T H E R A P E U T I C S
`
`D O I 1 0 . 1 1 1 1 / j . 1 3 6 5 - 2 1 3 3 . 2 0 0 6 . 0 7 6 2 1 . x
`
`A pilot study of the safety and efficacy of picolinic acid gel
`in the treatment of acne vulgaris
`M.P. Heffernan, M.M. Nelson and M.J. Anadkat
`
`Division of Dermatology, Washington University School of Medicine, St Louis, MO, U.S.A.
`
`Summary
`
`Correspondence
`Michael P. Heffernan, Division of Dermatology,
`Wright State University School of Medicine,
`Dayton, OH 45408, U.S.A.
`E-mail: michael.heffernan@wright.edu
`
`Accepted for publication
`25 July 2006
`
`Key words
`acne vulgaris, picolinic acid
`
`Conflicts of interest
`M.P.H. has been active in industry-sponsored
`research with picolinic acid. He has conducted
`reimbursed investigations for Novactyl, Inc. and
`has received travel grants from Novactyl, Inc.
`M.M.N. and M.J.A. have no financial conflicts of
`interest to declare.
`
`Background Cost limitations, adverse effects or lack of efficacy limit the use of cur-
`rent topical therapies in mild to moderate acne vulgaris.
`Objectives To determine the safety and efficacy of picolinic acid, a novel zinc finger
`therapy, in the treatment of mild to moderate acne vulgaris.
`Methods Twenty subjects with mild to moderate acne vulgaris were treated at our
`centre during an open-label study with 10% picolinic acid gel (PCL-016) twice
`daily to the face over 12 weeks.
`Results Fifteen patients completed the 12-week open-label study. A reduction of
`58Æ2% (P < 0Æ001) in mean total
`lesion count, 55Æ5% (P < 0Æ001) in mean
`inflammatory lesion count and 59Æ7% (P < 0Æ005) in noninflammatory lesion
`count was seen in this population. No serious adverse events or clinically signifi-
`cant changes in laboratory values were noted.
`Conclusions Results from this study suggest that 10% picolinic acid gel applied
`twice daily may be safe and effective in the treatment of mild to moderate acne
`vulgaris.
`
`Acne vulgaris is a widely prevalent condition that affects
`nearly 80% of the U.S. population aged 11–30 years, and
`life.1–3
`most of
`the population at
`some point
`in their
`Patients with this condition are most bothered by their
`appearance.4,5 Affected patients are prone to embarrassment,
`social withdrawal, depression, anxiety, anger, scorn and stig-
`matization.6–10 Higher unemployment rates have also been
`demonstrated in adults with acne vulgaris compared with
`those without acne.11 Patients with acne vulgaris have sim-
`ilar
`levels of
`social, emotional and psychological
`impair-
`ments as patients with chronic illnesses
`such as asthma,
`arthritis and diabetes.12
`The pilosebaceous unit is believed to be the primary site of
`pathology in acne vulgaris. The distribution of acne favours
`sites with the highest concentration of pilosebaceous units,
`such as the face, chest or back.2,6,13,14 Four main processes
`have been suggested as factors in the development of acne
`vulgaris: sebaceous gland hyperplasia with increased sebum
`production, altered follicular growth and differentiation, fol-
`licular colonization with Propionibacterium acnes, and inflamma-
`tion.13,15–18 The primary lesion of
`acne
`vulgaris,
`the
`microcomedo, is formed as a result of sebaceous gland hyper-
`plasia and alteration in follicular growth and differentiation.
`Resultant noninflammatory (open and closed comedones) or
`inflammatory (papule, pustule, nodule) lesions may later
`evolve. Scarring often results in severe cases, but may occur in
`instances of mild to moderate disease.19,20
`
`Increasingly effective therapies have evolved in recent years
`as the pathogenesis of acne vulgaris has become better under-
`stood. Topical retinoids, antibiotics, benzoyl peroxide, azelaic
`acid and salicylic acid are currently the mainstays of treatment
`for mild to moderate acne vulgaris. Many patients fail
`to
`improve with these agents due to cost, adverse effects leading
`to noncompliance (i.e. irritation), or lack of therapeutic bene-
`fit. The use of oral antibiotics or systemic retinoids increases
`both the cost and the risks for adverse effects.
`Picolinic acid is an intermediate metabolite of the amino
`acid tryptophan. It appears to play a key role in zinc transport.
`As a therapeutic agent, the molecule seems to work by per-
`turbing zinc binding in zinc finger proteins (ZFPs). Picolinic
`acid has antiviral and antibacterial properties in vitro and in vivo,
`and also modifies the immune response alone and in conjunc-
`tion with other cytokines. Picolinic acid was first evaluated in
`the treatment of herpes labialis.
`Here we report the results in 20 subjects with mild to mod-
`erate acne vulgaris treated at our centre during an open-label,
`phase I study of 10% picolinic acid gel (PCL-016).
`
`Patients and methods
`
`Patients
`
`Subjects were eligible for study participation if they were at
`least 18 years of age and had a clinical diagnosis of mild to
`
`548
`
`Ó 2006 The Authors
`Journal Compilation Ó 2006 British Association of Dermatologists • British Journal of Dermatology 2007 156, pp548–552
`
`1 of 5
`
`Almirall EXHIBIT 2060
`
`Amneal v. Almirall
`IPR2019-00207
`
`

`

`moderate acne vulgaris of the face at baseline. Subjects were
`required to have between 10 and 100 inflammatory lesions
`(papules and pustules) and no more than two nodules. Sub-
`jects were judged to be in generally good health as deter-
`mined by the principal investigator. Subjects were excluded if
`they had other active skin diseases that may interfere with
`evaluation; had a beard or other facial hair that may interfere
`with evaluation; had a history of an allergic reaction or signifi-
`cant sensitivity to constituents of the study drug; had a poorly
`controlled medical condition; were female and pregnant or
`breastfeeding or considering becoming pregnant during the
`study; had a history of clinically significant drug or alcohol
`abuse in the last year; had participated in a clinical research
`study within 30 days of enrolment; or were considered unre-
`liable or unable to understand protocol directions in the esti-
`mation of the investigator. Subjects with other forms of acne
`such as acne rosacea, acne excorie´e, chloracne, acne conglo-
`bata, acne fulminans or drug-induced acne were excluded.
`Subjects with moderate to severe nodulocystic acne deemed
`by the investigator to require systemic treatment were also
`excluded.
`All
`subjects provided written informed consent before
`inclusion into the study. The study protocol was approved by
`the Institutional Review Board of the Washington University
`School of Medicine.
`
`Methods
`
`All subjects received open-label 10% picolinic acid (PCL-016)
`gel (NV-02; Novactyl,
`Inc., St Louis, MO, U.S.A.) to be
`applied in a thin layer to affected areas of the face twice daily
`for 12 weeks. Picolinic acid was stored at room temperature
`at the study site. Subjects stored study medication at home at
`room temperature after it was dispensed to them.
`Subjects were not permitted to use any treatments for acne
`vulgaris during the study. Subjects discontinued topical astrin-
`gents for 1 day and other topical medications, such as antibi-
`otics, antiseptics, corticosteroids and retinoids,
`for at
`least
`2 weeks. Subjects discontinued systemic corticosteroids and
`oral antibiotics for at least 4 weeks. Systemic retinoids were
`discontinued for at least 6 months. All other systemic therapy
`for
`acne
`vulgaris
`required discontinuation for
`at
`least
`3 months. Women using oral contraception were required to
`be taking the same contraceptive for at least 3 months prior to
`study entry and to agree to continue this therapy until after
`completion of the study.
`Clinical and laboratory assessments were performed at
`weeks 0, 4, 8 and 12 after the start of therapy. Clinical assess-
`ments
`included physical examination and an acne lesion
`count. A Physician Global Improvement score was also deter-
`mined at the final visit. Laboratory assessments included a full
`blood count, serum chemistry, urine pregnancy test (if applic-
`able) and plasma picolinic acid level. Concomitant medications
`and drug compliance were reviewed at each visit. All adverse
`events were assessed and recorded including date and time of
`onset, description, severity, time course, duration, outcome
`
`Picolinic acid gel for acne vulgaris, M.P. Heffernan et al. 549
`
`and relationship to study drug. An additional visit was con-
`ducted at week 1 following the initiation of
`therapy for
`review of concomitant medications, adverse event query and
`laboratory assessments.
`Photographs of subjects who gave written informed consent
`were taken at weeks 0, 4, 8 and 12. Photographs were taken
`with a Nikon N80 camera. Photographs were performed to
`document efficacy and were not used for statistical analysis.
`The primary efficacy endpoints included improvement in
`the total
`inflammatory lesion count, total
`lesion count and
`global severity score at week 12 compared with baseline. Sec-
`ondary efficacy endpoints included improvement in the total
`noninflammatory lesion count at week 12 compared with
`baseline. Safety variables evaluated included the incidence of
`adverse events, abnormalities in routing laboratory monitor-
`ing, and comparisons of pre- and post-treatment plasma picol-
`inic acid levels. Efficacy and safety outcomes were designed to
`direct planning for larger, blinded phase II–III investigations.
`
`Statistical analyses
`
`P-values were obtained for both per protocol and intent-to-
`treat analyses using a paired t-test. Analyses performed using a
`single-sample t-test yielded identical values.
`
`Results
`
`Baseline characteristics
`
`Twenty subjects who met all of the inclusion criteria and none
`of the exclusion criteria were enrolled in this study. Fifteen
`patients completed the 12-week open-label study per protocol.
`Four patients were lost to follow-up and one patient withdrew
`due to a localized adverse event (discussed later). Table 1
`summarizes the baseline characteristics for the participants.
`
`Efficacy
`
`All 15 patients who completed the study demonstrated reduc-
`tion in total lesion count and noninflammatory lesion count.
`Fourteen of these patients (93Æ3%) had a reduction in inflam-
`matory lesion count. A reduction of 58Æ2% (from 85Æ33 to
`
`Table 1 Baseline characteristics
`
`Male
`Female
`Age range (years)
`White
`African-American
`Hispanic
`Asian
`Total baseline lesions
`Total baseline inflammatory lesions
`Total baseline noninflammatory lesions
`
`5
`15
`20–48 (mean 29Æ6)
`12
`6
`1
`1
`14–172 (mean 78Æ15)
`12–58 (mean 27Æ45)
`2–148 (mean 50Æ7)
`
`Ó 2006 The Authors
`Journal Compilation Ó 2006 British Association of Dermatologists • British Journal of Dermatology 2007 156, pp548–552
`
`2 of 5
`
`

`

`550 Picolinic acid gel for acne vulgaris, M.P. Heffernan et al.
`
`0
`85.33
`30.40
`54.93
`
`1
`83.73
`30.00
`53.73
`
`4
`59.40
`20.27
`39.13
`Week
`
`8
`47.40
`15.20
`32.20
`
`12
`35.67
`13.33
`22.33
`
`Fig 1. Mean lesion counts using per protocol
`analysis.
`
`90.00
`
`80.00
`
`70.00
`
`60.00
`
`50.00
`
`40.00
`
`30.00
`
`20.00
`
`10.00
`
`0.00
`
`Lesion Count
`
`Total Lesions
`Inflammatory Lesions
`Noninflammatory Lesions
`
`35Æ67; P ¼ 0Æ0001) in mean total lesion count, 55Æ5% (from
`30Æ40 to 13Æ33; P ¼ 0Æ0002) in mean inflammatory lesion
`count and 59Æ7% (from 54Æ93 to 22Æ33; P ¼ 0Æ0007) in non-
`inflammatory lesion count was seen using per protocol analy-
`sis (Fig. 1).
`Similar findings were demonstrated using intent-to-treat an-
`alysis for all 20 subjects enrolled into the study. A reduction
`of 50Æ6% (from 78Æ15 to 38Æ60; P ¼ 0Æ0001) in mean total
`lesion count, 47Æ2% (from 27Æ45 to 14Æ30; P ¼ 0Æ0001) in
`mean inflammatory lesion count and 52Æ4% (from 50Æ70 to
`24Æ30; P ¼ 0Æ0012) in mean noninflammatory count was seen
`using intent-to-treat analysis.
`A Physician Global Improvement score was determined for
`each of the 15 patients completing the study at the final visit.
`Seven (47%) of these patients were judged to be almost clear
`(90–99% clearance) or to have marked improvement (75–
`89% clearance). Three patients (20%) had moderate (50–74%
`clearance) or minimal (25–49% clearance) improvement. Five
`patients (33%) were judged to have no change (0–24% clear-
`ance) from baseline.
`
`Safety
`
`Nineteen of the 20 patients enrolled were exposed to study
`drug for at least 1 week, 17 for at least 4 weeks, and 15 for
`all 12 weeks of the study. There were no deaths or serious
`adverse events noted during this study. There were no clinic-
`ally significant changes in any laboratory values (full blood
`count and serum chemistry) during the study. No patients
`became pregnant during the study.
`One of the 20 subjects enrolled (patient 2) experienced a
`drug-related adverse event
`leading to withdrawal from the
`study. This patient described ‘burning’ after application of
`study drug lasting 4 h that was ‘too much’. This was classified
`by the investigator to be mild and probably related to study
`drug. There were no sequelae from this event. Two other
`patients described adverse events determined as probably rela-
`ted to study drug. Patient 15 noted burning after application
`
`Table 2 Adverse events
`
`Patient
`
`Adverse event
`
`Week
`
`2
`6
`15
`12
`15
`9
`11
`
`Burning at application site
`Tingling at application site
`Burning at application site
`Sinusitis
`Allergic rhinitis
`Vaginal yeast infection
`Upper respiratory viral infection
`
`1
`1
`1
`5
`12
`8
`9
`
`Relation
`to study
`drug
`
`Probable
`Probable
`Probable
`Possible
`Possible
`Unlikely
`Unlikely
`
`lasting up to 1 h that resolved after the first week of therapy.
`Patient 6 described a sensation of ‘facial tingling’ on the first
`day of study drug application only. Table 2 summarizes each
`of the documented adverse events from this study.
`Plasma measurements of picolinic acid were done using a
`validated assay developed by ABC Laboratories (now known as
`ABC Pharma Services, Columbia, MO, U.S.A.) for Novactyl,
`Inc. There were no stipulations regarding timing of blood
`draws relative to last dosing. Samples were collected in vacu-
`tainers containing powdered heparin. After gentle mixing, the
`samples were kept on wet ice and centrifuged within 15 min
`of collection. Resulting plasma was aliquoted and kept at
`)20 °C until analysis. Plasma levels of picolinic acid varied
`widely between patients and within patients during the study
`)1. No
`(Table 3). The maximum level detected was 113 ng mL
`correlation between plasma picolinic acid levels and the occur-
`rence of adverse events was evident.
`
`Discussion
`
`This study was designed to assess the clinical efficacy and safety
`of 10% picolinic acid gel, a novel immunomodulatory therapy
`targeting ZFPs, in the treatment of mild to moderate acne
`vulgaris. Results from this open-label study show picolinic acid
`
`Ó 2006 The Authors
`Journal Compilation Ó 2006 British Association of Dermatologists • British Journal of Dermatology 2007 156, pp548–552
`
`3 of 5
`
`

`

`
`
`Table 3 Picolinic acid drug levels (ng mL)1)
`
`Patient Week 0 Week 1 Week 4 Week 8 Week 12
`13Æ6
`17Æ6
`11Æ3
`BQL
`17Æ9
`52Æ3
`BQL
`16Æ6
`72Æ6
`BQL
`15Æ5
`96Æ0
`21Æ2
`17Æ3
`
`54Æ5
`90Æ5
`BQL
`24Æ3
`113Æ0
`BQL
`BQL
`91Æ2
`24Æ3
`31Æ1
`
`BQL
`BQL
`BQL
`BQL
`44Æ9
`BQL
`BQL
`
`BQL
`56Æ9
`
`BQL
`
`47Æ0
`BQL
`BQL
`BQL
`BQL
`BQL
`BQL
`
`BQL
`BQL
`
`Picolinic acid gel for acne vulgaris, M.P. Heffernan et al. 551
`
`for 21 consecutive days. The result of this irritant study was that
`10% PCL-016 cream was clinically comparable with BlistexTM
`(Blistex Inc., Oak Brook, IL, U.S.A.).
`There was only one adverse effect, burning at the applica-
`tion site, which led to patient discontinuation from this study.
`This was judged to be mild in intensity and probably related
`to study drug by the investigator. Another patient experienced
`burning after application of study drug that resolved within
`1 week of the study. One patient described facial tingling pre-
`sent only on day 1 of study drug application. The remaining
`adverse effects discussed earlier were mild and judged as poss-
`ibly related or unlikely to be related to study drug. There were
`no deaths or serious adverse events noted in this study. There
`were no significant laboratory abnormalities during the study.
`It is estimated by the manufacturer that 10–20 mg of PCL-
`016 is delivered to the skin with each application of 10%
`picolinic acid gel. There was both intrapatient and interpatient
`variability in plasma levels of picolinic acid during the study.
`The maximum plasma level of picolinic acid detected was
`)1. No correlation between plasma picolinic acid
`113 ng mL
`levels and the occurrence of adverse events was evident. The
`minimum plasma picolinic acid level achievable before adverse
`effects are expected to occur, if a relation exists, remains to be
`elucidated.
`In conclusion, the results of this study suggest that 10% pi-
`colinic acid gel applied twice daily may be safe and effective
`in the treatment of mild to moderate acne vulgaris. This is the
`first reported use of NV-02 in humans, and the first reported
`use of a zinc finger drug in the treatment of acne vulgaris.
`Future randomized, double-blind, multicentre trials will be
`necessary to confirm and better define these findings.
`
`References
`
`1 Kraning KK, Odland GF, eds. Prevalence, morbidity, and cost of
`dermatological diseases. J Invest Dermatol 1979; 73:395–513.
`2 Leyden JJ. New understandings of the pathogenesis of acne. J Am
`Acad Dermatol 1995; 32:S15–25.
`3 Cunliffe WJ, Gould DJ. Prevalence of facial acne vulgaris in late
`adolescence and in adults. BMJ 1979; i:1109–10.
`4 Jowett S, Ryan T. Skin disease and handicap: analysis of the impact
`of skin conditions. Soc Sci Med 1985; 20:425–9.
`5 Shuster S, Fisher GH, Harris E, Binnell D. The effect of skin disease
`on self-image. Br J Dermatol 1978; 99 (Suppl. 16):18–19.
`6 Plewig G, Kligman AM. Acne and Rosacea, 3rd edn. New York: Sprin-
`ger-Verlag, 2000.
`7 Kellet SC, Gawkrodger DJ. The psychological and emotional impact
`of acne and the effect of treatment with isotretinoin. Br J Dermatol
`1999; 140:273–82.
`8 Koo J. The psychosocial impact of acne: patients’ perceptions. J Am
`Acad Dermatol 1995; 32:S25–30.
`9 Wu SF, Kinder BN, Trunnell N, Fulton JE. Role of anxiety and
`anger in acne patients: a relationship with the severity of the dis-
`order. J Am Acad Dermatol 1988; 18:325–33.
`10 Aktan S, Ozmen E, Sanli B. Anxiety, depression, and nature of acne
`vulgaris in adolescents. Int J Dermatol 2000; 39:354–7.
`11 Cunliffe WJ. Acne and unemployment. Br J Dermatol 1986; 115:386
`(Letter).
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`
`ND
`BQL
`ND
`BQL
`ND
`BQL
`ND
`BQL
`BQL
`BQL
`BQL
`BQL
`BQL
`BQL
`BQL
`BQL
`BQL
`BQL
`BQL
`BQL
`
`BQL
`BQL
`31Æ9
`22Æ3
`BQL
`BQL
`39Æ8
`
`BQL
`BQL
`
`BQL
`BQL
`BQL
`57Æ4
`
`BQL
`BQL
`
`BQL
`BQL
`
`BQL
`
`BQL
`BQL
`
`7Æ96
`BQL
`
`29Æ3
`
`ND, none detected on assay; BQL, below quantitative limit
`)1).
`(< 10 ng mL
`
`to be highly efficacious with 100% of the subjects who com-
`pleted the study per protocol achieving a reduction in total and
`noninflammatory lesion count and 93Æ3% of subjects achieving
`a reduction in inflammatory lesion count. A clinically signifi-
`cant reduction in mean total lesion count, mean inflammatory
`lesion count and mean noninflammatory lesion count was seen
`using both intent-to-treat and per protocol analysis. In add-
`ition, nearly half of the patients (47%) who completed the
`study were almost clear or had marked improvement at the
`final visit using the Physician Global Improvement score.
`Picolinic acid exists in vivo as a metabolite of the essential
`amino acid tryptophan. It is produced in approximately 25–
`50-mg quantities daily, assuming normal dietary intake. Picol-
`ions (i.e. Zn2+) and is
`inic acid chelates transition metal
`involved in the absorption and transport of transition metal
`ions.
`Picolinic acid has been demonstrated to possess immune-
`modulating properties. Zinc binding within ZFPs is perturbed
`in the presence of picolinic acid. This leads to an alteration in
`chemokine expression independently and in the presence of
`other chemokines such as interferon-c.21,22 Picolinic acid has
`also been shown to have antiviral properties against herpes
`simplex virus type 1 and type 2. ZFPs are involved in viral
`replication, viral packaging and normal cell homeostatic func-
`tions. An Investigational New Drug application has recently
`been submitted by the manufacturer for picolinic acid cream
`in the treatment of herpes labialis.
`A phase I cumulative irritant study was recently completed by
`Novactyl, Inc. assessing 10% picolinic acid cream in healthy vol-
`unteers. Patients applied 200-mg quantities daily under a patch
`
`Ó 2006 The Authors
`Journal Compilation Ó 2006 British Association of Dermatologists • British Journal of Dermatology 2007 156, pp548–552
`
`4 of 5
`
`

`

`552 Picolinic acid gel for acne vulgaris, M.P. Heffernan et al.
`
`12 Mallon E, Newton JN, Klassen A et al. The quality of life in acne: a
`comparison with general medical conditions using generic ques-
`tionnaires. Br J Dermatol 1999; 140:672–6.
`13 Gollnick HPM, Zouboulis CC, Akamatsu H et al. Pathogenesis and
`pathogenesis-related treatment of acne. J Dermatol 1991; 18:489–99.
`14 Cunliffe WJ, Gollnick H. Acne: Diagnosis and Management. London: Mar-
`tin Dunitz, 2001.
`15 Cunliffe WJ, Holland DB, Clark SM, Stables GI. Comedogenesis:
`some new aetiological, clinical and therapeutic strategies. Br
`J
`Dermatol 2000; 142:1084–91.
`16 Cunliffe WJ, Simpson NB. Disorders of the sebaceous gland. In:
`Textbook
`of Dermatology (Champion RH, Burton JL, Burns DA,
`Breathnach SM, eds), 6th edn. Oxford: Blackwell Science, 1998;
`1927–84.
`17 Burton JL, Shuster S. The relationship between seborrhoea and acne
`vulgaris. Br J Dermatol 1971; 84:600–1.
`
`J Am Acad Dermatol
`
`18 Leyden JJ, McGinley KJ, Mills OH, Kligman AM. Propionibacterium
`levels in patients with and without acne.
`J Invest Dermatol 1975;
`65:382–4.
`Inflammation in acne vulgaris.
`19 Webster GF.
`1995; 33:247–53.
`20 Layton AM, Henderson CA, Cunliffe WJ. A clinical evaluation of
`acne scarring and its incidence. Clin Exp Dermatol 1994; 19:303–8.
`21 Bosco MC, Rapisarda A, Massazza S et al. The tryptophan catabolite
`picolinic acid selectively induces
`the chemokines macrophage
`inflammatory protein-1 alpha and -1 beta in macrophages. J Immunol
`2000; 164:3283–91.
`22 Melillo G, Cox GW, Biragyn A et al. Regulation of nitric-oxide
`synthase mRNA expression by interferon-gamma and picolinic
`acid. J Biol Chem 1994; 269:8128–33.
`
`Ó 2006 The Authors
`Journal Compilation Ó 2006 British Association of Dermatologists • British Journal of Dermatology 2007 156, pp548–552
`
`5 of 5
`
`