Drug: Linzess
Generic molecule: linaclotide
Company: Ironwood Pharmaceuticals
Approval date: Aug. 30,2012

851199-59-2 CAS NO

L-Cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-L-tyrosine cyclo(1-6),(2-10),(5-13)-tris(disulfide)

Linaclotide is a peptide consisting of 14 amino acids. The sequence is

H–Cys¹–Cys²–Glu³–Tyr⁴–Cys⁵–Cys⁶–Asn⁷–Pro⁸–Ala⁹–Cys¹⁰–Thr¹¹–Gly¹²–Cys¹³–Tyr¹⁴–OH

There are three disulfide bonds: Between Cys¹ and Cys⁶, between Cys² and Cys¹⁰, and between Cys⁵ and Cys¹³.^[8]

Linaclotide (marketed under the trade name Linzess) is an experimentalpeptide agonist of guanylate cyclase 2C that is undergoing clinical trials for use in treating abdominal pain in patients with irritable bowel syndrome (IBS) accompanied by constipation. The drug also looks promising in the treatment of gastroparesis, chronic intestinal pseudo-obstruction (CIPO), andinertia coli as well.^[1] The drug was developed by Ironwood Pharmaceuticals, based in Cambridge, Massachusetts.

Linaclotide was approved by the FDA on August 30, 2012 for the treatment of chronic idiopathic constipation and to treat irritable bowel syndrome with constipation (IBS-C) in adults.^[2] It became available in US pharmacies on December 17, 2012. ^[3] That same month, it was forecast by market research firm Decision Resources to achieve blockbuster status by 2021.^[4]

The National Institutes of Health (NIH) estimates that as many as 20% of Americans may experience signs of irritable bowel syndrome, with approximately one-third of those affected experiencing constipation often accompanied by abdominal pain, affecting as many as 10 million Americans.Laxatives can assist with constipation but don’t treat pain, while use ofopiates to treat pain can aggravate constipation. While low-cost laxatives and pain killers would likely be tried first, linaclotide targets both associated conditions in a once-daily pill and could be used if standard treatments are unsuccessful in treating symptoms, though it would likely cost as much as several dollars per day.^[5]

The approval of partner Ironwood’s linaclotide in late August is one of many reasons Forest Labs has been oft-cited as a takeover target in biopharma. Forest markets the drug, which is OK’d for chronic idiopathic constipation and to treat irritable bowel syndrome with constipation. Morgan Stanley has estimated potential peak sales at $2 billion.

1. Tadataka Yamada, ed. (2011). Textbook of Gastroenterology. John Wiley & Sons. ISBN 9781444359411.
2. “FDA approves Linzess to treat certain cases of irritable bowel syndrome and constipation”. 30 Aug 2012.
3. “Ironwood and Forest Announce U.S. Availability of LINZESS”. 17 Dec 2012.
4. “Constella/Linzess Will Achieve Blockbuster Sales of $1.2 Billion in 2021 in the Irritable Bowel Syndrome Drug Market”. 19 Dec 2012.
5. Pollack, Andrew. “Drug for Irritable Bowel Achieves Goals in Trial”, The New York Times, September 13, 2010. Accessed September 14, 2010.
6. Jeffrey M Johnston , Caroline B Kurtz , Douglas A Drossman , Anthony J Lembo , Brenda I Jeglinski , James E MacDougall , Stephen M Antonelli & Mark G Currie . “Pilot Study on the Effect of Linaclotide in Patients With Chronic Constipation”, The American Journal of Gastroenterology 104, 125–132 (1 January 2009) | doi:10.1038/ajg.2008.59. Accessed September 15, 2010.
7. Staff. “Daily International Pharma Alert”, FDANews, September 17, 2007, Vol. 4 No. 182. Accessed September 15, 2010.
8. Albericio, F; Giraud, M; Gongora, M; Paradis, M; Tulla-Puche, J; Werbitzky, O. Solid-Phase Synthesis of the Cys-rich Peptide Linaclotide.

DR ANTHONY CRASTO,

Drug Name: Afinitor (everolimus)

Company: Novartis
Approval Status: Approved July 2012
Treatment Area: hormone receptor-positive, HER2-negative breast cancer

General Information

Everolimus (RAD-001) is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR).

It is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer and other tumours. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers.

It is marketed by Novartis under the tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine, and Afinitor in oncology.

1. R.N Formica Jra, K.M Lorberb, A.L Friedmanb, M.J Biaa, F Lakkisa, J.D Smitha, M.I Lorber (March 2004). “The evolving experience using everolimus in clinical transplantation”. Elsevier 36 (2): S495–S499.
2. “Afinitor approved in US as first treatment for patients with advanced kidney cancer after failure of either sunitinib or sorafenib” (Press release). Novartis. 2009-03-30. Retrieved April 6, 2009.
3. “Novartis receives US FDA approval for Zortress (everolimus) to prevent organ rejection in adult kidney transplant recipients” (Press release). Novartis. 2010-04-22. Retrieved April 26, 2010.
4. “Novartis’ Afinitor Cleared by FDA for Treating SEGA Tumors in Tuberous Sclerosis”. 1 Nov 2010.
5. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254350.htm
6. “US FDA approves Novartis drug Afinitor for breast cancer”. 20 Jul 2012.

Drug: Signifor

SIGNIFOR (pasireotide diaspartate) injection is prepared as a sterile solution of pasireotide diaspartate in a tartaric acid buffer for administration by subcutaneous injection. SIGNIFOR is a somatostatin analog. Pasireotide diaspartate, chemically known as (2-Aminoethyl) carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3ylmethyl)-4,7,10,13,16,19-hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18hexaazacyclopentacyclooctadecen-2-yl ester, di[(S)-2-aminosuccinic acid] salt, is a cyclohexapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin.

The molecular formula of pasireotide diaspartate is C₅₈H₆₆N₁₀O₉ • 2C₄H₇NO₄ and the molecular weight is 1313.41. SIGNIFOR is supplied as a sterile solution in a single-dose, 1 mL colorless glass ampule containing pasireotide in 0.3 mg/mL, 0.6 mg/mL, or 0.9 mg/mL strengths for subcutaneous injection.

isopropyl (5Z)-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxybut-1-en-1-yl]-3,5-dihydroxycyclopentyl}hept-5-enoate,

Drug: Zioptan
Generic molecule: tafluprost
Company: Merck
Approval date: Feb. 10, 2012

The scoop: Merck says this is the first (get ready for a mouthful) preservative-free prostaglandin analog ophthalmic solution and is for treating elevated eye pressure in some patients with the most common form of glaucoma. Merck sells the ointment in the U.S. and most of Europe, while it licensed it to Japanese drugmaker Santen in Japan, Germany and northern Europe.

Tafluprost (trade names Taflotan, marketed by Santen Pharmaceutical Co. and Zioptan, by Merck (U.S.)) is a prostaglandin analogue used topically (as eye drops) to control the progression of glaucoma and in the management of ocular hypertension. It reduces intraocular pressure by increasing the outflow of aqueous fluid from the eyes.^[1][2]

Taflotan contains 15 µg/ml Tafluprost. Taflotan sine is a preservative-free, single-dose formulation containing 0.3 ml per dose.^[3]

References

(1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-Dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H-2,8a-methanocyclopenta[a]cyclpropa[e][10]annulen-6-yl (2Z)-2-methylbut-2-enoate

Ingenol mebutate (ingenol-3-angelate, trade name Picato) cas no 75567-37-2

Drug: Picato
Generic molecule: ingenol mebutate
Company: leo pharma
Approval date: Jan. 23

Picato is a topical treatment for actinic keratosis (AK), a precancerous condition that can lead to squamous cell carcinoma (SCC), the second most common type of skin cancer. The topical gel treatment is completed within two or three days, compared with the weeks or even months other options require.

Ingenol mebutate (ingenol-3-angelate, trade name Picato) is a substance found in the sap of the plant Euphorbia peplus^[1] and an inducer of cell death. A gel formulation of the drug has been approved by the U.S. Food and Drug Administration (FDA) for the topical treatment of actinic keratosis.^[2] Two different strengths of the gel are approved for use on either the face and scalp (0.015%) or the trunk and extremities (0.05%), respectively.^[3]

Results from four multicenter, randomized, double-blind studies have shown that ingenol mebutate gel applied topically for 2 to 3 days is effective for field treatment of actinic keratoses.^[4]

The substance is an ester of a diterpene and angelic acid.

References