Daiichi Sankyo to seek approval of influenza drug (Super Relenza)

miso · Jan 23, 2009

"TOKYO, Jan 23 (Reuters) - Daiichi Sankyo Co (4568.T), Japan's third-largest drugmaker, said it plans to apply by March 2010 for marketing approval in Japan of an influenza drug candidate, and seek approval in Taiwan, Hong Kong and South Korea soon afterwards.

The company is developing CS-8958 with the aim of treating influenza through a one-time only inhalation of the drug.

Rival influenza drugs from Roche (ROG.VX) and GlaxoSmithKline (GSK.L) that are already on the market require use twice a day for five consequent days.

"Prompted by rapidly increasingly needs for new influenza treatment, we have sped up the development of the drug and are now set to complete all our six lines of clinical tests, three for use in adults and three for children, by March," said Daiichi Sankyo director Daisuke Hiro.

Daiichi Sankyo, which last year bought a controlling stake in generic drugmaker Ranbaxy Laboratories (RANB.BO) of India, is looking for a partner in the United States and Europe to develop and market CS-8958, he said. (Reporting by Yumiko Nishitani)"

Source : Reuters

"Side effects of CS-8958 have been very minor, the company said."

"Daiichi Sankyo expects CS-8958 to be more effective on mutated bird flu viruses which develop resistance to Tamiflu and Relenza, the company officials said.
CS-8958, like Relenza, is an inhaled powder medication and a single dose will be effective for a week.
As Tamiflu and Relenza do, CS-8958 inhibits a protein called neuraminidase which influenza viruses use to expand infection. "

"The company hopes to have enough production capacities for CS-8958 at the time of approval for possible stocking by the Japanese government in case of a bird flu pandemic, Daiichi Sankyo's Hiro said."

Source : Dowjones

gsgs · Jan 23, 2009

Re: Daiichi Sankyo to seek approval of influenza drug (Super Relenza)

it is inhaled ?
and effective for 1 week ?
So I assume it penetrates the respiratory cells and stays there.

We had heard about injectable Relenza but it wasn't done for
market reasons, not that it was less effective (AFAIR).

But when it targets the specific local cells, then it doesn't make
sense to distribute it with the blood.
And it won't last in the blood for a week, I assume.

It's still Relenza, or not ? So it should be affected by
the same resistance mutations

http://www.daiichisankyo.com/

http://www.daiichisankyo.com/4less/cgi-bin/cs4view_obj.php/b_newsrelease_n1_eng/646/081117v1-e.pdf

http://finance.google.com/finance?q=TYO:4568

http://finance.yahoo.com/q?s=D4S.F

Daiichi Sankyo to seek approval of influenza drug
Reuters - 6 hours ago

Daiichi Sankyo Close To Finishing New Influenza Drug Studies
Wall Street Journal - 17 hours ago

Moody's Investors Service Downgrades Rating on DAIICHI SANKYO CO., ...
Reuters Key Development - Jan 19, 2009

miso · Jan 23, 2009

Re: Daiichi Sankyo to seek approval of influenza drug (Super Relenza)

gsgs,

Yes it is inhaled. Using a more advanced inhaler than that used by GSK for Relenza. Another failing of GSK's Relenza, which is not recommended for young children (under 5), because small children find it difficult to "suck" hard enough to receive an effective dosed.
CS-8958 is two bound zanamivir (Relenza) molecules. One of a number of similar compound owned by Sankyo and Biota, and the one most advanced in clinical trials when they partnered.

I'll post more when I can quote sources.

gsgs · Jan 23, 2009

Re: Daiichi Sankyo to seek approval of influenza drug (Super Relenza)

just make the powder-corns smaller, so children needn't suck so hard ?
Why is Tamiflu not available in powder-form for sucking ?
Should be more efficient than through blood ?!?

it would also be interesting to know, what CS-8958 will cost,
can it replace panflu-stockpiles ?

Presumably it won't work so well for H5N1 which causes systemic
disease, not only respiratory organs. But it may have prophylactic
effect on viruses trying to enter respiratory.
H5N1 can also infect by eating but in a pandemic the main route
should be respiratory.

What will CS-8958 cost ?
If we get a pandemic this year, could they produce immediately,
skipping the usually required trials ?

miso · Jan 23, 2009

Re: Daiichi Sankyo to seek approval of influenza drug (Super Relenza)

gsgs,
It seems CS-8958 is a more than simply two zanamivir cobbled together.
CS-8958 or (R-118958), is an ester prodrug of the neuraminidase inhibitor, R-125489

CS-8958 is a long-acting neuraminidase inhibitor that is expected to be used as
single administration for treatment and once a week for prophylaxis. The compound
is under development as an inhalant that will act directly on the pulmonary and
tracheal sites of infection.

http://www.daiichisankyo.com/4less/cgi-bin/cs4view_obj.php/b_newsrelease_n1_eng/240/070418v1-e.pdf

R-125489, an active form of R-118958, potently inhibited the neuraminidase activity of the influenza viruses to an extent similar to zanamivir...
R-125489 inhibited the replication of influenza viruses in MDCK cells effectively with an IC[50] range of 0.71 to 3.9 nM against influenza A and B viruses, which was 1.6- to 6.4-fold stronger than that of zanamivir.....R-125489, a 4-guanidino-Neu5Ac2en derivative, has potent and specific inhibitory activity against the neuraminidases of various influenza virus strains and inhibits their replications in culture cells effectively.

http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=102266071.html

The results of the pharmacokinetic studies presented in the preceding abstract suggest that (R-118958) was retained in the lung as R-125489, for a long time after its administration.
After reaching the target site, (R-118958) was immediately converted to the active form, R-125489, at the site of viral replication. R-125489 was retained there and then exerted inhibitory action for a long time. The long pulmonary retention of R-125489 and the above-mentioned results suggest that R is a suitable candidate for use in the prevention and treatment of influenza infection.

http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=102266072.html

After its distribution to the lung in rats and mice, (R) was mostly metabolised to the active form, R-125489, in the lung and retained there for a long time. R-125489 was then slowly eliminated into the systemic circulation and excreted mainly into the urine.

http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=102266073.html

Safety, Tolerability and Pharmacokinetics (PK) in Healthy Male Volunteers
Single oral inhalations of 1, 2, 5 and 10mg R-118958 were generally well tolerated in a total of 24 male healthy subjects (6 per group). No serious adverse events, or clinically significant changes in laboratory tests or ECGs were noted. Approximately 2-4% of the parent compound was found unchanged in the urine. More than half of this amount was excreted during the first three hours. The urine levels of the active metabolite were quantifiable up to 96 hour in the 1 mg, 120 hours in the 2 mg and up to 144 hours in the 5 and 10 mg treatment groups after pulmonary deposition.The median total excreted amounts of R-125489 were 79, 229, 494 and 868 microg at 1, 2, 5 and 10 mg respectively, which equals about 8 to 11% of the dose.CONCLUSIONS: R-118958 was generally well tolerated up to 10 mg. The longer retention of the active metabolite R-125489 suggests more convenient regimens in clinical settings than other available neuraminidase inhibitors.

http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=102266075.html

Prophylaxis studies, 0.5 micro-mol/kg of R-118958 (R) or zanamivir (Z) was administered once intranasally 7 or 4 days before infection (500 pfu). On day 20, all mice administered R at -4d survived but only 20% of the mice administered Z at -4d survived. Among the mice given R at -7d, 50% survived but among those given Z at -7d, none survived. Based on the AUC values of viral titers between days 1 and 4 after infection, R was 33-fold more potent than Z. Furthermore, 80-100% of the mice that were administered R (0.5 micro-mol/kg, once) even +2 or +3 days after infection survived but no mice administered Z did....it was suggested that in human, a weekly administration of R-118958 may be sufficient for prophylaxis and a delayed, single administration after infection may be enough for treatment.

http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=102266076.html

gsgs · Jan 23, 2009

Re: Daiichi Sankyo to seek approval of influenza drug (Super Relenza)

thanks. We should keep watching this...

searching google for intravenous zanamivir :

Clinical Infectious Diseases 2009;48:S3–S13
© 2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2009/4801S1-0002$15.00
DOI: 10.1086/591851
SUPPLEMENT ARTICLE
Developing New Antiviral Agents for Influenza Treatment: What Does the Future Hold?
Frederick Hayden
Global Influenza Programme, World Health Organization, Geneva, Switzerland; and University of Virginia School of Medicine, Charlottesville
Antiviral agents for the treatment of influenza are urgently needed to circumvent the limitations of current drugs in several critical areas: high frequencies of resistance to M2 inhibitors among currently circulating strains and variable frequencies of resistance to oseltamivir among A(H1N1) strains, limited efficacy of treatment and treatment‐emergent antiviral resistance in cases of avian influenza A(H5N1) illness in humans, and lack of parenteral agents for seriously ill patients. Two neuraminidase inhibitors (NAIs), zanamivir and peramivir, have undergone or are undergoing clinical trials for use by intravenous or intramuscular administration, and one long‐acting NAI, designated CS‐8958, is under study for use by inhalation. Advances in understanding the mechanisms involved in influenza virus replication have revealed a number of potential targets that might be exploited in the development of new agents. Among these agents are T‐705, a polymerase inhibitor, and DAS181, an attachment inhibitor. Combination therapy with currently available agents is supported by data from animal models but has received limited clinical study to date.
Reprints or correspondence: Dr. Frederick Hayden, University of Virginia School of Medicine, PO Box 800473 Health System, Charlottesville, VA 22908 (fgh@virginia.edu).

------------------------------------------------

Intravenous zanamivir and intramuscular peramivir are currently under evaluation ... Intravenous zanamivir retains activity against most ...

Current Opinion in Infectious Diseases:Volume 21(6)December 2008p 626-638
The potential impact of neuraminidase inhibitor resistant influenza
----------------------------------

Glaxo trial:
http://clinicaltrials.gov/ct2/show/NCT00540501

miso · Jan 23, 2009

Re: Daiichi Sankyo to seek approval of influenza drug (Super Relenza)

gsgs said:
If we get a pandemic this year, could they produce immediately,
skipping the usually required trials ?

Let's hope we don't have to find out.

I.V. Relenza Trials

"GSK has decided not to further develop the intravenous formulation of Zanamivir, and
hence not to provide the drug needed to conduct SEA 003 and SEA 005 studies.
Immediate efforts are being undertaken to obtain the drug from other sources. The
start of both studies will be delayed but, as it is expected that these efforts will be
successful, all protocol and study development activities should continue."

Extract from:
Minutes for the Trial Operations Committee
SEA Influenza Clinical Research Network
Wednesday 07 November 2007

GSK are now supplying the drug, but the trial (Tolerability
and Efficacy of Intravenous Zanamivir) still hasn't started.

gsgs · Jan 6, 2010

Re: Daiichi Sankyo to seek approval of influenza drug (Super Relenza)

Antimicrob Agents Chemother. 2010 Jan 4. [Epub ahead of print]
CS-8958 ( laninamivir prodrug), a long-acting neuraminidase inhibitor, shows superior
anti-influenza virus activity after a single administration.
Kubo S, Tomozawa T, Kakuta M, Tokumitsu A, Yamashita M.
Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan.
... CS-8958 administered just once 7 days before infection showed significant efficacy in vivo. {mice ?}
Then, the efficacy by a single administration of CS-8958 after viral infection was compared with
that by repeated administrations of oseltamivir phosphate or zanamivir in mice and ferrets
and CS-8958 showed superior or similar efficacy to the two licensed NA inhibitors.
CS-8958 also significantly reduced the virus titers of an oseltamivir-resistant H1N1 virus with a neuraminidase H274Y substitution in a mouse infection model.

gsgs · Aug 13, 2010

Re: Daiichi Sankyo to seek approval of influenza drug (Super Relenza)

Laninamivir to be approved within 2 months for usage in Japan ?

http://translate.google.com/transla...A5+%EC%8A%B9%EC%9D%B8%EA%B6%8C%EA%B3%A0&hl=en

Dai Ichi Japanese new flu drug developed by San Kyo 'raninamibireu' (laninamivir) approved the recommendations received from Japan.

Ministry of Health, Pharmaceutical and Food Hygiene Committee of the Council that the 29th Medical pumje 2 yigat according to a decision sooner or later fall through the formal approval is expected to be released this fall. . Ministry of Health, a member from the epidemic period should be to align the supply of opinions and policies naome rush the approval process and about two months is expected to formally approve this even close.

gsgs · Sep 14, 2010

Re: Daiichi Sankyo to seek approval of influenza drug (Super Relenza)

approved now
http://www.cidrap.umn.edu/cidrap/content/influenza/general/news/sep1010antiviral.html

" Inavir "

price ?

is it legal to buy it in Japan and import it ?
(with prescription ?, without prescription ?)

what's the Japanese name

------------------------------------------

http://translate.googleusercontent....le.com&usg=ALkJrhgxo1vEeeDTrOmNbRFJ-1FO-BQFtQ

http://www.daiichisankyo.co.jp/news/20100910_イナビル承認_final.pdf

2010年9月10日 PDF
抗インフルエンザウイルス薬「イナビル（R）吸入粉末剤20㎎」製造販売承認取得のお知らせ

10th September 2010 PDF
Anti-influenza virus drug, "Ina Bill (R) 20 mg inhalation powder," Information obtained marketing approval
Anhören
Umschrift

「イナビル = "Bill Ina
オンライン薬局 = online pharmacy
出荷 = shipping

-----------------------------------

http://www.google.com/search?hl=en&q=「イナビル+価格&aq=f&aqi=&aql=&oq=&gs_rfai=

---------------------------------
http://www.daiichisankyo.co.jp/news/20100910_イナビル承認_final.pdf

--------------------------------------------------
http://translate.google.de/translat...&sa=X&ei=-hAKUf-HH8TotQbg7YFg&ved=0CDsQ7gEwAQ

http://translate.googleusercontent....2.html&usg=ALkJrhi7lso-nTfrhum2wRGezLFZAS8iDg

20mg inhalation powder Inabiru
Drug prices 2080.5 yen per kit = $23

--------------------------------------------------------

gsgs · May 17, 2011

Re: Daiichi Sankyo to seek approval of influenza drug (Super Relenza)

MELBOURNE, Australia--(EON: Enhanced Online News)--Biota Holdings Limited (ASX:BTA) advises that it has received written notification from Daiichi Sankyo that sales of Inavir® were JPY 3.9 billion and royalties to Biota were AUD 1.6 million in the three months to 31 March 2011.

--------------------------------

3.9B Yen ~40M$ ~ 2M doses sold

as compared to .... in Japan for Tamiflu

--------------------------------------------

Tamiflu Sales in the first quarter 2009 were $347 million worldwide, of which Roche noted
that $264 million were pandemic stockpiling and $84 million were from seasonal use.
The large majority of this stockpiling came from Japan at $217 million. Sales in Japan were
up 1200% in the first quarter thanks to the stockpiling. By comparison, U.S. sales in the
first quarter were only $13 million, down 94% year-over-year, as much of the U.S. stockpiling
took place in 2007 and 2008.

gsgs · Jul 1, 2011

Re: Daiichi Sankyo to seek approval of influenza drug (Super Relenza)

protective efficacies of a single, inhaled dose of CS-8958 of 20mg and 40mg as measured
by the Risk Reduction Rate (RRR) were 43.7% and 43.2% respectively but were lower
than the preset RRR endpoint of 70%.
A Phase II/III trial of inhaled CS-8958 in children in Japan also demonstrated equivalent safety and efficacy to Tamiflu dosed orally twice daily for five days; ? CS-8958 is effective against all strains of influenza A and B,

Daiichi Sankyo to seek approval of influenza drug (Super Relenza)

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