RESEARCH & DEVELOPMENT

'Thzarotene heads for success in psoriasis

-Rodger Hall-

The lull results of a double-bllod, phase m study of tazarotene involving patients witb psoriasis were presented at this year's Dennatology Update (Montreal, CtuuultI.; October 1995]. The data showed that tazarotene gel significantly reduced lesion development, compared with placebo, and was weD tolerated. These results bode wdl for the new retinoid, which was submitted to the US FDA in June 1995 ror marketing approval as a treatment for acne and psoriasis.

Natural retinoids, such as retinok acid and its analogues, are very flexible molecules that can bind to a variety of retinoid receptors. including those from the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family. The interactions that occur between retinoids and receptors can lead to a wide range of effects, including antiproliferative and anti-inflammatory actions.

When developing the new acelyienic retinoid tazarotenc, researchers from Allergan made a number of structural changes to the basic retinoid structure. including: • the introduction of conformational rigidity to increase

receptor selectivity • changes to the chemical structure in order to create

an ethyl-ester. Le. a prodrug. which has a better topical therapeutic index and is rapidly converted to the active form of drug (absorption of the parent compound is very low, with levels below 0.15 ng/ml found in 3% of patients; the active primary meta­bolite, tazarotenic acid. has a very short half-life of 13-14 hours)

• the replacement of a carbon ring with a sulphur­containing ring, which is rapidly oxidised to inactive metabolites. This less flexible. conformationally restricted mol­

ecule is particularly suitable for topical use. Its effi­cacy was demonstrated in a phase III study conducted by Dr Weinstein and colleagues from Allergan (see boxed text]. The following conclusions were drawn from the study. • Once daily treatment is effective. • Both concentrations oftazarotene gel (0.05 or 0.1 %)

are significantly more effective than placebo. • Significant clinical improvement is seen as early as

1 week after treatment initiation. • The therapeutic effect of tazarotene is maintained

for 12 weeks after treatment tennination. • Treatment with either concentration of tazarotene gel

is well tolerated with adverse effects limited to local irritation. One of the study investigators, Dr Ros

Chandraratna, commented that 3 participants in the trial became pregnant during treatment, but that no adverse effects were detectable in the mothers or their offspring. Furthermore, no systemic effects were noted. even in 7 patients who had plasma concen­trations of tazarotenic acid greater than I ng/ml.

'Thzarotene gel is acceptable oosmetiaIlIy At a pre-conference workshop, researchers

commented that tazarotene gel may be of particular use for the treatment of face and scalp psoriasis as, at present, there are no cosmetically acceptable products for successfully treating these areas. Animal and

1l'5W7CMI5I1017~'.ocI' Ad" IrItIMnItIoNlI L..IrnIt.d , • • All rlght8 ~

Double bind parallel study of _ala Ie

. gel in plaque psoriasis P.tlant population: 324 patients (mean age 48.6 years) with stable plaque psoriasis entered the stu­dy . The mean duration of psoriasis for this patient group was 17.5 years, with a mean psoriatiC in· volvement of 6.9%. T .... tment: tazarotene 0.1 or 0.05% • vehicle , or vehicle alone, we~ applied once daily to all lesions tor 12 weeks. Patients were a llowed to use ·emol­lients on a ll areas except for 2 target lesions on trunkllimbs and knees/elbows. Ev.luatlon: assessments took place during treat­ment at weeks 1, 2, 4, 8 and 12, and post-treatment at weeks 16, 20 and 24. Re.ula: 318 patients were evaluated. During treat· ment, the reduction in severity of plaque elevation, erythema and scaling was significantly greater in tazarotene recipients than in patients treated with vehicle alone (p < 0.05). After 12 weeks of therapy, treatment was successful (good, excellent or com­plete clearing of trunkllimb target lesions) in 70, 59 and 35% of patients receiving 0.1 % gel, 0.05% gel or vehicle , respectively (p < 0.001). Results were similar for knee/elbows and for all other body lesions. The therapeutic effect of tazarotene was maintained for up to 12 weeks' post-treatment. Adveru Effects: tazarotene did not appear to be associated with any adverse systemic effects, ac­cording to the results of urinalysis and haemato­logical tests. Dose-related local effects, which are typically associated with retinoid US8, were seen (s8e graph].

Local adverse effects associated with tazarotene or vehicle

"""In. Burning Irrttation Erythema

human studies with tazarotene gel have found no evidence of photo-allergic, phototoxic or contact sensitivity reactions.

Tazarotene is formulated in an aqueous, non­alcoholic gel, which is non-drying, spreads easily and is non-comedogenic.

INPKARMA- II Dec 1ft!!

9

10 RESEARCH & DEVELOPMENT

'Thzarotene - conlinlU!d

Future Developments Clarification is still required regarding potential

tazatotene regimens. Possibilities include mainten­ance treatment every second day or weekly. pulse therapy, drug holidays and combination therapy with other agents. Furthermore, if the low irritation level of tazarotene is confirmed, it may prove useful in fold psoriasis.

New retinoid agents under investigation with AJlergan --AGN-193f1OO; AGN-193455 -AGN-192867;AGN-193174; -AGN-193199

AGN-193109 -AGN-193818; AGN-l93644 -lIAR,.

""'" !WI

""""AAR A number of companies are investigating new

retinoid compounds. The aim is to develop retinoid agents that have fewer adverse effects than retinoic acid itself. Currently at Allergan. both agonists and antagonists of various retinoid receptors are under investigation (see table 2] .

""", .. " .. Editori," com.nrent: Tazarotene is also in p~cIinical devefopnrent as a possible treatment/or skill C(J1Icer.

0156-21O:w5Il011-OOO1Q,101.000AdI.Im.m.tlonel LlmlUod 1185. AU rlghtlo rnerwd