`
`IC-351 ICOS Corp
`Peter Norman
`
`Address
`Norman Consulting
`18 Pink Lane
`Burnham
`Bucks
`SL1 8JW
`Email: pn29@student.open.ac.uk
`
`Current Opinion in CPNS lnvestigational Drugs 19991(2):268-271
`© Current Drugs Ltd ISSN 1464-844X
`
`IC-351 (GF-196960), an inhibitor of phosphodiesterase 5 (PDE5) from
`!COS Corp, is in phase II trials for the treatment of mild to moderate
`erectile dysfunction (ED) [2745681, [296831]. A randomized, placebo(cid:173)
`controlled, crossover study assessed the safety and physiological effects
`ofIC-351 in patients with ED [274568]. Enrollment was completed in
`April 1998 [284935]. Results from the trial showed that IC-351
`demonstrated significant benefit over placebo [311566]. In October
`1998, !COS entered into a joint venture agreement with Eli Lilly for
`the development. and commercialization of IC-351 for the treatment of
`sexual dysfunction [300118], [310951]. IC-351 is also in development
`for the treatment of female sexual dysfunction [321995].
`
`In March 1998, the company announced that the compound was in
`preclinical evaluation for the treatment of hypertension [284638].
`
`A collaboration with Glaxo Wellcome (GW) was terminated in March
`19~7 [240438] and intellectual property n"ghts were assigned to ICOS.
`Thzs left ICOS to develop the compounds with royalties payable to
`GW. Although GW reserved the right to pursue its own program, it
`does not appear to be doing so.
`
`In February 1999 Deutsche Bank predicted sales of $200 million in
`2002 rising to $400 million in 2003 for IC-351 [316821].
`
`Introduction
`The development of selective inhibitors of GMP specific
`phosphodiesterases has received a vast amount of attention
`following the recent launch of the selective PDES inhibitor
`sil~enafil (Viagr~) _by Pfizer for the treatment of ED. Although
`this drug had ongmally been intended as an anti-angina! drug,
`the profile in early clinical trials indicated its ability to induce
`erections and resulted in a repositioning for ED and launch,
`with much hype, in 1998.
`
`The rapid uptake of this drug in the US market led to forecasts
`of first year sales in excess of $1 billion. Although concerns
`about cardiovascular safety and reimbursement have blunted
`the growth, the first year sales, at $788 million, were close to
`projections. Certainly this is the most dramatic success for a
`newly
`launched pharmaceutical product, particularly
`considering it was not available in most international markets
`outside the US.
`
`in ED
`it represents a major breakthrough
`Although
`management, as the first truly-effective oral treatment, it may
`not be ideal therapy, but is substantially more convenient for
`the patient than earlier treatments for this condition. Sildenafil
`has only modest selectivity for PDES over PDE6 and may
`inhibit other isozymes at the relatively high plasma levels
`achieved, particularly at the highest (100 mg) dose. The drug is
`
`Originator ICOS Corp
`
`Licensees Eli Lilly & Co
`
`Status Phase 2 clinical
`
`Indication Sexual dysfunction, hypertension
`
`Action PDE5 inhibitor
`
`Synonyms GF-196960, GG-960
`
`also contraindicated in angina patients taking, or likely to
`take, nitrates. The onset of action (approx 1 h) is also
`considered by many to be less than optimal. Overall, it is
`theoretically possible to improve on the overall clinical
`profile
`of
`sildenafil
`by
`pharmacodynanic
`or
`pharmacodynamic manipulations. ICOS was one of the
`earliest companies to also seek to develop selective PDE5
`inhibitors for this indication and IC-351 was a compound
`that resulted from its earlier collaboration with Glaxo
`Wellcome.
`
`Synthesis and SAR
`In the absence of information on the identity of IC-351 it is
`not possible to discuss the synthesis or SAR. However, all
`the available patents describe compounds with potencies of
`2 to 10 nM as PDES inhibitors, comparable to sildenafil,
`which has a Ki value of 4 nM.
`
`The collaboration had used the chemical expertise of Glaxo
`France with patents being filed describing pyrazino(cid:173)
`(2',l ':6,1)-pyrido-(3,4-b)indole-1,4-diones
`(W0-09519978)
`and claiming their use for the treatment of impotence (W0-
`09703675).
`ICOS now appears
`to be synthesizing a
`structurally-distinct class of PDE5 inhibitors (W0-09743287).
`
`Pharmacology
`!COS has yet to publish any pharmacological data on IC-351.
`Glaxo France, its former collaborators, has described the
`activity of the novel selective PDE5 inhibitor 1,3-dimethyl-6-
`(2-propoxy-5-methanesulfonylamidophenyl)-pyrazolo(3,4d)(cid:173)
`pyrimidin-4-(5H)-one (DMPPO) [210793], [225926], [295703].
`The compound is a potent inhibitor of the enzyme with a K,
`value of 3 nM [210793], and an effective vasodilator both in
`vitro [295703] and in vivo at 5 mg/kg po [225926].
`
`Whilst it is unlikely that DMPPO is IC-351, it is reasonable to
`assume that IC-351 displays enhanced in vivo potency and
`possibly in vitro potency.
`
`Clinical Development
`
`Phase I
`Phase I studies were initiated in 1995 [191529] and have
`been reported as free from adverse reactions to IC-351
`[298769], [311566].
`
`ATI 1032-0001
`
`ATI v. ICOS
`IPR2018-01183
`
`
`
`IC-351 Norman 269
`
`Phase II
`Two phase II studies, in 175 and 300 patients, have now
`been reported as completed [311566]. In these studies, IC-351
`demonstrated significant efficacy in stimulating a sexual
`response. This confirmed the reported effects in an earlier 44
`patient study [298769].
`
`Current Opinion
`The initial indication of PDE5 inhibitors was intended to be
`the treatment of cardiovascular disease and Pfizer initially
`developed sildenafil for that indication. The observation of
`pronounced penile vasodilation and consequent erections
`led to the development of sildenafil as the first orally(cid:173)
`administered agent for the treatment of ED (impotence).
`Whether the overall clinical profile can be improved upon
`with the design of more selective PDE5 inhibitors remains to
`be determined, but the race is certainly on. Since gaining
`FDA approval in the US, sildenafil has displayed a dramatic
`sales growth and some analysts are predicting it has a global
`sales potential that could exceed $10 billion per annum.
`
`IC-351 is the only other selective PDE5 inhibitor known to be
`in advanced clinical development and therefore has the
`
`potential, if it demonstrates comparable efficacy, to gain a
`significant share of this market (the limited biological data
`presented in patents suggests that it has comparable in vitro
`activity). If the market for PDE5 inhibitors develops as
`analysts forecast, then IC-351 has the potential to make ICOS
`into a major pharmaceutical company. The only caveat
`would be if restrictions, on the use of such agents, were
`enforced due to their potential to induce heart failure,
`because of excessive vasodilation, as has currently been
`reported for a small number of patients with sildenafil.
`
`its
`to abandon
`The decision by Glaxo Wellcome
`in hindsight,
`collaboration with ICOS now appears,
`injudicious given the rapid development of this market.
`There is no evidence that Glaxo Wellcome is currently
`developing an alternative molecule. However, it was no
`surprise
`that another major company, Eli Lilly, was
`prepared to step in and fund the development of IC-351
`through
`the creation of a
`joint venture. Until more
`information is forthcoming on the biological effects of IC-351
`it is not possible to decide whether it should prove
`therapeutically superior to sildenafil but IC-351 is believed
`to have an improved profile of activity.
`
`Licensing
`
`Eli Lilly & Co
`ICOS and Lilly entered into an agreement in October 1998 for the joint development and commercialization of PDES
`inhibitors for the treatment of male and female sexual dysfunction. ICOS will receive an initial payment of $ 75 million,
`followed by milestone payments as IC-351 progresses through clinical development [300118].
`
`Development History
`DEVELOPER
`COUNTRY
`UK
`
`Glaxo Wellcome pie
`
`STATUS
`DX
`
`INDICATION
`
`Inflammation
`
`Glaxo Wellcome pie
`
`Glaxo Welleome pie
`
`Glaxo Wellcome pie
`
`Glaxo Wellcome pie
`
`ICOS Corp
`
`Eli Lilly & Co
`
`ICOS Corp
`
`ICOS Corp
`
`ICOS Corp
`
`ICOS Corp
`
`ICOS Corp
`
`UK
`
`UK
`
`UK
`
`UK
`
`UK
`
`us
`
`us
`
`Western Europe
`
`UK
`
`UK
`
`UK
`
`DX
`
`DX
`
`DX
`
`DX
`
`DR
`
`DR
`
`DR
`
`C2
`
`C1
`
`C1
`
`C1
`
`Asthma
`
`Impotence
`
`Angina
`
`Cardiac failure
`
`Sexual dysfunction
`
`Sexual dysfunction
`
`Hypertension
`
`Impotence
`
`Impotence
`
`Angina
`
`Cardiac failure
`
`DATE
`01-APR-97
`
`01-APR-97
`
`01-APR-97
`
`01-APR-97
`
`01-APR-97
`
`02-0CT-98
`
`02-0CT-98
`
`01-MAR-98
`
`13-JAN-98
`
`13-NOV-95
`
`13-NOV-95
`
`13-NOV-95
`
`REF
`240438
`
`240438
`
`240438
`
`240438
`
`240438
`
`300118
`
`300118
`
`284638
`
`274568
`
`191529
`
`191529
`
`191529
`
`ATI 1032-0002
`
`
`
`270 Current Opinion in CPNS lnvestigational Drugs 1999 Vol 1 No 2
`
`Literature classifications
`Key references relating to the drug are classified according to a set of standard headings to provide a quick guide to the
`bibliography. These headings are as follows:
`Chemistry: References which discuss synthesis and structure-activity relationships.
`Biology: References which disclose aspects of the drug's pharmacology in animal models.
`Metabolism: References that discuss metabolism, pharmacokinetics and toxicity.
`Clinical: Reports of clinical phase studies in volunteers providing, where available, data on the following: whether the
`experiment is placebo-controlled or double- or single-blind; number of patients; dosage.
`
`RESULT
`Announcement of initiation of phase II trial.
`
`REF
`274568
`
`Clinical
`EFFECT STUDIED
`Efficacy in ED.
`
`Efficacy in ED.
`
`MODEL USED
`Phase II, randomized placebo(cid:173)
`controlled, crossover study to
`assess the safety and physiological
`effects of IC-351 in patients with mild
`to moderate ED.
`
`Phase 11 trial in 44 patients
`assessing the safety and efficacy of
`IC-351 for the treatment of ED.
`
`Safety and
`pharmacokinetics.
`
`Phase I trials of IC-351 in healthy
`volunteers.
`
`IC-351 was well-tolerated.
`
`IC-351-treated patients showed significant
`improvement relative to placebo-treated patients in the
`primary endpoint (p < 0.001) and all secondary
`endpoints.
`
`298769
`
`298769
`
`Associated patent - W0-09519978
`
`Title Tetracyclic derivatives, process of preparation and use.
`
`Assignee Labs Glaxo SA
`
`Publication W0--09519978 27-JUL-95
`
`Priority GB-1090 21-JAN-94
`
`Inventors Daugan AC
`
`Bibliography
`••
`of outstanding interest
`•
`of special interest
`
`100676 Stimulation of fatty acid oxidation in myocytes by
`phosphodiesterase inhibitors and adenosine analogues Abdel(cid:173)
`Aleem S, Sadr M, Frangakis C LIFE SCI 1991 48 18 PL97-PL 102
`
`136652 Comparison of the ability of various phosphodiesterase
`(PDE) inhibitors to relax rat aorta (RA) and guinea pig trachea
`(GPT). Thompson D, Queen K, Stone R, Rimele T FASEB J 1989 3
`A286
`
`superoxide
`neutrophil
`in
`144534 Species differences
`modulation by cyclic nucleotide phosphodiesterase inhibitors.
`Boucheron JA, Verghese MW, lrsula O FASEB J 1991 5 A51 o
`
`144976 The stimulation of lipolysis and fatty acid oxidation by
`the phosphodiesterase
`inhibitors are not mediated by
`adenosine receptors. Abdel-Aleem S, Ropchak T, Frankgakis C
`FASEB J 1991 5 A1572
`
`Abstract
`Novel tetracyclic derivatives are claimed which have PDE
`inhibitory activity. The compounds are claimed for the
`treatment of cardiovascular disorders including angina,
`hypertension, pulmonary disease and congestive heart
`failure, and
`inflammatory diseases, stroke, bronchitis,
`asthma and rhinitis. Inhibition of cGMP-PDE activity was
`measured using a one-step assay adapted from Wells el al
`(Biochem Biophys Acta (1975) 384:430). IC50 values were in the
`range 10 nM to 10 µM. An in vivo antihypertensive test in
`rats is also described. 119 Compounds are exemplified by
`syntheses. Seven formulatory examples are given. (6R,12aR)-
`2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxy(cid:173)
`phenyl)-pyrazino(2',1 ':6,1 )pyrido (3,4-b )indole-1,4-dione is
`one of 11 compounds specifically claimed.
`
`1 OK
`Form
`173038
`COMMUNICATION 1993
`
`ICOS
`
`Corporation.
`
`COMPANY
`
`173041 ICOS Corp. ANNUAL REPORT1993
`
`175157 ICOS Corp. ANNUAL REPORT1994
`
`175193 ICOS Corp. FORM 10-K1994 December 31
`
`191529 ICOS PDES inhibitor in phase I trials in the UK. ICOS
`Corp PRESS RELEASE 1995 November 08
`.. Announcement of initiation of phase I trials with IC-351.
`
`192678 Glaxo Wellcome's R&D challenge. SCRIP 1995 2080 8-9
`
`193105 Glaxo Wellcome to increase R&D productivity three-fold
`by the year 2000. Glaim Wellcome pie PRESS RELEASE 1995
`November 08
`
`197517 GF 196960. CUN TRIALS MONITOR 1995 4 12 P6
`
`215840 GW predicts potential blockbusters. SCRIP 1996 2135
`10
`
`ATI 1032-0003
`
`
`
`IC-351 Norman 271
`
`240438 Drug Development Digest:
`PHARMACEUTICALS 1997 6 4 13
`
`ICOS Corp. EMERGING
`
`298769 ICOS announces clinical results and initiation of trials
`ICOS Corp PRESS RELEASE 1998 September 17
`
`266462 ICOS reports 1997 Third Quarter results. ICOS Corp
`PRESS RELEASE 19970ctober 16
`
`271748 Analyst Report 1997. BancAmerica Robertson Stephens
`ANALYST REPORT 1997
`
`274568 ICOS announces initiation of overseas phase II trial
`with IC351. ICOS Corp PRESS RELEASE 1998 January 12
`•• Press release on phase II studies
`
`300118 Lilly and ICOS establish a joint venture to develop and
`market PDES compounds to treat sexual dysfunction. Eli Lilly &
`Co PRESS RELEASE 1998 October 1
`
`302256 ICOS reports 1998 third quarter results. ICOS Corp
`PRESS RELEASE 1998 October 22
`
`303192
`in $75M deal for sexual dysfunction.
`ICOS, Lilly
`BIOWORLD WEEK 1998 6 40 4
`
`276755 ICOS reports 1997 year end and fourth quarter results
`and development update. ICOS Corp PRESS RELEASE 1998
`February 3
`
`281528 DRUG DEV PIPELINE. 1998 3 2 1
`
`284638 ICOS Corp. ANNUAL REPORT1998 March
`
`284639 ICOS Corp. FORM 10-K1998 March 11
`
`284935 ICOS reports 1998 first quarter results and development
`update. ICOS Corp PRESS RELEASE 1998 April 22
`
`295703 Effects of cyclic GMP elevation on isoprenaline-induced
`increase in cyclic AMP and relaxation in rat aortic smooth
`muscle: role of phosphodiesterase 3. Delpy E, Coste H, Gouville
`AC BR J PHARMACOL 1996 119 3 471-478
`
`296831 Biotechnology Quarterly. BancAmerica Robertson
`Stephens. June 25, 1998. Simon MJ, Miliotes GJ, Woolf NL,
`Freudenthal P, Silverman JB, Wright LJ, Silverman E, Perlin B
`ANALYST REPORT 1998
`
`310951 Pharmaceutical and Biotechnological Bulletin. Merrill
`Lynch ANALYST REPORT 1998 October 19
`
`311566 ICOS announces erectile dysfunction results, initiation
`of psoriasis trial and a new clinical candidate. ICOS Corp
`PRESS RELEASE 1999 January 14
`
`313384 Enbrel enables lmmunex to shine in 1998; stock gains
`133%. FOG REPORTS PINK SHEET 1999 61 3 28-31
`
`314691
`erectile
`Phentolamine Mesilate. Treatment of
`dysfunction. Graul A, Castaner J DRUGS FUTURE 1998 23 7 725-
`728
`
`315799 HU23F2G for potential inhibition of neutrophil-mediated
`injury in ischemic stroke /BC ANN CONF ISCHEMIC STROKE
`1998 7 Washington DC
`
`316821 US Equity Research Eli Lilly. Deutsche Bank Research
`ANALYST REPORT 1999 February 1
`
`321995 ICOS Website (http://www.icos.com)
`
`ATI 1032-0004
`
`