The oral pipeline for psoriasis

Oral treatment for moderate-to-severe psoriasis has not kept pace with biologic therapies, despite the recent FDA approval of apremilast (Otezla, Celgene). There is a need for safe, effective long-term oral psoriasis therapies, researchers wrote in their review, published June 2015 in the Journal Expert Opinion on Emerging Drugs.

There is an important place, however, for oral treatments like apremilast in the care of psoriasis patients, according to Joel Schlessinger, M.D., president of LovelySkin.com and a dermatologist practicing in Omaha, Neb.

“Apremilast has become a useful alternative for patients who either aren’t willing or aren’t able to use the injectable new forms of treatment for psoriasis or are not topical treatment candidates,” Dr. Schlessinger says.

Two bright spots on the oral pipeline horizon, according to the dermatologist, include medications with fumaric acid, which has been used successfully in Europe to treat psoriasis patients, as well as Janus kinase, or JAK, inhibitors.
“JAK inhibitors are also an exciting area of potential exploration in not only the treatment of psoriasis but also alopecia areata, and many other conditions,” Dr. Schlessinger says.

“Generally speaking, the benefits of injectables that are available are superior to oral treatments that are available but that doesn’t mean that oral treatment isn’t respected. It just means that many patients will try injectables before they try apremilast, and the apremilast is generally used in situations where the psoriasis isn’t quite as prevalent or PASI score is lower than necessary for injectables to be approved or if there are some other health conditions that are important to avoid injectables,” he says.

Price challenges

The big problem with the existing psoriasis treatments, including oral therapies, is price, according to Dr. Schlessinger.
“Price has been extraordinarily challenging for many insurers and most if not all patients. The existence of patient assistance programs has been a challenge because to some degree of the interplay between insurance companies and pharmaceutical companies,” he says.

“Oral treatment is modestly less expensive than the injectable treatments, with a significant decrease in efficacy in comparison. We have tried to get several people on the oral treatments with minimal success. The limitations for many insurance companies are affecting our patients’ access.”

NEXT: Pipeline lineup

Pipeline lineup

While there isn’t much public information on oral psoriasis drugs in the pipeline, the National Psoriasis Foundation lists about 10 orals for psoriasis in phase 2 or phase 3 trials.

They are:
Prurisol (Cellceutix) is a small molecule that acts through immune modulation and PRINS (psoriasis associated RNA induced by stress) reduction and which is over-expressed in psoriasis. The drug has completed a phase 2 FDA trial under the U.S. Food and Drug Administration’s 505(b)(2) pathway. The placebo-controlled, randomized, double-blind trial tested efficacy and safety of three separate, twice-daily, dosing regimens: 50 milligram (mg) (50mg QD), 100mg (50mg BD), and 200mg (100mg BD). At the end of the 84-day treatment period, 35% of patients in the 200-mg arm demonstrated clinically significant improvements compared with 16.7% in the placebo only group, according to the recent press release. The primary endpoint was the percent of patients who achieved at least a two-point improvement from baseline on the IGA 5-point scale as measured by visual inspection of patient lesions at the end of treatment period. Further analysis showed the greatest efficacy was in patients with moderate disease (IGA 3), according to the company. Only one Serious Adverse Event was reported in the 50-mg arm. Additional Adverse Events were reported similarly across each dosing arm and the placebo arm, the company notes.

XP23829 (Dr. Reddy’s Laboratory), in phase 2 research, is an anti-inflammatory (fumaric acid), according to Psoriasis.org. In a March 28, 2016 press release, Dr. Reddy’s Laboratories and XenoPort announced the companies had a U.S. Licensing Agreement for XP23829, in which Dr. Reddy’s Laboratories has exclusive U.S. rights for XP23829 development and commercialization. Plans are to develop XP23829 as a treatment for moderate-to-severe chronic plaque psoriasis. Discovered by XenoPort, XP23829 is an oral fumaric acid ester compound that is a prodrug of monomethyl fumarate (MMF). Mark Jackson, M.D., clinical professor of medicine, dermatology, University of Louisville, was quoted in the release as saying that fumaric acid esters feature a unique anti-inflammatory mechanism of action and have been used to treat psoriasis in Germany for more than 20 years. “XP23829, a novel fumaric acid ester, has the potential to be a meaningful treatment option for patients with moderate-to-severe psoriasis,” Dr. Jackson says.

KD025 (Kadmon Corporation), is an orally bioavailable, potent and highly selective inhibitor of ROCK2 (Rho-associated coiled-coiled kinase 2, in phase 2 research, according to company information. Kadmon announced January 6, 2015 that it started a phase 2 clinical trial evaluating KD025 in moderate-to-severe psoriasis vulgaris patients who had failed first-line therapy. The open-label, dose-finding study is looking at KD025 administered at doses of 200 mg twice daily and 400 mg once daily for three months in 24 patients at six U.S. sites. The company’s phase 2a single-arm safety study showed positive changes in inflammatory markers, including a specific decrease in the secretion of the pro-inflammatory cytokine IL-17. In the same phase 2a study, three of the eight patients showed a decrease in Psoriasis Area and Severity Index (PASI) scores of up to 66% after one month of treatment, according to the release.

“Therapies targeting IL-17 have shown significant efficacy in treating psoriasis,” Mark G. Lebwohl, M.D., professor and chair of dermatology at the Icahn School of Medicine at Mount Sinai and primary investigator of Study 206, said in the press release. “KD025 represents a novel oral approach to treating psoriasis by blocking IL-17 secretion while concurrently increasing the suppressive function of regulatory T-cells (Treg), helping to resolve inflammation with a minimal effect on the rest of the immune response.”

Alitretinoin (9-cis-retinoic acid; Stiefel, a GSK company) is indicated for psoriasis (pustular). It is a skin cell inhibitor (a retinoid) in phase 2 research, according to psoriasis.org.  Alitretinoin is FDA approved for the treatment of skin sores and lesions in patients with AIDS-related Kaposi sarcoma. The study Efficacy of Alitretinoin Treatment in Patients With Pustular Form of Psoriasis has been completed but no results posted on ClinicalTrials.gov. Alitretinoin is thought to have promise for patients with palmoplantar pustular psoriasis recalcitrant to conventional therapies, according to an article in the June 2015 Cutis.

Apo805k1 (ApoPharma) has an undisclosed mechanism of action. Authors of an article in the July 2015 Cutis, write a phase 2 randomized, placebo-controlled, double-blind trial on Apo805k1 on moderate to severe psoriasis is complete. Twelve patients in each treatment group received a 12-week daily dosing regimen of 10, 30, 60 or 100 mg or placebo. Among the results: 16.7% patients in the 10-mg and placebo groups achieved a PASI 75. There were no patients achieving PASI 75 in the 30-mg and 60-mg groups. And 8.3% of those in the 100-mg group achieved PASI 75, according to the Cutis article by Feely MA, Smith BL and Weinberg JM.

FP187 (Forward-Pharma) is an anti-inflammatory (fumaric acid). FP187 is based on the small molecule dimethylfumarate (DMF) in a patented controlled release erosion matrix tablet with enteric coating, according to company information. The development of FP187 benefits with a long term track record of  DMF  in Germany, where a DMF formulation combined with three salts of monoethylfumarate was approved for psoriasis in 1994 and has gained first-line status and endorsement in German and international guidelines, according to Forward Pharma. ClinicalTrials.gov has posted for the “Efficacy Study on Dimethyl Fumarate to Treat Moderate to Severe Plaque Psoriasis,” a multicenter, randomized, double-dummy, Fumaderm and placebo-controlled, parallel-group study to compare the efficacy and safety of 500 mg of FP187 (250 mg twice daily) compared to 720 mg Fumaderm (240 mg three times daily) over 20 weeks of treatment. The phase 3 study has not yet opened for participant recruitment, according to the government website.

LEO 22811 (LEO Pharma) is an antiinflammatory oral with a proprietary mechanism, in phase 2 trials, according to Psoriasis.org. LEO 22811 is among a new generation of highly selective p38 inhibitors under development, according to LEO Pharma literature.

Baricitinib (Eli Lilly/Incyte), an anti-inflammatory (JAK1 and JAK2 inhibitor) in phase 2 trials, is the only once-daily oral selective JAK1 and JAK2 inhibitor in late-stage clinical studies for inflammatory and autoimmune diseases. In phase 3 studies for rheumatoid arthritis, baracitnib is in ongoing phase 2 trials in psoriasis, diabetic nephropathy, atopic dermatitis and systemic lupus erythematosus, according to PharmaTimes Online.

ZPL-389 (Ziarco Pharma Ltd.) is a small molecule selective histamine H4 receptor antagonist in phase 2 research. A phase 2a proof of concept study in moderate to severe psoriasis has begun. Results are expected in H1 2017, according to the company’s website.

TP-43742 (Vitae Pharmaceuticals) is an anti-inflammatory (IL-17 blocker) in phase 2 research. Vitae Pharmaceuticals announced March 16, 2016 positive results from its Phase 2a proof-of-concept clinical trial of VTP-43742 in psoriatic patients. VTP-43742 is a first-in-class, orally active RORγt inhibitor, which inhibits IL-17 secretion from Th17 cells and blocks the action of IL-23. VTP-43742 demonstrated efficacy with patients at a dose of 350 mg - a group of patients achieving a 24% reduction in the Psoriasis Area Severity Index (PASI) score relative to placebo. In the 700 mg dose group, patients achieved a 30% placebo-adjusted PASI score reduction, according to the company. DT

Disclosure: Dr. Schlessinger was an investigator for one of the apremilast studies. The information cited above was the most recent data available at press time.

Reference:
Mahmood T, Zaghi D, Menter A. Emerging oral drugs for psoriasis. Expert Opin Emerg Drugs. 2015 Jun;20(2):209-20. Epub 2015 Feb 3. Review.