Sept. 22th, by Biotechinvest
ALXA (strong buy)
ALXA (inhaled loxapine or AZ-004) is old generic drug delivered by Staccato technology i.e. evaporated form of loxapine inhaled in lung. Loxapine (LOXITANE) is old drug with tranquilization or calming effects and suppression of aggressive behavior.
LOXITANE is indicated for the management of the manifestations of psychotic disorders. The antipsychotic efficacy of LOXITANE was established in clinical studies which enrolled newly hospitalized and chronically hospitalized acutely ill schizophrenic patients as subjects.
What is the difference between AZ-004 and LOXITANE? AZ-004 is just pure 2-Chloro-11-(4-methyl-1-piperazinyl)-dibenz[ b,f ] [1,4]oxazepine sublimated by high temperature. Inhaled in lung it passes first pass metabolism that actually eliminates one third of the oral form. But most important difference is that with oral loxapine signs of sedation were seen only within 20 to 30 minutes after administration and were most pronounced within 1 1/2 to three hours. Inhaled loxapine has intravenous (IV) absorption profile i.e. very short Tmax. Loxapine is available only in oral (capsules and solution) and intramuscular (IM) forms. Surprisingly, but T max was significantly longer for the IM administration than the oral administration (approximately 5 vs. 1 hour).
ALXA Phase 3 studies showed that Staccato loxapine was effective in relieving the symptoms of agitation, with an onset of effect occurring in as little as 10 minutes. PK study reported that following inhalation, the tmax median (25%, 75%) was 2 (1, 3) minutes.
In case of such serious disease as schizophrenia or bipolar disorder 10 minutes and 1-1.5 hours is very big difference.
My opinion: The efficacy of AZ-004 in term of T max is out of questions.
Loxapine never was delivered through lung epithelium, only by oral and IM. Well, ALXA already performed “Staccato Loxapine Pulmonary Safety in Patients With Asthma” with the purpose of this study is to assess the safety of 2 inhaled doses of Staccato Loxapine within a day in patients with asthma.
Indeed, regular deep lung delivery of some chemical may induce lung inflammation or lung tissue changes. Mannkind described "small, non-progressive differences" pulmonary function decline over time and the risk of respiratory difficulty immediately post-inhalation after using of Afrezza (inhaled insulin). So, MNKD performed 649-patient study examining changes in pulmonary function after patients stopped use of Afrezza and resumed usual insulin. MannKind said the changes disappeared three months after patients resumed usual therapy.
So, lung safety questions can be a big problem for ALXA innovation in drug delivery. However, loxapine is a small molecule without any cancerogenic properties. Absorption time after inhalation is very short, so drug wash out from lung must be very fast. This drug is not each day use drug. However, some very low probability exists that FDA will ask about some long term lung safety study.
Why low? There are many inhaled drugs already on market (like Sepracor’s Xopenex or Migranal® Nasal Spray) and FDA not always asked the companies to have long term lung safety trial before approval.
Recently MAP Therapeutics presented Levadex which is a novel formulation of dihydroergotamine (DHE), a drug used intravenously (IV) in clinical settings to effectively and safely treat migraines. MAPP performed clinical trials where they measure pulmonary artery pressure in Levadex and placebo patient. Pressure was higher in a group of patients receiving the drug intravenously. So, MAPP converted IV drug to inhaled one and nobody worry that FDA will ask about additional lung safety trial.
If approved ALXA pps will jump at least 150-200% i.e. $6-7 range because of innovative drug delivery technology. Staccato (thermal sublimation) can be used for hundreds small molecules drugs (especially with water solubility problem). It cannot be used to deliver therapeutics protein and peptides because possible thermal denaturation. Thus Staccato and MNKD's DreamBoat are not competitors.
If FDA ask ALXA about lung safety ALXA may get Approvable Letter and stock price will go back to $1.5-2 range i.e. 25-30% losses .
So, I will keep ALXA through PDUFA. Medium risk, high reward.
Oct. 11th, by Biotechinvest
Well, sometimes it happens... ALXA got FDA CRL about lung safety concern.
“A CRL is issued by the FDA's Center of Drug Evaluation and Research indicating that the NDA review cycle is complete and that the application is not ready for approval. In the CRL received by Alexza, the FDA stated that their primary clinical safety concern was related to data from three Phase I pulmonary safety studies with AZ-004. This concern was based on observed, dose-related post-dose decreases in forced expiratory volume in one second, or FEV1, a standard measure of lung function, in healthy subjects, and in subjects with chronic obstructive pulmonary disease (COPD) and asthma. Alexza intends to meet with the FDA in the near future to discuss steps necessary to address this FDA concern. Alexza has previously reported that there were no serious or severe respiratory adverse events in these trials or reported in the two Phase III clinical trials of AZ-004. All respiratory symptoms that developed after treatment in Phase I subjects with COPD and asthma were either self-limiting or readily managed with an inhaled bronchodilator.
It means that healthy patients were OK after Staccato but COPD and asthma patients were in trouble.
Interesting, but MNKD inhaler Dreamboat also decreases FEV1. But MNKD showed that these changes are “disappeared, regardless of the duration of exposure to AFREZZA.”
Unfortunately, we know nothing about reversibility of Staccato effect on FEV1. If ALXA doesn’t have this data it will delay FDA approval for many months.
"During the parent trials, small, non-progressive differences in mean changes from baseline in forced expiratory volume in 1 second (FEV1) and carbon monoxide diffusing capacity (DLCO) were observed in the AFREZZA group. During the follow-up trial, these changes disappeared, regardless of the duration of exposure to AFREZZA, when the groups were compared three months after ending treatment with AFREZZA and resuming usual antidiabetic therapy (FEV1: -0.08 L in the ex-AFREZZA group, -0.11 L in the non-AFREZZA group [p=0.1388]; DLCO: -1.29 mL/min/mm Hg in the ex-AFREZZA group, -1.37 mL/min/mm Hg in the non-AFREZZA group [p=0.9360]). There was also no statistical difference in FEV1 between the treatment groups when examining subjects with Type 1 and Type 2 diabetes (p=0.6158 and p=0.1795, respectively).
ALXA also ran a study in 30 patients that were healthy and notedthat there were no systematic differences in post-dose pulmonaryfunction between AZ-004 and placebo, and no respiratory adverse events. Does it mean that Staccato Loxapine is not safe only for COPD and asthma patients? In this case FDA and ALXA may agree to note in contraindication that it’snot safe to use Staccato Loxapine for patients who haveschizophrenia/bipolar disorder and COPD and/or asthma.
Conclusions: FDA is really crazy about safety now. May be best case scenario for ALXA will be an approval of Staccato Loxapine with black box warning that drug may cause serious adverse effects in patients with COPD and asthma.
I'll keep ALXA in watch list.
December 28, 2010 by BiotechInvest
I still believe that ALXA has strong potential for 2011 investment. The recent news are supporting this. I bought ALXA for long-term investment in 2011.
This news are also very promising:
"Alexza also announced today that it has met with the European Medicines Agency (EMA) and has received written confirmation that AZ-004 is eligible for submission of a Marketing Authorization Application (MAA) under the centralized registration procedure. In addition, Alexza has been notified of the Rapporteur and Co-Rapporteur appointments for the AZ-004 review. The Company believes that the comprehensive clinical development program for AZ-004 meets the requirements for the MAA filing. Alexza expects to submit the MAA mid-year 2011."
January 25, 2011 by BiotechInvest
I'm continue to play short-term with ALXA. Recent news (publication in British Journal of Psychiatry) supports an idea of possible Europe approval of AZ-004.
BTW what is the difference between Staccato® loxapine device and "electronic cigarette"?
Almost no difference, both were attacked by FDA:
"The Food and Drug Administration (FDA) has classified electronic cigarettes as drug delivery device and subject to regulation under the Food, Drug, and Cosmetic Act (FDCA). As a result, they require market authorization prior to importation and sale into the country. This classification was overruled by Judge Richard J. Leon citing that “the devices should be regulated as tobacco products rather than drug or medical products” ". Leon continued, saying “This case appears to be yet another example of F.D.A.’s aggressive efforts to regulate recreational tobacco products as drugs or devices”. However, in March 2010, a US Court of Appeal Stayed the injunction until the appeal is heard. The FDA argued the right to regulate electronic cigarettes based on their previous ability to regulate nicotine replacement therapies such as nicotine gum or patches. Further, the agency argued that tobacco legislation enacted last year "expressly excludes from the definition of 'tobacco product' any article that is a drug, device or combination product under the FDCA, and provides that such articles shall be subject to regulation under the pre-existing FDCA provisions.". The appeals court heard oral arguments on September 23rd 2010. On December the 7th, The appeals court ruled against the FDA in 3-0 unanimous decision."
12.12.11 by BiotechInvest (well it's exactly 1 year before 12.12.12 that will a magic combination for all of us)
So, ALXA won! But may be it’s a Pyrrhic victory and tomorrow we will see a huge sell off?
Nope! This is a real victory, the victory of a new drug delivery method. Every drug that can be sublimated (sublimation) will be good for fast and effective ALXA technology.
Well, FDA is still crazy and maniacal for safety concerns (may be the current FDA head influence?), but panel members (mostly doctors and scientists) are not. They see that "Alexza was able to recruit participants “very quickly” for the clinical trials because “patients wanted to use this product,” James Cassella, Alexza’s senior vice president for research and development, said today in a presentation to the panel. Adasuve is “non-invasive, non-coercive and helps maintain the patient-physician therapeutic alliance.”
It's true: the patients just want a fast and “non-invasive” release from this terrible schizophrenia agitation. And several Adasuve puffs are OK for them. Fortunately doctors from panel understood this.
So, what is next? ALXA buyout… Or Adasuve successful lunch in Europe and in USA… Or next clinical trial for old drug that should delivered with shortest Cmax…
It doesn’t matter actually… ALXA won It’s matter now.
Disclosure: I have ALXA positions and will keep them through PDUFA.