Next item in the SPA basket: Orexigen

One of my long term SPA positions is Orexigen (OREX), whose lead candidate Contrave (Naltrexone 4mg, 8mg/Bupropion HCL 90mg extended release tablet, referred to as NB in the excerpts from FDA materials below) is in development for the treatment of obesity and weight management, including weight loss and maintenance of weight loss, in patients with an initial body mass index ≥30 kg/m² or ≥27 kg/m² with one or more risk factors (e.g. diabetes, dyslipidemia, or hypertension).

I am not going to review the entire clinical development history here, but instead will focus on safety and the LIGHT Study, and my thoughts on likelihood for approval long-term.  

In terms of efficacy in achieving weight loss, my personal assessment is that the categorical weight loss achieved with Contrave is slightly better overall than Arena’s Belviq, and slightly inferior overall compared with Vivus’ Qsymia.

The company has been asked to perform a cardiovascular outcomes study to better characterize CV risk prior to approval of this product.  This was requested because of a signal detected in review of the original NDA safety database.  Readers should refer to the FDA briefing document from the first Advisory Committee meeting for full information.

“Bupropion, as an inhibitor of neuronal reuptake of norepinephrine, has the capacity to increase blood pressure and pulse. In the NB phase 3 clinical trials, subjects treated with NB32 had small but statistically significant mean increases in systolic and diastolic blood pressure and pulse rate relative to placebo. The treatment effect was most pronounced during the first eight weeks of treatment. NB32-treated subjects who lost at least 5% of baseline body weight (i.e., responders) had more favorable changes in blood pressure and pulse than NB32 nonresponders, but placebo responders had the most favorable changes overall in blood pressure and pulse. The frequency of hypertension-related adverse events was significantly higher in NB32 compared with placebo subjects.

Given the study subject demographics, and the size and duration of the phase 3 studies, the number of major adverse cardiac events (MACE) was too small to make reliable inferences about NB’s effect on cardiovascular risk. A rigorous assessment of NB’s cardiovascular risk profile would require a dedicated study in an appropriate population of overweight and/or obese individuals. The Division and Orexigen are in the early stages of discussing the design elements of such a study”.

What did the original reviewer find in terms of CV safety?

Here is a recap of the relevant CV findings:

•                    A greater percentage of subjects experienced blood pressure and pulse TEAEs in the Total NB group compared with the placebo group (5.9% and 4.2%, respectively). This was primarily attributable to the Hypertension (5.3% Total NB and 4.0% placebo). No serious blood pressure and pulse events were reported.

•                    Blood pressure-related TEAEs (including hypertension and increased blood pressure terms) in both the NB32 and placebo groups were reported mostly by subjects with a history of hypertension or antihypertensive medication use at baseline, occasionally led to treatment discontinuation, and required medication in approximately two-thirds of subjects.

•                    In Trial NB-304 (individuals with diabetes), 40 (12.0%) subjects in the NB32 group and 11 (6.5%) in the placebo group had a blood pressure-related TEAE during double-blind treatment. Ten percent (4/40) in the NB32 group were severe compared to none (0/11) in the placebo group.

Pulse:

•                    At both Weeks 4 and 8, the Total NB group had a statistically significant difference from placebo of +2.1 bpm.

•                    By Week 56, the statistically significant difference from placebo was +1.4 bpm.

•                    Increases in pulse from baseline (≥5, ≥10, and ≥20 bpm) and pulse increases ≥90 bpm at two consecutive or the final visit were observed at higher incidences in NB-treated subjects.

Systolic Blood Pressure:

•                    At Week 4 and at Week 8, the Total NB group had a statistically significant difference from placebo of +2.4 mm Hg.

•                    By Week 56, the statistically significant difference from placebo was +1.5 mm Hg.

•                    Subjects in the Total NB group were 2.5 x as likely to experience 2 or more SBP readings ≥150 mm Hg and were 2x as likely to experience 2 or more SBP readings ≥160 mm Hg.

Diastolic Blood Pressure:

•                    At Weeks 4 and 8, the Total NB group had a statistically significant difference from placebo of +1.9 and +2.1 mm Hg, respectively.

•                    By Week 56, the statistically significant difference from placebo was +1.2 mm Hg.

•                    Shifts to high potentially clinically significant (PCS) DBP values were 3 to 4 times more frequent in the Total NB group as compared to Placebo in the first 12 weeks. The incidence remained higher in the Total NB group until Week 28 where the incidence of shifts to high PCS between groups was generally similar between placebo and Total NB until trial end.

Cardiovascular Events

•                    MACE events (CV death, MI, CVA) occurred in 3 NB patients vs 1 Pbo patient.

•                    Overall Cardiovascular AEs—including atherosclerotic disease, arrhythmias, and congestive heart failure-- were similar between the Total NB and placebo groups.

•                    Ischemic CV events were too few in number to adequately assess CV risk in this patient population.

It is important to note that CV events were not centrally adjudicated and were very small in number for the total database; N=4

Key Points:

Table 34 in the briefing document is very helpful.  It shows that at baseline, the average systolic BP is 119 mmHg in the Contrave group, this increases to 120.5 mmHg by week 56 for patients on therapy.  In my opinion a systolic BP of 121 mm Hg would most likely be considered normal and not associated with any increased CV risk.   Similarly Table 37 looks at changes in diastolic blood pressure.  The diastolic BP was 77 mm Hg at baseline and was reduced to 76 mm Hg by week 56 (+0.51 mm Hg placebo adjusted change).  Again, to me the absolute magnitude of this change does not suggest any increased risk of CV events.

Table 40 looks at absolute changes in pulse rate, another concern flagged by the reviewer. At baseline, the mean bpm was 72, at week 56 it was 72.3. Again, this to me is not really a red flag in terms of incremental CV risk.

Ultimately the company reached agreement with FDA to conduct a cardiovascular outcomes study prior to approval for which the protocol received a SPA. The details are here:

This trial is set to recruit N=9880 obese patients at high risk for CV events (assuming a background event rate of ~1.5%). An important factor is that patients not achieving pre-defined weight loss goals at 16 weeks of therapy must discontinue treatment, thus reducing the risk of unnecessary drug exposure (something that did not happen in the SCOUT trial for Meridia). Contrave CV risk will be deemed acceptable if OREX can exclude a doubling of CV risk (i.e., the upper bound of 95% CI not crossing 2.0) in the interim analysis, or if it can exclude 1.4 x risk in the final analysis. The interim analysis can be conducted after 87 events (expected to occur in 2013). OREX believes that if 50 or less of the 87 CV events occur in the Contrave arm, it will be able to reach approvable safety in the interim analysis.  The important point here is that if the interim safety analysis fails to exclude a doubling of risk, it does not mean the trial has failed overall, but will continue with further safety analyses prior to study end.

What has impressed me most about this trial has been the rapidity with which enrollment has occurred. The trial opened on 6/6/2012 and was ~50% enrolled by 8/31/2012. Enrolling nearly 5,000 patients in 3 months is pretty impressive in my opinion.  The company expects to close enrollment by the end of Q4 12 and to have accrued sufficient CV events for the interim analysis sometime in 2013. 

What are my concerns with the trial?

This trial is enriched with obese patients at higher risk for CV disease than the patients who were enrolled in the original phase 3 studies.  The inclusion criteria for greater CV risk are below:

1. At increased risk of adverse cardiovascular outcomes:

·         Cardiovascular disease (confirmed diagnosis or at high likelihood of cardiovascular disease) with at least one of the following:

·         History of documented myocardial infarction >3 months prior to screening

·         History of coronary revascularization

·         History of carotid or peripheral revascularization

·         Angina with ischemic changes (resting ECG), ECG changes on a graded exercise test (GXT), or positive cardiac imaging study

·         Ankle brachial index <0.9 (by simple palpation) within prior 2 years

·         ≥50% stenosis of a coronary, carotid, or lower extremity artery within prior 2 years

AND/OR

·         Type 2 diabetes mellitus with at least 2 of the following:

·         Hypertension (controlled with or without pharmacotherapy at <145/95 mm Hg)

·         Dyslipidemia requiring pharmacotherapy

·         Documented low HDL cholesterol (<50 mg/dL in women or <40 mg/dL in men) within prior 12 months

·         Current tobacco smoker

There is a chance that Contrave and exacerbate risk and lead to significantly worse outcomes in this group. Per the review of the original NDA, blood pressure related adverse events occurred more often in patients with pre-existing hypertension, in some cases leading to patients coming off the study. However, a couple of factors are reassuring; Firstly, patients who are non-responders will discontinue therapy mitigating long term inappropriate drug exposure risk.  Secondly, from the FDA’s responder analysis (see figures 7, 9 & 11) for individual CV parameters, you can see that Contrave non-responders experienced increases in blood pressure and heart rate, whereas Contrave responders experienced reductions in the same parameters.  By eliminating the non-responders from the trial, we should in theory mitigate any potential risk posed by the small observed increases in blood pressure and heart rate.

The other concern is around costs of the study and the company’s state of funding.  While the cost of the trial is estimated to be ~$100MM, Orexigen does not have sufficient funds today to finance through approval.  In a best case scenario, if sufficient events accrue for a positive interim analysis by Q4 13, one would anticipate a filing of a response to the CRL by mid-2014, and approval late 2014.  The study still needs to run to completion until 2017. The company's guidance is that current cash, cash equivalents and marketable securities will last through the anticipated timing of the resubmission of the Contrave NDA alone, so they will definitely have to raise cash at some point, I would guess before the interim safety analysis.  I will be watching to add more to my position at that point.

Overall, I think the pro’s outweigh the cons for holding this position long term, especially given the significant potential near term catalysts.

This article is not meant as trading advice.  Please conduct your own due diligence and trade securities at your own risk.

My thoughts on Sarepta

Although I do not have any positions in Sarepta Therapeutics (SRPT), yesterday I was consistently berated by the entire Twitterverse for suggesting that their phase 2 for Eteplirsen in Duchenne Muscular Dystrophy (DMD) study would not in fact be sufficient to pass the FDA’s sniff test for accelerated approval.  Here I will spell out why:

1.       Regulatory Precedent

The FDA has laid out guidance for any sponsor developing a therapy for rare diseases which is nicely summarized here.   The presentation includes a nice description of the size of NDA submission programs for recently approved orphan therapies.

The good news is that orphan products are eligible for Fast-Track, Accelerated approval paths and Priority reviews, however, the same regulatory standards that apply to regular drugs still have to be met:

Regulatory Approval Standard

                        Orphan drugs are held to the same statutory requirements for demonstrating effectiveness and safety

                        Orphan drugs must: Demonstrate substantial evidence of effectiveness/clinical benefit (21CFR 314.50)

                        Substantial evidence of benefit requires: Adequate and well-controlled clinical study(ies) (§314.126)

 “Study has been designed well enough so as to be able “to distinguish the effect of a drug from other influences, such as spontaneous change…, placebo effect, or biased observation” (§314.126)”

So, does the P2 study in question have “Substantial Evidence of Effectiveness”, is it “adequate and well-controlled”?

There is absolutely no rational argument that n=4 patients receiving therapy is adequate to establish conclusive efficacy.  I have yet to see any baseline demographics on these study participants so who knows if it was well controlled between the two study arms, not to mention the selection bias for who was entered into this study to begin with.  Only the initial 24 weeks were blinded to treatment so the risk of observer bias cannot be excluded for the 48 week data presented yesterday; the investigators knew all study participants were on treatment at that data point.  Single center studies also introduce an element of bias which must be taken into consideration when reviewing these results.  Bias aside, all participants had to be on steroids to be enrolled in the study.  Steroids can effect ambulation performance; can anyone tell me what dosage of steroid these participants had throughout the course of the study and if there were any differences between the two groups?

According to the FDA Guidance:

What constitutes substantial evidence of effectiveness?

-Typically two adequate and well-controlled studies

Independent substantiation of experimental results – single clinical experiment not usually considered adequate scientific support for conclusion of effectiveness

Let’s just assume for one wildly optimistic second that that FDA was to consider Accelerated approval with a single study, what would be the regulatory requirements?

                        Accelerated Approval  is based on surrogate endpoint  where  the surrogate is reasonably likely to predict clinical benefit

                        and usually requires post-marketing studies to verify and describe clinical benefit

OK, that doesn’t sound too bad. Afterall we have the muscle biopsy data.  But wait a second, let’s take a closer look at that.  According to the company data which can be found here:

Treatment Arm			Mean Change from Baseline in % Dystrophin-Positive Fibers		p-value
Eterplirsen (both doses): 48 wks of Tx (n=8)			47.0		≤0.001
	Eteplirsen 50 mg/kg (n=4)		41.7		≤0.008
	Eteplirsen 30 mg/kg (n=4)		52.1		≤0.001
Placebo/Delayed Tx: 24 wks of Tx (n=4)			38.3		≤0.009
	Placebo/50 mg/kg Delayed-Tx (n=2)		42.9		ns
	Placebo/30 mg/kg Delayed-Tx (n=2)		34.2		ns

                         

The patients in the 30mg/kg arm actually generate more dystrophin positive fibers than the higher dose group, yet, this did not translate into a significant improvement on the 6-minute walking test.

Treatment Arm		Mean Change from Baseline in 6MWT (meters)		Estimated Treatment Effect (Eteplirsen minus Placebo/Delayed-Tx)		p-value
Placebo/Delayed-Tx (n=4)		-60.3
Eteplirsen 50 mg/kg (n=4)		+27.1		87.4 m		≤0.001
Eteplirsen Both Doses (n=6)		+7.3		67.3 m		≤0.001
Eteplirsen 30 mg/kg (n=2)		-31.5		28.8 m		ns

In other words, taken as is, this surrogate does not predict clinical benefit (as defined by distance on the 6MWT) at all.  Can anyone explain this?  I doubt it, I am certainly not convinced this is an accurate biomarker, nor is it particularly pleasant to be subjecting these participants to multiple muscle biopsies.  (For the sake of brevity, I’m going to skip what I have learned about DMD trial end points and biomarkers from a brief review of the literature).  Surely a blood based biomarker would be more practical?  It seems that is what the company had in mind.  According to the original study protocol here they were prospectively testing this as a secondary outcome.

Secondary Outcome Measures:

·         Secondary efficacy endpoints will be the change from baseline in: CD3, CD4, and CD8 lymphocyte counts in muscle biopsy tissue

The presence of these lymphocytes is correlated with muscle damage in DMD, so you would hope treatment would show a depletion in counts with treatment. So what happened to these data, did they mysteriously disappear?  I have feeling they were negative and the company just decided not to disclose them.

2.       The regulatory bar set for other companies developing DMD therapies

Obviously Sarepta is not the only company in the race to develop a therapy for DMD.  A quick search on clinicaltrials.gov reveals numerous open, industry-supported, phase 3 clinical programs in this condition -in other words, phase 3 programs are required despite the unmet medical need.

The most similar agent to Eteplirsen in development is GSK2402968. Of note, they have N=54 patients in their phase 2 study

and over N=180 in their phase 3 programs.

If you examine the P2 GSK protocol, you can see that they actually reduced variability in the results of their study by having subjects complete 2 separate 6MWT at baseline as part of the inclusion criteria. 

“Able to complete 6 Minute Walk Distance (6MWD) test with minimal distance of at least 75 meters, with reproducible results (within 20% of each other) at Screening Visit 1, Screening Visit 2 and at the baseline visit prior to randomization”.  This reduces the risk that any differences at important study visits were due to normal variability.

They also had tighter controls around changes to steroid doses that were allowed during the study. 

Sarepta did not assess the reproducibility of their results at baseline at all.

What I find particularly interesting is the statistical powering of the GSK phase 3 program:

Primary Outcome Measure: To assess the efficacy of subcutaneous 6 mg/kg GSK2402968 versus placebo; specifically to have 90% power to detect a difference in 6MWD between GSK2402968 and placebo of 30 meters, assuming a common standard deviation of 55meters.    In other words, 6MWT is so variable that a 55 meter difference between 2 individuals would not even be considered significant.

Clearly the clinical development folks at GSK have put a lot thought into their study protocol and have looked at baseline individual variability a bit harder than Sarepta.  What would the Sarepta data look like if they were adjusted for such a measure of standard deviation? 

To reiterate, I have no financial position in Sarepta.  I advise everyone to take a closer look at the data and consider the prospect that this drug may not be all it has been hyped up to be.  Based on these facts, the suggestion that it will be approved via an accelerated approval pathway based on the existing data is frankly ridiculous.

This article is not intended as trading advice.  Conduct your own due dilligence prior to buying or selling securities.

Introduction to the "SPA basket"

I have spent some time thinking about diversifying my portfolio with some very long term horizon trading ideas.  I don’t always have time to watch the markets daily so need to augment my short term positions with something less labor intensive.  I came up with the “SPA (Special Protocol Assessment) basket” concept; a collection of long term speculative positions. 

A SPA is a written agreement between the sponsor and the FDA providing comments on a proposed phase 3 study design.  Once FDA accepts a phase 3 protocol, the sponsor proceeds with greater assurance; if the prospectively defined efficacy criteria are met, the ensuing NDA submission will be sufficient for the proposed efficacy claim. This in theory reduces the surprise factor that a positive phase 3 study may be insufficient for approval if the FDA does not agree with the study design. The SPA does minimize risk, but does not guarantee approval. Case in point from 2012: Ariad Ridaforolimus in advanced sarcoma. This sponsor had a SPA in place, the clinical trial had a statistically significant outcome, but on review, the FDA rejected the application questioning the overall clinical benefit and safety risk profile for a maintenance indication.  This underscores the need to study the totality of an NDA submission package and understand regulatory precedents for approval before taking a position.

In 2012, looking across at positive pivotal studies that had a SPA in place, they definitely seem to have a higher approval rate compared with standard submissions that did not.  I compiled a list of companies with currently ongoing phase 3 SPA agreements, and decided to start a new portfolio with these stocks, and hold them for a minimum of 3-8 years.  (Anyone looking for a run-up play or short term strategy should click away now).  Why the SPA basket?  One example, Amarin (AMRN) traded at ~$1.25 when they announced their SPA agreements back in 2009.  The drug went on to gain full approval in 2012 and has seen heady heights of above $19 in the year prior to approval. I plan to hold stocks for an extended period of time and see how the whole basket fares.  This does not mean that I won’t trade in and out of the same positions based on market conditions and key catalysts.

So what’s in the SPA basket?

First up, Galena Biopharma

Love it or hate it, Galena Biopharma (GALE) is an interesting trading idea for biotech junkies.  I have received multiple questions and comments since posting a recent tweet declaring an initiation of a long position in this stock.  A lot of comments directed me to Adam’s series of articles on NeuVax™ (E75 peptide vaccine with GM-CSF adjuvant) suggesting this is a complete scam and you can read them here and here.  Here are my thoughts covering its’ appeal and some general cautions:

What is this vaccine?

Human Epidermal growth factor Receptor 2 (HER2/neu) is a proto-oncogene, and its protein product is highly expressed in many epithelial-derived cancers such as breast, prostate and ovarian cancer. The HER2/neu protein has been found to be an immune-recognized tumor-associated antigen and several immunogenic peptides recognized by cytotoxic T lymphocytes (CTLs) have been described from the HER2/neu sequence. E75 has become the most studied HER2/neu-derived peptide both in vitro and in vivo and has been found to induce a peptide-specific, CTL-mediated immune response.

Peptide-based vaccination techniques involve inoculating patients with immunogenic epitopes from tumor-associated antigens, typically given with an immunoadjuvant, to stimulate proliferation of peptide-specific lymphocytes. Peptide-specific lymphocytes then identify and eliminate tumor cells presenting the vaccine-targeted epitope (in this case the HER2). Peptide-based vaccines are attractive immunotherapeutic options because they have no malignant potential, have low toxicity profiles, are simple and inexpensive, are easily monitored and studied, and eventually will be easily exportable to the community. Additionally, the peptide-specific immunity must be maintained at sufficient levels over an adequate duration to accomplish the clinical objective.

NeuVax consists of the E75 peptide derived from HER2 combined with the immune adjuvant granulocyte macrophage colony stimulating factor (GM-CSF).  Unlike dendritic cell based vaccines, this is an off-the-shelf vaccine which can be mass produced. The GM-CSF component is administered at a sub-therapeutic level. Treatment with NeuVax stimulates cytotoxic (CD8+) T cells in a highly specific manner to target cells expressing any level of HER2.  NeuVax is given as an intradermal injection once a month for six months, followed by a booster injection once every six months.

The company states on its website, that according to the National Cancer Institute, over 230,000 women in the U.S. are diagnosed with breast cancer annually.  Of these women, about 75% test positive for HER2 (IHC 1+, 2+ or 3+).  Only 25% of all breast cancer patients, those with HER2 3+ disease are eligible for Herceptin® (trastuzumab; Roche-Genentech) which had revenues of over $5 billion in 2010.  NeuVax targets the remaining 50%-75% of low-to-intermediate (also known as HER2-Negative, not eligible for Herceptin) who achieve remission with current standard of care, but have no available HER2 targeted adjuvant treatment options to maintain their disease free status. NeuVax is being developed as an adjuvant immunotherapy for women with early-stage breast cancer at high risk (node positive, HER2 IHC 1+/2+) for recurrence. In early studies, after screening for eligibility criteria, patients with NPBC were enrolled into the studies and then HLA typed to determine their HLA-A2 status, because E75 binds this specific HLA allele found in approximately 40% to 50% of the general population.

How does it work?

In simple terms, breast cancer cells that express HER2 behave more aggressively with poorer clinical outcomes compared with breast cancer cells not expressing HER2.  The vaccine contains part of the HER2 protein that is recognized by the body’s own natural killer cells (CTL’s) and it stimulates the body to clone more and more of these killer cells.  When these circulating killer cells come across other cells in the body that express HER2, an immune response is triggered resulting in the death of the HER2+ cancer cells.

Why would this work in mild disease but not in more advanced/aggressive disease?

The same reason why you wouldn’t treat someone suffering with fulminant tuberculosis with a BCG inoculation.  The body’s immune system can fight against certain levels of antigenic challenge, but it can be overpowered.  This is why healthy adults can still get sick with flu and common infections.  It wouldn’t make sense to try to treat a patient with advanced metastatic disease with a vaccine as the immune response just would not be sufficient to overpower the cancerous cells.  NeuVax is instead aimed at treating patients with no evidence of disease (following breast cancer resection, chemotherapy and radiation therapy) where there is minimal residual disease.  Even if cancer is not visible on scans, there is a chance that there are microscopic cancer cells circulating in the body.  It is these cells that NeuVax is targeting, using the body’s natural defenses.

Why isn’t it working in HER2 3+ disease?

I have not actually found any study looking prospectively at the use of NeuVax this group of patients.  It would be extremely difficult to conduct a randomized trial in the HER2-positive (3+) adjuvant setting because of the availability of approved agents –it’s unethical in my opinion to randomize patients to an investigational therapy so we may never have this question answered.

What do I think of the Phase 2 results?

A quick search on E75 or breast cancer vaccines will provide an abundance of literature on pubmed.  A lot of the publications and poster presentations out there focus on the combined results of two phase 2 studies which were conducted to establish safety and correct NeuVax dosing , in node-positive and node-negative HER2 1+/2+ breast cancer patients.  As the company is proceeding with a pivotal phase 3 study in node positive patients, I have looked at published results specific to node positive patients.

A phase1/2  study in this population was originally published in J Clin Oncol. in 2005- a credible, peer-reviewed journal. J Clin Oncol. 2005;23(30):7536-7545.

Here is a breakdown of the patient demographics in the study for those vaccinated (n=24) and the controls (n=29). Table 

Prognostic Factors in Node-Positive Breast Cancer-Vaccinated Versus Control Groups

	Vaccinated, HLA-A2+ (n = 24)	Observed, HLA-A2− (n = 29)	P
Median age, years	54	53
Range, years	30-73	33-80
Race
White, %	87	73
Black, %	13	27	.14
Tumor size
T1, %	37	59
T2-T4, %	63	41	.12
Histological grade
I-II, %	42	62
III, %	58	38	.14
Median + nodes	2.5	2.0
Range	1-15	1-25
ER-negative/PR-negative overall, %	33	14	.09
No XRT, %	33	24
No chemoprevention, %	37	17	.09

As can be seen, of the patients in the active arm, a greater proportion had larger size tumors, worse histologic grade, more were ER/PR negative and fewer received XRT and chemoprevention.  These factors would actually suggest a worse overall prognosis for the active arm.

Survival and Recurrence Rates for the Vaccinated and Prospectively Observed Control Groups of Patients With Node-Positive Breast Cancer

Median Follow-Up*	Vaccinated, HLA-A2+ (n = 24) (%)	Observed, HLA-A2− (n = 29) (%)
Overall survival	100	93
Disease-free survival	85.7	59.5
Recurrence rate	8.3	20.7

• ↵* Median follow-up was 22 months (range, 6 to 48 months).

Despite a preponderance of negative prognostic factors in the active arm, at ~2 years, there was a trend towards improved disease-free survival and lower recurrence rates in the patients who received the vaccine.

As with any vaccine, immunity wanes over a period of time, and this too was observed in the follow-up period of early studies.  Additional studies were conducted to establish the efficacy of the vaccine with initial as well as booster doses to evoke a sustained immunologic effect.  These studies included SN-33 in node positive patients and SN-34 in node negative patients, the results of which are available on the company website.

The following results are reported for a group of patients who were deemed adequately boosted with vaccine and who were followed for 60 months. In my opinion these would seem to be consistent with the original phase 1/2 JCO publication in patients that were not boosted which is a positive.

What about the phase 3 program?

The company has a Special Protocol Assessment (SPA) for the phase 3 program, the schema for which is shown below:

The SPA in place means that Galena is armed with sufficient information about the development requirements for NeuVax that if positive, could support regulatory approval. The end point in this study is DFS at 36 months (same regulatory benchmark as Herceptin for the adjuvant indication).  Of note, the Herceptin adjuvant indication studies enrolled >3000 patients and with a mixed population of node positive and negative patients.  The indication that NeuVax would be seeking would  be different from a straight adjuvant indication. They are seeking an indication to prevent recurrence in early stage patients with node-positive disease with low-to intermediate HER2 expression, that would be used following standard of care.  I would state that I want to see more information about how this phase 3 study is powered and what effect size it is looking to detect, based on what projected event rate. At this point I do not have a reality check on the study design.

In the last series of investigator communications, Galena has indicated that they have opened 37 sites in the United States, and by Thanksgiving, they will have 80 sites open globally. The company is targeting 100 sites in total ~7-10 patients per site.  I like to look at how often records are updated on Clinicaltrials.gov for trials that I am following.  The history of changes show that they are fairly good at keeping the records relating to study sites current in the public domain which I think is a good sign.  It's usually a red flag if a study page has not been updated or verified for long periods of time. They have also communicated that they are targeting an aggressive completion of enrollment by mid-2013, and a pre-planned interim safety analysis after the first 70 events (expected by end of 2013). 

So ultimately, what do I like about $GALE as a long position in my SPA basket?

·         Plausible scientific rationale and proof of concept studies, albeit with small number of patients. I think the results so far suggest a definite signal in node-positive patients when followed for a sufficient period of time (60 months)

·         Plethora of supportive scientific literature in the peer-reviewed press

·         SPA in place for pivotal P3 program reduces regulatory uncertainty around study design

·         Credible Principal Investigator in Elizabeth Mittendorf, MD from MD Anderson Cancer Center.  She has authored over 100 articles on breast cancer vaccines and immunotherapy so I would consider her a Key Opinion Leader in this area. You can read her bio here:  Credible PIs from MDACC go along way in trial completion and regulatory discussions at ODAC (Oncologic Drug Advisory Committee meetings). A good example is Talon Marquibo and their successful partnership with Susan O’Brien as PI on phase 2 and phase 3 studies

·         Credible Scientific Advisory Board including Hope Rugo, MD and Gabriel Hortobagyi, MD- a past President of ASCO.  Highly respected breast cancer key opinion leaders.  In my opinion, such experts are far too busy and successful to be involved in questionable ventures

·         2 potential albeit soft “catalysts” in 2013; completion of P3 enrollment, interim safety event analysis n=70

·         Company sufficiently funded to complete enrollment in my opinion by 2H13. Currently have ~19 MM plus ~4MM to call on. 

·         Good IP position: Issued a key patent from the U.S. Patent and Trademark Office for NeuVax™ (nelipepimut-S or E75). The patent covers the use of NeuVax, a HER2/neu peptide vaccine, for inducing immunity to breast cancer recurrence in HER 2 negative patients (low-to-intermediate IHC levels of 1+ or 2+ and a FISH rating of less than 2.0). This is the patient population targeted for Galena’s ongoing Phase 3 PRESENT trial. The patent provides NeuVax exclusivity for this indication until 2028, not including any patent term extensions

What am I concerned about in the short term as it relates to my position?

·         N=700 patients in the P3 program, are the numbers sufficient to detect a difference in DFS at 36 months?  What effect size has been agreed upon in the SPA? Can the sites enroll patients quickly?

·         Company will definitely need to raise cash to complete the P3 study, when will they need to raise and how much?

·         What happens if they run out of money to complete the study?

·         Any recurring CMC issues that could interfere with the supply of study medication and compromise the protocol

I am hoping to attend some investor meetings and get some of these questions answered in the future.

As a final note, the contents of this article are not intended as investment advice.  All views expressed are my own.  Please conduct your own due diligence before acquiring or selling securities.

More posts on the SPA basket to follow...