Keeping Track: Approval Elusive For Biosimilar Neulasta; Valeant Gets A Nod And A No From FDA; Submissions From Amgen, Puma, Bristol

The latest drug development news and highlights from our FDA Performance Tracker

The complete response letters keep on coming from FDA, this week with non-approval actions for a new molecular entity (Valeant Pharmaceuticals International Inc.'s Vesneo) and a biosimilar (Sandoz Inc.'s pegfilgrastim).

Sandoz' disclosure of the pegfilgrastim biosimilar complete response letter makes it the third 351(k) application known to have received a letter citing reasons the product is not approvable.

Vesneo (latanoprosten bunod) is at least the sixth new molecular entity or novel biologic to receive a CR letter from FDA's Center for Drug Evaluation and Research in 2016. (Also see "FDA New Drug Approval Count May Fall Back To Earth In 2016" - Pink Sheet, 18 Jul, 2016.)

FDA action on another novel agent, Merck & Co. Inc.'s bezlotoxumab, was expected on the anti-C. difficile product's July 23, 2016 user fee goal, but instead the company announced submission of new data extending the user fee goal into October.

The NME pipeline also saw some restocking, with submissions for Puma Biotechnology Inc.'s neratinib and Amgen Inc.'s romosozumab. Bristol-Myers Squibb Co. also submitted another breakthrough-designated indication for the immunotherapy Opdivo.

New formulations took center stage in the week's approvals news, with FDA clearance of a once-daily version of Eisai Inc. and Arena Pharmaceuticals Inc.'s obesity drug Belviq and an oral form of Valeant's opioid-induced constipation therapy Relistor. Avedro Inc.'s eye drug Photrexa received its second indication, CSL Behring's Berinert extended its labeling for pediatric and geriatric hereditary angioedema patients.

Sandoz Pegfilgrastim Biosimilar Stumbles; Is Pegylation A Problem?

Amgen's Neulasta (pegfilgrastim) remains safe from biosimilar competition for now as Sandoz became the second company understood to have received a complete response letter for a biosimilar version of the pegylated granulocyte-colony stimulating factor (G-CSF).

Sandoz parent Novartis AG included a note deep in its July 19 second quarter earnings announcement that a "complete response" letter had been received for its pegfilgrastim biosimilar. (Also see "Biosimilars Still Flummoxed By Neulasta: Sponsors Now 0 For 2 At FDA" - Pink Sheet, 19 Jul, 2016.) The 351(k) application's expected review goal was in July, based on its September 2015 filing date.

Apotex Inc., which also was pursuing a biosimilar Neulasta, seems to have received a CR letter for the application, based on FDA's biosimilar performance report. Apotex filed the 351(k) application in October 2014, and a company official indicated that it remains under review.

Sandoz' stumble with pegfilgrastim is especially noteworthy because the Novartis subsidiary essentially created the US biosimilar by taking on Neulasta's predecessor granulocyte-colony stimulating factor (G-CSF) molecule. Sandoz's Zarxio (filgrastim-sndz), which references Amgen's Neupogen (filgrastim), is the first US-approved, and still the only US-marketed, biosimilar.

The two CRLs for the pegylated form of G-CSF suggests that pegylated molecules could pose a development challenge for biosimilar sponsors.

(Keep track of FDA action letters with the FDA Performance Tracker's Complete Response Letters chart. Follow the progress of 351(k) applications with the Pending Biosimilars chart.)

Manufacturing Trouble Trips Vesneo; CRL Caps Busy Week For Valeant

Deficiencies found during an FDA inspection of Valeant subsidiary Bausch & Lomb Inc.'s Tampa, Fla. manufacturing facility were cited in a complete response letter for Valeant's Vesneo, a once-daily ophthalmic solution developed to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

Bausch & Lomb and Nicox Ophthalmics, Inc. developed the nitric oxide-donating prostaglandin F2-alpha analog. Valeant acquired eye care specialist Bausch & Lomb in 2013.

"FDA's letter did not identify any efficacy or safety concerns with respect to the NDA or additional clinical trials needed," Valeant reported in its July 22 announcement of the CRL. The latanoprostene bunod NDA had a July 21 user fee goal.

The CRL capped a busy, if mixed, week for the troubled company. On July 19, FDA approved a more convenient formulation of its opioid-induced constipation therapy Relistor (methylnaltrexone), while an agency advisory committee recommended psoriasis therapy Siliq (brodalumab) for approval, albeit with extensive post-marketing monitoring and a warning about suicidality. (Also see "Valeant's Siliq Clears FDA Panel But Faces Prospect Of Post-Marketing Registry" - Pink Sheet, 19 Jul, 2016.)

The opioid antagonist Relistor was first approved by FDA in 2008 as a subcutaneous injection for treatment of OIC in adults with advanced illness who are receiving palliative care and have insufficient response to laxatives. The injectable drug added a broader indication for treatment of adults with chronic non-cancer pain in 2014.

The oral 450mg tablet formulation of Relistor is only indicated for the chronic non-cancer pain claim. The approval was supported by a Phase III trial comparing once-daily oral Relistor with placebo. Treatment demonstrated statistically significant improvements in rescue-free bowel movement (RFBM) within four hours of administration over 28 days of dosing compared to placebo, the primary endpoint of the study. Efficacy of oral methylnaltrexone was comparable to that reported in clinical studies for the subcutaneous product and safety was comparable to placebo.

Relistor oral tablets will be better positioned to compete against AstraZeneca PLC's Movantik, the first oral mu-opioid receptor antagonist approved for the treatment of OIC in adults with non-cancer pain. (Also see "Valeant’s Oral Relistor Poised To Face-Off Against AstraZeneca’s Movantik" - Scrip, 20 Jul, 2016.). Movantik was approved in September 2014, but launch was held up until early 2015 by Drug Enforcement Agency scheduling.

Unintentional Overdose Concerns Underpin CRL For Elite's SequestOx

FDA concluded that Elite Pharmaceuticals Inc.'s abuse-deterrent immediate-release opioid SequestOx poses a risk of unintentional overdose if it is taken after a heavy meal, when the drug appears to have a delayed effect, Elite President and CEO Nasrat Hakim told a July 18 conference call.

Elite announced the receipt of an FDA complete response letter for SequestOx (oxycodone/naltrexone) late on July 15, but waited for the weekend to pass before disclosing details (Also see "Keeping Track: Xiidra, New Repatha Regimen Approved; Abuse-Deterrent Opioid Gets Negative, But Timely, Response" - Pink Sheet, 15 Jul, 2016.).

Elite had conducted a three-arm study in which SequestOx was shown to be bioequivalent to Purdue's OxyContin (oxycodone) under fasted conditions and in fed conditions with a light meal. But under fed conditions with a fatty meal, SequestOx was bioequivalent to OxyContin under two parameters, AUC and Cmax, but not for Tmax, which Hakim said meant there was a delay in getting drug effect. (Also see "Elite's Opioid Carries Risk Of Overdose After Heavy Meal, FDA Says" - Pink Sheet, 18 Jul, 2016.).

Hakim said a small effect of food could have been dealt with in labeling by instructing patients to take the drug one hour before or two hours after a meal. He said that was FDA's stance in 2014 when the company met with the agency.

"FDA today believes this is a safety issue," Hakim said. FDA stated in the complete response letter that the extent of the delay in the absorption and concentration of SequestOx "under the fed conditions is unacceptable as it leaves patients at risk of unintentionally overdosing." FDA added that because the proposed indication is for acute pain and the product is to be taken as needed, product labeling cannot adequately mitigate this risk.

Hakim said that if the company had known FDA considered this to be a safety issue rather than a labeling issue it could have run another arm of the study in which SequestOx beads would be sprinkled on applesauce and taken with a heavy meal.

Merck Bezlotoxumab Goal Pushed To October By FDA Request For New MODIFY Analyses

FDA has extended the user fee goal date for Merck's bezlotoxumab, an antibody for prevention of Clostridium difficile infection recurrence, from July 23 to October 23, 2016, Merck announced July 21. The three-month extension was triggered by a major amendment to the biologics license application (BLA).

FDA "has requested the submission of new data and analyses from the MODIFY I and MODIFY II clinical trials previously submitted" as the basis of the bezlotoxumab BLA, Merck explained.

Bezlotoxumab earned an endorsement from FDA's advisory committee on June 9. Despite concerns about trial design and efficacy rate, the panel voted 10-5 with one abstention that the antibody showed substantial evidence of efficacy and safety in preventing the recurrence of C. diff infection. (Also see "C.Diff Unmet Need Overcomes Bezlotoxumab Panel's Efficacy Concerns" - Pink Sheet, 9 Jun, 2016.)

(Keep track of FDA submissions and approvals with the User Fee Goal Dates chart.)

Amgen Submits Bone-Forming Agent For Osteoporosis NDA Supported By FRAME

Amgen announced submission of a BLA for the sclerostin-inhibiting monoclonal antibody romosozumab for treatment of osteoporosis in postmenopausal women at increased risk of fracture on July 21. A standard review would put the user fee goal in July 2017.

The BLA is based on the FRAME trial, a placebo-controlled 7,200-patient Phase III study that has produced results suggesting romosozumab could face trouble clinically differentiating itself in the crowded osteoporosis space. (Also see "Amgen Files Osteoporosis Drug In US Ahead Of Rival Merck" - Scrip, 22 Jul, 2016.)

Top-line FRAME data showed the antibody reduced incidence of new vertebral fractures through months 12 and 24 but failed to meet endpoints for reducing nonvertebral fractures at the same time points. Romosozumab did meet a secondary endpoint of reducing incidence of clinical fractures, a composite of vertebral and nonvertebral fractures, at 12 months. (Also see "Amgen/UCB's Phase III Success May Not Be Enough To Top Osteoporosis Rivals" - Pink Sheet, 22 Feb, 2016.)

Amgen and UCB share development costs for romosozumab. Amgen will lead commercialization in North America and Japan, and UCB in Europe and Australia. Amgen says the agent increases bone formation and decreases bone resporption.

Puma's Neratinib NDA Reaches FDA At Last

Puma's July 21 announcement of an NDA submission for neratinib offers the chance for redemption after multiple delays that punished the company's stock and public perception. Puma had earlier predicted submitting in the first quarter of 2015, then the first quarter of 2016, then mid-2016 (Also see "Puma Plummets On Another Neratinib NDA Delay" - Scrip, 29 Mar, 2016.).

The NDA seeks approval of neratinib (PB272), an irreversible tyrosine kinase inhibitor, for extended adjuvant treatment of patients with early stage HER2-overexpressed/amplified breast cancer who have received prior adjuvant therapy with Genentech's Herceptin (trastuzumab).

The application is supported by the Phase III ExteNET trial in 2,840 women with early stage HER2-positive breast cancer who had undergone surgery and adjuvant trastuzumab therapy. Patients were randomized to one year of extended adjuvant treatment with neratinib or placebo.

Some of the submission delays were caused by FDA asking Puma to amend its statistical analysis plan, which shifted the time at which recurrent disease events and deaths were assessed and included in the Phase III ExteNET study's primary endpoint of two-year invasive disease-free survival (DFS).

Neratinib treatment in ExteNET was associated with a 33% reduction of risk of invasive disease recurrence or death versus placebo, Puma declared in its NDA submission announcement. The effect looks more modest when described as DFS rates: the two-year DFS rate for neratinib was 93.9%; for placebo, it was 91.6%. The company also pointed to a 49% reduction in risk of invasive disease recurrence or death in a pre-defined subgroup of patients with hormone receptor-positive disease; in those women, the two-year DFS rate for neratinib was 95.4% and was 91.2% for placebo.

Puma is investigating neratinib in other breast cancer settings. The drug was one of the first to graduate from the Phase II I-SPY 2 trial for neoadjuvant treatment of early breast cancer, but has not yet proceeded to Phase III in the setting where it showed potential in the basket trial: hormone receptor-negative and HER2-positive primary breast cancer in combination with chemotherapy. (Also see "I-SPY Graduates: Where Are They Now?" - Pink Sheet, 10 Jul, 2016.)

Bristol's Next Target For Opdivo Is Head And Neck Cancer

Bristol's PD-1 inhibitor Opdivo (nivolumab) has a Nov. 11, 2016 user fee goal for use in patients with previously treated recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), the company reported.

The sBLA has been granted priority review by FDA, not surprising given that Opdivo holds a breakthrough therapy designation for the indication.

The NDA is based on the open-label Phase III Checkmate-141 trial, which evaluated overall survival in SCCHN patients after platinum therapy. Patients were randomized to Opdivo or investigator's choice of methotrexate, docetaxel or cetuximab. The trial was stopped early in January 2016 when it met its primary OS endpoint.

"Opvido is the first and only PD-1 inhibitor to show an overall survival benefit in a Phase III trial in these patients," Bristol said.

Will Once-Daily Formulation Lift Belviq's Prospects?

Eisai and Arena plan to make the newly approved once-daily formulation of the anti-obesity drug lorcaserin, Belviq XR, available in the fall of 2016. FDA approved the extended-release 20mg tablet formulation on July 15, based on two Phase I registrational trials in healthy adults that compared bioequivalence and bioavailability of Belviq XR with twice-daily Belviq 10mg.

FDA originally approved lorcaserin in 2012 for use in combination with a reduced-calorie diet and increased physical activity for chronic weight management in adults who have a BMI equal to or greater than 30 or BMI of 27 or greater with at least one weight-related medical condition such as high blood pressure, high cholesterol, or type 2 diabetes.

Sales of Belviq have been disappointing, battering developer Arena. Commercial partner Eisai cut back marketing efforts since spring 2015. (Also see "Arena Looks To Partnering Strategy While Hoping For Belviq Resurrection" - Pink Sheet, 1 Mar, 2016.)

Photrexa Rounds Out Orphan Eye Condition Label With Second Claim

Avedro now has FDA approval for both of the orphan eye conditions requested in NDAs for its Photrexa ophthalmic riboflavin (vitamin B2) products, which are used as photoenhancers for use with the KXL System for corneal collagen cross-linking.

FDA had administratively separated the indications, treatment of progressive keratoconus and treatment of corneal ectasia following refractive surgery, and approved only the keratoconus claim on April 15, 2016. (Also see "Keeping Track: Mycapssa Stumbles; Carnexiv Returns; Keytruda Follows Opdivo In Hodgkin Lymphoma" - Pink Sheet, 25 Apr, 2016.)

FDA's July 15 approval letter for the corneal ectasia indication reveals that Avedro submitted a major amendment for that claim on April 15, extending the goal date by three months.

CSL Behring Berinert Boosts HAE Label In Pediatrics And Geriatrics

CSL Behring's Berinert became the only treatment for hereditary angioedema attacks indicated for patients under 12 years of age with an FDA approval announced July 18, the company emphasized.

Berinert, a plasma-derived C1 esterase inhibitor (human) for treatment of acute abdominal, facial, or laryngeal attacks of HAE, was initially approved by FDA in 2009 for adult and adolescent patients.

"In addition to the pediatric indication, the FDA approved an update to the Geriatric Use section of the package insert. The safety and efficacy of Berinert have been established in both children and adults, with safety profiles observed in the pediatric and geriatric populations similar to that observed in other populations," the company said.