Mavenclad Approved for Multiple Sclerosis

In continuation of my update on Mavenclad (cladribine)

  

Mavenclad (cladribine) tablets have been approved by the U.S. Food and Drug Administration to treat relapsing multiple sclerosis (MS) in adults.

An agency news release said the drug is recommended for people who have had an inadequate response to, or are unable to tolerate, another medication approved for MS. Mavenclad is not sanctioned for a form of MS called clinically isolated syndrome.

MS is a chronic autoimmune disease of the central nervous system that disrupts communication between the brain and other parts of the body. Most people have initial symptoms between ages 20 and 40, more often in women than men. The disease progresses over time and typically leads to lifelong disability.

Mavenclad's effectiveness was shown in clinical studies involving 1,326 people with relapsing forms of MS who had least one relapse in the prior 12 months. The drug significantly decreased the number of relapses compared to a placebo, the FDA said.

Mavenclad must be dispensed with a patient medication guide that describes the drug's uses and risks. The medication's label includes a boxed warning of increased risk of cancer, worsening existing cancer, and fetal harm. The drug should not be used in pregnant women and among people of reproductive age who do not use contraception during treatment and for six months afterward, the FDA said. Mavenclad should be stopped if the user becomes pregnant.

Other significant warnings include a risk of a drop in white blood cells called lymphocytes, infections, bone marrow suppression and liver injury. The most common adverse reactions include upper respiratory tract infection and headache.

https://en.wikipedia.org/wiki/Cladribine

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Mavenclad Approved for Multiple Sclerosis 

Celgene Submits Application to FDA for Ozanimod for the Treatment of Relapsing Forms of Multiple Sclerosis

In continuation of my update on ozanimod

Celgene Corporation (NASDAQ:CELG)  announced that the Company has submitted a New Drug Application to the U.S. Food and Drug Administration (FDA) for ozanimod for the treatment of adults with relapsing forms of multiple sclerosis (RMS). Ozanimod is an oral, sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity selectively to S1P subtypes 1 (S1P1) and 5 (S1P5).

The pivotal efficacy and safety data provided in the application result from the SUNBEAM™ and RADIANCE™ Part B phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled trials.

“New oral treatment options with differentiated profiles like ozanimod are needed to help address an unmet need for people with relapsing forms of MS,” said Jay Backstrom, M.D., Chief Medical Officer for Celgene. “With concurrent applications in the U.S. and EU, we look forward to advancing this promising medicine through the regulatory review process to provide a new option for the treatment of RMS in 2020.”

Earlier this month, the Company also submitted a Marketing Authorization Application to the European Medicines Agency for adults with relapsing-remitting multiple sclerosis.

Ozanimod is an investigational compound that is not approved for any use in any country.

About SUNBEAM™

SUNBEAM is a pivotal, phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled trial evaluating the efficacy, safety and tolerability of two doses of oral ozanimod (0.92 mg and 0.46 mg, equivalent to 1 mg and 0.5 mg ozanimod HCI respectively) against weekly intramuscular interferon beta-1a (Avonex®) for at least a 12-month treatment period. The study included 1,346 people living with RMS across 152 sites in 20 countries.

The primary endpoint of the trial was annualized relapse rates (ARR) during the treatment period. The secondary MRI endpoints included the number of new or enlarging hyperintense T2-weighted brain MRI lesions over 12 months, number of gadolinium-enhanced brain MRI lesions at month 12 and percent change from baseline in whole brain volume at month 12. Cortical grey and thalamic volume changes were also prospectively assessed versus active comparator.

An analysis of the time to onset of 3-month confirmed disability progression was pre-specified using pooled data from both the SUNBEAM and RADIANCE Part B phase 3 trials.

About RADIANCE™

RADIANCE Part B is a pivotal, phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled trial evaluating the efficacy, safety and tolerability of two doses of oral ozanimod (0.92 mg and 0.46 mg, equivalent to 1 mg and 0.5 mg ozanimod HCI respectively) against weekly intramuscular interferon beta-1a (Avonex®) over a 24-month treatment period. The study included 1,320 people living with RMS across 150 sites in 21 countries.

The primary endpoint of the trial was ARR over 24 months. The secondary MRI endpoints included the number of new or enlarging hyperintense T2-weighted brain MRI lesions over 24 months, number of gadolinium-enhanced brain MRI lesions at month 24 and percent change from baseline in whole brain volume at month 24. Cortical grey and thalamic volume changes were also prospectively assessed versus active comparator.

An analysis of the time to onset of 3-month confirmed disability progression was pre-specified using pooled data from both the SUNBEAM and RADIANCE Part B phase 3 trials.

About Ozanimod

Ozanimod is an oral, sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity selectively to S1P subtypes 1 (S1P1) and 5 (S1P5). Ozanimod causes lymphocyte retention in lymphoid tissues. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve the reduction of lymphocyte migration into the central nervous system.

Ozanimod is in development for immune-inflammatory indications including RMS, ulcerative colitis and Crohn's disease.

https://en.wikipedia.org/wiki/Ozanimod

Celgene Submits Application to FDA for Ozanimod for the Treatment of Relapsing Forms of Multiple Sclerosis

Eisai and Imbrium Therapeutics Announce U.S. FDA Filing Acceptance of New Drug Application for Lemborexant for the Treatment of Insomnia

In continuation of my update on lemborexant

Eisai Co., Ltd. (CEO: Haruo Naito, “Eisai”) and Imbrium Therapeutics L.P. (Imbrium Therapeutics), a clinical-stage biopharmaceutical company and operating subsidiary of Purdue Pharma, L.P. (President and CEO: Craig Landau, MD),  announced that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for lemborexant, an investigational agent being studied for the treatment of insomnia, a sleep-wake disorder. A Prescription Drug User Fee Act (PDUFA) date is set for December 27, 2019.

The NDA submission was based on data from the clinical development program including two pivotal Phase 3 studies of lemborexant – SUNRISE 1 (Study 304) and SUNRISE 2 (Study 303).

• SUNRISE 1: a one-month Phase 3 clinical study to evaluate the efficacy and safety of lemborexant versus placebo and versus an active comparator (zolpidem tartrate extended release, “zolpidem ER”) in 1,006 patients 55 years and older (45 percent of all patients were aged 65 years and older) with insomnia disorder. This study assessed sleep latency (using latency to persistent sleep; primary objective); sleep efficiency and wake after sleep onset (effect on maintaining sleep; key secondary objectives) objectively using polysomnography, and achieved its primary and key secondary objectives. The most common adverse events (AEs) reported in the lemborexant arms were headache and somnolence.1
• SUNRISE 2: a 12-month placebo-controlled (first six months) Phase 3 clinical study to evaluate the long-term efficacy and safety of lemborexant in 949 adult patients (18 to 88 years of age) with insomnia disorder. This study evaluated subjective (patient-reported) sleep onset latency (primary objective), sleep efficiency, and wake after sleep onset (key secondary objectives) using sleep diaries, and achieved its pre-specified primary and key secondary efficacy objectives. The most common AEs reported in the lemborexant arms were somnolence, nasopharyngitis, headache, and influenza.2

“Our ultimate goal for the development of a sleep-wake treatment is to bring to patients living with insomnia a new option that has the potential to improve their ability to fall asleep, stay asleep and wake the next morning without impairment,” said Lynn Kramer, MD, Chief Clinical Officer and Chief Medical Officer, Neurology Business Group, Eisai. “This milestone for lemborexant brings us one step closer to addressing unmet needs for millions of patients who experience insomnia.”

“Insomnia, a disorder of sleep quality and quantity, causes significant impairment in daily functioning and has long-term consequences for health and well-being,”3 said John Renger, PhD, Vice President, Head of Research & Development and Regulatory Affairs, Imbrium Therapeutics. “We are committed to working with our partner Eisai to make this investigational treatment available to patients, pending regulatory approval.”

Lemborexant is being jointly developed by Eisai and Imbrium Therapeutics for the treatment of multiple sleep-wake disorders, including insomnia disorder. Information about ongoing clinical studies is available at clinicaltrials.gov.

Eisai and Imbrium Therapeutics are striving to address new unmet medical needs and to improve the lives of patients and their families.

This release discusses investigational uses of an agent in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that such an investigational agent will successfully complete clinical development or gain health authority approval.

About Lemborexant

Lemborexant is a novel investigational small molecule compound, discovered and developed by Eisai in-house scientists, that inhibits orexin signaling by binding competitively to both orexin receptor subtypes (orexin receptor 1 and 2). In individuals with normal daily sleep-wake rhythms, orexin signaling is believed to promote periods of wakefulness. In individuals with sleep-wake disorders, it is possible that orexin signaling that regulates wakefulness is not functioning normally, suggesting that inhibiting inappropriate orexin signaling may enable initiation and maintenance of sleep. Eisai and Imbrium Therapeutics are investigating lemborexant as a potential treatment option for multiple sleep-wake disorders, such as insomnia. Additionally, a Phase 2 clinical study of lemborexant in patients with irregular sleep-wake rhythm disorder (ISWRD) and mild to moderate Alzheimer's dementia is underway.

About SUNRISE 1 (Study 304)

SUNRISE 1 was a multicenter, randomized, double-blind, placebo-controlled, active comparator, parallel-group study evaluating the efficacy and safety of lemborexant in 1,006 male or female adult patients 55 years and older (45 percent of patients were 65 years and older) with insomnia disorder conducted in North America and Europe. SUNRISE 1 included a pre-randomization phase of up to 35 days (including a two-week placebo run-in period) and a randomization phase comprised of a 30-day treatment period and a minimum two-week period without treatment prior to the end-of-study visit. In this study, patients were randomized to receive placebo or one of three treatment regimens (lemborexant 5 mg, lemborexant 10 mg, zolpidem ER 6.25 mg).

The primary objective for SUNRISE 1 was to demonstrate using polysomnography that lemborexant at either the 5 mg or 10 mg dose is superior to placebo on objective sleep onset, as measured by latency to persistent sleep after the last two nights of one month of treatment. Key secondary objectives included change from baseline in sleep efficiency and wake after sleep onset (WASO) for both lemborexant doses compared to placebo, and WASO in the second half of the night (WASO2H) for both lemborexant doses compared to zolpidem ER, each after the last two nights of one month of treatment.

About SUNRISE 2 (Study 303)

SUNRISE 2 was a 12-month multicenter, global, randomized, controlled, double-blind, parallel-group study of the efficacy and safety of lemborexant in 949 male or female adult participants 18 to 88 years of age with insomnia disorder. SUNRISE 2 included a pre-randomization phase of up to 35 days (including a two-week placebo run-in period) and a randomization phase comprised of a six-month placebo-controlled treatment period, a six-month period of active-only treatment and a two-week period without treatment prior to the end-of-study visit. In this study, during the placebo-controlled treatment period, patients were randomized to receive placebo or one of two treatment regimens (lemborexant 5 mg or 10 mg). During the active-only treatment period, patients who received placebo during the first period were re-randomized to receive lemborexant 5 mg or 10 mg. Patients who received active treatment during the first period continued on the treatment to which they were originally randomized.

The primary objective was change from baseline in subjective sleep onset latency after six months of placebo-controlled treatment using patient reported (subjective) sleep diaries. Key secondary endpoints were change from baseline in subjective sleep efficiency and subjective wake after sleep onset (sWASO) by using patient reported (subjective) sleep diaries for both lemborexant doses after six months of placebo-controlled treatment.

https://en.wikipedia.org/wiki/Lemborexant

Eisai and Imbrium Therapeutics Announce U.S. FDA Filing Acceptance of New Drug Application for Lemborexant for the Treatment of Insomnia

FDA Approves Mayzent (siponimod) for Secondary Progressive Multiple Sclerosis

 Novartis  announced that the US Food and Drug Administration (FDA) has approved Mayzent (siponimod) for the treatment of adults with relapsing forms of multiple sclerosis, including secondary progressive multiple sclerosis (SPMS) with active disease, relapsing remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS)*. SPMS is a debilitating form of multiple sclerosis (MS) characterized by progressive and irreversible neurological disability[4]. Mayzent is expected to be available in the US in approximately one week**. Patients will not require a first dose observation (FDO, cardiac monitoring upon initiation) unless they have certain pre-existing cardiac conditions.

"One of the most important aims of MS treatment is delaying disability progression and preserving cognition," said Paul Hudson, Chief Executive Officer, Novartis Pharmaceuticals. "With Mayzent, SPMS patients with active disease will have access to the first effective oral therapy directed towards disease progression, even when MS transitions to a stage where deterioration is less dependent on the usual relapse activity. Mayzent is a testament to the Novartis mission to reimagine medicine. We are delighted that our ongoing commitment to stop MS has led to a much awaited treatment for these patients in need."

Most patients transition from RRMS to SPMS over time[2]. Therefore, starting therapy early is critical for patients to help slow the rate of disability progression. Disability progression most frequently includes - but is not limited to - an impact on ambulation, which could lead to patients needing a walking aid or a wheelchair, bladder dysfunction and cognitive decline[5]. 

"We are grateful that there is a new treatment option for adults with active secondary progressive MS," said Bruce Bebo, PhD, Executive Vice President, Research, US National MS Society. "We are hopeful this approval will stimulate a conversation between patients and healthcare professionals about disability progression after relapsing remitting MS and its early management."

The approval of Mayzent is based on groundbreaking data from the Phase III EXPAND study, a randomized, double-blind, placebo-controlled study, comparing the efficacy and safety of Mayzent versus placebo in people living with SPMS. Patients enrolled in EXPAND were representative of a typical SPMS population: at study initiation, patients had a mean age of 48 years, had been living with MS for approximately 16 years and more than 50% had a median Expanded Disability Status Scale (EDSS) score of 6.0 and relied on a walking aid[3]. Mayzent significantly reduced the risk of three-month confirmed disability progression (CDP) (primary endpoint; 21% reduction versus placebo, p=0.013; 33% reduction versus placebo in patients with relapse activity in the two years prior to screening, p=0.0100)[3]. Additionally, Mayzent meaningfully delayed the risk of six-month CDP (26% versus placebo, p=0.0058) and reduced the annualized relapse rate (ARR) by 55%[3]. Furthermore, EXPAND showed significant favorable outcomes in other relevant measures of MS disease activity, including cognition, MRI disease activity and brain volume loss (brain shrinkage)[3].

Most common adverse reactions (incidence greater than 10%) were headache, hypertension, and transaminase increase.

"With the approval of Mayzent, we now have a much-needed therapeutic option to address SPMS with active disease," said EXPAND Steering Committee member Bruce Cree, MD, PhD, MAS, Clinical Research Director and George A. Zimmermann Endowed Professor in Multiple Sclerosis, University of California, San Francisco, School of Medicine. "Importantly, healthcare professionals now have even more reason to help patients identify changing symptoms and uncover early signs of progression."

Novartis is committed to bringing Mayzent to patients worldwide, and additional regulatory filings are currently underway with other health authorities outside the US. Regulatory action for Mayzent in the European Union is anticipated in late 2019, with additional regulatory action anticipated in Switzerland, Japan, Australia and Canada this year.

*Clinically isolated syndrome (CIS) is defined as a first episode of neurologic symptoms that lasts at least 24 hours and is caused by inflammation or demyelination in the central nervous system[6].

**Time of availability may vary as healthcare providers integrate Mayzent into their practices.

https://en.wikipedia.org/wiki/Siponimod

FDA Approves Mayzent (siponimod) for Secondary Progressive Multiple Sclerosis

U.S. FDA Grants Priority Review for Fedratinib New Drug Application in Myelofibrosis

Celgene Corporation (NASDAQ:CELG)   announced the U.S. Food and Drug Administration (FDA) has accepted the company’s New Drug Application (NDA) for fedratinib and granted a Priority Review. Fedratinib is a highly selective JAK2 inhibitor intended for the treatment of patients with myelofibrosis, a serious bone marrow disorder that disrupts the body’s normal production of blood cells.1 Under the Prescription Drug User Fee Act, the FDA has set its action date as Sept. 3, 2019.

  

“The acceptance of the NDA and granting of Priority Review for fedratinib represent the first potential new treatment option after many years for patients affected by myelofibrosis.” said Jay Backstrom, M.D., Chief Medical Officer for Celgene. “Patients with myelofibrosis, including the number who are ineligible for or failed existing therapy continues to increase, representing a well-defined unmet medical need. We believe fedratinib can play an important role in the treatment of myelofibrosis and we look forward to working with the FDA as the review process advances.”

The NDA for fedratinib is based on results from a randomized, placebo-controlled, phase 3 trial (JAKARTA)in patients with primary or secondary myelofibrosis, as well as a single-arm, open-label phase 2 trial (JAKARTA2) in patients with primary or secondary myelofibrosis previously exposed to ruxolitinib, the only FDA-approved treatment for the disease. Results of these two trials have been previously published in peer-reviewed journals. The FDA has also provided fedratinib Orphan Drug designation for the treatment of secondary and primary myelofibrosis.

Celgene also plans to evaluate fedratinib in combination with luspatercept.

https://en.wikipedia.org/wiki/Fedratinib

https://pubchem.ncbi.nlm.nih.gov/compound/Tg-101348#section=Structures

U.S. FDA Grants Priority Review for Fedratinib New Drug Application in Myelofibrosis

TB Medicine Pretomanid Enters Regulatory Review Process in the United States

 TB Alliance’s new drug application (NDA) for the novel tuberculosis (TB) drug candidate pretomanid has been accepted for review by the United States Food and Drug Administration (FDA). The application is for the use of pretomanid as part of a new regimen, in combination with bedaquiline and linezolid, for the treatment of extensively drug-resistant (XDR) TB, treatment intolerant multidrug-resistant (MDR) TB, and treatment non-responsive MDR-TB.

The NDA for pretomanid has been granted Priority Review by FDA. The Prescription Drug User Fee Act (PDUFA) action date for an FDA decision is in third quarter 2019.

TB Alliance will work with manufacturing partners to ensure that pretomanid, if approved for use in the BPaL regimen, will be accessible to those who need it.

About Pretomanid and the BPaL Regimen

Pretomanid is a new chemical entity and a member of a class of compounds known as nitroimidazooxazines. It has been studied in 20 clinical trials alone or in combination with other anti-TB drugs. Since TB Alliance began development of pretomanid in 2002, it has been administered in a clinical trial setting to more than 1,200 people in 14 countries.

The BPaL regimen (comprised of bedaquiline, pretomanid and linezolid) was first studied clinically in the Phase 3 Nix-TB trial. Nix-TB participants with XDR-TB and treatment intolerant or nonresponsive MDR-TB were enrolled for treatment with the BPaL regimen for six months, extendable to nine months, with the intent to cure. Nix-TB is an open label, single arm trial. According to a modified intention-to-treat analysis of interim results on the first 75 participants presented at the 2018 Union World Conference on Lung Health, 89% of the trial participants had a favorable outcome with their clinical infection resolved and sputum cultures negative for TB after six months of treatment and six months of post-treatment follow-up.

https://www.tballiance.org/portfolio/compound/pretomanid

https://en.wikipedia.org/wiki/Pretomanid

https://www.drugbank.ca/drugs/DB05154

TB Medicine Pretomanid Enters Regulatory Review Process in the United States

Intellipharmaceutics Announces Resubmission of New Drug Application to the U.S. FDA for its Oxycodone ER

 In continuation of my update on Oxycodone ER

ntellipharmaceutics International Inc. (NASDAQ: IPCI, TSX: IPCI) ("Intellipharmaceutics" or the "Company"), a pharmaceutical company specializing in the research, development and manufacture of novel and generic controlled-release and targeted-release oral solid dosage drugs,  announced that it has resubmitted its New Drug Application ("NDA") to the U.S. Food and Drug Administration ("FDA") for its Oxycodone ER product candidate.

The Company's NDA for an abuse-deterrent version of Oxycodone ER was initially accepted for filing by the FDA in February 2017. Intellipharmaceutics resubmitted the NDA in response to a Complete Response Letter ("CRL") received from the FDA, which provided certain recommendations and requests for information. The FDA granted us an extension to February 28, 2019 to resubmit our NDA under section 505(b)(2) of the U.S. Federal Food, Drug and Cosmetic Act and the Company has now met this deadline.

There can be no assurance that Intellipharmaceutics will not be required to conduct further studies for Oxycodone ER, that the FDA will approve any of the Company's requested abuse-deterrent label claims or that the FDA will ultimately approve the NDA for the sale of Oxycodone ER in the U.S. market, or that it will ever be successfully commercialized.

About Intellipharmaceutics

Intellipharmaceutics International Inc. is a pharmaceutical company specializing in the research, development and manufacture of novel and generic controlled-release and targeted-release oral solid dosage drugs. The Company's patented Hypermatrix™ technology is a multidimensional controlled-release drug delivery platform that can be applied to a wide range of existing and new pharmaceuticals. Intellipharmaceutics has developed several drug delivery systems based on this technology platform, with a pipeline of products (some of which have received FDA approval) in various stages of development. The Company has ANDA and NDA 505(b)(2) drug product candidates in its development pipeline. These include the Company's abuse-deterrent oxycodone hydrochloride extended release formulation ("Oxycodone ER") based on its proprietary nPODDDS™ novel Point Of Divergence Drug Delivery System (for which an NDA has been filed with the FDA), and Regabatin™ XR (pregabalin extended-release capsules).

Cautionary Statement Regarding Forward-Looking Information

Certain statements in this document constitute "forward-looking statements" within the meaning of the United States Private Securities Litigation Reform Act of 1995 and/or "forward-looking information" under the Securities Act (Ontario). These statements include, without limitation, statements expressed or implied regarding our expectations regarding our plans, goals and milestones, status of developments or expenditures relating to our business, plans to fund our current activities, and statements concerning our partnering activities, health regulatory submissions, strategy, future operations, future financial position, future sales, revenues and profitability, projected costs and market penetration and risks or uncertainties related to our ability to comply with the Nasdaq and TSX continued listing standards and our ability to develop and implement a plan of compliance with the Nasdaq continued listing standards acceptable to a Nasdaq Panel. In some cases, you can identify forward-looking statements by terminology such as "appear", "unlikely", "target", "may", "will", "should", "expects", "plans", "plans to", "anticipates", "believes", "estimates", "predicts", "confident", "prospects", "potential", "continue", "intends", "look forward", "could", "would", "projected", "goals", "set to", "seeking" or the negative of such terms or other comparable terminology. We made a number of assumptions in the preparation of our forward-looking statements. You should not place undue reliance on our forward-looking statements, which are subject to a multitude of known and unknown risks and uncertainties that could cause actual results, future circumstances or events to differ materially from those stated in or implied by the forward-looking statements. Risks and uncertainties relating to us and our business can be found in the "Risk Factors" section of our latest annual information form, our latest Form 20-F, and our latest Form F-1 and Form F-3 (including any documents forming a part thereof or incorporated by reference therein), as amended, as well as in our reports, public disclosure documents and other filings with the securities commissions and other regulatory bodies in Canada and the U.S., which are available on www.sedar.com and www.sec.gov. The forward-looking statements reflect our current views with respect to future events and are based on what we believe are reasonable assumptions as of the date of this document and we disclaim any intention and have no obligation or responsibility, except as required by law, to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

https://www.drugbank.ca/drugs/DB00497

Intellipharmaceutics Announces Resubmission of New Drug Application to the U.S. FDA for its Oxycodone ER

Allergan Announces FDA Acceptance of New Drug Application for Ubrogepant for the Acute Treatment of Migraine

   Allergan plc (NYSE: AGN)  announced that the U.S. Food and Drug Administration (FDA) has accepted the company's New Drug Application (NDA) for ubrogepant for the acute treatment of migraine in adults. The NDA filing is based on the successful completion of four clinical trials – two pivotal studies, ACHIEVE I and ACHIEVE II, which demonstrated the efficacy, safety and tolerability of ubrogepant, as well as two additional safety studies. A 10-month review period has been assigned with the Prescription Drug User Fee Act (PDUFA) in the fourth quarter of 2019.

"Following the acceptance and expected review of this NDA, we anticipate ubrogepant to be the first approved oral CGRP receptor antagonist for the acute treatment of migraine, and may be used in conjunction with other available migraine treatments," said David Nicholson, Chief Research and Development Officer, Allergan. "As a leader in Chronic Migraine research for more than 20 years, Allergan looks to provide options for patients who need new acute and preventative treatments for migraine. In addition to ubrogepant, we are continuing to advance the Phase 3 clinical program for atogepant, the company's second orally-administered investigational CGRP receptor antagonist specifically for migraine prevention."

In the four clinical studies (ACHIEVE I, ACHIEVE II, UBR-MD-04 and 3110-105-002) supporting the NDA, ubrogepant demonstrated efficacy, safety and tolerability in the acute treatment of migraine among a broad patient population, including those who had an insufficient response to a triptan or those patients in whom triptans were contraindicated, as well as in patients who had moderate to severe CV risk profile. Following are topline results from the key clinical studies:

Phase 3 Clinical Trials (ACHIEVE I & ACHIEVE II)

The two pivotal Phase 3 clinical trials demonstrated the efficacy, safety and tolerability of orally administered ubrogepant (ACHIEVE I at 50 mg and 100 mg; and ACHIEVE II at 25 mg and 50 mg) compared to placebo to treat a single migraine attack in adults.

• The 50 mg and 100 mg doses met the studies' co-primary endpoints, demonstrating a statistically significant greater percentage of ubrogepant patients achieving pain freedom and absence of most bothersome symptom at two hours after the initial dose as compared to placebo patients; there was continued separation from placebo up to 48 hours.
• The 50 mg and 100 mg doses also met key secondary endpoints, demonstrating a statistically significant greater percentage of ubrogepant patients achieving pain relief at two hours after the initial dose compared to placebo patients.

Additional Safety Studies (UBR-MD-04 & 3110-105-002)

Study UBR-MD-04: Phase 3, multicenter, randomized, 52-week open-label extension trial in which adults with migraine were randomized 1:1:1 to usual care, ubrogepant 50 mg, or ubrogepant 100 mg to assess long-term safety and tolerability.

• Intermittent use of ubrogepant 50 mg or 100 mg for the acute treatment of migraine attacks over one year was well-tolerated. The three most frequently reported adverse events were nasopharyngitis, upper respiratory tract infection and sinusitis.

Study 3110-105-002: Phase 1, multicenter, double-blind, parallel-group trial evaluated the safety and tolerability of ubrogepant 100 mg, focusing on hepatic safety in healthy participants administered high frequency intermittent  dosing (2 days of ubrogepant 100 mg followed by 2 days of placebo for 8 consecutive weeks).

• Ubrogepant 100 mg was well-tolerated following frequent dosing and was not associated with persistent increases in ALT/AST compared to placebo, supporting liver safety.

"Despite its prevalence and burden, migraine remains an undertreated disease, with many patients continuing to seek additional treatment options from their physicians," said Dr. Jessica Ailani, a neurologist and Director of the Medstar Georgetown Headache Center. "If approved, ubrogepant, the first innovation in the acute treatment of migraine in over 25 years, will be used across the entire spectrum of the disease (from episodic to chronic) helping patients achieve relief in the moments when they most demand it."

About Ubrogepant

Ubrogepant is a novel, highly potent, orally-administered CGRP receptor antagonist in development for the acute treatment of migraine. CGRP and its receptors are expressed in regions of the nervous system associated with migraine pathophysiology. CGRP receptor antagonism is a novel mechanism of action for the acute treatment of migraine that clearly differs from the mechanisms of currently available triptans (serotonin 1B/1D agonists), opioids and ergots.

https://pubchem.ncbi.nlm.nih.gov/compound/Ubrogepant

https://en.wikipedia.org/wiki/Ubrogepant

Allergan Announces FDA Acceptance of New Drug Application for Ubrogepant for the Acute Treatment of Migraine

Karyopharm Announces FDA Extension of Review Period for Selinexor New Drug Application

  

Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a clinical-stage pharmaceutical company,  announced that the U.S. Food and Drug Administration (FDA) has extended the Prescription Drug User Fee Act (PDUFA) action date for the New Drug Application (NDA) for selinexor. The NDA, which is currently under Priority Review by the FDA, is seeking accelerated approval for selinexor in combination with dexamethasone for the treatment of patients with relapsed refractory multiple myeloma who have received at least three prior therapies and whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and one anti-CD38 monoclonal antibody. The previously disclosed April 6, 2019 PDUFA date has been extended by three months to July 6, 2019.

On February 26, 2019, the FDA'sOncologic Drugs Advisory Committee (ODAC) met to discuss the selinexor NDA and voted 8 to 5 recommending that the FDA wait for the results from Karyopharm's randomized, open-label, Phase 3 BOSTON study evaluating selinexor in patients with relapsed or refractory multiple myeloma, before making a final decision regarding approval.  Although the FDA considers the recommendation of this panel, the final decision regarding the approval of the product is made by the FDA solely, and the recommendations by the panel are non-binding.

Following the ODAC meeting, at the FDA's request,  Karyopharm submitted additional, existing clinical information as an amendment to the NDA, which allowed the FDA to extend the PDUFA action date by three months. "We look forward to the continued collaboration with FDA in trying to meet the needs of patients with relapsed refractory multiple myeloma," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm.

About Selinexor

Selinexor is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. In 2018, Karyopharm reported positive data from the Phase 2b STORM study evaluating selinexor in combination with low-dose dexamethasone in patients with triple class refractory multiple myeloma who have been previously exposed to all five of the most commonly prescribed anti-myeloma therapies currently available. Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. Karyopharm's New Drug Application (NDA) has been accepted for filing and granted Priority Review by the FDA, and oral selinexor is currently under review by the FDA as a possible new treatment for patients with triple class refractory multiple myeloma. The Company has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval and was granted accelerated assessment. Selinexor is also being studied in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In 2018, Karyopharm reported positive top-line results from the Phase 2b SADAL study evaluating selinexor in patients with relapsed or refractory DLBCL after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue. Selinexor has received Fast Track designation from the FDA for the patient population evaluated in the SADAL study.  Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade® (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in liposarcoma (SEAL), and an investigator-sponsored study in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm's clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

https://pubchem.ncbi.nlm.nih.gov/compound/Selinexor#section=2D-Structure

Karyopharm Announces FDA Extension of Review Period for Selinexor New Drug Application

FDA Issues Complete Response Letter for Zynquista (sotagliflozin)

In continuation of my update on Zynquista (sotagliflozin)

 The U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) regarding the New Drug Application for investigational Zynquista (sotagliflozin)*, a dual SGLT1 and SGLT2 inhibitor for the treatment of adults with type 1 diabetes in combination with insulin.

A CRL is a communication from the FDA that informs companies that an application cannot be approved in its present form.

Sanofi and Lexicon will work closely with the FDA to determine the appropriate next steps.

About Lexicon Pharmaceuticals

Lexicon (NASDAQ: LXRX) is a fully integrated biopharmaceutical company that is applying a unique approach to gene science based on Nobel Prize-winning technology to discover and develop precise medicines for patients with serious, chronic conditions. Through its Genome5000™ program, Lexicon scientists have studied the role and function of nearly 5,000 genes over the last 20 years and have identified more than 100 protein targets with significant therapeutic potential in a range of diseases. Through the precise targeting of these proteins, Lexicon is pioneering the discovery and development of innovative medicines to safely and effectively treat disease. In addition to its first commercial product, XERMELO® (telotristat ethyl), Lexicon has a pipeline of promising drug candidates in clinical and pre-clinical development in diabetes and metabolism and neuropathic pain. For additional information please visit www.lexpharma.com.

*Sotagliflozin is an investigational drug and is under regulatory review by the European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA). The EMA and FDA have conditionally accepted Zynquista™ as the trade name for sotagliflozin.

https://pubchem.ncbi.nlm.nih.gov/compound/lx-4211#section=Structures

FDA Approves Adhansia XR (methylphenidate hydrochloride) Extended-Release Capsules for the Treatment of ADHD

In continuation of my update on methylphenidate

Adlon Therapeutics L.P., a subsidiary of Purdue Pharma L.P., announced that the U.S. Food and Drug Administration (FDA) approved Adhansia XR (methylphenidate hydrochloride) extended-release capsules CII, a central nervous system (CNS) stimulant, for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in patients six years and older. In a simulated Adult Workplace Environment (AWE) study, Adhansia XR demonstrated statistically significant improvement over placebo at 1, 2, 5, 8, 11, and 16 hours post-dose, but not at hour 14 post-dose.1

“Methylphenidate medications, when used as prescribed and in conjunction with behavioral therapy and lifestyle interventions, are one of the preferred first-line treatments for certain patients diagnosed with ADHD,” said Marcelo Bigal, MD, PhD, chief medical officer, Purdue Pharma, and general manager, Adlon Therapeutics. “We are pleased to receive FDA approval for Adhansia XR, a new option for appropriate patients with ADHD who may benefit from a treatment with efficacy demonstrated at one hour and 16 hours post-dose in adults, and we look forward to making it available later this year.”

The Full Prescribing Information for Adhansia XR contains a boxed warning for abuse and dependence. CNS stimulants, including Adhansia XR, other methylphenidate-containing products, and amphetamines have a high potential for abuse and dependence. Healthcare professionals should assess the risk of abuse prior to prescribing Adhansia XR and monitor for signs of abuse and dependence while patients are on therapy.

“Some of my patients with ADHD, especially those who are balancing school or work and participating in social or civic activities, require the ability to sustain attention throughout the day,” said Andrew J. Cutler, MD, chief medical officer, Meridien Research, and an investigator on Adhansia XR clinical studies. “The approval of Adhansia XR offers a methylphenidate treatment option with a longer duration of efficacy, which may be appropriate for these patients.”

Adhansia XR is not appropriate for all patients, and healthcare professionals should work with their patients to determine the most appropriate treatment option. Additionally, Adhansia XR is contraindicated in patients with a known hypersensitivity to methylphenidate or product components, as well as patients receiving concurrent treatment with a monoamine oxidase inhibitor (MAOI) or who have used an MAOI within the preceding 14 days.

The Full Prescribing Information for Adhansia XR, including Boxed Warning, is available at this link. Additionally, please see Important Safety Information for Adhansia XR below, including the Boxed Warning, Contraindications, Warnings and Precautions including the potential for abuse and dependence, serious cardiovascular events, blood pressure and heart rate increases, psychiatric adverse reactions, priapism, peripheral vasculopathy, long-term suppression of growth, allergic-type reactions, and Adverse Reactions.

“ADHD affects a significant number of adolescents and adults and, when not optimally treated, can negatively impact various aspects of their lives. A subset of these patients experience impairment throughout the day. While Adhansia XR is not appropriate for all patients, a methylphenidate medication available in a single daily dose that, in adults, demonstrated efficacy at one hour and at 16 hours post-dose, has the potential to address the needs of certain individuals with ADHD,” said Craig Landau, MD, president and CEO, Purdue Pharma. “We are committed to providing information on safe prescribing practices for this medication and initiatives to support the responsible use, storage, and disposal of all medications in this class."

The FDA approval of Adhansia XR was based on four clinical studies evaluating the efficacy and safety of Adhansia XR in patients who met DSM-5 criteria for ADHD. Eight hundred and eighty-three (883) patients were exposed to Adhansia XR during 1- to 4-week long, controlled treatment periods (434 adult patients and 449 pediatric patients [156 (6 to 12 years); 293 (12 to 17 years)] from two clinical studies in adults, one analog classroom trial over a 13-hour study day in pediatric patients ages 6 to 12 years, and one safety and efficacy study in pediatric patients ages 12 to 17 years). The safety data for adult patients are based on two randomized, double-blind, placebo-controlled studies in doses of 25 mg to 100 mg per day. The safety data for pediatric patients (6 to 17 years) are based on randomized, double-blind, placebo-controlled studies in doses of 25 mg to 85 mg per day.

A double-blind, randomized, placebo-controlled crossover AWE study evaluated Adhansia XR in adult patients with ADHD. Efficacy assessments were conducted at pre-dose and 1, 2, 5, 8, 11, 14, and 16 hours post-dose. The primary endpoint was the mean Permanent Measure of Performance Total scores (PERMP-T), averaged across all time points compared to placebo. PERMP-T, an objective, validated skill-adjusted math test, is the combined score obtained by adding PERMP-A (number of math problems attempted) and PERMP-C (number of math problems answered correctly).

While receiving Adhansia XR, adults achieved statistically significant improvement over placebo, achieving greater mean PERMP-T scores averaged across all time points on the AWE days (post-dose score of 281.3 vs. 254.5; difference of 26.80, 95% CI [15.19, 38.41]). The secondary efficacy endpoints were onset and duration of clinical effect, as assessed by the treatment difference in PERMP-T scores at post-dose time points. Adhansia XR demonstrated statistically significant improvement over placebo at 1, 2, 5, 8, 11, and 16 hours post-dose, but not at hour 14 post-dose.

In this study, 10% of Adhansia XR-treated patients discontinued due to adverse reactions compared to 0% of placebo-treated patients. The following adverse reactions led to discontinuation at a frequency of 2% of Adhansia XR-treated patients: nausea, bronchitis, viral gastroenteritis, viral infection, increased blood pressure, and hypomania.

Sudden death, stroke and myocardial infarction have occurred in patients treated with CNS stimulants at recommended doses. Additional information about serious cardiovascular risks can be found in the Important Safety Information section below.

Adhansia XR will be available in six capsule strengths (25, 35, 45, 55, 70, and 85 mg), allowing for flexible dosing. The recommended starting dose of Adhansia XR for patients six years or older is 25 mg once daily. Healthcare professionals should titrate the dose in increments of 10 mg to 15 mg at intervals of no less than five days. Adhansia XR should be taken orally once daily in the morning, with or without food. Capsules may be taken whole or, for patients who have difficulty swallowing, capsules may be opened and the entire contents sprinkled onto a tablespoon of applesauce or yogurt. The entire mixture should be consumed without crushing or chewing, immediately or within 10 minutes. If the mixture is not consumed within 10 minutes after mixing, it should be discarded and not stored. The dose of a single capsule should not be divided and patients should not take anything less than one capsule per day. In the event of a missed dose, patients should not take their medication later in the day.

Prior to initiating treatment with Adhansia XR, healthcare professionals should also assess for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam). Healthcare professionals should assess the risk of abuse prior to prescribing Adhansia XR and monitor for signs of abuse and dependence while patients are on therapy. After prescribing and while patients are on therapy, healthcare professionals should maintain careful prescription records, educate patients and their families about abuse and proper storage and disposal of CNS stimulants, and periodically re-evaluate the need for Adhansia XR use.

Dosages above 85 mg daily in adults and 70 mg and above daily in pediatric patients are associated with disproportionate increases in the incidence of certain adverse reactions. If paradoxical aggravation of symptoms or other adverse reactions occur, healthcare professionals should reduce the dosage, or, if necessary, discontinue treatment with Adhansia XR. Treatment with Adhansia XR should also be periodically discontinued to assess the patient's condition. If improvement is not observed in a patient after appropriate dosage adjustment over a one-month period, healthcare providers should discontinue treatment with Adhansia XR.1 Healthcare professionals should refer to the Full Prescribing Information for additional Dosage and Administration information.

Prescription stimulants, which include methylphenidate, the active ingredient in Adhansia XR, are federally controlled substances (CII) and have a high potential for abuse and dependence.1,2 The selling or giving away of methylphenidate medications may harm others or lead to death, and is against the law. It is important for healthcare professionals to ask patients if they or a family member have ever misused prescription medicines or abused alcohol or street drugs. Patients should be counseled that they should not give Adhansia XR to anyone else, and to keep methylphenidate medications in a safe place, such as a locked cabinet, to help prevent accidental exposure, diversion, and abuse.  They should also be advised to dispose of remaining, unused, or expired Adhansia XR by a medicine take-back program at authorized collection sites such as pharmacies or law enforcement locations, if available. If no take-back program or authorized collector is available, patients should mix Adhansia XR with an undesirable, nontoxic substance to make it less appealing to children and pets, place the mixture in a container such as a sealed plastic bag, and discard of it in the household trash.1 Patients should be encouraged to read the Medication Guide that accompanies their stimulant prescription, which contains the most important FDA-approved information that a patient should know about the medication

REf: https://en.wikipedia.org/wiki/Methylphenidate