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Fyi, there is an up to date XOMA RMF available on the Biotech Values board
XOMA ReadMeFirst
(PoC Program Update: Results of Phase 2 Study for Moderate to Severe Acne Vulgaris)
Hopefully, this RMF will save folks some time and make it easier to research the company. It is meant to be a convenient jumping off point but, of course, it's not a substitute for your own dd.
Company Overview
#msg-83090011 Recent Company Presentations
#msg-83090054 Credit Suisse Investment Thesis
#msg-83090160 Servier Partnership Terms
#msg-83091150 Recent Financings and Baker Bros Investment
XOMA 052 (Gevokizumab) Overview
#msg-83090144 XOMA/Servier to commercialize gevokizumab (XOMA 052) for the treatment of multiple inflammatory disorders
#msg-83091229 IL-1B has emerged as a therapeutic target for inflammatory disorders
#msg-83091258 Is Gevokizumab a “best-in-class” anti-IL-1ß therapeutic antibody?
#msg-83090127 Current Clinical Trials
Uveitis Program
#msg-83091071 Uveitis Market Forecast
#msg-83090431 Uveitis of Behçet’s Disease Pilot Trial Results
#msg-83090221 FDA Grants Orphan Drug Status to Gevokizumab
#msg-83090262 Servier Initiates Behçet's Phase 3 Clinical Trial (EYEGUARD-B)
#msg-83090953 Phase 3 clinical trial in patients with non-infectious uveitis intermediate, posterior, or pan-uveitis (NIU) (EYEGUARD-C)
Proof of Concept Program
#msg-83106427 Phase 2 Study of gevokizumab in moderate to severe acne vulgaris
#msg-83122761 Results of Phase 2 Study for Moderate to Severe Acne Vulgaris
#msg-83091380 Phase 2 study of gevokizumab in active inflammatory, erosive osteoarthritis of the hand
#msg-83091342 Non-Infectious Anterior Scleritis selected as next PoC candidate
Diabetes Program
#msg-83090114 Phase 2b trial of XOMA 052 in Type 2 diabetes patients did not achieve the primary endpoint
#msg-83091405 XOMA Discovers Two New Classes of Insulin Receptor-Regulating Antibodies
Cardiovascular Program
#msg-83091327 PoC Gevokizumab Study in Patients With a History of Acute Coronary Syndrome
Aceon Program (Perindopril/Amlodipine)
#msg-83091483 Aceon Phase 3 PATH Trial Meets Primary Endpoint
#msg-83091538 Credit Suisse' Take on the Aceon Opportunity
Competition
i#msg-83091092 Lux Biosciences declares intent to halt application efforts for uveitis treatment
#msg-83091763 Eyegate Pharma's pivotal Phase III study of EGP-437 in patients with anterior uveitis
#msg-83091599 XBiotech Announces Positive Phase II Results in Acne Vulgaris
Well, it's not a home run but the drug is clearly active. I'd like to see a trial run at a higher dose but based solely on these results, my guess is that out of the three PoC trials, this won't end up being the next Phase 3 candidate.
XOMA ReadMeFirst
Hopefully, this RMF will save folks some time and make it easier to research the company. It is meant to be a convenient jumping off point but, of course, it's not a substitute for your own dd.
Company Overview
#msg-83090011 Recent Company Presentations
#msg-83090054 Credit Suisse Investment Thesis
#msg-83090160 Servier Partnership Terms
#msg-83091150 Recent Financings and Baker Bros Investment
XOMA 052 (Gevokizumab) Overview
#msg-83090144 XOMA/Servier to commercialize gevokizumab (XOMA 052) for the treatment of multiple inflammatory disorders
#msg-83091229 IL-1B has emerged as a therapeutic target for inflammatory disorders
#msg-83091258 Is Gevokizumab a “best-in-class” anti-IL-1ß therapeutic antibody?
#msg-83090127 Current Clinical Trials
Uveitis Program
#msg-83091071 Uveitis Market Forecast
#msg-83090431 Uveitis of Behçet’s Disease Pilot Trial Results
#msg-83090221 FDA Grants Orphan Drug Status to Gevokizumab
#msg-83090262 Servier Initiates Behçet's Phase 3 Clinical Trial (EYEGUARD-B)
#msg-83090953 Phase 3 clinical trial in patients with non-infectious uveitis intermediate, posterior, or pan-uveitis (NIU) (EYEGUARD-C)
Proof of Concept Program
#msg-83106427 Phase 2 Study of gevokizumab in moderate to severe acne vulgaris
#msg-83091380 Phase 2 study of gevokizumab in active inflammatory, erosive osteoarthritis of the hand
#msg-83091342 Non-Infectious Anterior Scleritis selected as next PoC candidate
Diabetes Program
#msg-83090114 Phase 2b trial of XOMA 052 in Type 2 diabetes patients did not achieve the primary endpoint
#msg-83091405 XOMA Discovers Two New Classes of Insulin Receptor-Regulating Antibodies
Cardiovascular Program
#msg-83091327 PoC Gevokizumab Study in Patients With a History of Acute Coronary Syndrome
Aceon Program (Perindopril/Amlodipine)
#msg-83091483 Aceon Phase 3 PATH Trial Meets Primary Endpoint
#msg-83091538 Credit Suisse' Take on the Aceon Opportunity
Competition
i#msg-83091092 Lux Biosciences declares intent to halt application efforts for uveitis treatment
#msg-83091763 Eyegate Pharma's pivotal Phase III study of EGP-437 in patients with anterior uveitis
#msg-83091599 XBiotech Announces Positive Phase II Results in Acne Vulgaris
XOMA Initiates Gevokizumab Phase 2 Study for Moderate to Severe Acne Vulgaris
**Note: Results from this trial were expected 4Q2012 so I suspect we'll see the data shortly. This is the first of three PoC programs that will read-out during 2013 ( the other two being erosive osteoarthritis of the hand and non-infectious anterior scleritis)
BERKELEY, Calif., Dec. 21, 2011 (GLOBE NEWSWIRE) -- XOMA Ltd. (Nasdaq:XOMA) today announced it has begun dosing patients in its Phase 2 proof-of-concept study to evaluate the efficacy and safety of gevokizumab (XOMA 052), a potent inhibitor of interleukin-1 beta (IL-1 beta), for the treatment of the inflammatory lesions seen in moderate to severe acne vulgaris. Approximately 170 patients will be randomized to receive one of two dose levels of gevokizumab or placebo administered subcutaneously over a three-month period. The primary study efficacy endpoint is the mean absolute change from baseline in inflammatory facial lesion count after three months of therapy. Additional study information has been submitted for publication on www.clinicaltrials.gov
"XOMA's Phase 2 proof-of-concept program is designed to expand the value of gevokizumab, the company's lead clinical asset, by demonstrating its potential in diseases characterized by interleukin-1 beta over-expression. This is the first in a series of clinical studies that we plan to conduct in separate indications over the next 12 to 18 months," commented John Varian, Interim Chief Executive Officer of XOMA Ltd. "Upon completion of this series of proof-of-concept studies, we believe we will have sufficient evidence to initiate a further development program in at least one of these indications."
Moderate to severe acne vulgaris is estimated to affect approximately three to four million people in the U.S. Acne is characterized by the presence of a bacteria known as Proprionumbacterium acne, which promotes the production of proinflammatory substances including IL-1 beta in experimental models of the disease.
Moderate to severe acne that does not respond to topical agents is often treated with orally administered antibiotics. For the most severe, non-responsive acne, isotretinoin (an oral retinoid drug) treatment may be prescribed, although it is only available through a restricted distribution program due to its side effect profile.
http://investors.xoma.com/releasedetail.cfm?ReleaseID=634770
That's all from me for now. Hopefully, the information will be useful. I'll organize the individual posts into a consolidated RMF later this weekend. Thanks for everyone's patience.
XOMA - Eyegate Pharma's pivotal Phase III study of EGP-437 in patients with anterior uveitis
* Note: This trial is focused on anterior uveitis which is distinct from XOMA's target of intermediate, posterior, or pan-uveitis.
EYEGATE PHARMA ENROLLS LAST PATIENT IN PIVOTAL
PHASE III ANTERIOR UVEITIS STUDY OF EGP-437
Waltham, MA – December 17, 2012 – EyeGate Pharma, a privately held specialty
pharmaceutical company developing a non-invasive ocular drug delivery platform and
ocular therapeutics, announces today that they have enrolled the last patient in the
pivotal Phase III study of EGP-437 in patients with anterior uveitis.
The study's objective is to evaluate the safety and efficacy of ocular iontophoresis with
dexamethasone phosphate ophthalmic solution (EGP-437) as compared to treatment
with topically applied prednisolone acetate (1%) ophthalmic suspension eyedrops. In
order to be enrolled into this multi-center randomized double-masked study, subjects
need to be between 12 - 85 years of age with a diagnosis of non-infectious anterior
uveitis, defined as an anterior chamber cell count of = 11 cells. About two hundred
patients were randomly assigned into one of two treatment arms in a 1:1 ratio. The
primary efficacy endpoint evaluates the proportion of patients with anterior chamber cell
count (ACC) of zero at Day 14. Safety will be assessed by the incidence and severity of
adverse effects (AEs), and measures of intraocular pressure and best-corrected visual
acuity. “Last Patient, Last Visit” is anticipated to be mid-February 2013. The company
expects to have top-line data in the early Spring of 2013.
A previous Phase I/II study demonstrated that a single EGP-437 treatment, administered
using iontophoresis, lowered ACC scores to zero (a complete response) in the majority
of patients, caused only minor AEs, and no non-ocular systemic corticosteroid mediated
side-effects were observed (Ophthalmology 119, 66 (2012)).
Principal study investigator Dr. John Sheppard of Virginia Eye Consultants said: “While
corticosteroids are widely used as treatments for ocular inflammation such as uveitis,
conventional 1% suspensions applied topically do not readily penetrate the intact ocular
surface; therefore, they require frequent dosing in order to achieve and maintain
adequate steroid levels. EyeGate's iontophoresis drug delivery approach has shown
promise in reducing anterior chamber cell scores in patients with uveitis after a single
treatment, suggesting that adequate levels of steroid are reaching the anterior segment of the eye.
http://www.eyegatepharma.com/pdf/news2012/EyegatePR_lastPatient_UveitisPH3_Final.pdf
XOMA - Competition
**note The results from XOMA's PoC P2 trial in Acne Vulgaris are expected in early 2013.
XBiotech Announces Positive Phase II Clinical Trial Results for Lead Candidate MABp1 in Acne Vulgaris
Safety of True Human(TM) Monoclonal Antibody Therapy Enables Development of First Biologic Treatment Targeting Inflammatory Cytokine IL-1a for Moderate to Severe Acne
AUSTIN, Texas, Dec. 12, 2012 /PRNewswire via COMTEX/ -- XBiotech Inc., a privately held biotechnology company, today announced positive Phase II clinical trial results in the treatment of acne vulgaris. The trial was conducted as an open label study using XBiotech's lead candidate, True Human(TM) monoclonal antibody MABp1, in patients with moderate to severe disease. Patients enrolled in the study demonstrated continual improvement in lesions over the course of therapy, with up to 42 percent reduction in eight weeks. The excellent safety profile of MABp1 demonstrated across multiple therapeutic indications to date, and strong initial results in this trial, provide the basis for further development of the first biologic therapy targeting the inflammatory cytokine IL-1a for acne treatment.
Acne vulgaris is a common skin disease that affects an estimated 80% of Americans at some time during their lives. Twenty percent will have severe acne, which results in permanent physical and mental scarring. Acne vulgaris is America's most common skin disease and is characterized by non-inflammatory, open or closed comedones and by inflammatory papules, pustules, and nodules.
Currently, there are several approved topical and systemic treatments however no biological therapy has yet been approved for the treatment of acne. The Phase II clinical trial involving the XBiotech proprietary platform technology was a multicenter study, and included leading investigators such as Dr. Ronald Moy, recent President of the American Academy of Dermatology, former Co-Chief of Dermatology, and Chief of Dermatological Surgery at UCLA Medical Center.
http://www.marketwatch.com/story/xbiotech-announces-positive-phase-ii-clinical-trial-results-for-lead-candidate-mabp1-in-acne-vulgaris-2012-12-12
Credit Suisse' Take on the Aceon Opportunity (see message #83091483 )
Aceon Meets Primary Endpoint -
Underappreciated and Partnerable Asset
-Potential Future Upside if Asset is Partnered: While our recommendation
and valuation are based primarily on the opportunity of its lead antibody
program gevokizumab, the positive Phase III results for Aceon could lead to
a new and potentially lucrative partnership in the next six months.
- Substantial Economics for XOMA: XOMA licensed exclusive US
marketing rights to Aceon from Servier and has the right to seek a partner
for commercial sales. XOMA owes Servier up to a mid-teen royalty on Aceon
sales, which provides significant retained profitability for XOMA to seek a
marketing partner for this derisked asset.
-Not a Blockbuster But a Potential Value Driver: Aceon is a fixed dose
combination of a proprietary ACE inhibitor and a calcium channel blocker for
the treatment of hypertension. This market is largely generic, but Aceon
would be differentiated by its fixed dose formulation. In Europe, Servier sells
approximately $150M/year of Aceon. In the right hands, this product could
generate significant non-dilutive cash flow for XOMA.
-Next Events: For Aceon, we expect XOMA will seek a partner in H1:13 and
subsequently file for FDA approval (with a partner). For gevokizumab, we
still anticipate a Phase II readout for the acne trial and announcement of a
third Phase II indication in Q4. Phase II data for osteoarthritis of the hand
and the third indication are expected in mid-2013.
XOMA Announces Perindopril and Amlodipine Fixed-Dose Combination Meets Primary Endpoint in Phase 3 PATH Trial
BERKELEY, Calif., Nov. 20, 2012 (GLOBE NEWSWIRE) -- XOMA Corporation (Nasdaq:XOMA) today announced the 837-patient Phase 3 PATH trial (Perindopril Amlodipine for the Treatment of Hypertension) has demonstrated the fixed-dose combination (FDC) of perindopril arginine combined with amlodipine besylate is statistically significantly superior to either compound alone in reducing both sitting diastolic and sitting systolic blood pressure after six weeks of treatment. This FDC, containing a patent-protected proprietary form of perindopril, was licensed by XOMA as part of a U.S. commercial and development rights agreement signed with Servier for their perindopril franchise. Servier markets the fixed-dose combination product, COVERAM®, in 91 countries outside the U.S.
"The perindopril/amlodipine FDC is an important asset in Servier's cardiovascular franchise. We believe that based upon our previous conversations with FDA, the positive PATH results combined with the body of existing clinical data for this FDC will support an NDA submission," stated John Varian, Chief Executive Officer of XOMA. "We are extremely proud of our team for completing this trial ahead of schedule and now will be working to identify appropriate potential ways to move this FDC forward to the U.S. market. XOMA does not intend to directly market this FDC, but rather intends to sublicense this product to a third-party organization that is dedicated to commercializing products for the cardiovascular marketplace."
The FDC appeared to be well tolerated in the trial, and there were no unexpected serious adverse events reported. The most common adverse events included mild to moderate edema, cough and headache, which are known side effects of the individual components of the FDC.
Perindopril, an angiotensin converting enzyme inhibitor (commonly called an ACE inhibitor), has been studied in seven landmark clinical trials involving more than 54,000 patients. This body of clinical evidence supports its beneficial impact in treating essential hypertension and stable coronary artery disease. Amlodipine, a calcium channel blocker (commonly called a CCB), is the most-prescribed antihypertensive in the U.S. Because ACE inhibitors and CCBs target different cardiovascular functions, physicians often use them in combination to treat their hypertensive patients.
XOMA Discovers Two New Classes of Insulin Receptor-Regulating Antibodies
http://www.ncbi.nlm.nih.gov/pubmed/22403294
http://diabetes.diabetesjournals.org/content/early/2012/02/27/db11-1578.abstract
SAN DIEGO, June 27, 2011 (GLOBE NEWSWIRE) -- XOMA Ltd. (Nasdaq: XOMA), a leader in the discovery and development of therapeutic antibodies, announced the first presentation of results from its discovery of two new classes of fully human monoclonal antibodies that activate or sensitize the insulin receptor in vivo, each representing a distinct new therapeutic approach to the treatment of patients with diabetes. The data were presented at the American Diabetes Association 71st Scientific Sessions in San Diego.
Insulin is the key metabolic hormone for regulating blood sugar and exerts its action on cells by signaling through the insulin receptor. Alterations in insulin signaling occur in Type 2 diabetes and its precursor, metabolic syndrome. Highly specific human antibodies that activate or sensitize the insulin receptor offer new direct mechanisms for treating different aspects of the diabetes disease spectrum.
Insulin receptor-activating antibodies such as XOMA's XMetA antibody are designed to provide long-acting insulin-like activity to diabetic patients who cannot make sufficient insulin, potentially reducing the number of insulin injections needed to control their blood glucose levels. In contrast, insulin receptor-sensitizing antibodies such as XOMA's XMetS are designed to reduce insulin resistance and could enable diabetic patients to more effectively use their own insulin to control blood glucose levels.
Studies presented on the XMetA antibody demonstrated that it reduced fasting blood glucose levels and improved glucose tolerance in a mouse model of diabetes. After six weeks of treatment, there was a statically significant reduction in hemoglobin A1c levels, a standard measure of average blood glucose levels over time, in mice treated with XMetA compared to control. In addition, there was a statistically significant reduction in elevated non-HDL cholesterol levels.
Studies of the XMetS antibody in a mouse model of obesity-induced insulin resistance showed enhanced insulin sensitivity and statistically significant improvements in fasting blood glucose levels and glucose tolerance in mice treated with XMetS as compared to control. In addition, there was a statistically significant reduction in elevated non-HDL cholesterol levels.
Presentation details:
High Affinity Partial Agonist Insulin Receptor Antibodies Stimulate Insulin Activity and Improve Glycemic Control in Murine Models of Diabetes; ADA Abstract No. 0417-PP presented during General Poster Session III
High Affinity Insulin Receptor Antibodies Sensitize the Insulin Receptor to Insulin and Restore Glycemic Control in Murine Models of Diabetes; ADA Abstract No. 1008-P presented during Pharmacologic Treatment of Diabetes – Novel Therapies III
XOMA Initiates Phase 3 Gevokizumab Trial in Patients With Non-Infectious Uveitis and Phase 2 Gevokizumab Trial in Patients With Erosive Osteoarthritis
BERKELEY, Calif., June 27, 2012 (GLOBE NEWSWIRE) -- XOMA Corporation (Nasdaq:XOMA) today announced it has opened enrollment in two clinical trials to determine gevokizumab's potential to treat interleukin-1 beta-mediated inflammatory diseases. The first trial is XOMA's global Phase 3 study investigating the ability of gevokizumab to reduce the signs and symptoms, including vitreous haze, in patients with non-infectious uveitis (NIU) involving the intermediate and/or posterior segment of the eye. The second trial is a Phase 2 study to evaluate the potential for gevokizumab to improve pain symptoms, physical function and structural abnormalities in patients with erosive osteoarthritis of the hand. Patients currently are being screened in both trials.
"Today represents an historic milestone for XOMA, as we launch the first global Phase 3 program for a XOMA-created product to which we retain U.S. commercial rights," stated John Varian, Chief Executive Officer of XOMA. "Our clinical and regulatory teams have worked diligently with their colleagues from Servier to design the gevokizumab NIU trial to meet the requirements of regulatory agencies, including the FDA, in this indication."
In this study, titled A Randomized, Double-masked, Placebo-controlled Study of the Safety and Efficacy of Gevokizumab in the Treatment of Active Non-infectious Intermediate, Posterior, or Pan-Uveitis, the Company intends to enroll patients with active non-infectious intermediate, posterior, or pan-uveitis with a vitreous haze score equal to or greater than 2+ on the Standardization of Uveitis Nomenclature (SUN) / National Eye Institute (NEI) scale in at least one eye. They will be randomized to receive either one of two doses of gevokizumab or placebo. The study's primary endpoint is the proportion of patients demonstrating a significant reduction in vitreous haze score on Day 56. The study also will assess the effect of gevokizumab on additional endpoints, including response rates at other time points and changes from baseline in visual acuity.
http://investors.xoma.com/releasedetail.cfm?ReleaseID=686986
Paul Rubin, M.D., XOMA's Senior Vice President of Research and Development and Chief Medical Officer, stated, "As preclinical and clinical data have shown that IL-1 beta is an important contributor to the inflammation seen in uveitis, we believe gevokizumab's ability to potently inhibit IL-1 beta signaling could be relevant in controlling this inflammation, as well as the inflammation associated with other conditions. Because of this, we established a proof-of-concept program in November 2011 to lead us to additional indications for this antibody. Included in this program is the ongoing trial in moderate to severe acne vulgaris from which we anticipate top-line data by year end. Today, we opened enrollment in the second POC indication, erosive osteoarthritis of the hand, which we believe will complete enrollment sometime around the end of 2012."
XOMA's Phase 2 proof-of-concept study of gevokizumab in active inflammatory, erosive osteoarthritis of the hand is designed to enroll approximately 90 patients who will be randomized to receive gevokizumab or placebo. The study is designed and powered to detect a significant improvement from baseline versus placebo in the mean Australian/Canadian Hand Osteoarthritis Index (AUSCAN™) pain score in the target hand at three months. The study also will capture multiple outcome measures including pain, stiffness, physical function, radiographic and MRI changes, as well as changes in C-reactive protein and concomitant acetaminophen use.
XOMA Selects Non-Infectious Anterior Scleritis as Next Indication in Gevokizumab Proof-of-Concept Program
BERKELEY, Calif., Dec. 31, 2012 (GLOBE NEWSWIRE) -- XOMA Corporation (Nasdaq:XOMA), a leader in the discovery and development of therapeutic antibodies, today announced it has selected active non-infectious anterior scleritis, which is the inflammation of the sclera (the fibrous white membrane surrounding the eyeball excluding the cornea), as the third indication in XOMA's gevokizumab proof-of-concept program. The Company is working with the National Eye Institute ("NEI"), one of the U.S. National Institutes of Health, on designing the protocol for this study.
"Both non-infectious scleritis and non-infectious uveitis have been associated with interleukin-1 beta. As we narrowed our potential therapeutic targets for inclusion in our POC program, we felt there was a strong rationale to conduct one of the studies in a second ocular indication, particularly one that is treated by the same physician specialist as the NIU patient population," stated Paul Rubin, Senior Vice President of Research and Development and Chief Medical Officer of XOMA.
http://investors.xoma.com/releasedetail.cfm?ReleaseID=730866
XOMA Announces Servier Has Initiated a Proof-of-Concept Gevokizumab Study in Patients With a History of Acute Coronary Syndrome
BERKELEY, Calif., Nov. 29, 2012 (GLOBE NEWSWIRE) -- XOMA Corporation (Nasdaq:XOMA) today announced its partner, Servier, has initiated the first Servier-sponsored proof-of-concept study in a cardiovascular indication. The study has opened for patient enrollment. The study is expected to enroll 45 patients who have experienced Acute Coronary Syndrome (ACS) in the past three to twelve months. The objective of this study is to evaluate the effect of subcutaneous administration of 30 mg gevokizumab as compared to placebo in reducing arterial wall inflammation in patients with marked atherosclerotic plaque inflammation. The primary endpoint Servier will be assessing is the change in the mean target to background ratio (TBR) of the radioactive tracer FDG assessed by PET/CT after three months of treatment. The study also will determine gevokizumab's effect on a number of cardiac and vascular biological blood biomarkers.
"Servier is recognized for its global cardiovascular franchise and is well positioned for developing gevokizumab in cardiovascular disease," stated John Varian, Chief Executive Officer of XOMA. "While Servier has world-wide rights and pays all gevokizumab development costs for cardiovascular indications, XOMA has the option to acquire the U.S. and Japanese rights in this therapeutic area. As Servier develops gevokizumab in cardiovascular indications, it could become significantly more valuable to XOMA."
"Servier is very committed to developing innovative treatments for cardiovascular diseases with clear unmet medical needs, such as the Acute Coronary Syndrome. The potential anti-inflammatory properties of gevokizumab may ultimately prove its clinical value in this disease. Servier is delighted by this new and important step in the clinical development of the drug," said Isabelle Tupinon-Mathieu, M.D., Head of Therapeutic Research and Development at Servier.
**Note: A study, published online Dec. 2 in Nature Genetics, provides insights into the molecular pathways causing coronary artery disease.
"Perhaps the most interesting results of this study show that some people may be born with a predisposition to the development of coronary atherosclerosis because they have inherited mutations in some key genes related to inflammation," said Themistocles (Tim) Assimes, MD, PhD, a Stanford assistant professor of medicine and one of the study's lead authors. "There has been much debate as to whether inflammation seen in plaque buildup in heart vessels is a cause or a consequence of the plaques themselves. Our network analysis of the top approximately 240 genetic signals in this study seems to provide evidence that genetic defects in some pathways related to inflammation are a cause." http://www.sciencedaily.com/releases/2012/12/121202164436.htm?utm_source=twitterfeed&utm_medium=twitter&utm_campaign=Feed%3A+sciencedaily%2Fhealth_medicine+%28ScienceDaily%3A+Health+%26+Medicine+News%29
XOMA -- Is Gevokizumab a “best-in-class” anti-IL-1ß therapeutic antibody?
These articles discuss the role that IL-1ß plays in the development of many inflammatory, autoimmune, metabolic and oncological diseases and make the case that Gevokizumab is a “best-in-class” anti-IL-1ß therapeutic antibody,
XOMA 052, a potent, high-affinity monoclonal antibody for the treatment of IL-1ß-mediated diseases
Interleukin-1ß (IL-1ß) is a potent mediator of inflammatory responses and plays a role in the differentiation of a number of lymphoid cells. In several inflammatory and autoimmune diseases, serum levels of IL-1ß are elevated and correlate with disease development and severity. The central role of the IL-1 pathway in several diseases has been validated by inhibitors currently in clinical development or approved by the FDA. However, the need to effectively modulate IL-1ß-mediated local inflammation with the systemic delivery of an efficacious, safe and convenient drug still exists.
Several inhibitors of the IL-1 pathway have been developed and have provided important proof of concept to illustrate that this pathway has great potential for the development of new therapeutic drugs. While providing proof of concept in many diseases, these inhibitors require frequent or high dosing regimens to achieve and maintain efficacy, which is possibly due to their mechanism of inhibition together with their pharmacokinetic properties. This is particularly true for diseases like rheumatoid arthritis, where a therapeutic agent, in order to exert its inhibitory effect, must penetrate the synovial compartment and maintain a steady-state of local efficacious levels.
To overcome these limitations, we sought to design and develop a “best-in-class” anti-IL-1ß therapeutic antibody, XOMA 052. This high affinity antibody specifically inhibits IL-1ß activity
with a unique mechanism of action. Such specificity for IL-1ß alone will have the added advantage of sparing both IL-1a, which could provide a safety margin for protection against potential infections and IL-1Ra, which is the natural antagonist of the IL-1 signaling pathway. Indeed, inactivation of IL-1Ra would work against the very purpose of the therapeutic drug.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038011/
One Target-Two Different Binding Modes: Structural Insights into Gevokizumab and Canakinumab Interactions to Interleukin-1ß
Blech M, Peter D, Fischer P, Bauer MM, Hafner M, Zeeb M, Nar H.
Source
Department of Lead Identification and Optimization Support, Structural Research Group, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany; Department of NBE Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany; Institut für Medizintechnologie der Ruprecht-Karls-Universität Heidelberg & Hochschule Mannheim, Heidelberg und Mannheim, Germany. Electronic address: michaela.blech@boehringer-ingelheim.com.
Abstract
Interleukin-1ß (IL-1ß) is a key orchestrator in inflammatory and several immune responses. IL-1ß exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1ß monoclonal antibodies. Canakinumab is known to neutralize IL-1ß by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1ß bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1ß signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1ß. Furthermore, we characterized the epitopes on IL-1ß employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1ß and provide insight into the mechanisms leading to their distinct modulation of IL-1ß signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1ß causes competitive inhibition of the association of IL-1ß and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1ß and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1ß pathway attenuation.
http://www.ncbi.nlm.nih.gov/pubmed/23041424
XOMA -- IL-1B has emerged as a therapeutic target (See IL-1 targeted therapies http://bit.ly/VqAeRv and http://bit.ly/TCP88Q ) for an expanding number of systemic and local inflammatory conditions called autoinflammatory diseases. For these, neutralization of IL-1B results in a rapid and sustained reduction in disease severity. Treatment for autoimmune diseases often includes immunosuppressive drugs whereas neutralization of IL-1B is mostly anti-inflammatory. Although some autoinflammatory diseases are due to gain-of-function mutations for caspase-1 activity, common diseases such as gout, type 2 diabetes, heart failure, recurrent pericarditis, rheumatoid arthritis, and smoldering myeloma also are responsive to IL-1B neutralization. This review summarizes acute and chronic inflammatory diseases that are treated by reducing IL-1B activity and proposes that disease severity is affected by the anti-inflammatory members of the IL-1 family of ligands and receptors.
http://bloodjournal.hematologylibrary.org/content/117/14/3720.abstract
XOMA - Recent Financings
XOMA Announces Pricing of $40.0 Million Public Offering of Common Stock
BERKELEY, Calif., Oct. 24, 2012 (GLOBE NEWSWIRE) -- XOMA Corporation (XOMA) announced today the pricing of 13,333,333 shares of its common stock at a price to the public of $3.00 per share. In addition, XOMA has granted the underwriters a 30-day option to purchase up to an additional 1,999,999 shares of common stock on the same terms and conditions, solely to cover over-allotments, if any. The shares will be issued pursuant to a prospectus supplement filed as part of a shelf registration statement previously filed with the Securities and Exchange Commission (SEC) on Form S-3. XOMA anticipates its aggregate net proceeds from the offering will be approximately $36.9 million after deducting the underwriting discount and estimated offering expenses payable by XOMA. The offering is expected to close on or about October 29, 2012, subject to customary closing conditions.
Credit Suisse Securities (USA) LLC and Cowen and Company, LLC are acting as joint book-running managers. Wedbush Inc. is acting as a financial advisor to
Tuesday, 6 Mar 2012 -- XOMA Corp announced the pricing of 29,669,154 shares of its common stock and accompanying warrants to purchase one half of a share of common stock for each share purchased at a price to the public of $1.32. The warrants are exercisable at an exercise price of $1.76 per share beginning on the date of issuance and will expire on the fifth anniversary of the date of issuance. All of the shares and warrants in the offering are to be sold by XOMA. The shares and warrants will be issued pursuant to a prospectus supplement filed as part of a shelf registration statement previously filed with the Securities and Exchange Commission (SEC) on Form S-3. XOMA anticipates that its aggregate net proceeds from the offering will be approximately $36.2 million after deducting the underwriting discount and estimated offering expenses payable by XOMA. The offering is expected to close on or about March 9, 2012, subject to customary closing conditions. RBC Capital Markets and Cowen and Company are acting as joint book-running managers and Roth Capital Partners is acting as co-manager of the offering. Ladenburg Thalmann & Co. Inc. is acting as a financial advisor to XOMA for the offering.
After the March financing, Adam Feuerstein wrote:
"Why is Xoma up 50% for the month?"
The spark that sent Xoma shares higher was the $40 million financing announced March 6. Normally, dilutive financings undertaken by money-losing biotech firms don't send stock prices higher. That's particularly true for companies like Xoma with a sad history of drug development futility.
What's different here is that Baker Bros., a well-respected and closely followed health-care hedge fund, bought half the Xoma deal.
The question you're probably asking now is, "Wait a second -- Xoma? What the hell can Baker Bros. see in Xoma?" [I wondered the same thing.]
Xoma is apparently getting a new lease on life, thanks to a top-to-bottom restructuring -- a new CEO and chief medical officer, cost cutting and a new business model. Xoma is still developing the same lead drug XOMA 052 (given a new name, gevokizumab) but money-wasting efforts in diabetes and cardiovascular indications have been shelved in favor of clinical trials for Behcets uveitis and non-infectious uveitis -- both diseases of the eye.
A phase III study of gevokizumab is expected to start this summer with data likely available by the end of 2013.
Whether Xoma succeeds with gevokizumab and breaks a three-decade-long streak of internal drug development failures is still an open question, but what's different today is that the company has some big-name investor support.
http://www.thestreet.com/story/11466875/1/biotech-stock-mailbag-xomas-big-backers-fda-approvals-contest.html
XOMA - Competition
December 28, 2012 -- Lux Biosciences declares intent to halt application efforts for uveitis treatment
Lux Biosciences Inc. does not intend to advance its application for regulatory approval of voclosporin for treatment of noninfectious uveitis in the U.S. and Europe, according to a press release from Isotechnika, with whom Lux Biosciences has a license agreement to develop voclosporin for ophthalmic indications.
The company announced that primary endpoints established in phase 3 clinical trials, which were to demonstrate a change from baseline in vitreous haze at 12 weeks or at the time of treatment failure or sooner, were not met, effectively ending their intent to move forward with the drug’s development for uveitis.
Isotechnika, which has developed voclosporin in the area of nephrology, had “granted Lux worldwide rights to develop and commercialize voclosporin for ophthalmic indications in the hope that the expansion of its platform into other medical specialties might help to maximize the drug's full medical and commercial potential,” according to the release.
XOMA - Uveitis Market Forecast
According to Global Data, the uveitis therapeutics market is expected to grow at 26.4% annually for the next seven years and reach $1.6 billion by 2017. This significant growth is primarily attributed to increasing therapeutic options for the treatment of uveitis. In addition, the successful launch of some targeted therapies such as Luveniq (voclosporin), AIN457 and the approval of Humira may significantly stimulate market growth in the near future. However, the complex etiology of the condition will continue to be a barrier for market growth.
The current competition in the uveitis therapeutics market is weak and the available treatment options have only been moderately successful in meeting market demand. The products currently available in the market are associated with low safety and as the products currently available do not serve the markets unmet need the market continues to present opportunities for stronger pipeline candidates. The extent of unmet need in the uveitis therapeutics market is considered to be at a high level and can be filled by technologically advanced products possessing improved safety and efficacy profiles which are disease targeting.
Uveitis Market Opportunity
The following market analysis is summarized from the Lux Biosciences website. Lux Biosciences recently halted its application efforts for uveitis treatment (See message #83091092)
UVEITIS
The Disease: Uveitis is a collective term for variety of ophthalmic conditions that result in chronic inflammation of the eye. Uveitis can be of infectious or autoimmune origin and is generally classified by anatomical location. Anterior uveitis affects the front of the eye, intermediate and posterior uveitis affect the back of the eye and panuveitis affects all parts of the eye. There is substantial evidence indicating the involvement of T-lymphocytes, key immune system cells involved in inflammatory processes, in the development of autoimmune uveitis.
Uveitis is an under-diagnosed and under-recognized medical condition that causes ocular pain and loss of vision. Uveitis afflicts the young – the median age at time of diagnosis is 39 years - and the disease typically persists chronically. The general course of uveitis is similar to other autoimmune diseases. The disease flares causing inflammation in the eye and symptoms such as ocular pain, redness vision loss, and floaters and then remits with treatment. The goal of treatment is to reduce the frequency and intensity of disease flares, as active inflammation is believed to cause cumulative damage to the eye resulting in persistent loss of vision. Experts estimate that 10-22% of new cases of blindness in the United States result from this disease. In the US alone, approximately 350,000 people suffer from uveitis; of these, approximately 130,000 are afflicted with the more severe forms, intermediate, posterior and panuveitis. These forms are typically not responsive to treatment with topical corticosteroids, and require systemic treatment. The chronic use of oral corticosteroids, the only systemic therapy approved by FDA for these forms of the disease, is burdened with multiple side effects including osteoporosis, hypertension, hyperglycemia, hypercholesterolemia, impaired wound healing, weight gain, cosmetic effects, and mood disorders, and in the eye, cataract formation and glaucoma.
The Market Opportunity: There is a major need for a safe, effective, and approved medication in uveitis. In North America and Europe, approximately 250,000 patients combined are afflicted with noninfectious uveitis involving the intermediate or posterior segments of the eye, i.e., the target group for LUVENIQ. As uveitis affects a young patient population, the socio-economic impact of the disease is greater than that of age-related macular degeneration (AMD) or diabetic macular edema (DME). In addition, a new medication may have the potential to change the course of the disease leading to better outcomes, such as a major delay in the mean time to vision loss, similar to the drugs found to be disease modifying in rheumatoid arthritis. The dearth of available treatment options for the treatment of uveitis at the current time is, indeed, comparable to the situation in rheumatoid arthritis in the early 1990’s, before the advent of novel disease-modifying therapies.
http://www.luxbio.com/Uveitis.htm
XOMA Initiates Safety and Efficacy Study of Gevokizumab in Patients With Non-Infectious Uveitis Currently Controlled by Systemic Treatment
BERKELEY, Calif., Oct. 3, 2012 (GLOBE NEWSWIRE) -- XOMA Corporation (Nasdaq:XOMA) today announced it has opened enrollment in a Phase 3 clinical trial, titled A randomizEd, double-masked, placebo-controlled study of the safetY and Efficacy of GevokizUmAb in the tReatment of subjects with non-infectious intermeDiate, posterior or pan-uveitis currently controlled with systemic treatment (EYEGUARD™-C), to determine gevokizumab's potential to reduce the risk of recurrent uveitic disease in patients with non-infectious uveitis intermediate, posterior, or pan-uveitis (NIU). The Company intends to enroll patients with NIU who have experienced active uveitic disease but whose disease currently is controlled with oral corticosteroids with or without immunosuppressive medications.
"Patients often arrive at a physicians' office with active NIU disease that requires immediate treatment to control symptoms. After the active disease is treated, both the patient and the physician want to maintain the disease in a quiet state over the long term. Today, physicians have to resort to high-dose corticosteroids and immunosuppressives to aid them, yet both carry long-term health consequences. With this new study design, we believe that we will be able to determine if gevokizumab can allow physicians to reduce the corticosteroid treatment currently used to maintain the uveitis in a controlled state," stated John Varian, Chief Executive Officer of XOMA. "While we could have chosen to conduct a standard supplemental safety-only study, we decided to expand our study to an efficacy and safety study for an incremental investment of $5 million, as we believe the investment has significant value creating opportunities for XOMA. Our International Phase 3 study in active NIU, now named EYEGUARD™-A, which started in June, is designed to evaluate the use of gevokizumab for the treatment of active disease, and this trial, EYEGUARD-C, gives us the opportunity to potentially aid in the prevention of future exacerbations in patients receiving treatment with less desirable options."
EYEGUARD-C is designed to enroll 300 patients worldwide. They will be randomized to receive either doses of gevokizumab or placebo, monthly for twelve months. All patients will undergo a predetermined reduction in their steroid doses. The study's primary endpoint is the proportion of patients with an occurrence of uveitic disease through Day 168. The study also will assess other important measures of improvement in their uveitic disease including the reduction of steroid use.
Paul Rubin, M.D., XOMA's Senior Vice President of Research and Development and Chief Medical Officer, stated, "It was a natural decision to expand the required safety study to a full efficacy trial, particularly in the NIU patient population. Long-term treatment with corticosteroids is detrimental to the patient's overall health, and the immunosuppressants being used today put the patient at significant risk of infection. We believe our antibody may be able to prevent acute exacerbation of the disease and allow physicians to reduce or even eliminate the use of corticosteroids and other immunosuppressant medications."
SERVIER (Suresnes, France), XOMA's partner jointly developing gevokizumab and holding rights outside the U.S. and Japan for the NIU indication, hails this additional entry into Phase 3 for gevokizumab. "NIU is a very debilitating disease with no therapeutic options beside potentially harmful long-term corticotherapies. Servier is very delighted by this important step in the clinical development of gevokizumab, which may ultimately prove its clinical value in inflammatory diseases," said Isabelle Tupinon-Mathieu, M.D., Head of Therapeutic Research and Development at Servier.
XOMA Will Host a Conference Call at 4:30 p.m. Eastern Time Today to Discuss the Global Phase 3 Gevokizumab Program http://bit.ly/WuSk3P
XOMA -- Poster for XOMA 052 (Gevokizumab) in Resistant Uveitis of Behçet’s Disease
Findings of this pilot trial suggest that IL-1ß plays a major role in Behcet's uveitis. Intraocular inflammation began to resolve in all 7 patients on Day 1, with a median time to first response of 4 days. Five out of 7 patients were in remission by Day 28. One patient, after a single infusion, remained in remission on Day 98. http://bit.ly/13a2zjF
Uveitis of Behçet’s Disease Pilot Trial Results http://bit.ly/Wfmg3k
Development of Immunopathogenesis Strategies to Treat Behçet's Disease
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324914/
XOMA Announces Servier Has Initiated Phase 3 Gevokizumab Trial in Patients With Behcet's Uveitis
BERKELEY, Calif., Sept. 27, 2012 (GLOBE NEWSWIRE) -- XOMA Corporation (Nasdaq:XOMA) today announced its partner, Servier has received authorization to initiate the Servier-sponsored Behçet's uveitis Phase 3 clinical trial in several European countries. The study is titled A randomisEd, double-masked, placebo-controlled studY of the Efficacy of GevokizUmAb in the tReatment of patients with Behçet's Disease uveitis (EYEGUARD™-B). The objective of this study is to evaluate the efficacy of gevokizumab as compared to placebo on top of current standard of care (immunosuppressive therapy and oral corticosteroids) in reducing the risk of Behçet's disease uveitis exacerbations and to assess the safety of gevokizumab.
"Behçet's uveitis patients now have the opportunity to participate in the gevokizumab Phase 3 clinical trial designed specifically for their unique condition," stated John Varian, Chief Executive Officer of XOMA. "Servier's commitment to this underserved market merits recognition, and we continue to be impressed by their team's passion to design the best trial to determine gevokizumab's efficacy in treating this disease."
"Servier is committed to developing innovative treatments for diseases with clear unmet medical needs, such as Behçet's disease. In addition, we strongly believe gevokizumab has a real potential in other inflammatory diseases," said Emmanuel Canet, MD, PhD, President R&D Servier.
The global EYEGUARD-B study is designed to enroll 110 patients with a history of Behçet's disease uveitis with ocular involvement of the posterior segment who have experienced a recent ocular exacerbation that was treated successfully with high doses of corticosteroids. Patients will be randomized to either a 60mg dose of gevokizumab or placebo administered subcutaneously every four weeks on top of their current immunosuppressive and corticosteroid therapies. The study's primary endpoint is the time to first acute ocular exacerbation, which will be measured once a predefined number of exacerbations have been observed.
XOMA - FDA Grants Orphan Drug Status to Gevokizumab
August 29, 2012 — The US Food and Drug Administration (FDA) has granted orphan drug status to gevokizumab ( Xoma 052, Xoma Corp), a monoclonal antibody that binds strongly to interleukin 1ß (IL-1ß), for the treatment of noninfectious intermediate uveitis, posterior uveitis, or panuveitis, or chronic noninfectious anterior uveitis.
The Orphan Drug Act of 1983 was passed to encourage companies to develop treatments for rare diseases (diseases that affect fewer than 200,000 people in the United States). Because the market is so small, such treatments can be unprofitable to develop. Companies that develop orphan drugs receive a 50% tax credit for the cost of conducting human clinical trials, 7-year marketing exclusivity, and other incentives.
Behçet's disease is a rare multisystem disease that causes blood vessel inflammation throughout the body. Common symptoms are mouth sores, genital sores, and a type of panuveitis known as Behçet's uveitis, an inflammation of the uvea, retina, and vitreous humor that can lead to retinal detachment, vitreous hemorrhage, glaucoma, and blindness.
"A genetic association has been shown between Behçet's disease and the IL-1 gene cluster, and IL-1ß has been implicated as a mediator in Behçet's disease pathogenesis," Christine Kay, MD, the director of Retinal Clinical Research and the director of the Electrophysiology Service in the Vitreoretinal Division of the Department of Ophthalmology at the University of Florida in Gainesville, told Medscape Medical News. Dr. Kay is a clinical correspondent for the American Academy of Ophthalmology.
"Gevokizumab regulates the activation of IL-1 receptors and can be intravenously or subcutaneously administered," Dr. Kay added.
Patients with Behçet's uveitis have few treatment options. "There are currently only 2 drugs FDA-approved for the treatment of chronic noninfectious intermediate, posterior, and panuveitis (Retisert [Bausch & Lomb] and Ozurdex [Allergan]), and both are extended-release corticosteroid ocular implants," Dr. Kay said.
Results of a proof-of-concept phase 2 trial of intravenous gevokizumab in 7 patients with Behçet's uveitis were published in the April issue of the Annals of Rheumatic Diseases. In that trial patients were given a single infusion of gevokizumab (0.3 mg/kg), and all patients experienced complete reduction of intraocular inflammation in between 4 and 21 days (median, 14 days). There were no treatment-related adverse events.
"In clinical trials, so far, gevokizumab has been studied in nearly 500 patients. The studies have shown that gevokizumab is well-tolerated, and no drug-related adverse events have been reported," Fred Kurland, chief financial officer of Xoma, said in an email interview with Medscape Medical News.
Although it appears that gevokizumab "may offer a viable treatment option in Behçet's disease, it remains to be seen if an IL-1 antibody will have an effect in other forms of noninfectious uveitis. A phase 3 clinical trial to evaluate the efficacy of [gevokizumab] in the treatment of noninfectious uveitis is in the recruitment process," Dr. Kay said.
"Gevokizumab does offer the possibility of a pathophysiology-driven targeted therapy for IL-1 related uveitis, and if proven safe and effective in a phase 3 trial, this could provide a valuable option in the treatment of noninfectious intermediate uveitis, posterior uveitis, and panuveitis. Even if this drug is only shown to be effective in Behçet's disease, this could provide a useful and targeted treatment for an extremely aggressive condition, perhaps limiting broader and more toxic immunosuppression," Dr. Kay said.
Other Potential Indications
"As an IL-1ß inhibitor, gevokizumab has potential in a very large number of indications that are driven by inflammation, such as noninfectious uveitis.... [W]e are also engaged in 2 proof-of-concept phase 2 trials using gevokizumab in patients with moderate to severe acne vulgaris and in erosive osteoarthritis of the hand, and we will initiate a third proof-of-concept trial in another indication later this year," Kurland explained.
"With respect to the [noninfectious uveitis] market specifically, we estimate that there are approximately 150,000 patients in the [United States who have noninfectious uveitis]," Kurland added, noting they are not discussing the drug's pricing yet.
Dr. Kay has disclosed no relevant financial relationships.
http://www.medscape.com/viewarticle/769952
XOMA Announces Manufacturing Agreement With Les Laboratoires Servier and Boehringer Ingelheim
BERKELEY, Calif., Aug. 3, 2012 (GLOBE NEWSWIRE) -- XOMA Corporation (Nasdaq:XOMA) announced today its partner Les Laboratoires Servier (Servier) and the Company have entered into an agreement with Boehringer Ingelheim to transfer XOMA's technology and process for the commercial manufacture of gevokizumab, XOMA's novel interleukin 1-beta (IL-1ß) allosteric modulating antibody. Gevokizumab currently is in Phase 3 clinical development in patients with non-infectious uveitis (NIU) involving the intermediate and/or posterior segment of the eye. The global development plan includes a Phase 3 trial to be conducted by Servier in patients with Behçet's uveitis. Upon completion of the transfer and the establishment of biological comparability, Boehringer Ingelheim is expected to produce gevokizumab at its facility in Biberach, Germany, for XOMA's commercial use. XOMA and Servier retain all rights to the development and commercialization of gevokizumab. Financial terms of the agreement were not disclosed.
"Together with Servier, we selected Boehringer Ingelheim because they are recognized globally as a leader in manufacturing monoclonal antibodies at a commercial scale," said John Varian, Chief Executive Officer of XOMA. "During our conversations with the team at Boehringer Ingelheim, we concluded they are the right partner for both XOMA and Servier. They have a well-established track record of successful technology transfers, which gave us confidence in their ability to transfer the gevokizumab production process from our Berkeley facility to their Biberach facility and to be fully prepared with documentation to support regulatory filings in U.S. and other countries. Ultimately, we wanted a partner who could produce materials in both Europe and the U.S., and with Boehringer Ingelheim, we will have that capability."
Simon Sturge, Corporate Senior Vice President Biopharmaceuticals at Boehringer Ingelheim, commented, "We are delighted to be chosen by Servier and XOMA as their manufacturing partner for gevokizumab, and we look forward to leveraging our more than 35 years expertise in this area to support both companies in further executing their clinical development strategies for gevokizumab."
XOMA - Servier Partnership Terms
Xoma, a US-based developer of therapeutic antibodies, has
signed a regional licensing pact with Les Laboratoires
Servier, France’s largest privately held pharmaceutical
company, which is potentially worth US$835 M (Deal no.
38740). Servier and Xoma will co-develop XOMA 052,
Xoma’s leading anti-inflammatory drug candidate, in multiple
indications. XOMA 052 is a human engineered antibody that
is designed to inhibit the pro-inflammatory cytokine
interleukin-1 beta, which is believed to activate pathologic
inflammation in multiple diseases, including rheumatoid
arthritis and diabetes.
The companies will first develop XOMA 052 for Behcet’s
uveitis, a chronic and debilitating ophthalmic inflammatory
condition for which the drug has received Orphan Drug
Designation in both the US and Europe. Behcet’s uveitis is
one of the most severe forms of uveitis, a vasculitis of the
blood vessels in the eye, and can lead to blindness. It affects
approximately 50% of Behcet’s disease patients and around
250,000 patients have been diagnosed with Behcet’s
disease worldwide. At present there are no approved
treatments for the disease in the US. Xoma reported positive
data from a Phase II pilot study for XOMA 052 in Behcet’s
uveitis in June 2010 and is expected to advance the drug
into Phase III for this indication in 2011.
Under the terms of the agreement, Xoma will receive
approximately US$35 M upfront, consisting of US$15 M and
a €15 M (US$20 M) loan that Xoma need not repay until
2016. Servier will fund the initial US$50 M of development
expenses for XOMA 052 and 50% of the additional
expenses for Behcet’s uveitis. Xoma will retain the
development and commercialisation rights for Behcet’s
uveitis and other inflammatory and oncology indications in
the US and Japan, while Servier has similar rights in the rest
of the world. Servier will also continue parallel Phase II
programmes for XOMA 052 in diabetes and cardiovascular
disease in exchange for global rights, although Xoma has
the option to regain these rights in the US and Japan if its
pays an option fee and partially reimburses Servier’s
incurred development expenses. It is believed that Xoma is
able to exercise its option at quite a late stage of
development, possibly after Phase III data have become
available. If Xoma reacquires these rights, then it will still be
eligible to receive milestone payments of up to US$470 M
and it would also be able to license the product to one or
more third parties in the future. If it chooses not to exercise
its option, then the milestone payments could reach US$800
M. Xoma is eligible to receive tiered royalties up to a midteens
percentage rate and will be responsible for manufacturing
XOMA 052 throughout clinical development and launch.
The company also anticipates being a long-term
manufacturer of the drug.
Xoma will benefit from Servier’s development and
commercialisation expertise, particularly in the
cardiovascular and diabetes therapy areas, which it has
gained thanks to products such as Diamicron® MR
(gliclazide) for type 2 diabetes and Procoralan® (ivabradine)
for congestive heart failure. It is worthy of note that Servier’s
licensing deals typically allow the licensor to retain US rights.
For example, in 2010 it signed an ex-US licensing
agreement with Osteologix for a Phase II drug candidate for
post-menopausal osteoporosis (Deal no. 36941) and formed
a strategic alliance with Galapagos to develop new therapies
in osteoarthritis under which Galapagos retained US
commercialisation rights (Deal no. 36574).
This regional deal is attractive for both parties. It provides a
large cash injection for Xoma, which was forced to reduce its
workforce by almost half in 2009 owing to diminishing royalty
revenue and escalating debt, thus delaying development of
XOMA 052. The agreement will also reduce the company’s
rate of cash burn and allow it to retain potential future
upside. For Servier, the deal provides the company with a
drug candidate that has demonstrated proof-of-concept in
one indication and which has potential in the treatment of a
number of inflammatory diseases. As an orphan disease,
Behcet’s uveitis offers a relatively quick and inexpensive
route to market for XOMA 052, allowing the companies to
then target larger markets such as rheumatoid arthritis
http://ojs.pharmadeals.net:5555/index.php/pdr/article/view/cr1422/html
XOMA and Servier to develop anti-IL-1ß antibody for inflammatory diseases
Nature Reviews Drug Discovery 10, 166 (March 2011)
BIOBUSINESS BRIEFS: Deal watch: XOMA and Servier to develop anti-IL-1ß antibody for inflammatory diseases
XOMA and Servier have agreed to jointly develop and commercialize the interleukin-1ß (IL-1ß)-targeted monoclonal antibody gevokizumab (XOMA 052) for the treatment of multiple inflammatory disorders. Following recent positive Phase II trial results, XOMA 052 has been granted orphan drug status by the US Food and Drug Administration (FDA) for Behçet's disease (BD), and the agent is currently undergoing Phase II trials in type 2 diabetes and cardiovascular disease.
Under the terms of the agreement, XOMA will retain development and commercialization rights for BD, as well as other indications, in the United States and Japan, whereas Servier will receive similar rights in the rest of the world. Servier will also gain worldwide rights for diabetes and cardiovascular disease indications. In return, XOMA will receive upfront and milestone payments potentially totalling over US$500 million.
BD is a multisystem, relapsing chronic vasculitic disorder, and its underlying cause remains unknown. Characteristic disease manifestations include recurrent oral ulcers, genital ulcers and vision-threatening uveitis (ocular inflammation). Symptoms are typically treated by corticosteroids or immunosuppressive drugs, although these agents can induce significant side effects.
The inflammatory cytokine tumour necrosis factor (TNF) has been implicated in the pathogenesis of BD, and targeting TNF has emerged as an alternative therapeutic approach, but this is not the answer for all patients. “Although the TNF-targeted monoclonal antibody infliximab [Remicade; Centocor] has proved to be highly effective for most patients, it is contraindicated in some patients and ineffective in others,” explains James Rosenbaum, from the Oregon Health & Science University, Portland, USA. He adds: “XOMA 052 is an innovative potential alternative.” Charles Dinarello, from the University of Colorado School of Medicine, Denver, USA, explains further: “In patients with BD, IL-1ß blockade with agents such as XOMA 052 could have a substantially better safety profile than TNF inhibition, particularly in regions where reactivation of tuberculosis infection could be a major concern.”
By binding to the pro-inflammatory cytokine IL-1ß, XOMA 052 inhibits IL-1 receptor activation and prevents downstream signalling events that mediate inflammatory processes in BD. In June 2010, XOMA reported that all seven participants in a Phase II trial displayed a rapid reduction in intraocular inflammation and improvement in visual acuity after a single treatment. These patients were suffering from vision-threatening disease exacerbations despite taking maximal doses of immunosuppressive agents. In addition, five patients who were re-treated with XOMA 052 — owing to recurring uveitis — responded to the antibody again and maintained their response for several months. According to the report, there were no drug-related adverse events.
As elevated IL-1ß activity is characteristic of inflammatory diseases, XOMA 052 is likely to have multiple applications. It is currently undergoing Phase II trials in type 2 diabetes and cardiovascular disease and is also being investigated in myeloma models. Several other agents that target IL-1ß activity are also in development for various indications, with three already approved by the FDA (see Supplementary information S1 (table)). “Rheumatoid arthritis, gout, pseudogout and several rare autoinflammatory diseases such as cryopyrin-associated periodic syndromes are effectively treated by inhibition of IL-1ß,” notes Rosenbaum. “The potential uses for blocking IL-1ß in inflammatory diseases continue to expand,” adds Dinarello. “These also include diabetes, heart failure after myocardial infarction, smouldering myeloma and stroke. In addition, IL-1ß is highly pro-angiogenic and the time has come to add anti-IL-1ß to cancer treatments,” he proposes.
Importantly, targeting IL-1ß appears to be well-tolerated and safe: “To date, this strategy has an excellent safety profile and has superior efficacy for selected syndromes,” concludes Rosenbaum.
http://www.nature.com/nrd/journal/v10/n3/full/nrd3390.html
XOMA -- Current Clinical Trials
Safety and Efficacy Study of Gevokizumab to Treat Active Non-infectious Uveitis (EYEGUARD™-A)
http://clinicaltrials.gov/ct2/show/NCT01684345?term=xoma&rank=11
Safety and Efficacy Study of Gevokizumab to Treat Non-infectious Uveitis Controlled With Systemic Treatment (EYEGUARD™-C)
http://clinicaltrials.gov/ct2/show/NCT01747538?term=xoma&rank=10
Efficacy and Safety Study of Gevokizumab to Treat Moderate to Severe Acne Vulgaris
http://clinicaltrials.gov/ct2/show/NCT01498874?term=xoma&rank=15
Safety and Biologic Activity Study of Gevokizumab to Treat Erosive Osteoarthritis of the Hand
http://clinicaltrials.gov/ct2/show/NCT01683396?term=xoma&rank=17
XOMA - Recent Setback
In early 2011, the company announced that the Phase 2b trial of XOMA 052 in Type 2 diabetes patients did not achieve the primary endpoint. Over the next 9 months, XOMA market cap would decline ~ 80%.
March 22, 2011
XOMA 052 Phase 2b Top Line Results: Glucose Control Not Demonstrated, Positive Anti-inflammatory Effect, Cardiovascular Biomarker and Lipid Improvement and Safety Confirmed
Conference Call and Webcast Today at 5:00 P.M. ET (2:00 P.M. PT)
BERKELEY, Calif., March 22, 2011 (GLOBE NEWSWIRE) -- XOMA Ltd. (Nasdaq:XOMA), a leader in the discovery and development of therapeutic antibodies, today announced that its Phase 2b trial of XOMA 052 in Type 2 diabetes patients did not achieve the primary endpoint of reduction in glycosylated hemoglobin, or HbA1c, after six monthly treatments with XOMA 052 compared to placebo. Biological activity of XOMA 052 supporting its potential in cardiovascular disease was observed with highly significant (p < or = 0.0005) decreases in C-reactive protein, or CRP, a biomarker for the risk of heart attack, stroke and other cardiovascular diseases, in all dose groups versus placebo. In addition, statistically significant (p<0.05) improvements in high-density lipoprotein, or "good" cholesterol were observed in two of four XOMA 052 dose groups versus placebo. XOMA 052 was well-tolerated in this trial, with no serious drug-related adverse events and a safety profile consistent with previous trials. XOMA is developing XOMA 052 in collaboration with Servier.
"While this trial did not demonstrate glycemic improvement, the potent anti-inflammatory effects and continued positive safety profile reinforce our Phase 3 development program for Behcet's uveitis, which we anticipate starting this year pending completion of regulatory agency discussions. We are also encouraged by the improvements in C-reactive protein and 'good' cholesterol, which support the further evaluation of XOMA 052 in cardiovascular disease and other inflammatory indications," said Steven B. Engle, XOMA's Chairman and Chief Executive Officer.
"Pending completion of the ongoing Phase 2a trial and analyses of both studies, we will be working with XOMA to determine the next steps in the XOMA 052 diabetes program. In parallel, we anticipate initiating the Phase 3 program in Behcet's uveitis this year. We also expect to take XOMA 052 into clinical development in cardiovascular disease in 2012," said Isabelle Tupinon-Mathieu, M.D., Head of Therapeutic Research and Development, Servier.
Phase 2b Trial Top Line Results
The randomized, placebo-controlled dose-ranging Phase 2b trial enrolled 421 patients at multiple sites in the United States during 2010. Eligible patients had Type 2 diabetes and were receiving metformin monotherapy, the standard of care for initial treatment of diabetes. Patients were randomized to receive one of four XOMA 052 doses or placebo monthly over six months via subcutaneous administration. The primary endpoint of the study was the change in HbA1c levels from baseline compared to placebo at six months.
Baseline characteristics were similar between the XOMA 052 and placebo groups. At study entry, the mean CRP was 4.8 mg/L and 4.2 mg/L in the XOMA 052 and placebo groups, respectively. Mean HbA1c was 7.8% for the XOMA 052-treated patients and 7.7% for placebo-treated patients. Mean duration of Type 2 diabetes was approximately six years in both groups.
At six months, all XOMA 052 doses had reductions in CRP, with adjusted mean percent changes from baseline that were highly significant compared to placebo with p-values (adjusted for multiple comparisons) at 0.0005 or less. Consistent with prior XOMA 052 studies, the median reductions in this trial were 33% to 54% in the four dose groups, compared with zero reduction for placebo.
In addition, despite the fact that more than half of the patients were receiving lipid-lowering medication, XOMA 052-treated patients demonstrated statistically significant increases in high-density lipoprotein, or "good" cholesterol, in two of the four XOMA 052 dose groups versus placebo (p<0.05).
The safety and tolerability profile in this population was consistent with previous XOMA 052 clinical trials, and there were no serious drug-related adverse events. The most common adverse events were upper respiratory infections with no differences between XOMA 052 and placebo groups. There were no reported opportunistic infections.
XOMA - Credit Suisse Investment Thesis - November 2012
In the past 12 months, Xoma has made several positive strategic changes that have
positioned it well with upcoming data flow, higher probability of clinical/regulatory success,
multiple shots on goal, cost cutting and refocusing, commercial infrastructure, and an
improved capital structure.
Our investment thesis is based on expectation of positive clinical data in its lead uveitis
Phase III trials in 2013-14 and multiple opportunities for positive incremental data flow
from three proof-of-concept Phase II trials. The primary risks are clinical trial failure,
competition, and potential future dilution.
-Phase III Ongoing: Xoma’s primary value driver is gevokizumab, its IL-1ß antibody, in
Phase III development for a form of sight-threatening eye inflammation called
noninfectious uveitis. Phase II results are positive and the ongoing Phase III program
is broad, global, well designed, and partially funded by its ex-U.S. partner Servier. We
assign a high probability of success in this indication, valued at $4 per share if
successful.
-Multiple Shots on Goal with Gevokizumab: Three Phase II trials are ongoing or
planned. Each trial will provide a definitive readout versus placebo in a new indication.
These proof of concept trials will generate data in Q412 for acne vulgaris, mid-2013 for
osteoarthritis of the hand, and a third also in mid-2013. We currently assign a low 5%
probability of success to the first two indications, providing significant upside if data
are positive. Of the two disclosed indications, we have greater confidence in the
osteoarthritis indication, and see this as a substantial new market opportunity.
-Aceon Program Is an Underappreciated Asset: Xoma licensed U.S. commercial
rights to Servier’s proprietary ACE inhibitor called Aceon. Xoma recently reported that
it met the primary endpoint in its 816 patient Phase III trial of a fixed dose combination
of Aceon and a generic calcium channel blocker. While we do not see Xoma launching
this product, we believe it is substantially derisked and could generate a licensing deal
in 2013.
-Ultra-Orphan Opportunities: Xoma has identified several ultra-orphan indications for
gevokizumab and for its earlier stage candidate xMetD. The indications that have been
disclosed are readily addressable by small, relatively low cost trials, which should
provide definitive efficacy and a potentially rapid path to approval. This new strategy is
not fully understood by the Street.
Significant Clinical Newsflow in 2012-13
Timing Expected News Flow Program
Q4:12 Initiate 3rd POC Phase II trial Gevokizumab
Q4:12 Servier to initiate Phase II trial (CV disease) Gevokizumab
Q1:13 Phase 2 POC readout for moderate/severe acne vulgaris Gevokizumab
H1:13 Partnership for ACEON
Mid-2013 Phase 2 POC data readout for erosive osteoarthritis Gevokizumab
Mid-2013 Data read-out from 3rd POC Phase II study Gevokizumab
Q4:13 Results from EYEGUARD A (Active NIU trial) Gevokizumab
Q1:14 Results from EYEGUARD B (Behcet's trial) Gevokizumab
Mid-2014 Results from EYEGUARD C (Controlled NIU trial) Gevokizumab
Source: Company data, Credit Suisse estimates
Several members of the board, myself included, have recently taken positions in XOMA. I thought it might be helpful to share some of the research that led to my decision. Hopefully, this will generate an ongoing discussion that can help better assess the opportunity. With that in mind, I'll be making a series of posts this morning that will then be consolidated into a RMF. Enjoy!
The expansion of the phase 3 trial into non-infectious uveitis (NIU) was one of the reasons I decided to take a position. While there are only around 7,500 Behcet's pts in the US, NIU is a much larger opportunity - around 150,000 pts.
I also recently started a position in XOMA (although at slightly higher prices than Dew, lol). My understanding is that a lot has changed in the past year. First, they've got a solid partnership with Servier in place. Second, they've got a new CEO that has the company clearly focused on commercializing their lead candidate. They've also initiated a targeted P2 PoC program focused on orphan indications while retaining upside in the CV opportunity. I've done a lot of dd that I'd be more than happy to share with the board. I plan on making a series of posts over the next week or so that will hopefully form the basis for an RMF on the company.
Well, considering half the pts in the bosutinib trial had failed only ONE tki (gleevec) while 94% of ponatinibs pts had failed MULTIPLE tki's, a comparison is kind of pointless.
Given that ARIA has gone up after each of the last three financing's, I'm not sure why you are expecting there will be weakness next time. It all depends on the situation/context at the time. If the company is raising $'s to fund a growing world-wide opportunity in multiple wholly-owned drugs then the stock isn't going down. Of course, if they have to raise $'s because the Iclusig sales don't develop as expected then that's a different story but you just said that you "doubt Iclusig will disappoint".
Yes, but I think it is going to require the EPIC trial data to get the broad label. Keep in mind that the EPIC trial is based on MMR at 12 months and Iclusig generates an MMR much faster(5.6 months)than gleevec (30 months in the DASISION trial), so i have a lot of confidence that Iclusig will be approved in a front-line setting. And if it does get approved in a front-line setting, i'm not sure what the benefit would be of running a separate 2nd-line trial at that point.
A) The initial uptake is going to be in patients who have already failed tasigna/sprycel and/or have the T315I mutation in which tasigna/sprycel are ineffective, so, I really don't expect the initial uptake will be affected by the label at all.
B) Tasigna is on track to sell over $1 billion with its black box label. Iclusig is a better drug.
C) If Iclusig had only a "marginally" better MMR, then perhaps NVS's marketing tactics would have an impact but its going to be a hard argument for them to win based on the merits. Plus, key opinion leaders such as Cortez are clearly in the camp of using Iclusig as early as possible.
D) By the time, Ariad is ready to ramp sales into 1/2nd-line, the EPIC trial data will be available which I believe will show that the AE's experienced in the 3/4 line PACE trial won't carry over to a front-line population of younger, healthier patients.