Short Watch List (comments).
XOMA (short)


In spite of good science basis of XOMA, this stock was heavily pumped and inflated.
Moreover, I don't like this XOMA statement: "Engineered as a broad anti-inflammatory agent, XOMA 052 has potential as a treatment for many diseases, including diabetes, cardiovascular disease, rheumatoid arthritis, acute gout, and systemic juvenile idiopathic arthritis (sJIA). This multi-indication potential makes it the most versatile and exciting product in our pipeline." Sounds like they found some "panacea"...

"XOMA 052 is currently in Phase 2 development for Type 2 diabetes and Type 1 diabetes and cardiovascular disease. XOMA 052 could prove to be a disease-modifying therapy by addressing inflammation as an underlying cause of this many disease, whereas current therapies focus almost exclusively on improving the body’s ability to produce and process insulin."

"XOMA 052 binds strongly to Interleukin-1 beta (IL-1β), a pro-inflammatory signaling protein, called a cytokine, that is believed to be a primary cause of inflammation."

What about possible side effects?

"IL-1β is a member of the interleukin 1 cytokine family. This cytokine is produced by activated macrophages as a proprotein, which is proteolytically processed to its active form by caspase 1 (CASP1/ICE). This cytokine is an important mediator of the inflammatory response, and is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis. The induction of cyclooxygenase-2 (PTGS2/COX2) by this cytokine in the central nervous system (CNS) is found to contribute to inflammatory pain hypersensitivity. This gene and eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2."


BTW, "at September 30, 2010, XOMA had cash and cash equivalents of $16.9 million, compared with $23.9 million at December 31, 2009. Subsequent to September 30, 2010, XOMA's cash position was strengthened by $2.0 million received as final payment under its antibody discovery collaboration with Kaketsuken and $1.5 million in gross proceeds from equity issuances under an At Market Sales Agreement entered into in 2009 which has now been fully utilized."

So, the probability of direct offering is very high now. XOMA may use this opportunity to raise money at highest for 6 months price.

What is the nearest future big news for XOMA?

May be this one?

Study of the Safety and Biologic Activity of XOMA 052 in Subjects With Type 2 Diabetes Mellitus
Condition: Type 2 Diabetes Mellitus
Interventions: Drug: XOMA 052; Drug: Placebo

Primary Outcome Measures:

* Safety assessed by pre- and post-treatment serial measurements of vital signs, clinical laboratory assessments, daily fasting blood glucose measured by the subject using a glucose monitor, and treatment-emergent adverse events. [ Time Frame: Day 0 pre-dose through Day 336 ] [ Designated as safety issue: No ]

Estimated Enrollment: 80
Study Start Date: May 2010
Estimated Study Completion Date: October 2011
Estimated Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)

Locations
Mexico
Mexico City, Mexico


Almost 1 year before results release. OK, may be after good and promising results (if any) I'll include XOMA in my Hot Watch List. But now XOMA is a good candidate for short.


Disclosure: I short XOMA today at $6.80 level. Low risk, medium reward.


January 04, 2011 by BiotechInvest

Good news for XOMA today, so prepare to short XOMA again. It will be strange if XOMA not use these news to earn some money (I mean direct offering or dilution). I'll short it if price reach $6.80 (like last time).

Today XOMA chart and volume inspired me to invent a new word for this situation: "investomadness". 49M shares sold when 23.5M shares outstanding...

It's seems like that there are no limits for the investomadness...

I'm still very skeptic about XOMA 052 "panacea" properties and I'm thinking that there is a very low probability that XOMA 052 will improve Type 2 diabetes.

Phase II trial:
Safety and Efficacy of XOMA 052 in Subjects With Type 2 Diabetes Mellitus on Stable Metformin Monotherapy.

The study hypothesis is that XOMA 052 improves glycemic control in subjects with Type 2 Diabetes.

Do somebody mention this: "study hypothesis"?

Primary Outcome Measures:
* Mean change from baseline (Day 0 pre-dose) in HbA1c at Day 182 [ Time Frame: Day 0 pre-dose and Day 182 ] [ Designated as safety issue: No ]

Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)

Strange, but in phase I trial for XOMA 052 they measure HbA1c at Days 0 and 28.

"Single-dose, Dose-escalation Study of Safety, PK, and Preliminary Efficacy of XOMA 052 in Type 2 Diabetes Mellitus"

Primary Outcome Measures:

* Glycated hemoglobin (HbA1c) at Days 0 and 28. [ Time Frame: Day 0 and Day 28 ] [ Designated as safety issue: No ]


So, now they will measure at Days 0 and 182...

"In the normal 120-day lifespan of the red blood cell, glucose molecules react with hemoglobin, forming glycated hemoglobin. In individuals with poorly controlled diabetes, the quantities of these glycated hemoglobins are much higher than in healthy people.

Once a hemoglobin molecule is glycated, it remains that way. A buildup of glycated hemoglobin within the red cell, therefore, reflects the average level of glucose to which the cell has been exposed during its life-cycle. Measuring glycated hemoglobin assesses the effectiveness of therapy by monitoring long-term serum glucose regulation. The HbA1c level is proportional to average blood glucose concentration over the previous four weeks to three months."

182 days are equivalent to 6 months, so I don't understand why XOMA needs so long period to measure the changes in HbA1c.

I'm sure that
XOMA 052 will do nothing with HbA1c level because only fast postprandial insulin can change this parameter.

For example, even with fastest MNKD insulin HbA1c changes were very modest: -0.1%

"In the intent-to-treat population, AFREZZA lowered HbA1c by -0.10% (mean change from baseline HbA1c) as compared to -0.03% in the lispro group. The difference of 0.07% between the two groups fell well within the non-inferiority margin of 0.4% (95% CI [-0.31, 0.17]). Similar results were also observed in the intent-to-treat with last observation carried forward population (-0.04%; 95% CI [-0.25, 0.18]).


Two small biotechs BIOD (recently) and EMIS (7 years ago) failed to show any significant HbA1c lowering:

"In 2006, Emisphere performed a 90-day double-blind phase II clinical study in India with 145 patients with type 2 diabetes on oral antidiabetes drugs (OADs; Metformin). The patients were randomized in four different groups and treated with three different insulin doses or placebo. No significant differences in metabolic control [hemoglobin A1c (HbA1c)] between the groups were observed despite treatment with up to 1000 U of oral insulin per day."


So, XOMA investors (long) should prepare to meet very bad phase II trial results. Sure that XOMA management know it and they will sell stock before it.


By the way, what is this new "panacea" XOMA 052?

"XOMA used its antibody expertise and technologies to develop XOMA 052, a highly potent and highly specific antibody IL-1 inhibitor that is the first in a new generation of anti-inflammatory IL-1 blocking agents. XOMA 052 binds strongly to Interleukin-1 beta (IL-1β)."

Sounds very familiar for me... Yes, Regeneron (REGN) pipeline.

"Rilonacept is a fusion protein designed to attach to and neutralize interleukin-1 (IL-1) before IL-1 can bind to cell-surface receptors and generate signals that trigger inflammation."

Rilonacept is being evaluated as a therapeutic drug candidate for the prevention of gout flares in patients who are initiating uric acid-lowering therapy.

2 Phase III trials: "PREventative Study Against URate-lowering Drug-induced Gout Exacerbations 1 (PRE-SURGE1)"

This study has been completed.

"PREventative Study Against URate-Lowering Drug-Induced Gout Exacerbations (PRE-SURGE 2)"


This study is currently recruiting participants.

Estimated Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)


BTW, "XOMA 052, a monoclonal antibody for the treatment of Type 2 diabetes, rheumatoid arthritis, gout, and other diseases"

So, if REGN Rilonacept successes in gout treatment may be XOMA 052 will too. But REGN never say that Rilonacept will cure such different diseases as Type 2 diabetes, rheumatoid arthritis and gout. 

http://www.regeneron.com/il_1trap.html


Will not advise XOMA investors "don't be crazy"... "Investomadness" is contagious disease and it spreads very fast.


January 05, 2011 by BiotechInvest

"XOMA shares are higher after announcing that it was going to license its XOMA 052 diabetes drug to France-based Laboratoires Servier for $15 million. Servier is also loaning the company $20 million. XOMA, however, has retained the right to buy back the U.S. and Japan rights for the drug, for which phase 2 trial results will be out this month, for an undisclosed amount."

That's interesting: phase 2 trial results for diabetes will be out this month. As I already said it's extremely unlikely that XOMA 052 will decrease HbA1c

This phase 2 trial is "Randomized, Double-blind, Placebo-controlled, Dose-ranging Study of the Safety and Efficacy of XOMA 052 in Subjects With Type 2 Diabetes Mellitus on Stable Metformin Monotherapy"

Estimated Enrollment: 325 (so, will be enough good statistics)

Arms Assigned Interventions Placebo: Placebo Comparator
Intervention: Drug: Placebo
Drug: Placebo
Sterile solution subcutaneously administered monthly for 6 months

XOMA 052: Experimental
Intervention: Drug: XOMA 052
Drug: XOMA 052
Sterile solution subcutaneously administered monthly for 6 months

That is strange, why they choose SC injection instead of IV?

Inclusion Criteria:

* Diagnosed with T2D (disease duration ≥ 6 months)
* HbA1c ≥ 6.8% and ≤ 10.0%
* Have been on a stable regimen of metformin monotherapy for at least 12 weeks prior to Day 0
* Willingness to maintain stable diet and exercise regime throughout the study
* Willingness to maintain current doses/regimens of vitamins and dietary supplements through the end of the study

The including the diet and exercise was very wise. It's already should decrease HbA1c in both arms.

"A meta-analysis of research done to identify the effect of two different kinds of training programs (combined aerobic and eccentric resistance exercise program and aerobic exercise only) on the glycosylated hemoglobin levels of individuals with T2DM found that the effect of combining resistance exercise with aerobic exercise improved the glucose control more than just the aerobics alone. The average effect of the training programs included reductions of glycosylated hemoglobin of 0.8 %, which was a result similar to that of long-term diet and drug or insulin therapy (which result in a reduction of 0.6–0.8 %)."

So, the prediction is: both arms will show some HbA1c decreasing (average -0.2-0.3%) and no significant difference between drug and placebo groups.


January 07, 2011 by BiotechInvest

Covered XOMA today at $6.09 (shorted at $6.82). Trial news were really bad for XOMA 052. May be this data supports "support safety and some biological activity" but not efficacy against diabetes:

"Median reduction from baseline in hemoglobin A1c levels at day 84 was 0.2% in the XOMA 052 group versus 0.1% in the placebo group. Hemoglobin A1c is a measure indirectly reflecting blood glucose levels as averaged over a 90 to 120 day period."

Someone may say that other parameter changed:

"C-reactive protein (CRP) levels decreased by a median of 49% in the XOMA 052-treated group and 2% in the placebo group."

Well, may be XOMA 052 is just anti-inflammatory drug (very expensive one). Many drugs decrease CRP, for example statins:

"Ridker et al.[8] reported a 13.3% decrease in CRP in an 8-week cerivastatin study. In the Cholesterol and Recurrent Events study[2] (CARE) a similar decrease was found in a 5-year follow-up. In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS),[9] the decrease in plasma CRP associated with the use of lovastatin was 14.8%. In all three studies a decrease was observed in plasma CRP independent of the LDL-C change achieved; this is consistent with our results. The decrease of 47% in plasma CRP that we achieved with atorvastatin is high when compared with studies using other statins.[2, 8, 9] This difference could be attributed to our choice of patients. Another reason may be that different statins may have variable anti-inflammatory effects.[10] We think that studies assessing the anti-inflammatory effect of different statins should be performed."

Don't want to eat statins?


A: Here are five nutritionally-oriented ways to lower C-reactive protein (CRP):

1) Vitamin E and Coenzyme Q10 were found to lower CRP by an average of 30% in research with baboons fed a high fat and high cholesterol diet.

2) Vitamin C (1000 mg daily) in human research reduced CRP levels by 25%.

3) Krill oil (300 mg daily) taken for two weeks in human research reduced CRP by 30%. Krill are marine crustaceans (similar to tiny shrimp) whose oil is a rich source of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), vitamins A and E, and the antioxidant astaxanthin.

4) Eating plenty of vegetables and fruits daily can lower CRP levels by an average of 30%.

5) Regular, small amounts of dark chocolate can reduce CRP levels by an average of 20%.

I like #5 way.

So, XOMA 052 failed in diabetes treatment, 3 months was enough to show it. But many investors think "may be next 3 months will show some efficacy" or  "there is no way that big pharma paid money for bluff drug".
Well, just remember LA JOLLA PHARMA (now LJPC.PK pps $0.039) with their "innovative" lupus drug. They also got upfront money from big pharma, but phase III trial was terminated because of lack of any efficacy.


 I'll wait for next wave of "investomadness" to short XOMA. Sure that this wave will happens before final trial results release.

March 22, 2011 by BiotechInvest

I completely forgot to short XOMA. Well, it's too late now:

Xoma diabetes drug fails Phase II trial

San Francisco Business Times - by Ron Leuty
Date: Tuesday, March 22, 2011, 1:40pm PDT


Xoma Ltd.’s much-watched experimental diabetes drug failed a key Phase II study, the company said.

XOMA-052 did not hit its primary goal of reducing glycosylated hemoglobin, or HbA1c, compared to a placebo, after six monthly treatments in the Phase IIb trial.

The drug has been discussed as a potential once-a-month treatment for type 2 diabetes that targets inflammation by inhibiting the protein interleukin-1, or IL-1.

A Phase IIa trial is continuing.

Isabelle Tupinon-Mathieu, head of therapeutic research and development with Xoma partner Servier, said her company will work with Xoma to determine the next steps for the diabetes program.

The Berkeley company (NASDAQ: XOMA) said the drug still has potential as a cardiovascular drug since the trial showed significant decreases in C-reactive protein — a biomarker for the risk of heart attack, stroke and other diseases — in all dose groups versus placebo. Plus, the company said patients in two of the four dose groups showed improvements in so-called “good” cholesterol."

It's time to put XOMA in archive. May be for very long time...
































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