Alexza Pharmaceuticals, Inc. focuses on the development and commercialization of proprietary products for the treatment of acute and intermittent conditions. The company develops products by utilizing its proprietary technology, Staccato system, which vaporizes unformulated drug compounds to form a condensation aerosol that allows rapid systemic drug delivery through deep lung inhalation. The company has four clinical stage product candidates that include: AZ-001 (Staccato prochlorperazine) to treat patients suffering from acute migraine headaches, AZ-002 (Staccato alprazolam) for the acute treatment of panic attacks associated with panic disorder, AZ-003 (Staccato fentanyl) for the management of acute breakthrough pain, and AZ-004 and AZ-104 (Staccato loxapine) for the treatment of acute agitation in patients with schizophrenia and migraine. Alexza has a development agreement with Autoliv ASP, Inc. for the development of heat packages that can be incorporated into single dose drug delivery device. Alexza Pharmaceuticals, formerly known as FaxMed, Inc., was founded in December 2000. The company is based in Palo Alto, California and employs approximately 150 professionals.
Alexza has developed a proprietary novel drug delivery technology that vaporizes unformulated drug compounds to form a condensation aerosol that allows rapid systemic drug delivery through deep lung inhalation. The company has shown in studies that devices employing the Staccato system emit >90% of the loaded drug as a consistent small particle (1-3?m) size aerosol. Benefits of the system are rapid absorption and onset of action with an easy to administer and convenient delivery. In two recent phase II clinical trials, the company demonstrated that the Staccato device mechanism can perform with over 99% reliability.
The Staccato system is broadly applicable to a large number of small molecule compounds that could be useful in the treatment of acute and intermittent conditions. To date, approximately 200 compounds have demonstrated initial vaporization feasibility for the Staccato platform. The majority of these compounds are in the psychotherapeutic, migraine headache, analgesic, and sleep/sedative class. Several other areas where drugs could fit the platform are in cardiovascular, respiratory, antihistamine, and neurological disorders.
Alexza is actively looking to partner with larger pharmaceutical companies looking to expand the delivery and useful life of their product. Alexza will typically begin initial feasibility studies with a partner analyzing aerosol purity and particle size of vaporized products. Alexza also conducts chemical, mechanical, and temperature stability, followed by pharmacokinetic profiling of the product. Finally, Alexza conducts inhalation toxicology studies, early clinical trial design consultation, and GMP manufacturing services prior to the IND filing. The typical time from initial feasibility studies to an IND filing is roughly 12-18 months.
The most advanced clinical candidate under development at Alexza is AZ-001, a Staccato prochlorperazine that recently completed phase IIb trials for migraine headaches. Prochlorperazine (originally sold as branded Compazine at Glaxo) is used to treat the nausea and vomiting caused by radiation therapy, cancer chemotherapy, surgery, and other conditions. It is also used to treat psychotic symptoms such as hallucinations and vertigo. Recent clinical work demonstrated that prochlorperazine administered intravenously is effective in relief of migraine pain. However, intravenous injection of prochlorperazine has a delay in onset of action as long as 20 minutes. Staccato prochlorperazine demonstrates onset in as little as 4 minutes with no needles. Therefore, we believe that Alexza's AZ-001 potentially results in a speed of therapeutic onset advantage over oral tablets, with a convenience and comfort advantage over intravenous or subcutaneous (SC) injections.
According to the National Headache Foundation, approximately 13 million people in the U.S. have been diagnosed with migraine headaches. Patients with acute migraine headaches average one to four per month. The market desperately needs a faster-acting and more predictable therapy. The current prescription therapy headache market is dominated by a class of drugs know as triptans. Leading triptans are Glaxo's Imitrex (sumatriptan), Merck s Maxalt (rizatriptan), and AstraZeneca s Zomig (zolmitriptan). These compounds work in approximately 75% of patients for reducing migraine attacks, but also carry significant tolerability or side-effect disadvantages. Triptans are contra-indicated for patients with coronary artery disease due to an increased event risk rate. The FDA also recently warned about use of triptans with common anti-depressant (SSRI or SNRI) drugs due to risk on "serotonin syndrome". Glaxo's next generation triptan drug Trexima will have similar limitations.
AZ-001 is not a triptan. Prochlorperazine belongs to a class of compounds known as phenothiazines. Combining the Staccato platform with a drug that has been well studied and considered less risky in terms of side-effects could give Alexza a significant marketing advantage over Glaxo's Imitrex ($1.3 billion in sales in 2006).
Alexza completed and released data from a phase IIb trial in March 2007. The company also presented data from the trial at the annual American Headache Society Meeting in June. The trial enrolled 400 patients in an outpatient, randomized, double blind, placebo-controlled platform. The primary data is presented below:
Headache Pain Relief*:
The company also presented key secondary data presented below:
Pain Free at 2 Hours / P-value:
Pain Free at 24 Hours / P-value:
AZ-001 exhibited rapid onset of pain relief. The 7.5 mg dose showed statistically significant pain response, compared to placebo, at 15 minutes (p=0.016). At 30 minutes, all three doses of AZ-001 showed statistically significant pain response, compared to placebo 10 mg (p=0.0056), 7.5 mg (p=0.0003) and 5 mg (p=0.0056). Side effects were recorded throughout the clinical trial study period and a safety evaluation was made at each patient's closeout visit. There were no serious adverse events reported during the trial. The most common drug- related side effects reported across all three active dose groups in the clinical trial were taste (25 - 33%), throat irritation (18 - 30%), cough (16 - 30%), somnolence (6 - 10%), breathlessness (2 - 9%), and dizziness (0 - 9%). These side effects appeared to be dose related, with a lower incidence and severity of the side effects generally seen at the lower doses of AZ-001. These data seem to suggest the 7.5mg or 10mg dose may be selected for the next phase.
Management is to conduct a formal QT human clinical study and a 28-day animal inhalation toxicology study prior to beginning pivotal trials. Once these safety trials are completed management will request an end of phase II meeting with the FDA. We expect that meeting in the second quarter of 2008. While these studies are ongoing management should be actively looking for a development partner for AZ-001. We expect an announcement on a partnership potentially sometime next year. We expect a sizable (>$20 million) upfront payment with developmental and commercialization milestones, along with a royalty on worldwide sales. We currently model an approval and launch in 2009. We believe that Alexza will earn a 20% royalty on worldwide sales of AZ-001, which we believe has the potential to be a $400-500 million drug thanks to improved speed of action, duration of response and potential differentiating characteristics for triptan-resistant or intolerant patients.
Alexza is developing AZ-002 (Staccato alprazolam) for the treatment of acute panic attacks / panic disorder. Alprazolam belongs to a class of anti-anxiety drugs called benzodiazepines. The company completed a phase I (n=50) dose-escalation study in September 2005 looking for tolerability and safety. Management selected a 1mg dose to proceed with further development. In April 2006 Alexza initiated a phase IIa "proof-of-efficacy" study that looks to enroll 35 patients in total. Patients will be chemically induced into a panic attack, and Alexza will look for initial signs of efficacy with AZ-002. We expect data on this study during the first half of 2008. If positive, Alexza may either move to partner or progress with a larger phase IIb trial in 2008.
Also in April 2006, Alexza initiated a phase I trial on AZ-003 (Staccato fentanyl). The company is developing the drug for acute pain, including patients with breakthrough cancer pain and postoperative patients with acute pain episodes. The company completed top-line analysis of a phase I trial in late December 2006. The preliminary analysis suggests a similar pharmacokinetic and bioactive profile between AZ-003 and intravenously administered fentanyl. Peak plasma concentrations proportionate to dose were observed shortly after administration. There were no serious adverse events attributed to AZ-003 during the clinical study. We expect full analysis of both the pharmacokinetic and pharmacodynamic data to be presented in abstract form at the annual meeting of the American Society of Anesthesiology in October 2007.
Fentanyl is a drug that has been reformulated into several delivery systems including J&J's transdermal fentanyl patch (Duragesic) and Cephalon's fentanyl stick (Actiq). These new formulations are the result of less effective oral fentanyl and the highly addictive with potential for abuse injectable fentanyl. AZ-003 would also compete with other opioid products such as oxycodone, hydrocodone, and morphine. These opioid products are subject to more stringent control by the U.S. Drug Enforcement Administration (DEA). Regulations on manufacturing, storage, distribution, and prescriptions are all tighter for these types of agents. Fentanyl is a schedule II substance. At this time we are unsure of how the DEA will classify AZ-003. Alexza's inhalable fentanyl offers a viable alternative to either the patch or stick formulations, both widely used because they offer less potential for addictive use.
Given the intense competition in the fentanyl market, we expect Alexza to partner AZ-003 with a major pharmaceutical company for worldwide development. Management does not plan to progress with AZ-003 until a partnership is secured.
Yet another clinical stage candidate is AZ-004 (Staccato loxapine). Loxapine belongs to a subclass of anti-psychotic drugs known as dibenzoxazepines. Alexza is developing the candidate for acute agitation in patients with schizophrenia. A phase I (n=50) dose-escalation study was completed in November 2005 looking for tolerability and safety, results from which were presented at the annual NCDEU meeting in June. The annual NCDEU meeting was co-sponsored by the National Institute of Mental Health and the American Society of Clinical Psychopharmacology. In March 2007 the company released data from a phase IIa "proof-of-concept" trial assessing the safety and efficacy of a single dose of AZ-004 in acutely treating agitation in roughly 120 schizophrenic patients. The patients were randomized between three arms, placebo, 5mg AZ-004 and 10mg AZ-004. Below we summarize the data from the phase IIa study:
The 10 mg dose of AZ-004 also exhibited a rapid onset of effect. At 20 minutes post-dose, the 10 mg dose showed statistically significant improvement in the PEC scores, compared to placebo. The effectiveness of the 10 mg dose was sustained throughout the 24-hour study period, compared to placebo. Using the Behavioral Activity Rating Scale (BARS), the 10 mg dose of AZ-004 showed statistically significant improvement, compared to placebo, beginning at 30 minutes. This response was sustained throughout the 24-hour study period, compared to placebo. Clinical Global Impression-Severity (CGI-S) scale ratings to measure agitation were completed at baseline, immediately prior to AZ-004 administration. At the 2-hour post-dose time point, a Clinical Global Impression-Improvement (CGI-I) evaluation was completed for each patient. Both the 10 mg and the 5 mg doses of AZ-004 showed statistically significant improvements in the CGI-I scale, compared to placebo.
Management is now enrolling a multi-dose pharmacokinetic and tolerability study. Data from this study, along with the positive phase II results discussed above should provide the basis for the design of a pivotal phase III studies in the first quarter of 2008. The phase III program will include two trials, one to begin in the first quarter and the second to begin in the second quarter of 2008. Each trial is expected to enroll up to 300 patients.
In other developments, in June 2007, Alexza initiated a phase IIa proof-of-concept clinical trial of AZ-104 (Staccato loxapine) in patients with migraine headache, in collaboration with Symphony Capital LLC. AZ-104 is a lower dose version of AZ-004. The Phase IIa clinical trial is an in-clinic, multi-center, randomized, double-blind, single-administration, placebo-controlled study in approximately 160 migraine patients with or without aura. Three doses of AZ-104 (1.25, 2.5 and 5 mg) will be evaluated against placebo in the clinical trial. Using the IHS (International Headache Society) 4-point rating scale, the primary efficacy endpoint will be pain-relief response at 2 hours post-administration. Secondary efficacy endpoints for the trial include additional pain response assessments and other symptom assessments at various time points. The trial completed enrollment in December 2007. Data is expected in the first quarter of 2008.
In May 2007, management noted that they plan to bring another candidate into the clinical in 2007. This candidate will be AZ-007 (staccato zaleplon). Zaleplon is sold as a branded product by King Pharmaceuticals as Sonata for the treatment of insomnia and sleep disorder. Sonata only has an estimated 2% share in the insomnia market due to its weak duration of action. The effective duration of Sonata is only roughly 4 hours, and thus patients that dose the drug before bed often wake up in the middle of the night with an inability to return to sleep. Management believes that zaleplon can be formulated into the staccato device and provide a benefit to patients with sleep disorder because of the quick action provided by the staccato inhalation. Patients that wake up in the middle of the night may be able to dose staccato zaleplon and then return to sleep quickly without worrying that they will overdose and potentially miss waking up in the morning to start the day. The company has held a pre-IND meeting the FDA and plans a phase I trial perhaps later in early 2008.
Symphony Allegro, Inc.
In December 2006, Alexza and private equity firm, Symphony Capital Partners, established Symphony Allegro, Inc., a funding vehicle designed to accelerate clinical and other related development activities for AZ-002 and AZ-004. Alexza will provide the intellectual property for AZ-002 and AZ-004, whereas Symphony Capital will provide $50 million in funding. Alexza has an exclusive purchase option to reacquire the intellectual property by purchasing all of Symphony Allegro's equity at a predetermined price that reflects a compounded annual rate of return averaging approximately 27% during the anticipated four- year collaborative development period. The option exercise may be paid in cash or a combination of cash and Alexza common stock (up to 40% of the purchase price), at Alexza's sole discretion.
In exchange for the purchase option, Alexza will issue to Symphony Allegro investors a warrant, with a term of five years, to purchase two million shares of Alexza common stock at $9.91 per share. The transaction provides funding that allows Alexza to proceed with rapid clinical development of both AZ-002 and AZ-004 while retaining exclusive rights to both products. We are pleased with the partnership and look forward to seeing phase IIa data on both candidates in 2007.
Commercial Manufacturing & Supply
In November 2007, management signed a commercial manufacturing and supply agreement with Autoliv Inc. for chemical heat packages, a key component of the single-dose Staccato system. Autoliv is the worldwide leader in automotive safety, and a pioneer in the development of seatbelts and airbags. Autoliv has more than 40 years of experience in developing systems using energetic materials and continues to stand apart as a leader not only in technology but also in its manufacturing techniques.