Rob, How many patients are included in the $15 million trial? Thanks.


p.s. Are you sure you're getting the drug at cost ;-)

From Novartis 2011 Annual Report --
Gilenya (USD 494 million) is approved in more than 55 countries and showed continued rapid growth as a once-daily, oral disease modifying treatment for relapsing remitting and/or relapsing forms of MS in adult patients. Gilenya was approved in the EU in March 2011 as a disease modifying therapy in patients with highly active relapsing-remitting multiple sclerosis (RRMS) despite treatment with beta interferon, or in patients with rapidly evolving severe RRMS. Novartis also received approval for Gilenya in September 2011 in Japan for the prevention of relapse and delay of progression of physical disability in adults with MS. It is licensed from Mitsubishi Tanabe Pharma Corporation.

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$494 million global annual sales in its first full year. Approximately 30K patients treated.

http://www.bloomberg.com/news/2012-01-20/novartis-s-gilenya-reviewed-by-eu-after-11-patient-deaths-2-.html

This article from a year ago has some interesting information about the development of the drug by Mitsubishi Tanabe Pharma, royalty information, and sales forecasts.

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http://www.bloomberg.com/news/2011-02-02/himalayan-fungus-aids-mitsubishi-tanabe-sales-with-multiple-sclerosis-drug.html

Himalayan Fungus Aids Mitsubishi Tanabe Sales With Multiple Sclerosis Drug
By Kanoko Matsuyama - Feb 3, 2011 Tetsuro Fujita’s eureka moment about a Himalayan fungus in 1985 may mean part of a $5 billion payout for Mitsubishi Tanabe Pharma Corp. a quarter-century later.

While the scientist drove over a bridge between Japan’s Shikoku and Honshu islands on his way to take up a research post for traditional herbal remedies, Fujita realized the fungus, used in a Chinese medicinal soup, must be suppressing the immune system of the insects on which it grew.

His research at Kyoto University not only helped yield Gilenya, a new treatment for multiple sclerosis -- the debilitating condition afflicting more than 2 million people worldwide -- it also promises to bring Mitsubishi Tanabe its biggest money earner. Annual sales of the pill, the first for the autoimmune disease, may exceed $5 billion, UBS AG said.

“Little did I think that it would be a treatment for multiple sclerosis,” Fujita, 80, said in an in interview Kyoto. “I was more interested in immune suppression for organ transplants. I knew nothing about the disease back then.”

Novartis AG, based in Basel, Switzerland, began selling Gilenya in the U.S. in October. Projected sales of the medicine would rank it among the 10 best-selling drugs worldwide, based on data from IMS Health Inc., a Norwalk, Connecticut-based research company.

Mitsubishi Tanabe will probably book royalties equivalent to 10 percent of sales, based on the median of four analyst estimates in a Bloomberg News survey.

Better Than Expected
Kazuko Hamada, a spokeswoman for Mitsubishi Tanabe, declined to comment on the royalty payments that the Osaka, Japan-based drugmaker will receive. Novartis spokesman Eric Althoff also declined to comment on the royalties.

Gilenya’s fourth-quarter sales of $13 million were above expectations, Dhavalkumar Patel, who heads Novartis’s autoimmune research, said last week.

“Novartis says 2,000 people are already using the drug in three months,” Kenji Masuzoe, an analyst at Deutsche Bank AG in Tokyo, said by telephone on Jan. 28. “That’s great progress as I’ve been expecting 10,000 people by the end of this year, which will mean sales of about $350 million.”

Multiple sclerosis causes the immune system to attack the myelin sheath, which surrounds and protects nerve cells, leading to symptoms including numbness, difficulty in coordination and memory loss, according to Medline Plus, a website of the U.S. National Institutes of Health. In its severest form, it can shorten life and, in rare cases, lead to death, according to the U.S. National Multiple Sclerosis Society’s website.

Worst Performance
Mitsubishi Tanabe rose 2.1 percent to 1,369 yen at the 3 p.m. close of Tokyo trading. The stock gained 18 percent last year, outperforming Japan’s benchmark Topix index, which fell 1 percent.

Sales at the Japanese company declined 2.4 percent in the 12 months ended March 2010, the worst performance in five years, to 404.7 billion yen ($5 billion), according to data compiled by Bloomberg.

Annual sales of Gilenya may peak at $5.3 billion in 2018, Fabian Wenner, an analyst at UBS in Zurich, said Feb. 1.

Gilenya is approved for the relapsing-remitting form of multiple sclerosis, the most common type, and competes with injected drugs on the market including Biogen Idec Inc.’s Avonex and Teva Pharmaceutical Industries Ltd.’s Copaxone.

Superior Drug
The Novartis drug cut relapses by more than half compared with Avonex, an injected therapy from U.S. drugmaker Biogen Idec Inc., according to a patient study published in the New England Journal of Medicine last year.

Gilenya gained the support of a European medical committee in January, and a European Commission decision on approval may come in about three months. It’s also being reviewed by regulators in Japan.

In the U.S., the drug is priced at $4,000 for a monthly prescription. That’s 66 percent more than the $2,414.99 for a pre-filled syringe of 30 micrograms per milliliter of Avonex, a month’s supply, according to PharmacyChecker.com. Analysts including UBS’s Wenner expect Gilenya to be cheaper in Europe.

Current medicines require patients to inject themselves every other day or once a week, Kyoko Nakata, the Tokyo-based chairman of Japan’s MS Cabin, a support group for the condition, said in an e-mail.

“They are shots, so during the course of treatment, they are a constant reminder to patients of their condition,” said Nakata, who was diagnosed with multiple sclerosis in 1993 and has been taking Bayer AG’s Betaferon since 2000. “Gilenya would make it easier to treat the disease as it saves time and brings patients closer to having a normal life.”

Larva Invader
With the help of another researcher, Fujita partnered with Yo****omi Pharmaceutical Industries Ltd. and Taito Co., now respectively part of Mitsubishi Tanabe and Mitsui Sugar Co. The scientists began studying in 1986 the Cordyceps fungus known in Chinese and Japanese as “winter insect, summer plant,” so called because it invades insect larva during winter and grows out of the host by summer.

Fujita said he was inspired by the discovery of ciclosporin, also derived from a fungus, which spurred research into how the immune system may be subdued in transplant patients. Fujita, now a professor emeritus at Kyoto University, said he was unaware the immune-modulating properties of Cordyceps could eventually help multiple sclerosis patients.

“I knew from reading the Chinese medicinal encyclopedia that the fungus feeds off the larva, lives in a symbiotic relationship for a year, and comes out of the ground in summer by growing out of the carcass,” he said. “That made me think the fungus must be suppressing the larva’s immune response.”

Centuries-Old Remedy
Used as an herbal remedy for centuries, the fungus contains an insoluble, toxic compound called myriocin, said Kenji Chiba, who worked on the project at Yo****omi. It took scientists at least three more years before they could modify the compound into a usable form, creating fingolimod, or Gilenya.

Novartis licensed the overseas rights to fingolimod from Mitsubishi Tanabe in 1997.

“Although it took a quarter of a century, I’m happy it’s become a drug while I’m still alive,” Fujita said. “It makes me happy that something I did is making others happy.”

Link to second thread, same topic: http://www.als.net/forum/yaf_postst50000_MS-drug-may-help-ALS.aspx

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per·se·vere [pur-suh-veer] - to persist in anything undertaken; maintain a purpose in spite of difficulty, obstacles, or discouragement; continue steadfastly.

Let's use historic ALS trial data for progression foot print. If TDI 132 beats the existing progression rate then immediately declare safe and efficient. Please. Please no placebo. We are patients, Placebo's harm patients and families who watch their suffering. And everyone in the trial should be placed on the treatment when Phase II shows efficacy and safety. No repeat of Cytokinetics, and Neuraltus failure to provide for trial participants

Hello all,

ALS TDI is working with NEALS to develop them best clinical trial possible that can enroll quickly and get answers quickly. It is likely that there will be a placebo arm to this trial. With that said, we are also concerned that the trial be designed so that if there is a positive effect from administering Gilenya to ALS patients in the trial, that upon its completion there is a path forward to continue to provide the drug to not just those on the drug in the trial, but all participants.

The design of the trial will be discussed during our webinar on March 12, 2012. www.als.net/webinars

-Rob

PS - Let the bashing of my honest admission about placebo control in this trial begin!

the question remains what is the expected efficiency - few days in mice?

that's clear, but they have to know how mice did on it?

Hi Rob G.  Elsewhere we can read:

http://www.alzforum.org/new/detail.asp?id=3065

"The researchers have not finalized their study design, but it will likely include two phases. The first, Perrin said, will be a Phase 2a trial with perhaps 30-50 volunteers to make sure the drug is safe for people with ALS. Following that, he envisions a larger, Phase 2b of approximately 250 people."

http://www.alsconsortium.org/news_gilenya.php

“We are thrilled to work with ALS TDI on this important Phase II trial in ALS,” said Merit Cudkowicz, M.D., Director of the Neurology Clinical Trials Unit at Massachusetts General Hospital, one of the principal investigators of the clinical trial and member of MDA’s medical advisory committee. "We hope to learn from this study whether or not TDI 132 is safe to test in people living with ALS. Participants will be evaluated over a month-long exposure to the drug, and we’ll be monitoring their response closely." This initial study will provide important information on dosing and safety for a subsequent efficacy study."

Why so quiet here and in TDI direct communication, but vocal elsewhere?

I applaud Dr. Perrin for considering a very large phase 2b!  It's about time ALS phase 2 trials were sufficiently sized to give real answers, and NOT a repeat of the size of preclinical mouse studies!  It seems the ~55 of the Dex phase 2, lacking statistical significance, led to exaggerated hype an likely false hope.  What a shame that years were wasted waiting for a meaningfully sized trial with that drug, and the big jump from ~55 to ~940.  At nearly 2.5X as large, the NP001 phase 2 trial will provide a much more confident answer.  SB-509, with apparent success in phase 2 of 40 patients, was recently abandoned and we'll never know for sure. Cytokinetics' phase 2 studies were tiny. The phase 2b Gilenya trial will provide a very confident answer, a refreshing change.

http://www.alzforum.org/new/detail.asp?id=3065

"Gilenya is one of two treatments with which the ALS-TDI hopes to start trials this year. The Institute initially got into the immune system field when they discovered that blocking the interaction between CD40 on T cells and its ligand CD40L on antigen-presenting cells extended lifetime in ALS model mice.  The ALS-TDI partnered with Bioden Idec of Cambridge, Massachusetts, to develop an antibody that interferes with CD40L. However, the team expects this project to take a while, needing time to make a human version of the antibody and run a Phase 1 trial, Perrin said, so the researchers in parallel tested a handful of medicines they hoped would have similar immunomodulatory effects but a shorter development time."

This must be CDP7657, and already exists as a humanized version under clinical trial for Lupus.  Please explain the need to make another. We heard the same about 00846 many times, but it never was true.

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per·se·vere [pur-suh-veer] - to persist in anything undertaken; maintain a purpose in spite of difficulty, obstacles, or discouragement; continue steadfastly.

Fafut_1 - good question. No one has any idea what a day in a mouse equals in a person. Any attempt by us or someone else to do so would be not only foolish but dumb. After we (read: the field) get a few trials that actually lead to something that connects efficacy in the mouse model to efficacy in people with ALS maybe then we can start to actually make symbolic extrapolations between mouse to people effect. Even then, this is such a heterogeneous disease in people (while all the mice have a fairly tidy one) that any suggestion at that point would still have to include a huge margin of error in it.

Pers - Not sure why we are quieter here about this...but I am centralizing a bunch of info on a single page on our site about this forthcoming trial and will send around a link to it. I again encourage folks to join us for the webinar on March 12. I'll try to be more open here on the forum...my silence is not intentional at all.

on your first remark: our confidence that we can get 250 people enrolled in a multi-arm, multi-dose phase 2B may be considered misplaced, but we think that PALS will take a shot at something. I don't want to comment that those other trials were too small, but if you do the stats, you need larger numbers to get actually statistical evidence. Obviously other concerns come into play when designing a trial, not the least of which is cost. Besides, with multiple arms and doses, we may be able to lower the placebo arms, which also in turn drives up the cost (can you tell that I'm a bit preoccupied with cost of trials these days?). We hope to also do a brief washout with a re-randomization in the middle of that Phase 2B, based on dosing information gained....key word there is hope, as the trial design for that isn't done, but that would be our ideal approach. Again, that would provide more PALS the chance to go on drug and allow for even greater info on dosing and potential effect on people.

on your second question, yes, the antibody targeting CD40L is CDP7657 that we are developing in agreement with Biogen Idec and UCB. The quote in that article is wrong. Biogen and UCB have a humanized antibody that we would move forward with ideally. The quote that they write may have been in reference to a comment from Steve that if we went it alone, it would take us longer because we would have to make the humanized antibody.

-Rob