Keeping Track: A Massive Week Of Agency Approvals

The latest drug approval and development news from our US FDA Performance Tracker.

Here's your news in brief: Approvals galore was the theme of the week, with the US FDA approving at least nine product applications. The biggest regulatory development was clearance of the first indication based on a basket trial, Genentech Inc.'s supplemental approval of its kinase inhibitor Zelboraf (vemurafenib) for the treatment of patients with Erdheim-Chester Disease (ECD) with a BRAF V600 mutation.

Most notably in original approvals, the agency finally gave its blessing to Dynavax Technologies Corp.'s hepatitis B vaccine Heplisav-B (rHBsAg-1018 ISS), which had to overcome a series of setbacks following the initial submission in 2012.

Merck & Co. Inc.'s cytomegalovirus (CMV) infection and disease prevention treatment Prevymis (letermovir) also made it into the spotlight in what became new drug approval No. 38 for 2017.

Ionis Pharmaceuticals Inc. additionally filed a new drug application (NDA) for its hereditary TTR amyloidosis (hATTR) treatment inotersen, despite some concerning Phase III safety data unveiled earlier this year.

And here's your news in less brief:

Heplisav Gets FDA Greenlight Following Five Year Plus Regulatory Journey

It took two complete response letters and a three-month delay in the user fee goal date, but Dynavax finally reeled in a US FDA approval for its hepatitis B vaccine Heplisav-B more than five years after it submitted its first biologics license application (BLA) for the vaccine in June 2012.

The approval, announced Nov. 9, covers the prevention of infection caused by all known subtypes of hepatitis B virus in adults age 18 years and older.

Heplisav-B's efficacy has not been in question. In the largest of three Phase III trials, Dynavax's adjuvanted vaccine demonstrated a statistically significantly higher rate of protection of 95% versus 81% for GlaxoSmithKline PLC's hepatitis B vaccine Engerix-B.

FDA's concerns were related to the safety of the vaccine, as patients taking Heplisav-B in clinical development experienced higher rates of death and myocardial infarction than patients taking GSK's hepatitis B vaccine Engerix-B, which acted as the comparator. (Also see "Heplisav Vaccine Postmarketing Study Might Overcome FDA Safety Worries At Panel" - Pink Sheet, 26 Jul, 2017.)

In a July meeting, the agency's Vaccines and Related Biological Products Committee voted 12 to 1, with three abstentions, that the available data support the safety of Heplisav-B when administered to adults 18 years and older. Several panelists, however, wanted to see a stronger postmarketing proposal to assess the vaccine's safety. (Also see "Heplisav Seems Headed For Approval, But With More Robust Postmarketing Study" - Pink Sheet, 30 Jul, 2017.)

Dynavax CEO Eddie Gray said in a Nov. 9 conference call that the postmarketing study – which will take place at Kaiser Permanente Northern California – will enroll 50,000 patients, including 25,000 Heplisav-B patients and 25,000 Engerix-B patients, over approximately 10 months and follow them for one year after vaccination to evaluate the risk of acute myocardial infarction. This is an increase from the 40,000 patient-proposal the company initially proposed.
(Also see "Dynavax's Hep B Vaccine Finally Clears US FDA With Clean Label But Larger Safety Study" - Pink Sheet, 12 Nov, 2017.)

The study will additionally evaluate the rate of immune-mediated diseases in these patients.

In the days leading up to Heplisav-B's initial Aug. 10 Prescription Drug User Fee Action (PDUFA) date, FDA pushed the goal date forward by three months with a request for more information to ensure Dynavax has robust plans for a postmarketing study. (Also see "Heplisav Postmarketing Worries Push PDUFA Date Back; FDA Seeks More Details" - Pink Sheet, 4 Aug, 2017.)

The vaccine has nevertheless overcome a rocky road to approval, which included two previous complete response letters. One issued in 2013 was related to an insufficient safety database size, and the other issued in 2016 involved a series of outstanding questions FDA had about the vaccine. (Also see "Heplisav Vaccine Postmarketing Study Might Overcome FDA Safety Worries At Panel" - Pink Sheet, 26 Jul, 2017.)

Dynavax's selling point for Heplisav-B has been its two-dose regimen, while other hepatitis B vaccines on the US market have a three-dose regimen, including Engerix-B, Merck & Co. Inc.'s Recombivax HB, and GSK's combination vaccine Twinrix, which includes a hepatitis A vaccine component. Engerix-B and Recombivax HB, however, are approved for infants and children as well as adults. (Also see "Heplisav Vaccine Postmarketing Study Might Overcome FDA Safety Worries At Panel" - Pink Sheet, 26 Jul, 2017.)

The company expects to launch the vaccine in the first quarter of 2018. Gray noted in the conference call that the price will be disclosed closer to the launch date.

Also of note was that FDA approved Heplisav-B without a distinguishing, arbitrary four-letter suffix to add to the nonproprietary name. The agency has maintained that new biologic products approved since release of the guidance did not include suffixes as to avoid disrupting the ongoing reviews of the products and the agency's public health mission. But Dynavax submitted its biologics license application (BLA) for the vaccine in February, which was after the guidance on non-proprietary naming was released in January.

The nonproprietary naming guidance appears to apply to vaccines. However, a Dynavax spokeswoman tells the Pink Sheet that said that company did not include a proposal for a four-letter suffix when it submitted the BLA in February, and that FDA did not request the company to develop and submit one in the pre- or post-approval setting.

FDA Approves Merck's First-In-Class CMV Therapy

The other major highlight of the week in the novel product arena was FDA's Nov. 8 approval of Merck's first-in-class terminase complex inhibitor Prevymis (letermovir) for the prevention of cytomegalovirus (CMV) infection and disease in adult patients who have been exposed to CMV and have received a bone marrow transplant.

Approved in both tablet and injectable forms, Prevymis, unlike currently marketed therapies, is not a nucleoside derivative, but rather a quinazoline, and has no activity against other viruses.

Prevymis has also won the race against a series of a new generation of anti-CMV agents that are nearing the market. (Also see "New Anti-CMV Therapies Post-Transplant: Merck & Co Leads The Pack" - Scrip, 2 Mar, 2017.) Merck said in a statement that Prevymis is the first CMV infection drug approved in the US in 15 years.

In the pivotal Phase III trial, only 38% of patients in the Prevymis arm developed clinically significant CMV infection, discontinued treatment or had missing data through week 24 post-bone marrow transplant, compared with 61% of patients in the placebo arm.

FDA previously awarded Prevymis breakthrough therapy designation and orphan drug status. Merck expects to launch Prevymis in December with a list price of $195 per day for the tablets and $270 per day for the injection.

Alecensa, Zelborag Also Highlight Busy Week Of Approvals

FDA's backing Heplisav-B and Prevymis was hardly the only approval news of the week, as the agency approved a slew of supplemental indications.

It was a particularly positive week for Genentech,  which scored several victories at FDA. The Roche unit picked up a supplemental approval for its kinase inhibitor Alecensa as a first line treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test, the company announced Nov. 6.

Alecensa demonstrated a statistically significant, 47% reduction in progression-free survival (PFS) compared with crizotinib – a Pfizer Inc. kinase inhibitor sold under the brand name Xalkori – in the Phase III ALEX study. Median PFS was 25.7 months in the Alecensa arm versus 10.4 months for the crizotinib arm.

Genentech previously snagged a breakthrough therapy designation for Alcensa for the treatment of adults with advanced ALK-positive NSCLC who have not received prior treatment with an ALK inhibitor.

In addition, FDA also granted full approval to Alecensa's second-line indication. The agency initially awarded accelerated approval to Alecensa in December 2015 for the treatment of subjects with ALK-positive, metastatic NSCLC who have progressed on or are intolerant to crizotinib. The ALEX trial also supported the full approval of Alecensa. (Also see "Keeping Track: US FDA Approvals Of Mavyret, Idhifa, Vyxeos Headline Week Of Breakthroughs, Hematology And Hematology BTDs" - Pink Sheet, 4 Aug, 2017.)

Genentech stayed in the news throughout the week by reeling in a supplemental approval Nov. 6 for Zelboraf  for ECD with a BRAF V600 mutation. In addition to becoming the first FDA-backed treatment for the rare blood cancer, Zelboraf also became the first drug approved solely based on a basket trial. The supplemental new drug application (sNDA) relied on data from the tumor histology-independent Phase II VE-BASKET trial. The trial studied 22 ECD patients with the BRAF V600 mutation, 11 of which demonstrated a partial response, with one other patient experiencing a full response. The overall response rate was 54.5%. (Also see "Keeping Track: Zelboraf Takes Breakthrough Path For Rare Blood Disease; Teva Resubmits Generic EpiPen" - Pink Sheet, 11 Aug, 2017.)

FDA awarded Zelboraf breakthrough and priority review designations for the ECD indication, reinforcing the agency's interest in innovative precision medicine clinical trial designs in orphan settings. Zelboraf also received an orphan drug designation for the indication. (Also see "Master Protocols Are Both Welcome And Inevitable – US FDA's Woodcock" - Pink Sheet, 6 Jul, 2017.)

Zelboraf was first approved in August 2011 for the treatment of for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation.

Other approvals for the week include:

• Seattle Genetics Inc.'s Adcetris (brentuximab vedotin) for the treatment of adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) and CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy. In the Phase III ALCANZA trial, Adcetris met the primary endpoint of statistically significant improvement in objective response rate lasting at least four months versus standard of care options. The objective response rates were 56.3% and 12.5%, respectively. The approval gives Adcetris its fourth indication, with others including full approvals for two classical Hodgkin lymphoma indications, as well as accelerated approval for treatment of systemic anaplastic large cell lymphoma.
• UCB Group's Vimpat (lacosamide) as an oral option for the treatment of partial-onset seizures in pediatric patients ages four and older. The drug was initially approved in 2008 for the treatment of adults ages 17 and older. Vimpat's new pediatric approval applies only to the oral tablet and solutions formulation, and not the intravenous formulation.
• Bristol-Myers Squibb Co.'s Sprycel (dasatinib) tablets to include the treatment of children with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. The safety and efficacy of Sprycel were tested in 97 pediatric patients across two studies. The pediatric indication does not include specific ages, a Bristol spokeswoman tells the Pink Sheet, who noted that patients participating in clinical trials ranged from 1.9 to 20 years old. FDA previously granted priority review status and orphan drug designation to the pediatric indication.
• The addition of data to the labeling of Collegium Pharmaceutical Inc.'s Xtampza ER (oxycodone extended-release tablets). The main enhancements of the labeling include comparative pharmacokinetic data with OxyContin (oxycodone HCL) and an oral abuse deterrent claim. Collegium CEO Michael Heffernan said in a Nov. 7 statement that Xtampza ER is the only single agent oxycodone with oral, intranasal and intravenous abuse deterrent labelling.
• Keryx Biopharmaceuticals Inc.'s Auryxia (ferric citrate) for the treatment of iron deficiency anemia in adults with chronic kidney disease and not on dialysis. In a 234-patient Phase III trial, 52.1% of patients taking Auryxia demonstrated significant increases in hemoglobin levels of greater than 1 g/dL at any point during the 16-week efficacy period compared with 19.1% of patients in the placebo group. FDA first approved Auryxia in September 2014 for the control of serum phosphorus levels in people with chronic kidney disease who require dialysis.

Ionis Submits Inotersen NDA Amid Concerns About Safety Data

Ionis announced Nov. 6 that has filed an NDA for its hATTR treatment inotersen (IONIS-TTRRx) six months after that company announced results from its Phase III NEURO-TTR study, which revealed some serious safety issues.

The company announced in May that inotersen met the primary endpoints on measures of Neuropathy Impairment Score+7 (mNIS+7) and the Norfolk Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN). There were, however four serious adverse thrombocytopenia events, with one patient due to intracranial hemorrhage. There were additionally five severe adverse renal events, including one case of chronic renal insufficiency. (Also see "Ionis Touts Inotersen's Convenience As Phase III Safety Data Disappoints" - Scrip, 15 May, 2017.)

Inotersen, designed with Ionis's antisense platform, is a once-weekly subcutaneously-delivered treatment that inhibits the production of transthyretin (TTR).

Ionis has touted the convenience of inotersen versus that of a potential competitor: Alnylam Pharmaceuticals Inc.'s patisiran. Patisiran is given every three weeks by infusion in a healthcare provider's office and involves pre-treatment with high doses of steroids, as well as antihistamines and analgesics to prevent reactions. Inotersen is administered at home and does not require high-dose steroids.

Alnylam has recently completed its Phase III trial for patisiran, but has not yet filed the drug with FDA.

Cellvation Wins RMAT For Tramautic Brain Injury Therapy

FDA has granted a Regenerative Medicine Advanced Therapy (RMAT) designation to Fortress Biotech Inc. unit Cellvation Inc. for its traumatic brain injury treatment CEVA101 (autologous bone marrow-derived stem cells).

CEVA101 is currently undergoing placebo-controlled Phase II trials, one for adults ages 18-55 and one for children ages 5 to 17.