Pfizer's Immunology Pipeline Has Few Bright Spots Besides Xeljanz

| About: Pfizer Inc. (PFE)
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Summary

Negative results for PF-04171327 in rheumatoid arthritis were buried at ACR/ARHP 2014 in November.

Results for anti-IL-6 antibody in Lupus were highlighted in Pfizer's ACR/ARHP 2014 PR, but they were negative too. The anti-IL-6 is in ANDANTE, a Phase 2 trial for Crohn’s Disease.

The anti-MAdCAM candidate is also a 50-50 proposition in OPERA, another Phase 2 RCT for CD. Its best chance lies in TURANDOT, a Phase 2 study in ulcerative colitis.

The immunology product line of Pfizer (NYSE:PFE) has a rising presence in autoimmune diseases with Xeljanz ($205 million in sales for the first 9 months of 2014 and $114 million in 2013) approved for rheumatoid arthritis (or RA) to go along with the Amgen (NASDAQ:AMGN)-partnered Enbrel ($3.8 billion outside the U.S. and Canada in 2013), which is approved for RA, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis. This article examines Pfizer's immunology pipeline outside of Xeljanz. Phase 2 trials are ongoing or awaiting results in Crohn's disease (CD, with PF-04236921 and PF-00547659), RA (PF-04171327) and ulcerative colitis (UC, with PF-00547659).

PF-04171327 in Rheumatoid Arthritis

RA is a chronic, autoimmune disease often accompanied by pain, stiffness and inflammation, and in some cases, joint destruction and disability. In addition to increasing the chance of brittle bones, inflammation from RA may harden and block arteries and the sac surrounding the heart; it can also scar lung tissue. It is estimated that RA affects 1.5 million Americans, with an incidence of 53 per 100,000 in women and 28 per 100,000 in men. Mortality is twice as high in untreated people with RA compared with unaffected people the same age. RA is treated with corticosteroids (like prednisone), non-steroidal anti-inflammatory drugs (like ibuprofen), and disease-modifying antirheumatic drugs (DMARDs). Synthetic DMARDs include methotrexate (or MTX) and sulfasalazine, while biologic DMARDs include Embrel.

PF-04171327 is an orally-taken dissociated agonist of the glucocorticoid receptor (DAGR). As a partial agonist (opposite of antagonist or opponent) of GR, PF-04171327 displays potent anti-inflammatory activity at exposures that provide lower side effects on bone formation and glucose metabolism relative to prednisone, a full GR agonist. In two Phase 1 RCTs, PF-04171327 and its active metabolite had less impact than prednisone on plasma osteocalcin, a biomarker of adverse effects on bone.

A 2-week Phase 2a randomized, placebo-controlled trial (RCT) evaluated 2 doses of PF-04171327 relative to placebo (or PBO) and low-dose (5 mg) prednisone in 86 subjects with active RA and an inadequate response to MTX. The study met its primary endpoint, which was the change from baseline on Disease Activity Score (or DAS) 28(4) using C-reactive protein (or CRP) to Week 2 (see Appendix for formula). PF-04171327 10 mg and 25 mg demonstrated significant improvement (lowered DAS scores) over PBO by 0.73 (p=0.0141) and 1.26 (p<0.0001), respectively. Additionally, both doses of PF-04171327 showed a greater reduction in DAS28 than prednisone 5 mg. Prednisone did not significantly change DAS28 scores. Similar responses were seen for secondary outcome measures, which included American College of Rheumatology (ACR) 20/50/70 response rates (see Appendix for definitions) and DAS28CRP(3).

Recently, Pfizer presented data at the ACR/Association of Rheumatology Health Professionals (ARHP) 2014 Annual Meeting last November on a larger (323 patients) and longer (8-week) double-blind Phase 2 RCT comparing 4 doses of PF-04171327 (1, 5, 10, and 15 mg daily) to PBO and 5 or 10 mg prednisone. At 8 weeks, more patients attained the primary endpoint ACR 20 responses in the PF-04171327 dosage groups, but the rate was statistically significant in only the two highest DAGR doses (10 and 15 mg) compared with patients receiving PBO (see Table 1). The effects of PF-04171327 on secondary endpoints ACR 50 and ACR 70 were generally better than PBO and just as good as prednisone.

Table 1. American College of Rheumatology 20 Results

PF-04171327

Response Rate

1 mg

44%

5 mg

60%

10 mg

78%

15 mg

68%

Prednisone

5 mg

51%

10 mg

72%

Placebo

38%

PF-04236921 in Crohn's Disease

CD is an autoimmune disorder which causes inflammation of the gastrointestinal (or GI) tract and serious potential complications, such as increased colon cancer risk. CD can thicken intestinal walls and obstruct bowel movements, which may require surgery to remove the diseased section. Chronic inflammation can lead to ulcers anywhere in the GI tract. Fistulas occur if the ulcers go completely through the GI lining; depending on the location, fistulas may lead to malnutrition or become infected and form life-threatening abscesses. From a 2014 population-based study in Minnesota, it is estimated that CD affects 780,000 Americans, with an additional 33,000 new cases per year based on an incidence rate of 10.7 per 100,000 people. With medical treatment or surgery, about 50% of patients enter remission or have mild disease over the next five years, but once in remission, estimated relapse rates at 2, 5, and 10 years still occur at 40%, 67%, and 76%, respectively.

First-line therapy for moderate-to-severe CD includes corticosteroids and immunomodulators (azathioprine, 6-mercaptopurine, or MTX), all of which suppress the immune system that is mistakenly targeting the patient's own cells. Patients who fail conventional therapies move on to anti-tumor necrosis factor (TNF) agents, but about a third are non-responsive. Of the initial TNF inhibitor responders, another one-third subsequently lose response or become intolerant; these patients are then switched to a second anti-TNF antibody. Thus, there is a need for agents with novel mechanisms of action.

PF-04236921 is a fully human monoclonal immunoglobulin antibody that binds to circulating interleukin or IL-6 and neutralizes its activity. IL-6 is a cytokine (cell signaling protein) and like TNF-α is a central regulator of the immune response in various types of inflammatory diseases, including CD. Of IL-6's various actions, perhaps the most pro-inflammatory is when it confers resistance on T helper cells to programmed cell death.

PF-04236921 is being tested in Andante, a dose-ranging, double-blind RCT in 220 subjects with CD who are inadequate responders to anti-TNF treatments. The primary endpoint is the Crohn's Disease Activity Index (CDAI) 70 response rate at Week 8 or Week 12 (see Appendix for scoring). Completion is expected on March 2015, but September 2014 was the final data collection date for the primary endpoint.

PF-00547659 in Crohn's Disease and Ulcerative Colitis

Like CD, UC is an autoimmune disorder which causes inflammation of the GI tract, except it's restricted to the colon, and has its own set of complications, including risk of a perforated colon and toxic megacolon. However, UC complications are not limited to the GI tract, and can affect bones (osteoporosis), the eyes, skin, and rarely the liver. About 907,000 Americans have UC with an additional 38,000 new cases per year based on an incidence rate of 12.2 per 100,000 people. UC is more common in men than women, especially in the fifth and sixth decades of life.

In the development of bowel inflammation, leukocyte (white blood cells or WBCs) are recruited into the inflamed intestine as the WBCs roll along and attach to receptors on the endothelium (the lining of the interior surface of blood vessels). Blockade of adhesion molecules between the receptors of WBCs and endothelial cells, such as mucosal addressin cell adhesion molecule 1 (MAdCAM-1) or vascular cell adhesion molecule 1 (VCAM-1), has a consistent and potent effect in preventing or reversing established inflammation. This is proven as evidenced by approved drugs Tysabri from Biogen (NASDAQ:BIIB) and Entyvio from Takeda (OTCPK:TKPHF).

Tysabri is effective in CD and multiple sclerosis, but clinical use is limited due to the risk of developing progressive multifocal leukoencephalopathy (or PML), a fatal viral brain disease. The risk arises because Tysabri simultaneously blocks WBC to MAdCAM-1 and VCAM-1 interactions, which affects WBC recruitment in all organs, including the central nervous system, while Entyvio selectively blocks WBC to MAdCAM-1 interactions, which restricts the recruitment of immune cells to the gastrointestinal tract. The difference between Entyvio, which is approved in CD and UC, and PF-00547659 is that Entyvio, like Tysabri, blocks receptors on the WBC, while PF-00547659 blocks the endothelial side (anti-MAdCAM-1).

The efficacy of PF-00547659 was first assessed in a dose-escalating RCT of 80 patients with active UC. The primary outcome measures were of disease activity score changes as calculated using the Mayo Score (see Appendix for scoring) and endoscopic score changes as calculated using section 3 of the Mayo Score. Response rates were numerically higher in the PF-00547659 group than in the PBO group at 4 weeks (52% vs. 32%, p=0.102) and 12 weeks (42% vs. 21%, p=0.156). Endoscopic response rates were 50% and 42% versus 26% and 29%, at 4 and 12 weeks, respectively (not statistically significant either). By Week 12, the PF-00547,659 group had the advantage in remission rates over placebo, 22% to 0%, and came very close to statistical significance (p=0.056).

Nonetheless, the MAdCAM-1 blocker is now a candidate in Phase 2 RCTs for CD (Opera) and UC (TURANDOT). Opera expected to enroll 240 subjects and has a primary outcome measure of CDAI 70 response rate at Week 8 or Week 12 (see Appendix for scoring). It is slated for completion on December 2015, but February 2014 was the final data collection date for the primary endpoint. TURANDOT is on 300 subjects with moderate to severe UC, with a primary outcome measure of Clinical Remission at Week 12 using the Mayo Score (see Appendix). Completion is expected on July 2016. but September 2014 was the final data collection date for the primary endpoint.

Take Away Message

For the inflammatory bowel disease sector, it is expected that the CD market will increase 47% from $3.8 billion to $5.6 billion in 7 major markets for the decade of 2011-21, while the UC market will grow 56% from $2.7 billion to $4.2 billion for the decade of 2013-23. Decision Resources Group projects that biologics will account for $2.3 billion of the 2023 UC market. The RA market is larger but may experience only moderate growth, with a 30% increase in sales from $14 billion in 2013 to $18.2 billion in 2023. Alternative RA biologics such as Entyvio and Xeljanz are expected to challenge the TNF antagonists like Enbrel due to the initial 15-40% non-response rate with current meds and/or diminishing response over time from chronic TNF inhibition.

PF-04171327 is a total bust, as Pfizer didn't mention the compound in its ACR/ARHP 2014 press release. The safe but expensive DAGR had to beat prednisone in efficacy to justifying a very costly chronic use. Even the BUTTERFLY abstract made the ACR list after PF-04236921 missed its primary endpoint, inaccurate reports notwithstanding. So unless Pfizer thinks it can get a flare preventer approved, the IL-6 inhibitor has a bleak future in the lupus market, which is small but may show dramatic growth of over 400% from $900 million in 2012 to $4 billion in 2022. No anti-IL-6 candidate has made it past Phase 1 in CD patients, so Andante has at most a 50-50 shot at success. The same odds may apply to PF-00547659 for Opera, even though there is more clinical experience on it with UC; TURANDOT has a 60-70% chance of meeting the primary endpoint.

Appendix

American College of Rheumatology (ACR) 20 Response

Defined as a ≥ 20% improvement from baseline in swollen (66 joints) and tender (68 joints) joint counts and ≥ 20% improvement in 3 of the following 5 assessments:

1) Participant's assessment of pain by Visual Analog Scale (VAS) (0-10 cm),

2) Participant's global assessment of disease activity by VAS (0-10 cm),

3) Physician's global assessment of disease activity by VAS (0-10 cm)

4) Participant's assessment of physical function as measured by the Health Assessment Questionnaire (HAQ) and

5) C reactive protein.

ACR 50 Response is at least a 50% improvement in the above criteria.

ACR 70 Response is at least a 70% improvement in the above criteria.

Table 2. Crohn's Disease Activity Index (CDAI)

Variable

Description

Scoring

Multiplier

Number of liquid stools

Sum of 7 days

×2

Abdominal pain

Sum of 7 days' ratings

0 = none
1 = mild
2 = moderate
3 = severe

×5

General well-being

Sum of 7 days' ratings

0 = generally well
1 = slightly under par
2 = poor
3 = very poor
4 = terrible

×7

Extraintestinal complications

Number of complications listed

Arthritis/arthralgia, iritis/uveitis, erythema nodosum, pyoderma gangrenosum, aphtous stomatitis, anal fissure/fistula/abscess, fever > 37.8 °C

×20

Anti-diarrheal drugs

Use in the previous 7 days

0 = no
1 = yes

×30

Abdominal mass

0 = no
2 = questionable
5 = definite

×10

Hematocrit

Expected-observed hematocrit

Men: 47 observed
Women: 42 observed

×6

Body weight

Ideal/observed ratio

[1 − (ideal/observed)] × 100

×1 (not < −10)

Clinical response 70: CDAI decrease of ≥70 compared to baseline

Clinical response 100: CDAI decrease of ≥100 compared to baseline

Disease Activity Score 28 (DAS28) is an index to measure the disease activity in participants with rheumatoid arthritis combining tender joints (TJ, up to the 28 joints), swollen joints (or SJ), C-reactive protein (or CRP) / erythrocyte sedimentation rate (or ESR), and the patient's and physician's assessments of disease activity. The DAS28 score ranges from 0 (which is best) to 10 (worst).

Remission: DAS28 ≤ 2.6

Low Disease activity: 2.6 < DAS28 ≤ 3.2

Moderate Disease Activity: 3.2 < DAS28 ≤ 5.1

High Disease Activity: DAS28 >5.1

Response is improvement from baseline, with > 1.2 indicating a good or moderate response and ≤ 0.6 indicating no response

Alternative validated formulae

DAS28-CRP(4) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014*GH + 0.96

DAS28-CRP(3) = [0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1)] * 1.10 + 1.15

DAS28 = (1.072)*DAS) + 0.938

Mayo scores

Clinical Response: A decrease in Total Mayo Score by at least 3 points and at least 30% decrease in subscore for rectal bleeding of at least 1 point or absolute subscore of 0 or 1.

Clinical Remission: Total Mayo Score of 2 points or lower with no individual subscore exceeding 1 point and rectal bleed subscore of 0 or 1.

Endoscopic response: ≥1-point improvement in endoscopic subscore, and endoscopic remission as endoscopic subscore of 0 or 1.

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