Biotech Values

[DewDiligence]

Pfizer hedging AMD bets in case Macugen flops:

[This is a phase-1/2 trial for a locally-administered tyrosine kinase of the VEGF-2 receptor. The Pfizer trial presents some interesting comparisons with GENR’s main phase-2 Squalamine trial: 1) Pfizer’s trial is restricted to the minimally-classic/occult disease subgroups, while GENR’s trial is open to all disease subgroups; and 2) Pfizer’s trial is limited to patients with a lesion size <=9 disk areas, while GENR’s trial accepts lesions up to and including 16 disk areas; 3) Pfizer’s trial explicitly excludes patients with a high or high-normal QTc interval (as well as those with a history of stroke or severe heart disease). Restricting the QTc interval is rather surprising for a drug that is administered locally to the eye, and this suggests that Pfizer’s drug candidate is thought to be highly cardiotoxic.

Thanks to mid_swe (an OXGN fan and occasional contributor to this board) for this find.]

http://clinicaltrials.gov/ct/gui/show/NCT00090532;jsessionid=1B468BDD6A10842439C1531383782B7E?order=....

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An Investigational Drug in Subjects with Subfoveal Choroidal Neovascularization Associated with Age-related Macular Degeneration

This study is not yet open for patient recruitment.

Sponsored by Pfizer


Purpose

Investigational Drug is a selective inhibitor of the tyrosine kinase (TK) activity of the vascular endothelial growth factor receptor 2 (VEGF-R2) and is currently being developed for the treatment of subfoveal choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) as a sterile suspension for sub-Tenon (ST) injection into Tenon's space. This Phase 1/2 randomized, masked, placebo-controlled, dose-escalation study is the first-in-human administration of Investigational Drug. Study objectives are to determine the ocular and systemic safety of Investigational Drug following single and multiple ST injections over 52 weeks followed by an additional 52 week observation period and to determine the efficacy of Investigational Drug in subjects with age-related macular degeneration as assessed by visual acuity at 52 weeks. The secondary objectives are to evaluate the visual acuity change with several dose levels and multi-dose schedules over 52 weeks, to evaluate the change in lesion morphology over 52 weeks as determined by fundus photographs, fluorescein angiography, high-speed ICG angiography, optical coherence tomography, to evaluate systemic exposure pharmacokinetics of Investigational Drug after ST injection, and to evaluate the impact of Investigational drug treatment on vision-related quality of life. A total of 144 subjects may be enrolled in the trial. Subjects will be healthy male or female at least 55 years of age with angiographic evidence of minimally classic subfoveal choroidal neovascularization due to age-related macular degeneration.

Study Type: Interventional
Study Design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study

Official Title: Protocol A4321001, A Phase 1 / 2 Randomized, Masked, Placebo-Controlled, Single and Multiple-Dose, Sequential Dose-Escalation Study of the Safety and Efficacy of Investigational Drug in Subjects with Subfoveal Choroidal Neovascularization Associated with Age-related Macular Degeneration

Further Study Details:

Expected Total Enrollment: 144
Study start: November 2004


Eligibility

Ages Eligible for Study: 55 Years and above, Genders Eligible for Study: Both

Criteria

INCLUSION CRITERIA:

• Male and/or female subjects >=55 years of age. Females must be of non-childbearing potential, ie, surgically sterilized or at least 2 years postmenopausal, and not breast-feeding
• Subfoveal CNV with minimally classic CNV (classic component <50% of total lesion area) or occult CNV. CNV must comprise at least > 50% of the total lesion area. (Lesion characteristics will be independently verified by a central reading center to determine eligibility)
• For subjects with active occult neovascularization without any classic component: a.) Recent visual decline that in the opinion of the investigator is due to active AMD: subject report of recent visual decline with documentation of >= 2 lines decline in visual acuity within 12 weeks, OR b.) Subretinal blood or lipid deposition must be present, but must comprise <50% of the lesion, OR c.) Growth of the lesion by at least 10% increase in its greatest linear dimension within 12 weeks
• Some portion of the CNV must be under the center of the macula, as verified by the central reading center. If the center is obscured by blood and CNV surrounds the center (270 degrees or more), CNV will be considered to be present under the center
• No subfoveal fibrosis; total lesion fibrosis or scar must be <= 25% total lesion area
• Hemorrhage <50% of total lesion area
• Total lesion area <= 9 DA [disk areas]
• ETDRS best-corrected visual acuity (BCVA) score of 68 through 24 letters, inclusive (20/50 through 20/320)
• Visual acuity score in the fellow eye >= 24 letters (20/320 or better)
• Clear media and dilation to permit good stereo fundus photography
• WHO performance status of 0, 1 or 2
• Normal ECG or nonsignificant changes. Nonsignificant changes may include evidence of old myocardial infarction (MI), nonspecific ST changes, and old MI with RBBB. See also exclusion criteria 15
• Subjects who are informed of, and willing and able to comply with, the investigational nature of the study and are able to provide written informed consent in accordance with institutional and regulatory guidelines

EXCLUSION CRITERIA:

• Serous pigment epithelial detachment without surrounding neovascularization
• Other serious ocular diseases or conditions, including diabetic retinopathy and glaucoma, that are likely to compromise visual acuity within 1 year
• Prior subfoveal photocoagulation involving the center of the macula in the study eye; prior juxta-foveal photocoagulation is permitted
• Prior intravitreal, sub-Tenon, or systemic therapy for AMD, with the exception of nutritional supplements
• Subjects with prior photodynamic therapy, transpupillary thermotherapy or intravitreal steroids in study eye or those likely to undergo these therapies within 6 months of the start of the study
• Retinal pigment epithelial tear in study eye
• Cataract surgery is indicated in study eye within 12 months
• Intraocular surgery in study eye within past 3 months; eyelid surgery is permitted if well healed
• Prior vitrectomy or submacular surgery in study eye
• Prior scleral buckling surgery in study eye
• Presence of ocular infection in study eye
• Presence of severe myopia (–6 diopters or greater) in study eye
• Undiagnosed acute illness first observed during screening or stable or severe concurrent medical conditions that, in the investigator's judgment, pose a safety liability, including evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease excluding untreated, asymptomatic, seasonal allergies at time of dosing
• History of severe cardiac disease (New York Heart Association Class 3 or 4, unstable angina, MI within 6 months, ventricular tachycardia requiring treatment)
• Subject whose screening ECG demonstrates at least 1 of the following: heart rate >100 bpm, QRS >120 msec, QTc >430 msec (men) or 450 msec (women), PR >220 msec, any rhythm other than sinus rhythm or evidence of ischemia
• Greater than Stage 1 mild hypertension defined 2 out of 3 screening evaluations
• Stroke within past 12 months
• Physician diagnosed intermittent claudication
• Prior radiation therapy to head or neck
• Use of any investigational agent or participation in any other clinical trial in the past 60 days
• Current use, use within the last 4 weeks, or likely need within 1 year of systemic glucocorticoids. (Dermal glucocorticoids are allowed.)
• Current use or likely need within 1 year of treatment with anticoagulants (eg, warfarin) unless, in the opinion of the treating physician, the anticoagulants can be stopped at least 4 days before each sub-Tenon injection. (Anticoagulants can be resumed on the day following each sub-Tenon injection if no local hemorrhagic complication is evident.)
• Allergy to or prior significant adverse reaction to fluorescein
• Hemoglobin <10 g/dL, WBC <4 x 10 9 /L, platelets <150 x 10 9 /L at screening
• Creatinine or BUN >2 x upper limit of normal (ULN) at screening
• ALT, AST, and alkaline phosphatase >2 x ULN at screening
• Bilirubin >1.5 mg/dL at screening
• Proteinuria on urine dipstick greater than 1+ at screening
• Blood donation in excess of 500 mL within 60 days prior to the first dose of study medication
• History (within 180 days of screening) of alcohol consumption exceeding 7 drinks/week for women or 14 drinks/week for men (1 drink = 150 mL or 5 ounces of wine, 350 mL or 12 ounces of beer; or 44 mL or 1.5 ounces of hard liquor)
• History of drug abuse within 180 days of screening

Location Information

Call: 1-734-622-7600 [e-mail]
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