NEWS

In Wake of Actavis/Allergan Deal, CEOs Eye Growth

In the year's largest acquisition in any industry, Dublin, Ireland based specialty and generic drugmaker Actavis announced plans to acquire Allergan for $66 billion in cash and stock.

The transaction, still subject to the approval of shareholders of both companies and regulatory clearances, will create one of the top 10 global pharmaceutical companies by sales revenue, with combined annual pro forma revenues of more than $23 billion anticipated in 2015. Actavis will acquire Allergan for $219 per share, made up of about 60 percent in cash and the balance in stock.

The purchase price represents a significant increase over Allergan's trading price in the lead up to Valeant and Pershing Square's take-over bid. Speaking with Stephen Daily, Executive Editor, News, at Bryn Mawr Communications, Allergan Chairman and CEO David Pyott, noted, “This is the best year in terms of sales growth that we've ever had in our 64-year history. You know, in the second quarter on a local currency basis, the company grew 16%. In the third quarter, it was even better, 18%....We're the fastest growing integrated eye care company in the world, per IMS Health, growing about 14% in market worldwide. That's in excess of the world market growing at about 9% or 10%. In fact, double the speed of some of our major fully integrated competitors.”

Additionally, Actavis President and CEO Brent Saunders noted that the organizations have “complimentary culture.” “I think we both view innovation as incredibly important. We view supporting the medical communities in which we operate in as critical, and we view supporting our brands and people as compelling.”

The companies acknowledged that the new joint venture will reduce the combined R&D budget. “We feel that about a little more than half of that can come from back office and administrative and management side of R&D, so not programs,” Mr. Saunders said. “Things like pharmacovigilance, clinical trial management, informatics, medical writing, stuff like that. And the reason you can do that is, you have scale.”

“The other half will be from programs, but we will put all the programs, all the Actavis programs and all the Allergan programs, on the table. Those won't come out of just ophthalmology or aesthetics. They could come out of CNS. They could come out of GI. They could come out of women's health. We're going to put our best programs that we believe have the most innovation and the best chance of success forward, and we'll probably take the ones with less chance of success and less innovation off the table. But it won't be significant, it'll be a few programs here or there.”

Actavis still has an eye toward growth. “Our goal was to be the best at what we do, to be leaders in every therapeutic area in which we operate,” Mr. Saunders said. “We kind of coined a new phrase for what we believe our company is, which is ‘growth pharma.' We coined that because we believe there are only a few companies are growing at the pace at which the new combined organization will grow at in terms of revenue, or sales. We think it's going to be a very dynamic environment. We think it's going to be a place that will attract and develop the best talent, and the place where we will continue to drive innovation for physicians and patients.”

“This is a true win-win,” Mr. Pyott concluded. “We were very happy to take 41% of the consideration in Actavis stock, because we believe there's a great upside for Allergan stockholders who choose to remain stockholders when they receive the exchange into Actavis shares. Not just a good deal on day one, but a great deal as we generate this upside in the coming years.”

Nuplazid Submission For Parkinson's Psychosis Delayed

Acadia Pharmaceuticals says it has pushed back their targeted release date of the New Drug Application (NDA) for Nuplazid, a Parkinson's disease psychosis therapy. The company had previously planned to submit the NDA near the end of 2014, but will now shoot for first quarter of 2015.

The company said the decision to move back the planned submission is based on additional time required to complete preparations needed to support the FDA review of the drug.

Nuplazid is a proprietary small molecule that is a selective serotonin inverse agonist preferentially targeting 5-HT2A receptors that play an important role in psychosis. Acadia has reported positive Phase III trial results with Nuplazid, which has the potential to be the first drug approved in the United States for psychosis associated with Parkinson's disease. The drug is administered orally once a day.

Migraine Treatment on Hold

Originally expecting an approval decision by the end of November, Avanir Pharmaceuticals' experimental migraine drug-device has been delayed.

AVP-825 is a drug-device combination product consisting of low-dose sumatriptan powder (22mg), delivered intranasally utilizing a novel delivery technology. At issue appears to be device safety and efficacy of AVP-825 and use-related risks associated with it. The investment research publication Zacks noted, “given the FDA's advice to conduct additional human factor testing on AVP-825, we currently have low visibility on the timelines involved.“

Data Show Zetia Plus Statin Reduces Risk for CVEs

A nearly decade-long study shows that the cholesterol drug Zetia (ezetimibe) lowered the risk of heart attacks and strokes in high-risk heart patients when it was used with an effective statin.

The benefit was modest—a 6.4% reduction in all cardiovascular events—in a high-risk, aggressively treated population of patients. But the news was notable for being the first time that adding a non-statin cholesterol fighting drug to the statin class of cholesterol-lowering medicines was shown to lower the risk of serious consequences of cardiovascular disease.

The 18,144 patient population of the Improve It study had experienced a heart attack or unstable angina. All had their LDL reduced to a target level of about 70 by simvastatin with Zetia taking LDL down by another 20 percent.

Zetia taken with simvastatin cut heart attacks by 14 percent and strokes caused by diminished blood flow by 21 percent, compared with simvastatin alone. There was no difference in deaths.

“Although the combination of Ezetimibe and Simvastatin may be more effective than Simvastatin alone in reduction of the absolute LDL-C levels, this does not automatically translate into a having a positive impact on morbidity and mortality from a cerebrovascular standpoint,” said Réza Behrouz, DO, FANA, FAHA Associate Professor of Neurology at The Ohio State University College of Medicine, and who was not a part of the study.

“The benefits of statins in reducing the rates of stroke are independent of LDL-C levels,” he said. He added that treatment with this class of drugs reduces the incidence of strokes even among individuals who do not have high cholesterol concentrations. “Also, the 2013 American College of Cardiology/American Heart Association guidelines no longer target specific LDL-C levels for cardiovascular risk reduction. In essence, it is not about targeting ‘numbers' anymore, but the intensity of statin therapy based on risk factors.”

Promising Phase II Results Seen for Parkinson's Drug

Cynapsus Therapeutics released positive top-line results from its CTH-105 Phase II clinical trial of APL-130277 for the management of “off” motor symptoms of Parkinson's disease. Out of 16 patients treated with APL-130277, 14 converted from “off” to “on.” The therapy is a fast-acting, sublingual, thin filmstrip formulation of apomorphine.

The subjects consisted of patients with Parkinson's disease who experienced the effects of “off” episodes, with a total duration of “off” of at least two hours daily. All five doses of APL-130277 used in the study (10, 15, 20, 25 and 30mg) resulted in patients moving from “off” to “on.” The mean baseline UPDRS part III in an off state was 41.4, and the maximum mean change from baseline UPDRS part III was 18.4.

The mean dose required to convert patients to “on” was 18.4mg. The onset of a clinically meaningful improvement was seen in as early as 10 minutes and lasted up to 90 minutes, the last time point measured in this study. The mean time to “on” as reported by study staff was 22 minutes. Cynapsus believes that these data strongly support the conclusion that APL-130277 is associated with the robust and rapid management of “off” episodes.

Two patients dosed at the highest available dose (30mg) did not achieve a full “on” as assessed by the investigator, suggesting that higher doses may be required for some patients.

Treatment was safe and well tolerated. Nausea was reported by three subjects at doses of 10, 15 and 20mg. One of these patients also experienced a mild episode of emesis. There were no reports of nausea at higher doses. There were no reports of local irritation or hypotension in any subject treated.

Clinical Tests Help Differentiate Parkinson's from Atypical Parkinsonism

Two simple tests conducted during the neurological exam can help clinicians differentiate between early-stage Parkinson's disease and atypical parkinsonism, according to research published online Nov. 17 in the Journal of Parkinson's Disease.

The study notes the occurrence of a sideways or mediolateral balance impairment is a “red flag” of atypical parkinsonism conditions, such as multiple system atrophy (MSA), progressive supranuclear palsy, or vascular parkinsonism. As the condition progresses, patients with this deficit often compensate by adopting a wide-based walking pattern, probably reflecting widespread pathologic brain involvement of the cerebellum and brain stem.

In contrast, patients with PD develop a shuffling gait, maintaining a narrow distance between their feet. Because medio-lateral balance is preserved, a PD patient may still be able to ride a bicycle even when walking is difficult.

In the first test, 36 patients with PD and 49 patients with atypical parkinsonism were given a tandem gait test. Patients were instructed to take 10 consecutive steps along an imaginary straight,thin line,toe-to-heel.An abnormal tandem gait was scored if one or more side steps were needed to maintain balance. The researchers found that 18 percent of patients with atypical parkinsonism were able to perform the tandem gait test without a single side step, compared with 92 percent of patients with PD. The results were similar for patients with only early disease (< 3 years).

Another study included 45 patients with PD and 64 patients with atypical parkinsonism, all of whom said they previously rode bicycles before the onset of motor symptoms. When asked if they still were able to ride a bicycle, 52 percent of the atypical parkinsonism patients said they had stopped cycling compared to 2 percent of those with PD.

Test Can Make Epilepsy Surgery More Effective

A new statistical test that looks at the patterns of high- frequency network activity flow from brain signals can help physicians locate the precise location of seizures occurring in the brain and make surgery more effective, according to research from a small study in the Nov. 4 issue of Epilepsia. Researchers studied two groups of patients suffering from epileptic seizures: two patients who were awaiting surgery and eight who had already undergone surgery to eliminate their seizures.

The statistical test known as Granger causality spectral analysis was installed in a computer program, and the researchers found they were able to pinpoint where seizures were originating in the brain and detect them up to 10 seconds earlier than previously possible.

For the two patients in the study awaiting surgery, the researchers used Granger causality analysis to evaluate intracranial EEG (iEEG) recordings of the patients' brains, locate the seizures and determine which parts of the brain are not the sources of the seizures.

For the eight post-surgery patients, this analysis was not applied for surgical decision-making. The researchers analyzed iEEG recordings taken before surgery to determine if the correct part of the brain was removed. Two of the patients suffered relapses and weren't free of seizures, and the research team concluded the part of the brain that was removed during surgery was inconsistent with their statistical findings about which part was causing the seizures. The researchers identified where the seizures were originating, and doctors were able to prescribe medication to manage the seizures. Both patients improved and remain seizure-free one year later.

FDA ACTIONS

LEMTRADA APPROVED FOR MS, RECEIVES BOXED WARNING

FDA has approved Lemtrada (alemtuzumab) for the treatment of patients with relapsing forms of multiple sclerosis (MS). The FDA approval of Lemtrada is based on two pivotal randomized Phase III open-label rater-blinded studies comparing treatment with Lemtrada to Rebif (high-dose subcutaneous interferon beta-1a) in patients with relapsing remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II).

In CARE-MS I, Lemtrada was significantly more effective than interferon beta-1a at reducing annualized relapse rates; the difference observed in slowing disability progression did not reach statistical significance. In CARE-MS II, Lemtrada was significantly more effective than interferon beta-1a at reducing annualized relapse rates, and accumulation of disability was significantly slowed in patients given Lemtrada vs. interferon beta-1a. The clinical development program for Lemtrada involved nearly 1,500 patients with more than 6,400 patient-years of safety follow-up.

The Lemtrada label includes a boxed warning noting a risk of serious, sometimes fatal autoimmune conditions, serious and life-threatening infusion reactions and also noting Lemtrada may cause an increased risk of malignancies including thyroid cancer, melanoma and lymphoproliferative disorders.

Lemtrada is only available through a restricted distribution program, the Lemtrada REMS (Risk Evaluation and Mitigation Strategy). This program has been developed to ensure that access to Lemtrada in the U.S. is only through certified prescribers, healthcare facilities and specialty pharmacies and to also ensure that patients are enrolled in the REMS program.

Lemtrada has a unique dosing and administration schedule of two annual treatment courses. The first treatment course is administered via intravenous infusion on five consecutive days, and the second course is administered on three consecutive days, 12 months later.

HYSINGLA ER APPROVED WITH ABUSE- DETERRENT PROPERTIES

FDA has approved Hysingla ER (hydrocodone bitartrate), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Hysingla ER has properties that are expected to reduce, but not totally prevent, abuse of the drug when chewed and then taken orally, or crushed and snorted or injected. The tablet is difficult to crush, break or dissolve. It also forms a viscous hydrogel and cannot be easily prepared for injection. The Agency has determined that the physical and chemical properties of Hysingla ER are expected to make abuse by these routes difficult. However, abuse of Hysingla ER by these routes is still possible, FDA notes.

Strengths of Hysingla ER contain 20, 30, 40, 60, 80, 100 and 120 milligrams of hydrocodone to be taken every 24 hours. The safety and effectiveness of Hysingla ER were evaluated in a clinical trial of 905 people with chronic low back pain.

FDA is requiring post-marketing studies of Hysingla ER to assess the effects of the abuse-deterrent features on the risk for abuse of Hysingla ER and the consequences of that abuse in the community. In addition, Hysingla ER is part of the ER/LA Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS), which requires companies to make available to health care professionals educational programs on how to safely prescribe ER/LA opioid analgesics and to provide Medication Guides and patient counseling documents containing information on the safe use, storage, and disposal of ER/LA opioids.

INVEGA SUSTENNA GETS GREEN LIGHT, BOXED WARNING FOR SCHIZOAFFECTIVE DISORDER

FDA has approved Invega Sustenna (Paliperidone Palmitate Extended-Release Injectable Suspension) to treat schizoaffective disorder as either monotherapy or adjunctive therapy. It is a once-monthly atypical long- acting antipsychotic.

The drug becomes the first and only FDA-approved once-monthly medication to treat schizoaffective disorder as monotherapy; It's given by injection by a healthcare professional in the arm or buttocks.

The therapy—by Janssen Pharmaceuticals—had its supplemental New Drug Applications (sNDAs) approved under priority review, which is a designation for drugs that, if approved, would offer significant improvement in the treatment of serious conditions. However, FDA also mandated the company include a black box warning to warn of increased mortality in elderly patients with dementia-related psychosis.

The therapy should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older.