Patiromer

Patiromer

1260643-52-4 FREE FORM

CAS 1208912-84-8

(C₁₀ H₁₀ . C₈ H₁₄ . C₃ H₃ F O₂ . ¹/₂ Ca)_x

2-​Propenoic acid, 2-​fluoro-​, calcium salt (2:1)​, polymer with diethenylbenzene and 1,​7-​octadiene

RLY5016

RELYPSA INNOVATOR

Patiromer is a powder for suspension in water for oral administration, approved in the U.S. as Veltassa in October, 2015. Patiromer is supplied as patiromer sorbitex calcium which consists of the active moiety, patiromer, a non-absorbed potassium-binding polymer, and a calcium-sorbitol counterion. Each gram of patiromer is equivalent to a nominal amount of 2 grams of patiromer sorbitex calcium. The chemical name for patiromer sorbitex calcium is cross-linked polymer of calcium 2-fluoroprop-2-enoate with diethenylbenzene and octa-1,7-diene, combination with D-glucitol. Patiromer sorbitex calcium is an amorphous, free-flowing powder that is composed of individual spherical beads.
Veltassa is a powder for suspension in water for oral administration. The active ingredient is patiromer sorbitex calcium which consists of the active moiety, patiromer, a non-absorbed potassium-binding polymer, and a calcium-sorbitol counterion.

Each gram of patiromer is equivalent to a nominal amount of 2 grams of patiromer sorbitex calcium. The chemical name for patiromer sorbitex calcium is cross-linked polymer of calcium 2-fluoroprop-2-enoate with diethenylbenzene and octa-1,7-diene, combination with D-glucitol.

Mechanism of Action

Veltassa is a non-absorbed, cation exchange polymer that contains a calcium-sorbitol counterion. Veltassa increases fecal potassium excretion through binding of potassium in the lumen of the gastrointestinal tract. Binding of potassium reduces the concentration of free potassium in the gastrointestinal lumen, resulting in a reduction of serum potassium levels.

Treatment of Hyperkalemia
Hyperkalemia is usually asymptomatic but occasionally can lead to life-threatening cardiac arrhythmias and increased all-cause and in-hospital mortality, particularly in patients with CKD and associated cardiovascular diseases (Jain et al., 2012; McMahon et al., 2012; Khanagavi et al., 2014). However, there is limited evidence from randomized clinical trials regarding the most effective therapy for acute management of hyperkalemia (Khanagavi et al., 2014) and a Cochrane analysis of emergency interventions for hyperkalemia found that none of the studies reported mortality or cardiac arrhythmias, but reports focused on P_K (Mahoney et al., 2005). Thus, recommendations are based on opinions and vary with institutional practice guidelines (Elliot et al., 2010; Khanagavi et al., 2014). Management of hyperkalemia includes reducing potassium intake, discontinuing potassium supplements, treatment of precipitating risk factors, and careful review of prescribed drugs affecting potassium homeostasis. Treatment of life-threatening hyperkalemia includes nebulized or inhaled beta-agonists (albuterol, salbutamol) or intravenous (IV) insulin-and-glucose, which stimulate intracellular potassium uptake, their combination being more effective than either alone. When arrhythmias are present, IV calcium might stabilize the cardiac resting membrane potential. Sodium bicarbonate may be indicated in patients with severe metabolic acidosis. Potassium can be effectively eliminated by hemodialysis or increasing its renal (loop diuretics) and gastrointestinal (GI) excretion with sodium polystyrene sulfonate, an ion-exchange resin that exchanges sodium for potassium in the colon. However, this resin produces serious GI adverse events (ischemic colitis, bleeding, perforation, or necrosis). Therefore, there is an unmet need of safer and more effective drugs producing a rapid and sustained P_K reduction in patients with hyperkalemia.
In this article we review two new polymer-based, non-systemic oral agents, patiromer calcium (RLY5016) and zirconium silicate (ZS-9), under clinical development designed to induce potassium loss via the GI tract, particularly the colon, and reduce P_K in patients with hyperkalemia.
1. Patiromer calcium
This metal-free cross-linked fluoroacrylate polymer (structure not available) exchanges cations through the gastrointestinal (GI) tract. It preferentially binds soluble potassium in the colon, increases its fecal excretion and reduces P_K under hyperkalemic conditions.
The development program of patiromer includes several clinical trials. An open-label, single-arm study evaluated a titration regimen for patiromer in 60 HF patients with CKD treated with ACEIs, ARBs, or beta blockers (clinicaltrials.gov identifier: NCT01130597). Another open-label, randomized, dose ranging trial determined the optimal starting dose and safety of patiromer in 300 hypertensive patients with diabetic nephropathy treated with ACEIs and/or ARBs, with or without spironolactone (NCT01371747). The primary outcomes were the change in P_K from baseline to the end of the study. Unfortunately, the results of these trials were not published.
In a double-blind, placebo-controlled trial (PEARL-HF, NCT00868439), 105 patients with a baseline P_K of 4.7 mmol/L and HF (NYHA class II-III) treated with spironolactone in addition to standard therapy were randomized to patiromer (15 g) or placebo BID for 4 weeks (Pitt et al., 2011). Spironolactone, initiated at 25 mg/day, was increased to 50 mg/day on day 15 if P_K was ≤5.1 mmol/L. Patients were eligible for the trial if they had either CKD (eGFR <60 ml/min) or a history of hyperkalemia leading to discontinuation of RAASIs or beta-blockers. Compared with placebo, patiromer decreased the P_K (-0.22 mmol/L, while P_K increased in the placebo group +0.23 mmol/L, P<0.001), and the incidence of hyperkalemia (7% vs. 25%, P=0.015) and increased the number of patients up-titrated to spironolactone 50 mg/day (91% vs. 74%, P=0.019). A similar reduction in P_K and hyperkalemia was observed in patients with an eGFR <60 ml/min. Patiromer produced more GI adverse events (flatulence, diarrhea, constipation, vomiting: 21% vs 6%), hypokalemia (<4.0 mmol/L: 47% vs 10%, P<0.001) and hypomagnesaemia (<1.8 mg/dL: 24% vs. 2.1%), but similar adverse events leading to study discontinuation compared to placebo. Unfortunately, recruited patients had normokalemia and basal eGFR in the treatment group was 84 ml/min. Thus, this study did not answer whether patiromer is effective in reducing P_K in patients with CKD and/or HF who develop hyperkalemia on RAASIs.
A two-part phase 3 study evaluated the efficacy and safety of patiromer in the treatment of hyperkalemia (NCT01810939). In a single-blind phase (part A) 243 patients with hyperkalemia and CKD (102 with HF) on RAASIs were treated with patiromer BID for 4 weeks: 4.2 g in patients with mild hyperkalemia (5.1-<5.5 mmol/L, n=92) and 8.4 g in patients with moderate-to-severe hyperkalemia (5.5-<6.5 mmol/L, n=151). Part B was a placebo-controlled, randomized, withdrawal phase designed to confirm the maintained efficacy of patiromer and the recurrent hyperkalemia following that drug’s withdrawal. Patients (n=107) who completed phase A with a normal P_K were randomized to continue on patiromer (27 with HF) or placebo (22 with HF) besides RAASIs for 8 weeks. The primary endpoint was the difference in mean P_K between the patiromer and placebo groups from baseline to the end of the study or when the patient first had a P_K <3.8 or ≥5.5 mmol/L. In part A patiromer produced a rapid reduction in P_K that persisted throughout the study in patients with and without HF (-1.06 and -0.98 mmol/L, respectively; both P<0.001 vs. placebo); three-fourths of patients in both groups had normal P_K (3.8-<5.1 mmol/L) at 4 weeks. In part B patiromer reduced P_K (-0.64 mmol/L) in patients with or without HF (P<0.001). As compared with placebo, fewer patients, with or without HF, presented recurrent hyperkalemia in the patiromer group or required RAASI discontinuation regardless of HF status (Pitt, 2014). Patiromer was well-tolerated, with a safety profile similar to placebo even in HF patients. The most common adverse events were nausea, diarrhea, and hypokalemia.

INDICATIONS AND USAGE

Veltassa is a potassium binder indicated for the treatment of hyperkalemia.
Veltassa should not be used as an emergency treatment for lifethreatening hyperkalemia because of its delayed onset of action.
Patiromer (USAN, trade name Veltassa) is a drug used for the treatment of hyperkalemia (elevated blood potassium levels), a condition that may lead to palpitations and arrhythmia (irregular heartbeat). It works by binding potassium in the gut.^[1][2]

Medical uses

Patiromer is used for the treatment of hyperkalemia, but not as an emergency treatment for life-threatening hyperkalemia, because it acts relatively slowly.^[2] Such a condition needs other kinds of treatment, for example calcium infusions, insulin plus glucose infusions, salbutamol inhalation, and hemodialysis.^[3]
Typical reasons for hyperkalemia are renal insufficiency and application of drugs that inhibit the renin–angiotensin–aldosterone system (RAAS) – e.g. ACE inhibitors, angiotensin II receptor antagonists, or potassium-sparing diuretics – or that interfere with renal function in general, such as nonsteroidal anti-inflammatory drugs (NSAIDs).^[4][5]

Adverse effects

Patiromer was generally well tolerated in studies. Side effects that occurred in more than 2% of patients included in clinical trials were mainly gastro-intestinal problems such as constipation, diarrhea, nausea, and flatulence, and also hypomagnesemia (low levels of magnesium in the blood) in 5% of patients, because patiromer binds magnesium in the gut as well.^[2][6]

Interactions

No interaction studies have been done in humans. Patiromer binds to many substances besides potassium, including numerous orally administered drugs (about half of those tested in vitro). This could reduce their availability and thus effectiveness,^[2] wherefore patiromer has received a boxed warning by the US Food and Drug Administration (FDA), telling patients to wait for at least six hours between taking patiromer and any other oral drugs.^[7]

Pharmacology

Mechanism of action

Patiromer works by binding free potassium ions in the gastrointestinal tract and releasing calcium ions for exchange, thus lowering the amount of potassium available for absorption into the bloodstream and increasing the amount that is excreted via the feces. The net effect is a reduction of potassium levels in the blood serum.^[2][4]
Lowering of potassium levels is detectable 7 hours after administration. Levels continue to decrease for at least 48 hours if treatment is continued, and remain stable for 24 hours after administration of the last dose. After this, potassium levels start to rise again over a period of at least four days.^[2]

Pharmacokinetics

Patiromer is not absorbed from the gut, is not metabolized, and is excreted in unchanged form with the feces.^[2]

Physical and chemical properties

The substance is a cross-linked polymer of 2-fluoroacrylic acid (91% in terms of amount of substance) with divinylbenzenes (8%) and 1,7-octadiene (1%). It is used in form of its calcium salt (ratio 2:1) and with sorbitol (one molecule per two calcium ions or four fluoroacrylic acid units), a combination called patiromer sorbitex calcium.^[8]

• 

  2-fluoroacrylic acid
• 

  o-divinylbenzene
• 

  p-divinylbenzene
• 

  1,7-octadiene

Patiromer sorbitex calcium is an off-white to light brown, amorphous, free-flowing powder. It is insoluble in water, 0.1 M hydrochloric acid, heptane, and methanol.^[2][8]
Hyperkalemia Is a Clinical Challenge
Hyperkalemia may result from increased potassium intake, impaired distribution between the intracellular and extracellular spaces, and/or conditions that reduce potassium excretion, including CKD, hypertension, diabetes mellitus, or chronic heart failure (HF) (Jain et al., 2012). Additionally, drugs and nutritional/herbal supplements (Table 1) can produce hyperkalemia in up to 88% of hospitalized patients by impairing normal potassium regulation (Hollander-Rodríguez and Calvert, 2006; Khanagavi et al., 2014).
Although the prevalence of hyperkalemia in the general population is unknown, it is present in 1-10% of hospitalized patients depending on how hyperkalemia is defined (McMahon et al., 2012; Gennari, 2002). Hyperkalemia is a common problem in patients with conditions that reduce potassium excretion, especially when treated with beta-adrenergic blockers that inhibit Na⁺,K⁺-ATPase activity or RAAS inhibitors (RAASIs) [angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists or renin inhibitors] that decrease aldosterone excretion (Jain et al., 2012; Weir and Rolfe, 2010). The incidence of hyperkalemia with RAASIs in monotherapy is low (≤2%) in patients without predisposing factors, but increases with dual RAASIs (5%) and in patients with risk factors such as CKD, HF, and/or diabetes (5-10%) (Weir and Rolfe, 2010). Thus, hyperkalemia is a key limitation to fully titrate RAASIs in these patients who are most likely to benefit from treatment. Thus, we need new drugs to control hyperkalemia in these patients while maintaining the use of RAASIs.

History

Studies

In a Phase III multicenter clinical trial including 237 patients with hyperkalemia under RAAS inhibitor treatment, 76% of participants reached normal serum potassium levels within four weeks. After subsequent randomization of 107 responders into a group receiving continued patiromer treatment and a placebo group, re-occurrence of hyperkalemia was 15% versus 60%, respectively.^[9]

Approval

The US FDA approved patiromer in October 2015.^[7] The drug is not approved in Europe as of January 2016.

PATENT

WO 2010132662

PATENT

WO 2010022383

References

• 1 Henneman, A; Guirguis, E; Grace, Y; Patel, D; Shah, B (2016). "Emerging therapies for the management of chronic hyperkalemia in the ambulatory care setting". American Journal of Health-System Pharmacy 73 (2): 33–44. doi:10.2146/ajhp150457. PMID 26721532.
• 2FDA Professional Drug Information for Veltassa.
• 3Vanden Hoek TL, Morrison LJ, Shuster M, Donnino M, Sinz E, Lavonas EJ, Jeejeebhoy FM, Gabrielli A; Morrison; Shuster; Donnino; Sinz; Lavonas; Jeejeebhoy; Gabrielli (2010-11-02). "Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care". Circulation 122 (18 Suppl 3): S829–61. doi:10.1161/CIRCULATIONAHA.110.971069. PMID 20956228.
• 4Esteras, R.; Perez-Gomez, M. V.; Rodriguez-Osorio, L.; Ortiz, A.; Fernandez-Fernandez, B. (2015). "Combination use of medicines from two classes of renin-angiotensin system blocking agents: Risk of hyperkalemia, hypotension, and impaired renal function". Therapeutic Advances in Drug Safety 6 (4): 166. doi:10.1177/2042098615589905. PMID 26301070.
• 5Rastegar, A; Soleimani, M (2001). "Hypokalaemia and hyperkalaemia". Postgraduate Medical Journal 77 (914): 759–64. doi:10.1136/pmj.77.914.759. PMC 1742191. PMID 11723313.
• 6Tamargo, J; Caballero, R; Delpón, E (2014). "New drugs for the treatment of hyperkalemia in patients treated with renin-angiotensin-aldosterone system inhibitors -- hype or hope?". Discovery medicine 18 (100): 249–54. PMID 25425465.
• 7"FDA approves new drug to treat hyperkalemia". FDA. 21 October 2015.
• 8RxList: Veltassa.
• 9Weir, Matthew R.; Bakris, George L.; Bushinsky, David A.; Mayo, Martha R.; Garza, Dahlia; Stasiv, Yuri; Wittes, Janet; Christ-Schmidt, Heidi; Berman, Lance; Pitt, Bertram (2015). "Patiromer in Patients with Kidney Disease and Hyperkalemia Receiving RAAS Inhibitors". New England Journal of Medicine 372 (3): 211. doi:10.1056/NEJMoa1410853. PMID 25415805.

Systematic (IUPAC) name
2-Fluoropropenoic acid, cross-linked polymer with diethenylbenzene and 1,7-octadiene
Clinical data
Trade names	Veltassa
AHFS/Drugs.com	entry
Legal status	US: ℞-only
Routes of administration	Oral suspension
Pharmacokinetic data
Bioavailability	Not absorbed
Metabolism	None
Onset of action	7 hrs
Duration of action	24 hrs
Excretion	Feces
Identifiers
CAS Number	1260643-52-4 1208912-84-8 (calcium salt)
ATC code	None
PubChem	SID 135626866
DrugBank	DB09263
UNII	1FQ2RY5YHH
KEGG	D10148
ChEMBL	CHEMBL2107875
Synonyms	RLY5016
Chemical data
Formula	[(C3H3FO2)182·(C10H10)8·(C8H14)10]n [Ca91(C3H2FO2)182·(C10H10)8·(C8H14)10]n (calcium salt)

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The Year In New Drugs ..........Speedier development and regulatory process contributed to a peak in product approvals in 2015

 

 

SURGE

New drug approvals have risen sharply in recent years. SOURCE: FDA

The Year In New Drugs

Speedier development and regulatory process contributed to a peak in product approvals in 2015

 

 

read at 

 

Volume 94 Issue 5 | pp. 12-17
Issue Date: February 1, 2016

http://cen.acs.org/articles/94/i5/Year-New-Drugs.html
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Fresolimumab

Fresolimumab
GC 1008, GC1008
UNII-375142VBIA
cas 948564-73-6
Structure

• immunoglobulin G4, anti-(human transforming growth factors beta-1, beta-2 (G-TSF or cetermin) and beta-3), human monoclonal GC-1008 γ4 heavy chain (134-215′)-disulfide with human monoclonal GC-1008 κ light chain, dimer (226-226”:229-229”)-bisdisulfide
• immunoglobulin G4, anti-(transforming growth factor β) (human monoclonal GC-1008 heavy chain), disulfide with human monoclonal GC-1008 light chain, dimer

For Idiopathic Pulmonary Fibrosis, Focal Segmental Glomerulosclerosis,and Cancer
An anti-TGF-beta antibody in phase I clinical trials (2011) for treatment-resistant primary focal segmental glomerulosclerosis.
A pan-specific, recombinant, fully human monoclonal antibody directed against human transforming growth factor (TGF) -beta 1, 2 and 3 with potential antineoplastic activity. Fresolimumab binds to and inhibits the activity of all isoforms of TGF-beta, which may result in the inhibition of tumor cell growth, angiogenesis, and migration. TGF-beta, a cytokine often over-expressed in various malignancies, may play an important role in promoting the growth, progression, and migration of tumor cells.


Fresolimumab (GC1008) is a human monoclonal antibody^[1] and an immunomodulator. It is intended for the treatment of idiopathic pulmonary fibrosis (IPF), focal segmental glomerulosclerosis, and cancer^[2][3] (kidney cancer and melanoma).
It binds to and inhibits all isoforms of the protein transforming growth factor beta (TGF-β).^[2]

History

Fresolimumab was discovered by Cambridge Antibody Technology (CAT) scientists^[4] and was one of a pair of candidate drugs that were identified for the treatment of the fatal condition scleroderma. CAT chose to co-develop the two drugs metelimumab (CAT-192) and fresolimumab with Genzyme. During early development, around 2004, CAT decided to drop development of metelimumab in favour of fresolimumab.^[5]
In February 2011 Sanofi-Aventis agreed to buy Genzyme for US$ 20.1 billion.^[6]
As of June 2011 the drug was being tested in humans (clinical trials) against IPF, renal disease, and cancer.^[7][8] On 13 August 2012, Genzyme applied to begin a Phase 2 clinical trial in primary focal segmental glomerulosclerosis^[9] comparing fresolimumab versus placebo.
As of July 2014, Sanofi-Aventis continue to list fresolimumab in their research and development portfolio under Phase II development.^[10]

References

1 WHO Drug Information
2 National Cancer Institute: Fresolimumab

• 3 Statement On A Nonproprietary Name Adopted By The USAN Council – Fresolimumab
• 4 Grütter, Christian; Wilkinson, Trevor; Turner, Richard; Podichetty, Sadhana; Finch, Donna; McCourt, Matthew; Loning, Scott; Jermutus, Lutz; Grütter, Markus G. (2008-12-23). “A cytokine-neutralizing antibody as a structural mimetic of 2 receptor interactions”. Proceedings of the National Academy of Sciences 105 (51): 20251–20256. doi:10.1073/pnas.0807200106. ISSN 0027-8424. PMC 2600578. PMID 19073914.
• 5 http://www.independent.co.uk/news/business/news/cat-may-abandon-skin-drug-after-trial-results-disappoint-569445.html
• 6 http://www.bbc.co.uk/news/business-12477750
• 7 http://www.genengnews.com/gen-news-highlights/scientists-trigger-white-fat-to-become-brown-fat-like-to-treat-obesty-and-type-2-diabetes/81245389/
• 8 Clinicaltrials.gov for Fresolimumab
• 9 http://clinicaltrials.gov/show/NCT01665391
• 10 http://en.sanofi.com/rd/rd_portfolio/rd_portfolio.aspx

Fresolimumab

Monoclonal antibody
Type	Whole antibody
Source	Human
Target	TGF beta 1, 2 and 3
Clinical data
Legal status	Investigational
Identifiers
CAS Number	948564-73-6
ATC code	None
ChemSpider	none
KEGG	D09620
Chemical data
Formula	C6392H9926N1698O2026S44
Molar mass	144.4 kDa

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Monoclonal antibodies for the immune system
Immune system (“-l(i[m])-“)	Human (“-limu-“) immunosuppression: Abrilumab Adalimumab Anifrolumab Atorolimumab Belimumab Brodalumab Carlumab Dupilumab Durvalumab Eldelumab Fresolimumab Golimumab Lerdelimumab Lirilumab Mavrilimumab Metelimumab Morolimumab Namilumab Oxelumab§ Placulumab Sarilumab Sifalimumab Tabalumab Ulocuplumab Varlilumab immune activation: Ipilimumab Nivolumab Pembrolizumab Tremelimumab Urelumab other: Bertilimumab Zanolimumab Mouse (“-limo-“) Afelimomab Elsilimomab Faralimomab Gavilimomab Inolimomab Maslimomab Nerelimomab Odulimomab Telimomab aritox Vepalimomab Zolimomab aritox Chimeric (“-lixi-“) Basiliximab Clenoliximab Galiximab Gomiliximab Infliximab Keliximab Lumiliximab Priliximab Teneliximab Vapaliximab Humanized (“-lizu-“) immunosuppressive: Aselizumab Apolizumab Benralizumab† Cedelizumab Certolizumab pegol Daclizumab Eculizumab Efalizumab Epratuzumab Erlizumab Etrolizumab Fontolizumab Itolizumab Lampalizumab Ligelizumab Lulizumab pegol Mepolizumab Mogamulizumab Natalizumab Ocrelizumab Omalizumab Ozoralizumab Pascolizumab Pateclizumab Pembrolizumab Pexelizumab Pidilizumab PRO 140† Reslizumab Rontalizumab Rovelizumab Ruplizumab Quilizumab Samalizumab Siplizumab Talizumab Teplizumab Tocilizumab Toralizumab Tregalizumab Vatelizumab Vedolizumab Visilizumab TGN1412§ non-immunosuppressive: Ibalizumab† Chimeric + humanized (“-lixizu-“) Otelixizumab
Interleukin (“-k(i[n])-“)	Human (“-kinu-“) Briakinumab Canakinumab Fezakinumab Fletikumab Guselkumab Secukinumab Sirukumab Tralokinumab Ustekinumab Humanized (“-kizu-“, “-kinzu-“) Anrukinzumab Clazakizumab Enokizumab Gevokizumab Ixekizumab Lebrikizumab Olokizumab Perakizumab Tildrakizumab
Inflammatory lesions (“-les-“)	Mouse (“-leso-“) Besilesomab Fanolesomab‡ Lemalesomab Sulesomab
#WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III v t e Index of the immune system Description Physiology cells autoantigens autoantibodies complement surface antigens IG receptors Disease Allergies Immunodeficiency Immunoproliferative immunoglobulin disorders Hypersensitivity and autoimmune disorders Neoplasms and cancer Treatment Procedures Drugs antihistamines immunostimulants immunosuppressants monoclonal antibodies

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What was the drug in Clinical Trial Tragedy In France Jan 2016

BIA 10-2474
cas 1233855-46-3
3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide
1H-​Imidazole-​1-​carboxamide, N-​cyclohexyl-​N-​methyl-​4-​(1-​oxido-​3-​pyridinyl)​-
C₁₆ H₂₀ N₄ O_2, 300.36

Bial-Portela & Ca. S.A.

BIA 10-2474 is an experimental fatty acid amide hydrolase inhibitor^[1] developed by the Portuguese pharmaceutical company Bial-Portela & Ca. SA. The drug was developed to relieve pain,^[2][3] to ease mood and anxiety problems, and to improve movement coordination linked to neurodegenerative illnesses.^[4] It interacts with the human endocannabinoid system.^[5][6] It has been linked to severe adverse events affecting 5 patients in a drug trial in Rennes, France, and at least one death, in January 2016.^[7]

 Synthesis

 WO 2014017938

BIAL – PORTELA & Cª, S.A.
Example 5. 3-(l-(cyclohexyl(methyl)carbamoyl-lfl-imidazol-4-yl)pyridine l-oxide (compound A)

C₁₆H₂₀N₄O                                 C16H20N4O2
MW 284,36                                              MW 300,36
To a solution of N-cyclohexyl-N-methyl-4-(pyridm-3-yl)-lH-imidazole-l-carboxamide in dichioromethane at 25°C was added peracetic acid (38%; the concentration is not critical, and may be varied) in a single portion. The reaction mixture was then maintained at 25°C for at least 20 h, whereupon the reaction was washed four times with water (in some embodiments, the water for the extraction step may be supplemented with a small amount (e.g. 1%) of acetic acid, which helps to promote product solubility in the DCM). The dichioromethane solution was then filtered prior to diluting with 2-propanol. Dichioromethane (50%) was then distilled off under atmospheric pressure, whereupon, 2-propanol was charged at the same rate as the distillate was collected. The distillation was continued until >90% of the dichioromethane was collected. The resulting suspension was then cooled to 20°C and aged for at least 30 min. prior to cooling to 0°C and aging for a further 60 min. The reaction mixture was then filtered and the product washed with additional 2-propanol, before drying at 50°C under vacuum to afford the title compound as an off-white crystalline solid.
The purity of the product was ascertained by HPLC, with identity confirmable by NMR. The yield was consistently >80% in several production runs.

PATENT

WO 2012015324
Example 1. Preparation of N-cyclohexyl-N-methyl-4-(pyridin-3yl)-lH-imidazole-l-carboxamide

C₈H₇N₃ C₁₅H_{1 1}N₃0₂ C₁₆H₂₀N₄O
MW 145,16 MW 265,27 MW 284,36
To a suspension of 3-(l/ -imidazol-4-yl)pyridine in tetrahydrofuran (THF) containing pyridine at 25°C was slowly added a solution of phenyl chloroformate in THF over 60 to 90 min. The resulting fine white suspension was then maintained at 25°C for at least 60 min. before the addition of N-methyl- -cyclohexylamine in a single portion, causing the suspension to thin and become yellow in colour. The reaction mixture was then stirred for 90 min. before filtering and washing the filter cake with additional THF. The mother liquors were then maintained at 25°C for at least 18 h, whereupon 65% of the volume of THF was distilled off under atmospheric pressure. The resulting solution was then diluted with 2-propanol and maintained at > 50°C for 10 min. prior to cooling down to 20°C. The resulting suspension was aged at 20°C for 15 min. prior to cooling to 0°C and aging for a further 60 min. The reaction mixture was then filtered and the product was washed with additional 2-propanol, before drying at 50°C under vacuum to afford the title compound as an off-white crystalline solid.
The purity of the product was ascertained by HPLC, with identity confirmable by NMR. The yield was consistently around 50% in several production runs.
Example 2. 3-(l-(cyclohexyl(methyl)carbamoyl-l//-imidazol-4-yl)pyridine 1 -oxide (compound A)

C₁₆H₂₀N₄O Ci6H2oN₄0₂
MW 284,36 MW 300,36
To a solution of N-cyclohexyl-N-methyl-4-(pyridin-3-yl)-lH-imidazole-l-carboxamide in dichloromethane at 25°C was added peracetic acid (38%; the concentration is not critical, and may be varied) in a single portion. The reaction mixture was then maintained at 25°C for at least 20 h, whereupon the reaction was washed four times with water. The dichloromethane solution was then filtered prior to diluting with 2-propanol. Dichloromethane (50%) was then distilled off under atmospheric pressure, whereupon, 2-propanol was charged at the same rate as the distillate was collected. The distillation was continued until >90% of the dichloromethane was collected. The resulting suspension was then cooled to 20°C and aged for at least 30 min. prior to cooling to 0°C and aging for a further 60 min. The reaction mixture was then filtered and the product washed with additional 2-propanol, before drying at 50°C under vacuum to afford the title compound as an off-white crystalline solid.
The purity of the product was ascertained by HPLC, with identity confirmable by NMR. The yield was consistently >80% in several production runs. It will be appreciated that this gives an overall yield of compound A many times greater than that achieved in the prior art.
In a further run of this synthesis, in a 2L reactor to a mixture of N-cyclohexyl-N-methyl-4-(pyridin-3-yl)-l H- imidazole-l-carboxamide (90 g, 317 mmol) and dichloromethane (1350 ml) was added peracetic acid (84 ml, 475 mmol). The reaction mixture was stirred at 25°C. Completion of the reaction was monitored by HPLC for the disappearance of N-cyclohexyl-N-methyl-4-(pyridin-3-yl)-lH- imidazole- 1-carboxamide. After reaction completion a solution of sodium metabisulfite (60.2 g, 317 mmol) in water (270ml) was added to the reaction mixture maintaining the temperature below 30°C. After phase separation the organic phase was washed with water. After phase separation the organic phase was concentrated at atmospheric pressure until 5 vol. Then solvent was swapped to isopropanol (1350 ml) and the suspension was cooled to 0°C during 4 hours and stirred at that temperature for 1 hour. The resulting solid was collected by filtration and was rinsed with water (270 ml) and isopropanol (270 ml) to afford a white crystalline solid in 84.8g (89%).
PATENT
WO 2010074588
Preparation of compound 362 a) N-cyclohexyl-N-methyl-4-(pyridin-3-yl)- 1 H-imidazole- 1 -carboxamide

To a stirred suspension of 3-( 1 H-imidazol-4-yl)pyridine dihydrochloride (1.745 g, 8 mmol) in a mixture of tetrahydrofuran (29 mL) and DMF (2.90 mL) was added potassium 2-methylpropan-2-olate (1.795 g, 16.0 mmol) and the mixture was refluxed for 30 minutes. The resulting brown suspension was cooled to room temperature and treated with pyridine (0.979 mL, 12 mmol) and N,N-dimethylpyridin-4-amine (0.098 g, 0.8 mmol), followed by the addition of cyclohexyl(methyl)carbamic chloride (1.476 g, 8.4 mmol). The reaction was heated to 90 ⁰C overnight, whereupon the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried (MgSO^) and filtered. After evaporation, the crude product was chromatographed over silica gel using a dichloromethane/methanol (9:1) mixture. Homogenous fractions were pooled and evaporated to leave a white powder, (160 mg, 7 %).
b) 3-( 1 -(cyclohexyl(methyl)carbamoyl)- 1 H-imidazol-4-yl)pyridine 1 -oxide

To a stirred solution of N-cyclohexyl-N-methyl-4-(pyridin-3-yl)-l H-imidazole- 1 -carboxamide (90 mg, 0.317 mmol) in chloroform (5 mL) was added 3-chlorobenzoρeroxoic acid (149 mg, 0.475 mmol) in one portion. The reaction was allowed to stir at room temperature for 20 h. TLC showed the reaction to be complete and the mixture was evaporated to dryness. The residue was triturated with ether and the resulting white crystals were filtered off and dried in air. Recrystallisation from hot isopropanol gave a white powder (46 mg, 46 %).

Structure and action

French newspaper Le Figaro has obtained Bial study protocol documents listing the the chemical name of BIA-10-2474 as 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide.^[8] A Bial news release described BIA-10-2474 as “a long-acting inhibitor of FAAH”.^[9]
Fatty acid amide hydrolase (FAAH) is an enzyme which degrades endocannabinoid neurotransmitters like anandamide,^[10] which relieves pain and can affect eating and sleep patterns.^[11][12] FAAH inhibitors have been proposed for a range of nervous-system disorders including anxiety, alcoholism, pain and nausea.
The Portuguese pharmaceutical company Bial holds several patents on FAAH enzyme inhibitors.^{[12][13][14][15]}
No details of the preclinical testing of this molecule have been made public by the manufacturer Bial. However, the French newspaper Le Figaro has obtained and published an apparently legitimate copy of the full clinical trial protocol (BIA-102474-101).^[8] The protocol presents a summary of what appears to be a full package of pharmacodynamic, pharmacokinetic and toxicological studies that might be expected to support a first-in-man study, including safety pharmacology studies in two species (rat, dog) and repeated dose toxicity studies in four species (13 week sub-chronic studies in mouse, rat, dog and monkey). The summary presented however includes no assessment of the relevance of the animal species selected for study (that is, in terms of physiological and genetic similarities with humans and the mechanism of action of the study drug).
Of note, few adverse events were observed in any of the studies, with the 13-week oral No Observed Adverse Effect Level (NOAEL) varying between 10 mg/kg/day in mice to 75 mg/kg/day in monkeys. The authors suggest that these were the maximum doses tested in these studies, though it is not clear. The authors also report no effects of significance in the animal models used for the CNS safety pharmacology studies, which studied a dose of up to 300 mg/kg/day.^[8]
Notably absent from the protocol are calculations of receptor occupancy; predictions of in vivo ligand binding saturation levels; measures of target affinity; or assessment of the molecule’s activity in non-target tissues or non-target binding interactions as suggested by the European guidance for Phase I studies,^[16] assuming BIA 10-2474 could be considered ‘high risk’).^[8]
The trial protocol makes no reference to chimpanzee studies (only monkeys) which contradicts a previous statement to the media in which the French Health Minister stated that the drug had been tested on animals including chimpanzees.^{[4][17] [18]} Some experts had remarked that drug testing in chimpanzees was unlikely.^[19]
These findings provide no explanation for the type and severity of events observed in Rennes. In describing the rationale for the starting dose, the authors conclude that:

No target organ was identified during toxicology studies and few adverse clinical findings were observed at the highest dose tested. For the single ascending dose part [of the clinical trial], a starting dose of 0.25 mg was judged to be safe for a first-in-human administration. [8]

The protocol defines no starting dose for the multi-dose treatment groups, noting that this will be based on the outcome of the single dose portion of the trial (an approach known as adaptive trial design). The authors note that nonetheless, the starting dose will not exceed 33% of the maximum tolerated dose (MTD) identified in the single dose groups (or 33% of the maximum administered dose if the MTD is not reached).^[8]

Death and serious adverse events during phase I clinical trial

In July 2015 Biotrial, a contract research organization, began testing the drug in a human phase one clinical trial for the manufacturer. The study was approved by French regulatory authority, the Agence Nationale de Sécurité du Médicament (ANSM), on June 26, 2015, and by the Brest regional ethics committee on July 3, 2015.^[20] The trial commenced on July 9, 2015,^[21] in the city of Rennes, and recruited 128 healthy volunteers, both men and women aged 18 to 55. According to French authorities, the study employed a three-stage design with 90 of the volunteers having received the drug during the first two stages of the trial, with no serious adverse events being reported .^[17][20] Participants of the study were to receive €1,900 and, in turn, asked to stay at Biotrial’s facility for two weeks during which time they would take the drug for ten days and undergo tests.^[22]
In the third stage of the trial evaluating multiple doses, six male volunteers received doses by mouth, starting on 7 January 2016. The first volunteer was hospitalized at the Rennes University Hospital on January 10, became brain dead,^{[17][23][24][25]} and died on January 17.^[26] The other five men in the same dosage group were also hospitalized, in the period of January 10 through January 13^[27] four of them suffering injuries including deep hemorrhagic and necrotic lesions seen on brain MRI.^[7] The six men who were hospitalised were the group which received the highest dose.^[26] A neurologist at the University of Rennes Hospital Center, Professor Pierre-Gilles Edan, stated in a press conference with the French Minister for Health, that 3 of the 4 men who were displaying neurological symptoms “already have a severe enough clinical picture to fear that even in the best situation there will be an irreversible handicap” and were being given corticosteroids to control the inflammation.^[27] The sixth man from the group was not showing adverse effects but had been hospitalized for observation.^[25][28][29] Biotrial stopped the experiment on January 11, 2016.^[4]
No details of the trial have been made public by the manufacturer Bial. The study does not appear in searches of any of the key clinical trial registries, including EudraCT and ClinicalTrials.gov which would normally contain details of approved clinical studies.^{[30][31][32][33]} The trial protocol published by Le Figaro provides extensive detail on what was planned for the study, but many details of the key multi-dose part are not included and were to have been finalised at the conclusion of the single-dose part of the trial.^[8]
The French health minister Marisol Touraine called the event “an accident of exceptional gravity” and promised to investigate the matter.^[4] On January 18 it was reported authorities were investigating if a manufacturing or transport error might be involved.^[34]

Le Figaro posted a 96-page clinical study protocol for BIA 10-2474 that the French newspaper procured from an unnamed source.

According to the document, BIA 10-2474 is 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide.

BIA 10-2474 “is designed to act as a long-active and reversible inhibitor of brain and peripheral FAAH,” notes the protocol. The compound “increases anandamide levels in the central nervous system and in peripheral tissues.”

The clinical trial protocol also notes that the company tested BIA 10-2474 on mice, rats, dogs, and monkeys for effects on the heart, kidneys, and gastrointestinal tract, among other pharmacological and toxicological evaluations.

Six men in a Phase I clinical trial were admitted to the University Hospital Center of Rennes, France, (shown here) because of adverse reactions.Six men in a Phase I clinical trial were admitted to the University Hospital Center of Rennes, France, (shown here) because of adverse reactions.

Credit: Mathieu Pattier/SIPA/Newscom

One man is dead and five men were hospitalized after participating in a Phase I clinical trial in Rennes, France

The clinical trial, conducted by the company Biotrial on behalf of the Portuguese pharmaceutical firm Bial, was evaluating a pain relief drug candidate called BIA 10-2474 that inhibits fatty acid amide hydrolase (FAAH) enzymes. Blocking these enzymes prevents them from breaking down cannabinoids in the brain, a family of compounds that includes the euphoria-inducing neurotransmitter anandamide and Δ⁹-tetrahydrocannabinol, the major psychoactive component of marijuana.

Phase I clinical trials are conducted to check a drug candidate’s safety profile in healthy, paid volunteers. In this case, the drug caused hemorrhagic and necrotic brain lesions in five out of six men in a group who received the highest doses of the drug, said Gilles Edan, a neurologist at the University Hospital Center of Rennes.

The most severely affected man was pronounced brain-dead after hospitalization and then died on Jan. 17. Four men remain in the hospital in stable condition. The only man in the high-dose group who had no adverse symptoms has been released from the hospital.
Clinical trials are an essential part of the drug development process. In order to get life-improving and life-saving medicines to patients, they first have to go through an extensive series of tests. Even before a drug makes it to Phase 1 testing, where its safety, dosage amount, and side effects are tested in a small group of humans, it will undergo testing in animals. As a result, it is not common for a medicine undergoing clinical tests to have a very serious adverse effect on a human. This makes you wonder what happened to a group of patients involved in a clinical study in Rennes, France.
According to news reports, a drug undergoing testing in a French clinic has left one person dead, two others with what may be permanent brain damage, and and two others critically ill. The drug has thus far been unnamed, but it appears to have been produced by the Portuguese company Bial. The French health minister has stated the drug acted on natural receptors found in the body known as endocannibinoids, which regulate mood and appetite. It did not contain cannabis or anything derived from it, as was originally reported. All six trial participants were administered the doses simultaneously.
The trial was being performed at Biotrial, a French-based firm that was formed in 1989 and has conducted thousands of trials. A message on the company’s website stated that they are working with health authorities to understand the cause of the accident, while extending thoughts to the patients and their families. Bial has disclosed the drug was a FAAH (fatty acid amide hydrolase) inhibitor, which is an enzyme produced in the brain and elsewhere that breaks down neurotransmitters called endocannabinoids. Two scientists from the Nottingham Medical School who have worked with FAAH tried over the weekend to try and identify the drug by examining a list of drugs Bial currently has in its pipeline. They believe the culprit is one identified by the codename BIA 10-2474. That same codename appeared on a recruitment form that was given to a volunteer, which was published in a French newspaper. Little more is known about it, and there does not appear to be any entry for it in clinical trial registries.
The French health ministry is reporting the six patients were all in good health prior to taking the oral medicine, which was administered to 90 volunteers. The trial recruited 128 individuals, and the remaining participants received a placebo. Health minister Marisol Touraine, describing the situation as a very serious accident, noted the patients were taking part in a trial in Brittany, Rennes involving a medicine developed by a “European laboratory”, refusing to comment further until additional information became available. She has also asked the Inspector General of Social Affairs to lead an investigation into the circumstances around the trial, which has obviously been suspended. She notes the drug had been tested on animals, including chimpanzees. France’s National Agency for Medicine and Health Products Safety approved the trial on in June 2015.
One thing we do know is that the trial was a Phase 1 clinical study that included 90 healthy volunteers. Regulations that oversee all clinical trials in Europe do attempt to minimize the risk associated with trials, but there is always a risk involved with administering an unapproved medicine to humans. At this time the chief neuroscientist at the hospital where the patients are being treated has said there is no known antidote for the drug.
The drug, administered to men between the ages of 28 and 49, was intended to treat mood disorders such as anxiety. While the men were administered varying doses, the patients who are hospitalized were taking the drug “regularly”.

Old 2006 case

While safety issues like this are rare, they are not unheard of. In 2006, a clinical trial in London left six men ill. All were taking part in a study testing a drug designed to fight auto-immune disease and leukemia. Within hours of taking the drug TGN1412, all experienced a serious reaction, were admitted to intensive care, and had to be treated for organ failure. Two became critically ill, with one eventually losing all of his fingers and toes. All were told they would have a higher risk of developing cancers or auto-immune diseases.
This of course led many to wonder about the future of trials, and whether the situation could happen again. The Duff Report, written in response to the TGN1412 trial, noted the medicine should have been tested in one person at a time. It also helped to put additional safety measures in place. The Medicines and Health Products Regulatory Agency (MHRA) now requires committees to look at pre-clinical data to determine the proper initial dose, and rules are in place to stop the trial if unintended reactions occur.
However, since patients can fall ill immediately after being administered a medication, certain risks will still exist.
The company that manufactured TGN1412, TeGenero Immuno Therapeutics, later went bankrupt. However the drug was later purchased by a Russian investor and renamed TABO8. TheraMAB, a Russian biotech company, then conducted a new trial of the drug in a much lower dose. A later Phase 2 study was started in patients with Rheumatoid Arthritis.

Other pharmaceutical companies, including Merck, Pfizer, Johnson & Johnson, Sanofi and Vernalis, have previously taken other FAAH inhibitors into clinical trials without experiencing such adverse events (e.g. respectively, MK-4409,^[35][36] PF-04457845, JNJ-42165279,^[37] SSR411298 and V158866.^[38][39] Related enzyme inhibitor compounds such as URB-597 and LY-2183240 have been sold illicitly as designer drugs,^[40][41] all without reports of this type of toxicity emerging, so the mechanism of the toxicity observed with BIA 10-2474 remains poorly understood.
Following the events in Rennes, Janssen announced that it was temporarily suspending dosing in two Phase II clinical trials with its own FAAH inhibitor JNJ-42165279, headlining the decision as “precautionary measure follows safety issue with different drug in class”. Janssen was emphatic that no serious adverse events had been reported in any of the clinical trials with JNJ-42165279 to date. The suspension is to remain in effect until more information is available about the BIA 10-2474 study.^[42]

References

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• 8 “Drame de Rennes : le protocole de l’essai clinique en accusation”. sante.lefigaro.fr. Retrieved 2016-01-21.
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• Bisogno T, Maccarrone M. Latest advances in the discovery of fatty acid amide hydrolase inhibitors. Expert Opin Drug Discov. 2013 May;8(5):509-22. PMID 23488865 doi: 10.1517/17460441.2013.780021.
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• Shanks KG, Behonick GS, Dahn T, Terrell A. Identification of novel third-generation synthetic cannabinoids in products by ultra-performance liquid chromatography and time-of-flight mass spectrometry. J Anal Toxicol. 2013 Oct;37(8):517-25. PMID 23946450 doi: 10.1093/jat/bkt062.
• 41
• Uchiyama N, Matsuda S, Kawamura M, Shimokawa Y, Kikura-Hanajiri R, Aritake K, Urade Y, Goda Y. Characterization of four new designer drugs, 5-chloro-NNEI, NNEI indazole analog, α-PHPP and α-POP, with 11 newly distributed designer drugs in illegal products. Forensic Sci Int. 2014 Oct;243:1-13. PMID 24769262 doi: 10.1016/j.forsciint.2014.03.013.
• 
  

42. “Janssen Research & Development, LLC Voluntarily Suspends Dosing in Phase 2 Clinical Trials of Experimental Treatment for Mood Disorders”. Janssen.com. 17 January 2016. Retrieved 21 January 2016.

External links

• Bial pipeline
• Urea compounds and their use as faah enzyme inhibitors – Patent
• Selection patent

WO2005073199A1 *	Jan 15, 2005	Aug 11, 2005	Aventis Pharma Gmbh	Indazole derivatives as inhibitors of hormone-sensitive lipases
WO2010074588A2	Dec 23, 2009	Jul 1, 2010	BIAL – PORTELA & Cª, S.A.	Pharmaceutical compounds
WO2012015324A1	Jul 28, 2011	Feb 2, 2012	Bial – Portela & Ca, S.A.	Process for the synthesis of substituted urea compounds
US4051252 *	Nov 24, 1975	Sep 27, 1977	Bayer Aktiengesellschaft	3-aminoindazole-1 and 2-carboxylic acid derivatives
US4331678 *	Jan 14, 1980	May 25, 1982	Fbc Limited	Carbamoyl pyrazole compounds and their pesticidal application
US4973588 *	Feb 10, 1989	Nov 27, 1990	Mitsui Petrochemical Industries, Ltd.	Imidazole derivatives having anti-hypoxia properties
US5578627 *	Oct 27, 1993	Nov 26, 1996	Toyama Chemical Co., Ltd.	1,2-benzoisoxazole derivative or its salt and brain-protecting agent comprising the same

BIA 10-2474

Systematic (IUPAC) name
3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide
Clinical data
Legal status	Investigational New Medicine
Routes of administration	Oral
Identifiers
PubChem	CID: 46831476
Chemical data
Formula	C16H20N4O2 Molecular mass 300.36 g·mol−1 SMILES O=C(N1C=C(C2=C[N+]([O-])=CC=C2)N=C1)N(C3CCCCC3)C

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C1C(CCCC1)N(C)C(=O)n2cc(nc2)c3ccc[n+](c3)O

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