New Drugs in Development for Rheumatoid Arthritis

I decided to take a look at which new drugs and treatments were in development in order to treat Rheumatoid Arthritis. There are a number of small molecules in development and it is noticeable how Janus kinase (JAK) inhibitors seem to dominate the landscape. Quite a few companies listed on the stock market are developing new drugs for Rheumatoid Arthritis.

TNF Blockers

Unlike TNF blocker biologics like Humira (injected on alternate weeks) Enbrel (injected once a week) or Remicade (intravenous every month or so), these drugs (kinase inhibitors) tend to be taken orally. The three afore mentioned TNF blockers are responsive in 70% of patients, including some who do not respond to the first line treatment of methotrexate. They are expensive and have significant side effects.

JAK Inhibitors for Rheumatoid Arthritis

Janus kinases are receptor associated kinases that provide a pathway for the cytokines that are seen as playing a pivotal role in inflammation of the joints for the Rheumatoid Arthritis sufferer. Of the four JAKs that have been discovered JAK3 has attracted the most attention because it doesn’t seem to have actions outside of hematopoietic cells. I’ll go into more detail on the individual programs below. For reference, the other three JAKs are JAK1, JAK2 and TYK2.

New Drug Pipeline for RA

Company	Compound	Action Inhibitor	Timeline
Lexicon	LX2931	SP1L	Phase IIa ,top line results due by end 2010
Pfizer	CP 690,550	JAK 1/3	Completed Phase III. Four more studies before FDA submission in 2011
Galapagos	GLPG0259	MAPKAPK5	In Phase II, interim results due Q2 2011, top line Q4 2011
Vertex	VX509	JAK 3	In Phase IIa, results due 2011
Morphosys	MOR103	GM-CSF	In Phase Ia/IIb, final results due H1 2012
Incyte/Eli Lilly	INCB28050	JAK 1 / 2	Phase IIb begun in late 2010
Rigel/AstraZeneca	R788	SYK	Phase III begun in late 2010

Pfizer’s CP 690, 550  Tasocitinib

Pfizer’s CP 690 (tasocitinib) is in Phase III for both Rheumatoid Arthritis and Psoriasis. They recently gave Phase III results in Rheumatoid Athritis and it was claimed that CP 690 reduced inflammation in 71 percent of patients. Tasocitinib is an oral indication taken on a once a day regimen. According to the Reuters article

“On the study's first primary goal, 65.7 percent of patients who received 10 milligrams of tasocitinib twice a day achieved ACR20, meaning at least a 20 percent improvement in disease activity and symptoms, after three months of treatment. Nearly 60 percent of 5 mg patients reached ACR20, compared with 26.7 percent of those who received a placebo, researchers said.”

This would appear to be the leader here and Pfizer are developing tasocitinib for other inflammatory diseases such as ulcerative colitis, psoriasis, and Crohn’s disease. FDA submission could take place for RA in 2011.

Interestingly, a study was carried out in 2010 (Cohen) which demonstrated that there weren’t any clinically significant effects on the pharmacokinetics of either drug, if they were taken together. Therefore, there would be no dosage adjustment if taken together.

Rigel/AstraZeneca R788 Fostamatinib Disodium

R788 was in licensed by AstraZeneca early this year in a deal that is potentially worth $1.25bn. This was seen as a significant sign of approval for a drug that had failed one of three Phase II studies in 2009.  R788 or Fostamatinib Disodium is an orally taken (twice a day) SYK inhibitor. Despite the setback in 2009, they reported superb results in a six month Phase IIb study this year. According to Rigel

  “  - The ACR 20 response was achieved by significantly more patients in both the fostamatinib 100mg bid group and the fostamatinib 150mg qd group (67% and 57% respectively) than the placebo group (35%, p<0.001).
- The ACR 50* response rates were 43%, 32% and 19% for the fostamatinib 100mg bid group, 150mg qd group and placebo group respectively (p<0.01). The ACR 70* response rates were 28%, 14% and 10% for the fostamatinib 100mg bid group, 150mg qd group and placebo group respectively (p<0.001 for fostamatinib 100mg bid, p=0.34 for fostamatinib 150 mg qd)
- In addition, the DAS 28 remission rate was significantly higher in both the fostamatinib 100mg bid group and the fostamatinib 150mg qd group (31% and 21% respectively), compared to the placebo group (7%, p<0.01).”

Furthermore, 36 percent of patients achieved ACR20 after just one week, so these phase IIb results demonstrate that R788 has a faster mode of action than Pfizer’s CP 690. Furthermore, remission was statistical significant and this was something that Pfizer could not achieve in Phase III. 

Side effects included increased risk of diarrhoea and hypertension. Phase III trials will begin in late 2010.

Lexicon LX2931 

LX2931 inhibits sphingosine-1-phosphate  (S1P) lyase, which is an enzyme seen as being on a path to regulating the immune system. They’ve demonstrated-in pre-clinical- that inhibiting S1P has reduced inflammation in mice, however the Phase IIa trial is a 208 patient trial. What’s interesting about LX2931 is that it is intended as a combination therapy with methotrexate and is being trialled in this manner. Top line data is due by end 2010.

Incyte/Eli Lilly INCB 28050

Incyte has two JAK inhibitors in development. Its lead compound is INCB18424 which is in Phase III for myelofibrosis and Phase II for polycythemia and psoriasis, respectively.  INCB28050 is its JAK 1 / 2 inhibitor for RA. Eli Lilly paid $90m initially for this compound, with Incyte being eligible for $655m in milestones, as well as royalties on top. They recently presented results for a six month Phase IIa trial

“all three doses of oral INCB28050 (4 mg QD, 7 mg QD and 10 mg QD) improved on the primary endpoint, the percent of patients achieving American College of Rheumatology (ACR) 20 improvement, over the full 24-week treatment period. Importantly, ACR responses improved between week 12 and week 24 achieving up to 72% for ACR20, 44% for ACR50 and 30% for ACR70 at week 24. Results seen at 12 weeks for placebo were 32% for ACR20, 13% for ACR50 and 3% for ACR70, and for patients treated with INCB28050 the results were up to 59% for ACR20, 35% for ACR50 and 16% for ACR70.”
As with Rigel’s R788 adverse effects of diarrhoea and hypertension were reported. Eli Lilly plans to begin Phase IIb shortly. 

Vertex VX509 JAK3 II

I’ve previously discussed Vertex here but omitted to mention VX509. VX509 is a JAK3 inhibitor that Vertex has in a Phase IIa 200 patient proof of concept trial. Interim clinical data is expected in 2011.

Galapagos GLPG0259

Galapagos is another company I mentioned recently and MAPKAPK5 (a protein kinase) was discovered as playing a role in RA, via Galapagos’ proprietary discovery technology. It is a good illustration of their business model. Galapagos feel that it is involved in signaling a pathway to inflammation. GLPG0259 is orally taken, once a day regimen, and is compatible with methotrexate. Indeed, the initiated Phase II will be with methotrexate. Interim results are due in H1 2011 and top line results by end 2011.

Morphosys GSM-CF Inhibitor MOR103

I wrote a bit about MOR103 here and what makes MOR103 a novel antibody, is that it targets GM-CSF, which is seen as an inflammatory mediator that activates the JAK pathway. It is currently in Phase Ib/2a trial, with final results due in H1 2012.

Conclusion on New Treatments for Rheumatoid Arthritis

This new collection of drugs represents a potential improvement to the TNF blockers, in terms of regimen and side effects. Pfizer’s CP 690 is the leader and appears to be a blockbuster in the making. It should be well established by the time that Incyte and Vertex get their JAK inhibitors on the market. Pfizer’s is the only compound successfully through Phase III. Rigel’s R788 is very interesting due to its speed of action and efficacy, however this is yet to be confirmed in Phase III and it will be a while before they complete this. 

Lexicon and Galapagos present options for combination with the first line treatment of methotrexate. GLGP0259 is in early stage, but Lexicon’s LX2931 should give results soon in a Phase II trial. Morphosys MOR103 is early stage but potentially a blockbuster as they own the rights to GSM-CF inhibitors in inflammatory diseases in the US. I opened a small speculative position in Lexicon ahead of their Phase IIa data in LX2931.

Source:

Cohen S, Zwillich SH, Chow V, Labadie RR,Wilkinson B “Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment."  British Journal of Pharmacology, Volume 69, Issue 2, Pages 143-151, February 2010

Reuters “Pfizer Arthritis Drug Succeeds in Late Stage Trial”

Rigel Website (accessed Dec 2010) “Data Published Today Reveal That Novel Oral Therapy Fostamatinib Demonstrates Positive Response in Rheumatoid Arthritis Patients”

Incyte Website (accessed Dec 2010) “Incyte's Selective Oral JAK1 and JAK2 Inhibitor Demonstrates Positive Phase IIa Results in Patients with Active Rheumatoid Arthritis”