodies were detected in 55 patients (49.1%): 2 (3.6%) stopped due to JCv+ alone, 14 (25.5%) due to prolonged therapy (>2years), 1 (1.8%) due to prolonged therapy and past immuosuppression, 3 (5.5%) disability progression, 1 (1.8%) to conceive. (12.3% of JCv negative patients stopped due to prolonged therapy). No significant difference in mean Tysabri duration or disease-modifying therapy history between JCv Ab+ and Ab- groups (p>0.05). Other PML risks (>2 years, past immunosuppression) did not differ significantly between JCv+ patients who opted to continue compared to those choosing to stop (p>0.05).
COMMENT: Most JCV positive patients want to get off of this drug after two years and 12.3% of JCV negative patients stopped after two years. This study confirms what I have said about Tysabri in prior posts.
Biogen Idec Inc (BIIB) Management Discusses Q2 2013 Results - Earnings Call Transcript:
Moving to TYSABRI. Second quarter global in-market sales decreased by 2% versus the prior year. As I mentioned, in the U.S., a significant number of higher-risk TYSABRI patients transitioned to TECFIDERA, which slowed TYSABRI growth despite the fact that we believe we are continuing to generate solid demand.
During the quarter, approximately 2/3 of the patients who discontinued TYSABRI stayed within our franchise and started TECFIDERA. This creates another issue that we are well aware of and prepared for. Given that well over 1,000 higher-risk patients have transitioned from TYSABRI to TECFIDERA, we expect to see a number of cases of PML in these patients, just as has been observed in TYSABRI patients who have switched to other therapies. We believe that our competition will try to make an issue out of this, but we believe the physician community expects it. Our Medical Affairs team is having discussions with physicians, and we believe we are ready.
COMMENT: The reader should understand from prior posts that there is a low but, significant risk of developing PML, the longer a patient stays on therapy. Many patients elect to come off Tysabri after two years of therapy. Not only is a patient exposed to the risk of developing PML while on Tysabri but, the patient is also exposed to developing PML when withdrawing from therapy. ( Here in the US, we say, "Damned if you do and damned if you don't!") Withdrawal can lead to a rebound reactivation of disease within three to six months after stopping Tysabri. This rebound reactivation of disease can trigger PML in patients who have tested positive to JCV.
As I have said previously, if there is an alternative powerful therapy such as alemtuzumab, why would any neurologist recommend Tysabri to a patient? In this new era of oral therapies and alemtuzumab, the neurologist will probably reserve Tysabri for JCV negative patients or JCV positive patients who have failed just about everything else.
CONCLUSION: The study discussed above confirms that patients do not want to stay on Tysabri unless they have to. Biogen management is aware of the problem and wants to "help" patients stay on the medication by offering titers. Most patients understandably, are not listening to the Biogen management team.
(1) Tecfidera shows good efficacy and safety, and is doing very well in sales. Do you have any comments about Tecfidera as a competitor?
(2) In the event of FDA totally rejecting the drug, even though that is very remote, couldn't European sales count towards the first sales milestone? Others seem to have interpreted the value of the CVR as $0 in this case, but my interpretation would not find this to be $0. Who's right?
1. Tecfidera is a competitor. But in the future people will have to decide whether they want to be on an induction therapy such as alemtuzumab or on an oral maintenance therapy such as tecfidera. Alemtuzumab will start out as second line therapy, reserved for people who fail on the orals and injectables. Phase 3 studies show that one out of 6 people suffer a relapse per year while on tecfidera and more so, on injectables. In the era of zero tolerance, that is enough patients to meet at least the milestone of 1.8 billuion in sales. Eventually, it will be used as first line. But ocrelizumab will be coming up and this is the drug which will compete with alemtuzumab for induction therapy. That is why I cannot really predict what will happen beyond 2017-2018.
2. Milestones stipulate worldwide sales. Failuire to gain FDA approval causes a loss of $1in milestone payments. If you believe that SNY will not agressively seek FDA approval up through 2020, then you also probably believed that there was a real chance that the US government would have defaulted on the US debt.
Multiple sclerosis is a cruel disease. It strikes young adults, runs a chronic, unpredictable course, and is eventually disabling for many patients.
Multiple sclerosis is one of the great unsolved mysteries in modern medicine, with a number of striking epidemiologic features, including an increasing global frequency, an inverse relationship between serum 25-hydroxyvitamin D levels and disease risk, and a tantalizing association with Epstein–Barr virus infection.
Multiple sclerosis usually begins as a relapsing–remitting disease, but in most patients a steadily progressive neurologic disorder ultimately ensues. As a general rule, the relapsing phase of the disease is mediated by focal bursts of inflammation in white matter in the brain and spinal cord, whereas axonal and neuronal loss predominates during the progressive phase. (In other words, it destroys your gray matter which explains the ongoing, accelerated brain atrophy that occurs in MS patients despite being on a disease modifying therapy.)
For any given patient with relapsing–remitting multiple sclerosis, there is an annual risk of 2 to 3% for transition to the chronic, progressive form..
The consequences of inflammation in multiple sclerosis — demyelination, incomplete remyelination, and gliosis (scarring) — appear to sensitize surviving axons to additional insults, which in effect shortens their life span. Stated another way, a disease flare in 2008 may increase the risk of progressive multiple sclerosis many years later.
Although some permanent disability occurs as a consequence of relapses, chronic and progressive disease is the overwhelming cause of loss of ambulation. The prevention of inflammation during the relapsing–remitting phase appears to delay, or perhaps even prevent, the later development of secondary progression. Unfortunately, currently available first-line agents (including the beta interferons and glatiramer acetate), although effective in some patients, reduce the clinical relapse rate by only one third. The relatively modest clinical benefits of these drugs highlight the need for more effective therapies against the early inflammatory phase of the disease.
In this issue of the Journal, Coles et al. report on the remarkable outcomes of a clinical trial of alemtuzumab, a monoclonal antibody that produces sustained depletion (lasting many months to a year or longer) of CD52-expressing cells, including CD4 and CD8 T cells, natural killer cells, and monocytes. Circulating B cells are only transiently depleted and may increase from baseline levels within a few months after treatment, perhaps contributing to autoimmune complications. Dramatic reductions in clinical relapses, the development of new disability, and the lessening of focal inflammatory activity were observed in patients who were treated with once-yearly administration of alemtuzumab...
It is evident that protection by alemtuzumab against relapse comes at a substantial price. Thyroid autoimmunity was one expected complication, since it had been reported in earlier preliminary studies of anti-CD52 therapy. In the current study by Coles et al., thyroid autoimmunity occurred in nearly one quarter of treated patients. Although Graves' disease is well described as a complication of alemtuzumab treatment for other underlying diseases and is possibly attributable to an immune reconstitution syndrome, the very high prevalence of this complication in patients with multiple sclerosis suggests a special, unique predisposition in this population...
Another open question relates to the significance of the improvement in the progression of sustained disability associated with alemtuzumab, as compared with interferon beta-1a, in this trial. Such improvement was almost certainly due to a reduction in disability resulting from relapses and not from any effect on secondary progression. However, given the magnitude of the effects observed in relapsing–remitting disease, one would be optimistic that with longer durations of therapy, an effect on the risk of chronic, progressive multiple sclerosis might also be found.
For many years, therapy to prevent progressive disease has been the holy grail of research in multiple sclerosis. Alemtuzumab may in fact have this characteristic; however, if long-term therapy is required to sustain the clinical benefit, would the risk of toxicity then outweigh the benefit? A more hopeful scenario might presume that a relatively short course of alemtuzumab can restore immune homeostasis, which would eliminate the need for retreatment for many years. Indeed, there is suggestive evidence that an increase in the number of regulatory T cells, which are deficient in active multiple sclerosis, may occur during the early recovery period after therapy with alemtuzumab.
COMMENT: This editorial gives one the proper perspective on MS and current disease modifying therapies. Current DMT's have variable beneficial, effects on relapse rates but they don't have much effect on altering the course into the chronic progressive phase. If an induction therapy can induce a durable remission, will it be able to delay the eventual development of the chronic progressive phase of the disease? Do we have to wait another twenty years to find out? Or can the FDA release this medication to the MS population, manage the risks, and give them a chance? That is the question.
We have multiple maintenance therapies. Do we have a relatively safe induction therapy? We do in Europe.
Please note that there will be a hiatus in entering any further posts.
To be continued in 2-3 weeks.
This dialogue speaks to the revolution that is going on. To stay invested in GCVRZ, you need the confidence and knowledge that this medication is truly transformational. It is an induction therapy and the only one in existence, at least in Europe.
Sanofi's Lemtrada Drug May Be Too Risky, FDA Staff Says
Multiple serious and potentially fatal safety issues have been reported in patients treated with
In emailed statement, Sanofi says Lemtrada follow-up data consistent with trials:
* Sanofi says double-blind trial not possible b/c of drug differences
"However, because of the serious and potentially fatal safety issues, unless
certainly sounds like the staff member hasn't even reviewed it completely. And it's just one guy, all is not lost.... I'm probably buying more.
This looks complicated.
Here's a good article on what the review process means. Usually it means that there is greater than 50% chance of approval for drugs. http://bit.ly/1auvDmF
Chris has posted dozens of ideas and most will take time to mature and prosper. I think this one is indeed a winner despite yesterdays actions (as most of his ideas are in the long run).
However investing is not a game for the impatient. Yet if you do some DD on this name you may decide this is a buying opportunity. Good luck no matter how you play this going forward.
If this is a coin flip(and I dont have the experience to say it is), these represent a great risk reward. Sorry to the longs stuck into this gap, I hope it ends up working out for you.
(1) Chances of FDA Approval are not zero. They may be pretty close, but they aren't zero. Unfortunately, I don't have enough experience to put a % on approval after the FDA letter. Hopefully others will provide color on this.
(2) Remember the $2 payout for $400M in global sales. Here's the exact language:
"Product Sales Milestone #1: CVR holders are entitled to receive $2 per CVR in the event net sales for Lemtrada total $400 million or more on a global basis during specified periods following product launch."
"For the United States of America, the United Kingdom, Germany, France, Italy and Spain, sales achieved in the 4 calendar quarters immediately following the quarter in which Lemtrada is first sold in that country (after receipt of marketing approval in that country, including pricing and reimbursement approval, if necessary) are counted toward the $400 million sales milestone."
So, even without FDA approval, I think this is the best chance to recoup your capital. I also couldn't give you a probability of this being reached without being completely disingenuous, but I do think that it's high enough that it's worthwhile to hold on.
GL all
"Our company is confident that Lemtrada offers an important step forward in the way physicians and patients will think about treating multiple sclerosis. Given the importance of addressing unmet medical need, Genzyme decided to introduce a high bar to the demonstration of efficacy by comparing Lemtrada to the standard
These are, of course, issues that will be considered by the Advisory Committee and we look forward to our discussion with them."
I took a deep breath and added a bit. My gut is still for approval especially as it's a second-line therapy. But still reviewing...
People should be grateful that Chris has shared his views and provided this forum, in my opinion.
I think this is important. The outcomes assessor was blind.
And the patients in this trial had severe MS that had not responded well to treatment. Would it be ethical to give these folks a placebo?
Sanofi's presentation will need to address these concerns.
"Some patients who received the drug in the earlier phase 2 trial in 2004 and 2005 have not needed further treatment of any kind since,"
Suppose I hire a lawyer to review a contract. If the lawyer comes back and says, 'it's great, sign it,' how do I know the lawyer even looked at it? So the lawyer will say something such as, clause 3 in paragraph 5 needs to change. The provision in subparagraph i is untenable, etc.
If I hire a statistician, MD, etc to review a drug app, I don't want them to come back and say that there are no issue with the new drug app; I want them to do their best to tear it apart. That way, I know we are 'stress testing' the app and will do our best job in determining whether to approve.
A careful examination of the document would lead one to conclude that the FDA would like an in depth dialogue and guidance regarding the REMS, submitted by Genzyme. The Tysabri REMS is specifically referenced and the onus is on this advisory committee to ensure that all aspects of the proposed REMS for Lemtrada is not only water tight, but, air tight. This is being done to help ensure that Lemtrada is not pulled from the market at a later date, as happened to Tysabri.
Regulators are concerned with what could happen to a patient who is induced and then drops out. Are there mechanisms in place to ensure that this patient is tracked for the next five years? It is known from the trials that autoimmune thyroid disease can develop at some point, out to four years following induction.
The reaction in the market is overdone to an extreme. If you were successfully stopped out at a higher level or you have additional capital to deploy, this is an opportunity for you.
My opinion on the probability of approval has not changed and I am long GCVRZ,
In the future I probably won't do such exciting investing -- it's kind of distracting, not to mention difficult! I prefer watching grass grow.
They didn't get these concerns about the placebo effect from the FDA. That design may have been a better choice for the study. At the least I should have noticed this downside risk before it became "significant news" and the market sold off.
I do not have the background to estimate the magnitude of the placebo effect in this situation.
So the guy two below doubled his position? Is it ethical to champion that. Anyone adding now has to be aware the chances of approval have gone from a near certainty to < 20% once those briefing docs were released. I think an argument could be made that the cvr is actually overpriced.
I am not an expert but based on my reading and talking to people I *think* there was no possibility of a double-blind study unless a placebo was used (due to the huge differences in how and whn Rebif and Lemtrada are administered). So while double-blind is the gold standard, counterbalancing this is that rather than the baseline being no treatment at all (a placebo), the comparison is a very-well studied and effective treatment (Rebif/interferon) - so it is powerful to show that if you are significantly better than Rebif, and Rebif is significantly better than nothing/placebo, then it is a good thing.
I also put a fair amount of weight on the EU approval - different experts and different eyes but presumably the same issues were raised.
Finally the fact that it was on the market as Campath for a long period gives a lot of understanding about safety, side effects, etc.
Having said that all bets are off when dealing with bureaucracy.
Reading through the FDA paper as well as Sanofi's submission yesterday I feel like there is at least a 50/50 shot here.
If approved I think $3 of payouts are pretty achievable (perhaps more but I have always assumed $3). So at 75 cents you have 75 cents of downside and $2.25 of upside. Ignoring time value of money (we are in a ZIRP world after all...) the market is kind of saying there is a 25% chance this thing gets approved. I don't mind those odds given my feeling is more like 50/50. But of course I am a bagholder now so probably can't think straight, so haircut what I think by 50% and it's priced about right!
Have I captured the essence of it?
Reference your question, the reviewers are clearly hung up on the fact that Genzyme did not conduct a double blind study. This view taints the rest of their opinions. Perhaps the actual panel will be more forgiving or Sanofi/Genzyme will present a great rebuttal. I will count on neither.
I hope someone like Rootbeer will comment on the section discussing the statistical results at the end of the FDA document.
Lemtrada is twice as good as what most people take today. There are real risks. Safety issues need to be discussed, but also need to be put into perspective. What is the magnitude of the risks and – importantly – how do they compare to MS? The FDA decision centers around safety and how risk can be mitigated. Staff concerns are fairly reasonable. They want an in depth discussion and will get one. For more on FDA advisory committees:
What would a robust REMS program look like? It would probably look like the program devised for Tysabri after it was pulled from the market. The FDA is concerned with designing an effective REMS and ensuring compliance with the monitoring requirements. Doctors administering the drug will register with Genzyme in order to track patients for complications. Next week, the advisory committee with probably make recommendations for further strengthening the REMS program as well as enforcing compliance. Biogen is tracking all serious adverse events associated with Tysabri. According to the most currently available data, there have been 401 cases of Tysabri-induced progressive multifocal leukoencephalopathy (PML) as well as 88 deaths. A REMS works for Tysabri and a REMS would work for Lemtrada, which is the safer of the two drugs.
One if the complaints of the reviewer is the higher drop out rate for those patients on interferon.
"The sponsor attributes this difference in dropout rate to subjects who had previously failed interferon treatment refusing further treatment with the same drug.", on page 306
But this argument is not valid for the 323 trial involving only patient not on any MS medication before.
Still reading...
Just started reading it, but my initial impression is very good. I don't see any way that placebo affect and rater bias can cause the following results (page 17):
• A significant reduction in in the number of patients with new gadolinium enhancing lesions and new or enlarging T2-hyperintense lesions which are associated with acute
On page 314 a table with MRI outcomes.
The criticism is that self-injection with Rebif is so unpleasant that more people stop this medication. And the trial offers them other treatment if their MS worsens. This introduces a bias for extra relapses with Rebif in the trial.
On page 324 there is a quoted comment from the Lancet paper complaining about another bias and telling us that in the trial the lapse rate on Rebif was low as well.
The efficacy reviewer does acknowledge de reduced relapse rate.
On page 339 the statistical review starts. Also this reviewer does confirm the reduced relapse rate.
Both reviewers concluded that the 323 and 324 trials fail on time to sustained accumulation of disability (SAD).
but the bigger boys who play in the big pond seem to have decided, by the end of the day, that this was a wash.
the bottom line take home message seems to be
1. There is one study that shows effectiveness on subjective measures, but it is subject to placebo effect. There is another study that shows lack of effectiveness on subjective measures. combined this evidence is weak.
2. Neither study shows effectiveness on objective measures. This is more informative than the above.
3. "Collectively, the two studies rendered more evidence of ineffectiveness than effectiveness of
4."adequately designed and well controlled blinded studies need to be conducted in order to establish the possible efficacy for aletuzumab."
there does seem to be a greater focus on number of relapses than there is on progression of disability in the EU doc, and more of the opposite in the US staff report.
If anyone can site past examples of staff reports that negative that have resulted in positive panel recommendations, I would be all ears.
Also: does anyone know if the UK NHS will pay for lemtrada treatment for MS?
It's also instructive to compare the clinical/statistical reviews for Gilenya vs. Lemtrada overall, the highlighted study weaknesses and overall recommendations are night and day. On page 321 of the PDF'd Lemtrada briefing see "Table of 323 and 324 Protocol features that may have increased biased reporting" with a lot of simple things that should have been fixed. Also note page 304 Table 14 "Completion rates..."
Imagine it's 2009, when the Phase 3 studies were being recruited. The only approved treatment options at that time were the platforms (interferon and Copaxone, all with similar efficacy) and Tysabri (approved 2004, then pulled from market and re-approved in 2006 with severe side effect warnings). You have MS and you haven't responded to interferon treatment, so you beg your doctor to get you into this test for Lemtrada that has shown amazing published phase 2 results (maybe a cure!!!). When you join the study and find out you got picked for more interferon and not the miracle drug, you either drop out immediately or fake a relapse to get put on a potentially better drug. If you got picked for Lemtrada and know that showing severe relapse might get you taken off of it, you downplay your symptoms.
Excerpts from the briefing that are particularly worrisome:
"In the key 324 trial there were two groups of patients. One group took alemtuzumab once per year in five- and three-day courses of intravenous infusions in a clinical setting. This group received a drug that the patients in both treatment arms would view as more likely to be effective because of the widely known results of an open label phase 2 trial and because they have already continued to have relapses on the active comparator drug. Furthermore, the consent form suggests that they will have to stop taking the preferred drug if they provide evidence that their disease is worsening. The other group were required to inject themselves three times weekly with Rebif, a drug that could cause disfiguring skin changes at the injection site and flu-like symptoms in as many as 60% of the subjects. They also took yearly courses of methylprednisolone infusion corresponding to the infusions given the alemtuzumab group. This group also knew that the Rebif had failed to work for them before and that if they report worsening of their condition they may be able to stop taking the Rebif and switch to another treatment."
"In the 323 and 324 trials, any placebo effect may have been magnified by the unblinding of the patients and treating physicians. Patients who know they are on the preferred drug will be more likely to have a positive placebo effect. Patients who know they are on the drug that is poorly tolerated and has failed before are more likely to have a negative placebo effect."
"It is troublesome to see that so many patients were not assessed for baseline and were not treated until weeks after the randomization. Such delaying not only allowed patients to drop out before receiving any treatment and assessments when assigned treatment was undesired but also effectively invalidated the baseline scores. When screening EDSS score was used as baseline, the SAD events went down by more than 10% in all IFNB-1a groups and went up by more than 10% in all aletuzumab groups in the two studies, resulted a p-value of 0.2010 for treatment difference
There's your evidence of fraud right there, straight from the FDA. Lawsuit!!!
A preview of the 11-13 FDA meeting: http://goo.gl/BWZ6wz
"The issue is whether the risk of extra adverse events versus comparators can be justified given that the FDA analysis of the data suggests the efficacy is not necessarily distinct from Rebif (especially on disability measures)."
"Remember Xarelto: We would like to remind investors regarding the Xarelto (anticoagulant) FDA briefing documents, in which the FDA reviewer recommended a CRL for Xarelto in stroke prevention. This was based on the concern that Xarelto had not shown efficacy versus its comparator (warfarin) due to the clinical trial design (time in therapeutic range was too low). The AdCom panel then gave a positive vote for approval two days later (Yes 9, No 2, 1 abstain). The drug was subsequently approved at first pass, and has become a very successful product. As was seen in the Xarelto AdCom, the AdCom panel contains clinicians who are "on the ground" treating patients, and may be more likely to look through the fine detail of the statistics and be more inclined to opine on the benefit of the product for the patient. In Lemtrada's case, it is likely that there are panel members who have prescribed alemtuzumab off-label for many years, under the firm belief that it gives benefit to patients."
Dr. Cohen is a big proponent of Lemtrada and hitting MS early and hard (see Cohen's quotes from Rootbeer's post above "Zero Tolerance For Disease Activity in RRMS"). I was hoping he would help sway the committee, but it's not clear he'll be able to do that now though. Googling through the other Adcom members, I don't see anyone with a ton of MS expertise or with quotes suggesting they agree an aggressive early approach to treatment.
I think this will almost certainly be the outcome for Lemtrada. Plenty of new MS drug alternatives recently including Gilenya (52% reduction in ARR vs. interferon Avonex vs. Lemtrada's claimed 49-55% reduction vs. interferon Rebif). Plenty of new treatments being tested. I don't see the FDA overlooking shoddy/biased drug trials and setting a bad precedent.
Vyndaqel Briefing: http://goo.gl/KyvjHs
"There are 143,000 relapsing-remitting MS patients in the EU5 (Germany, France, Italy, Spain and the U.K.), FosterRosenblatt estimates. Assuming 50% are treated with drugs at a $60,000 first-year cost (equivalent to German pricing), 10% market share would be needed to achieve $400 million in aggregate first-year sales. Achieving 10% share in the first year is ambitious for any new drug, particularly in a disease where doctors are more cautious about new therapies."
"Novartis's Gilenya captured about 14% of European drug-treated multiple sclerosis patients, analysis of the first 12 months of sales ($293 million) shows. At $30,000 per patient, that equates to almost 10,000 patients on Gilenya outside the U.S. While Gilenya had some safety concerns and restrictive monitoring, it was the first oral MS drug. If Lemtrada matches this trajectory, it could achieve the first CVR milestone of $400 million in sales, even without U.S. approval."
"The EMA approved Sanofi's Lemtrada in June and the product has launched in Germany and Finland. While the FDA and EMA operate autonomously and these markets are independent, a strong, unexpected opinion by one agency can affect a product's commercial viability in other regions. For example, Pfizer's Xeljanz received U.S. approval, yet was not approved in the EU, where questions about efficacy and safety led to lackluster uptake in the U.S. market."
"Briefing documents released ahead of the Nov. 13 FDA panel for Sanofi's Lemtrada reveal an FDA decision is expected by Dec. 27 (PDUFA date). This is an update vs. [Bloomberg]'s previously expected "mid-to-late December"".
"Overall, documents are very negative, citing both safety concerns and inadequate demonstration of efficacy, given poorly conducted clinical trials. We currently forecast risk-adjusted peak sales of Eur950m, with cEur500m in the US (Lemtrada has already received EUapproval). A recommendation against approval, therefore, represents only c1-2% EPS risk [to Sanofi's income statement]".
"While the FDA acknowledges that clinical trials have shown a relapse rate benefit, it notes: 1) This cannot definitely be ascribed to Lemtrada, given that the study was not blinded and due to the subjective nature of the relapse rate endpoint. The FDA specifically states "The clinical trials lacked required procedures to ensure that relapse event reporting was uniform in the two treatment groups"; 2) Evidence on improvement in disability is "weak", given a benefit shown in only one of the two studies. The FDA also questions the extent of benefit in the single study that did demonstrate a disability improvement (after correcting for placebo effect and bias); 3) The most unbiased finding in the clinical studies was MRI lesion volume, on which Lemtrada failed to show a benefit."
"As described above, the FDA briefing documents are clearly cautious and suggest a recommendation against approval is most likely. However, within its questions, the FDA leaves open the option for a restricted approval as a last-line agent, with a potentially onerous REMS (largely what is assumed in forecasts anyhow).
Because of the irreversible side effects I think it is appropriate, ethical, to inform patients and doctors about the type of treatment. Genzyme took big risks in the trial set up but they did not have good alternatives either.
See the document that Genzyme wrote. It seems that the equity analysts haven't read it yet.
The main reason for the lack of efficacy is the trial 323, where the Rebif patients fared exceptionally well, much better than in the literature. I would think that this contradicts the perception of a bias towards alemtuzumab. It might be attributed to the selection of patients, in the initial stages of MS, where clinical differences are difficult to detect.
In the Genzyme doc I also read that the T2 lesion volume is statistically significantly less for alemtuzumab, but only after the first year. This can be inferred from the FDA document as well. The idea is apparently that it takes a while to see the effects of alemtuzumab.
It would be interesting to see how the adcom reacts on this defense from Genzyme, and how they react on the results of the extensions of the trials and what the Genzyme defense is to the implicit accusations that something is wrong with the data from Eastern-Europe and Israel.
My bottom line, up front, is that the shares will probably only payout $1 in 2020 as I believe the drug will be approved, but sales milestones will not be met. Therefore with 6% time value of money, the fair price is 0.65 cents today. If US approval is not met in time, meeting sales milestones will be near impossible and the ultimate price will be 0.00 but post PDUFA price might still be 0.20 allowing an exit. If approval on time is met, the ultimate price, IMO, will be 1.00, but there could be a spike >1.50, allowing for a successful exit. I believe the chance of approval is 60%, but before the documents felt the chance was 80-90%. My change in opinion comes from the efficacy concerns raised in the documents. I still think its very effective, but will they prove it to the FDA?
The AdCom has to discuss and answer the 5 questions on page 7, so I'll leave my two cents…
1. Has substantial effectiveness been shown in adequate and well controlled trials for RRMS? Primary outcomes were reduction in annualized relapse rates (ARR) and time to sustained accumulation of disability (SAD)--- if these are not satisfactory, then the other endpoints really don't matter. In retrospect, IMO, the sponsors should have picked one dose of alemtuzumab (12 mg) to carry forward from phase 2 to 3 and have done study one (naïve) vs. placebo and study two vs. Rebif. This would have improved the statistical power and have presented data against placebo. Dr. Marler and Yan present arguments that these endpoints may not really have been met. Some arguments are against the lack of patient blinding. Of course the FDA knew that all along and were ok with it. Blinding alemtuzumab would be very difficult as there are mild infusion reactions that would tell a patient they were definitely on drug. I believe blinding concerns are adequately addressed in the Sanofi response. Marler and Yan raise concern about 12.6% dropout from patients in CAMMS324 who were randomized to receive Rebif (MS patients who had tried and failed an IFN probably were not interested in retrying a similar or same drug). Free choice is a cornerstone of any drug trial. As these patient would likely have done same or worse during the 2 year study, I don't see a problem (it actually biases the other way). Of course dropout rates were higher with Rebif than alem (p.66); the alem patients just did 5 days and 3 days and then just needed required follow-up, Rebif patients still needed to actively treat. Effectiveness: Graphs on p.69 show the big concern. 323 failed to show significance for SAD. IMO, SAD should have been a secondary endpoint for 323 and a primary endpoint for 324. 323 used only never before treated patients (naïve), thus they had early MS. Disability does not rapidly accumulate over 2 years in this population, even with placebo. Some of the arguments about bias are always going to be present when there is an active comparator (i.e. Tecfidera CONFIRM; Gilenya AFFIRM) and a drug still gets approved. And of course, the EMEA (EU) was ok with the data. A negative vote by the panel on this point will be very bad for approval chances.
2. Have they proved a beneficial effect on disability? IMO, they have, as 324 clearly shows a good result. However, 323 with a naïve population did not and this vote could go either way. Note, that there is no argument as to whether or not the ARR endpoint was met, that is a given. A negative vote will not preclude approval by the FDA but would knock GCVRZ down hard.
3. Do safety concerns preclude approval? After the two sides present the safety issue data, this point becomes pure opinion. If the comparator was placebo, and all primary endpoints not met, the modest benefit would not offset safety risk. However, with an active comparator, I believe the need for additional effective treatments make the risks acceptable.
4. If approved, should alem be indicated for firstline use? I expect, if approved, the vast majority of use will be second line. So this is not an important point. The first line study (323) only met the ARR endpoint because proving superiority against an active comparator over two years with a naïve population is very difficult. ARR data was excellent. I would consider it first line in a highly active patient. A negative vote will not mean much (assuming 1 and 2 are positive). If approved, I expect language similar to Tysabri for indication
5. Discussion of REMs. Sanofi has set up a comprehensive REMS to ensure patients will be tested monthly. If many changes are recommended, the launch could be delayed but probably not the decision.
Milestones: Assuming approval in late December and launch in February, I expect a slow launch and slow acceptance. The REMS is going to scare a lot of patients and be too much hassle and concern for neurologists who treat less than 50 patients. Only about half the MS patients are followed by MS neurologists --- some aggressive, some conservative. Happy patients do not switch to a drug with safety issues. The main source of patients will be high titer Anti-JCV Ab positive patients who would have too much risk on Tysabri but need to switch for efficacy reasons. A second pool of patients will be highly active new patients. In 2015/2016 ocrelizumab comes on line. At that point, there will be 3 highly effective therapies: Tysabri, ocrelizumab and Lemtrada (I could include Novantrone but no one uses it much anymore)all competing for the same pool of patients. Thus, I expect a slow 2014 and 2015 launch followed by low steady use after 2016. I assume a price of 120,000 for year one and 72,000 for year 2 (adjusted up 5%/year). I expect a steady state of 2000 new patients/yr (and 1800 pts/yr for second 3 day course) so the drug will likely peak around 400-500MM annual sales.


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Saints coach Joe Vitt back from suspension
October 24, 2012
Associated Press
METAIRIE, La. - Fresh off his seven-week bounty-related suspension, New Orleans interim coach Joe Vitt did not wait an extra second to rejoin the team - in Florida. After watching Sunday's game from an undisclosed location in the Tampa area, Vitt, a graduate of Highland High School, flew back to New Orleans with the Saints after they beat the Buccaneers, 35-28, in a game Vitt was barred from attending. On Monday, he said his suspension was excruciating. "I agonized," the 58-year-old Vitt said.
An Nfl Survivor Moves On Again Highland Graduate Joe Vitt Has Coached In The League Since 1979.
March 17, 1999
By Marc Narducci, INQUIRER SUBURBAN STAFF
Joe Vitt says he watched the Super Bowl this year with a little bit of envy. After all, the 1972 Highland graduate could have envisioned himself high up in the press box, calling the defensive signals for the Atlanta Falcons. Instead of being a Super Bowl participant, though, Vitt is once again relocating. He is beginning a new job with a new team and attacking the situation with the same enthusiasm that has enabled him to survive the rigors of NFL coaching for more than two decades.
A Football Coach Who Has Tackled More Than Game Films Joe Vitt Is An Assistant With The Los Angeles Rams. Never Mind Games. He Has Beaten Cancer Twice.
October 26, 1992
By Marc Narducci, INQUIRER CORRESPONDENT
For a guy who claims to have never worked a day in his life, Joe Vitt has done quite well, thank you. Vitt, 37, who graduated from Highland High School, has has been an NFL assistant coach for 14 seasons and is in his first year as the assistant head coach for the Los Angeles Rams. Vitt is head coach Chuck Knox's first lieutenant. If Knox were unable to coach the Rams because of, say, an illness, Vitt would take over, he said. To survive as an NFL assistant for almost a decade and a half shows great resilience.
NFL commissioner Roger Goodell reinstates New Orleans Saints head coach Sean Payton
January 23, 2013
Sean Payton's season-long suspension for his role in the New Orleans Saints' bounty program was lifted by NFL commissioner Roger Goodell on Tuesday, nearly two weeks earlier than expected. The decision allows Payton to attend the Senior Bowl in Mobile, Ala., on Saturday, where some of the top college players available for the NFL draft will be competing. Payton, along with assistant head coach Joe Vitt, general manager Mickey Loomis, and four players including Jonathan Vilma, was suspended after an investigation found the club had a performance pool offering cash rewards for key plays, including big hits.
Drew Brees breaks record in Saints' loss to Denver
October 30, 2012
Associated Press
DENVER - Drew Brees welcomed back New Orleans interim coach Joe Vitt from his bounty banishment Sunday night by extending his NFL record to 50 consecutive games with a touchdown toss, the 300th of his career. Brees added another just before the two-minute warning Sunday night to surpass Denver Hall of Famer John Elway for sixth on the career list. But almost nothing else went right for the Saints in a 34-14 loss to the Broncos. The 2-5 Saints, who will host the 3-4 Eagles on Monday night, became the first team to allow 400-plus yards in seven straight games since at least 1950 - as far back as Stats LLC can search its NFL database.
Thirteen from S. Jersey make NFL rosters
September 8, 2012
By Marc Narducci, INQUIRER STAFF WRITER
Players from the seven-county South Jersey area have a long history in the NFL, and the tradition is continuing this season. Thirteen local players were on opening-day, 53-man NFL rosters. An additional five players were on injured reserve, the practice squad, or the reserve/non-football injury list. The most recognizable name is Audubon grad Joe Flacco, the fifth-year starting quarterback for the Baltimore Ravens, who guided his team to the AFC championship game last season.
For Vitt, one super reunion The Saints assistant will be joined by family members for the big game.
February 5, 2010
By Bob Brookover INQUIRER STAFF WRITER
Joe Vitt sent a letter to his sister and mother 25 years ago with some advice. His sister returned the letter this past Christmas. "It was my Christmas present from her," the New Orleans Saints assistant head coach said yesterday. "She had just had a baby girl in 1983, and in the letter I said, 'If you ever let your daughter marry a football coach, I'll disown you.' I was with the Seattle Seahawks at the time, and we had just got our butts kicked by the L.A. Raiders. " The point of the unusual gift: Football has been pretty good to Joe Vitt and his family.
Titans interested in Saints' Gregg Williams
January 28, 2013
Gregg Williams may be a step closer to returning to the NFL after being suspended indefinitely by commissioner Roger Goodell for his role in the New Orleans Saints' bounty program. Titans coach Mike Munchak has talked with the defensive coordinator and is interested in adding him to his staff, a person familiar with the situation said. The person spoke Sunday to the Associated Press on the condition of anonymity because the Titans do not discuss personnel moves until they are finalized.
NFL: Peyton Manning delights Denver fans
July 27, 2012
Associated Press
Peyton Manning put on a clinic of precise and powerful passes both short and long during Denver's training camp Thursday in Englewood, Colo. The former Indianapolis Colts quarterback looked right at home in his first public practice with his new team, drawing cheers and chants from the crowd of 4,371 - the largest ever at the Broncos' Dove Valley complex. Tebowmania, Part II As the New York Jets reported to training camp in Cortland, N.Y., some 50 reporters, cameramen, and broadcasters followed former Denver quarterback Tim Tebow at SUNY Cortland.
A Philly guy, Saints' Vitt won't make excuses
November 2, 2012
BY ED BARKOWITZ, Daily News Staff Writer
WHEN INTERIM Saints head coach Joe Vitt goes into owner Tom Benson's office at the end of the year, one thing he will not be bringing with him is an excuse. But Lord knows Vitt has one, with his team reeling at 2-5 in the wake of numerous suspensions following the infamous bounty scandal. "At the end of the year when I go in and I try to try to get another contract, I certainly can't use this as an excuse for failure," said Vitt, who grew up in Blackwood, N.J. "When our players go in and try to get their new contracts, they can't moan and whine that the reason they missed a block or missed a tackle or threw an interception or dropped a ball is because they had 'bountygate' hanging over their head.
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Titans hire Gregg Williams
February 8, 2013
Daily News Wire Reports
GREGG WILLIAMS thanked NFL commissioner Roger Goodell for reinstating him and he also apologized while taking "full responsibility" for his role in the New Orleans' bounty scandal. The NFL reinstated Williams on Thursday and the Tennessee Titans hired him as a senior defensive assistant. "I take full responsibility and apologize for my previous actions, and I've used this year to reorganize my life and put focus on positive energy and positive ways to inspire and coach and motivate in this profession," Williams said, reading from a statement.
Eagles Notebook: Saints head coach Sean Payton talks 'closure' at Senior Bowl
January 25, 2013
BY LES BOWEN, Daily News Staff Writer email@example.com
MOBILE, Ala.—New Orleans Saints coach Sean Payton kept using the word "closure" during an extraordinary, 45-minute news conference Wednesday morning following the North team practice at the Senior Bowl. But the size of the media throng around Payton, as he spoke for the first time since NFL commissioner Roger Goodell lifted Payton's 1-year suspension Tuesday in the "Bountygate" case, was maybe the first clue that putting the scandal in the past isn't going to be easy or simple.
NFL commissioner Roger Goodell reinstates New Orleans Saints head coach Sean Payton
January 23, 2013
Sean Payton's season-long suspension for his role in the New Orleans Saints' bounty program was lifted by NFL commissioner Roger Goodell on Tuesday, nearly two weeks earlier than expected. The decision allows Payton to attend the Senior Bowl in Mobile, Ala., on Saturday, where some of the top college players available for the NFL draft will be competing. Payton, along with assistant head coach Joe Vitt, general manager Mickey Loomis, and four players including Jonathan Vilma, was suspended after an investigation found the club had a performance pool offering cash rewards for key plays, including big hits.
Griffin on mend, back at practice
December 14, 2012
Robert Griffin III's knee is looking better. The Washington Redskins quarterback was back at practice Thursday, dealing with the effects of a sprained right knee as the team prepared for Sunday's game against the Cleveland Browns. Griffin stretched and made some basic throws during the 20 minutes that the practice was open to reporters. The rookie was still favoring his right leg somewhat, but he was able to plant and throw more smoothly than he did during Wednesday's practice.
Vitt: Lot of lying in bounty aftermath
December 14, 2012
Daily News Wire Reports
SAINTS ASSISTANT head coach Joe Vitt said Thursday witnesses in the NFL's bounty investigation of the New Orleans Saints have lied about him and the organization, and that their stories might change in federal court. Alluding to a defamation lawsuit filed by Saints linebacker Jon Vilma against NFL commissioner Roger Goodell, Vitt angrily said he feels the truth about the pay-for-pain system will come out before U.S. District Judge Ginger Berrigan, who is presiding over the pending case in New Orleans.
Victim's kin: 'Hearts truly broken'
December 4, 2012
Daily News Wire Reports
BREAKING THEIR silence, family members of the woman shot and killed by Kansas City Chiefs linebacker Jovan Belcher said Monday their "hearts are truly broken" and asked for privacy while they grieve the loss of two loved ones. Belcher shot and killed his 22-year-old girlfriend, Kasandra Perkins, at their Kansas City home Saturday before driving to Arrowhead Stadium, where Belcher committed suicide in the practice facility's parking lot, police said. The couple had a 3-month-old daughter, Zoey.
Eagles and Saints fighting to reclaim dismal seasons
November 6, 2012
By Zach Berman, Inquirer Staff Writer
METAIRIE, La. - As unsettling as the Eagles' season has been in Philadelphia, there's similar bewilderment in New Orleans about how a team with high expectations has struggled through the first half of the season. The Saints enter Monday night's game against the 3-4 Eagles with a 2-5 record, meaning two teams that started with postseason expectations and Super Bowl aspirations could possibly be floundering toward irrelevance in the season's second half. What appeared to be a marquee game is now a matchup of teams that badly need a victory just to stay competitive.
Saints' Jahri Evans proud of his Philadelphia roots
November 5, 2012
By Zach Berman, Inquirer Staff Writer
METAIRIE, La. - When Saints guard Jahri Evans arrived in New Orleans in 2006, teammates teased him for being an Eagles fan. A Nicetown native and Frankford High School alumnus, Evans is proud of his Philadelphia roots, even though he has become a Pro Bowl player for the Saints. "Basically follow all the [Philadelphia] sports teams but the Eagles," Evans said Friday afternoon. Evans will play the Eagles for the fifth time in his career on Monday night. He's still a devoted Philadelphian, making his offseason home in the area and focusing his charity efforts in his hometown.
Drew Brees keeps Saints dangerous
November 5, 2012
By Zach Berman, Inquirer Staff Writer
METAIRIE, La. - A source of optimism in New Orleans is that Drew Brees is the Saints' quarterback. So despite a 2-5 record and a disappointing start to the season, they conceivably have the chance to win every game. In 2011, Brees added to what will likely be a Hall of Fame resumé when he broke Dan Marino's single-season record for passing yards. In 2012, he is No. 2 in the NFL with 2,310 passing yards and leads the league with 20 touchdowns. He's on pace for his third 5,000-yard season and to match the 46 touchdowns he threw last season.
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30 years of experience
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After being denied a marriage license for his second wife after same-sex marriage was legalized, Nathan Collier plans to sue Montana for his right to marry.
A Vancouver man admitted to killing his wife, daughter and his sister on Facebook. He later burned his home to the ground, committing suicide.
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Because typhoid carriers are denied occupations involving food handling and care of children, are kept under surveillance by health departments and fear the possible infection of others, their successful treatment is greatly to be desired. Successful treatment would also be important in the present war emergency so as to prevent and control spread of the infection in military establishments. To this end, two general procedures and agents have been proposed: (1) the removal of foci of typhoid micro-organisms, usually by cholecystectomy, and (2) the administration of drugs which might be bactericidal. Curative results have been claimed for both these procedures.
For instance, Bigelow and Anderson1 in 1933 and Coller and Forsbeck2 in 1937 are among those who have reported cures by removal of the gallbladder. This is, however, a major undertaking, which fails to cure the patient in a considerable number of instances. For this reason, others have
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Bowl'd Korean Rice BarChinese, Korean, Restaurants
1479 Solano Ave
(510) 526-6223
Kristy K.
I got the normal bibimbap with spicy pork and mixed grain rice. It was pretty good, but not the bibimbap I was expecting. It had everything: the veggies,...read more
Jane C.
Generous portions, delicious food, and fantastic service! Bibimbap (stone pot): Unlike typical Korean restaurants, their version has a smoky flavor, as if...read more
Haruna S.
I know here because my instructor recommends here. So far, here's my best Korean food restaurant in Bay area. I and my boyfriend(Korean) love to go...read more
Island Bruin
go for the bbq- rice bowl was surprisingly bland, even with plenty of hot sauce. friendly staffread more
Laura P.
Urgh delicious! BBQ pork, fried Kim Chi dumplings, and spicy ramen are amazing.read more
The Organic Works is a rip off. Basically a way over-priced salad.read more
Craig W.
Waited forever. Nobody greeted or talked to our party. Left. Maybe our 3rd visit will be better.read more
David A.
Except for the name 'Bowl'd', this would not be out of place in LA Koreatown. Stays true to the cuisine while putting its own modern flair.read more
Regina W.
I lived in South Korea for almost nine years. These folks make an excellent 김치 볶음밥, kimchee bokkum bap. It's about 3 times more what you'd pay in Korea, but that's how it goes. It's worth it.read more
Christopher N.
Strip steamed dumplingsread more
Arnold G.
Get the spicy chicken wings. It's not as hot as you might think, and it's my fave Korean Fried Chicken in the Bay Area. Also available at Spoon Korean Bistro in Berkeley (same owners).read more
Andrew V.
The spicy chicken wings are a must have. I order them every time!read more
Tim D.
Omggg'.....the spicy chicken wings on HITTT!!read more
Saundra D.
Not Bowl'd over...the spicy chicken is good.read more
Carmen P.
Try the Kimchi Pancake (via @Foodspotting)read more
William "Billy" A.
Try the Seafood Pancake/Bitesread more
Rachel C.
Be sure to write your name on the list when you walk in the door.read more
Try the oyster pancakes, the citrus soy sauce is delish!read more
The fried kimchi dumplings are delicious even to non-kimchi fans.read more
jaireh t.
Have the grape soda with jelly it's a pretty delightful drunk.read more
Dennis K.
BBQ pork bowl is excellent. Place is very friendly towards kids.read more
Ryan B.
Kimchi pancakes are surprisingly good. Great flavor and textureread more
Best Hot N Sour soup and great shezuan beef (crispy), but poor service and bad attitudes: My wife and i ate here at least once a week, for over two years. We loved their hot n sour soup and shezuan beef, rice dishes are ok. But whenever my wife would go alone to pick up an order they treated her like royalty, but whenever I…read more
Rory O
Very Good Chinese food: There are so many Chinese food restaurants on Solano ave. but this one is one of the best. The food is delicious and the service is good. Their broccoli beef is spectacular along with their lemon chicken. The prices are good for the…read more


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September 27, 201611:11 AM ET
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September 27, 201611:14 AM ET
WASHINGTON (AP) — Law enforcement and intelligence agencies remain extremely concerned that violent militants will eventually flow out of Syria and Iraq and into other countries in hopes of committing attacks, FBI Director James Comey told Congress on Tuesday.
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WASHINGTON (AP) — Senate Democrats on Tuesday threatened to block must-do legislation to prevent the government from shutting down Friday at midnight, battle the Zika virus and help flood-ravaged Louisiana rebuild.
September 27, 20161:35 AM ET
HOUSTON (AP) — A disgruntled lawyer wearing military-style apparel with old Nazi emblems had two weapons and more than 2,500 rounds of live ammunition when he randomly shot at drivers in a Houston neighborhood before he was shot and killed by police, authorities said.
September 27, 20169:44 AM ET
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INDEPENDENCE, Ohio (AP) — Now that LeBron James has won a championship for the ages, he's set a loftier goal:
September 27, 20162:56 AM ET
NEW YORK (AP) — NBA players aren't just worried about their teams as they start a new season.
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September 27, 201611:23 AM ET
CHASKA, Minn. (AP) — Europe has won eight of the last 10 times in the Ryder Cup, and Rory McIlroy says it won't have a hard time getting motivated to win another.