Keeping Track: A Burst Of Breakthroughs, A Priority Review For Keytruda, And Some Supplemental Submissions

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

Here's your US review and approval news for the week in brief: Three more companies picked up breakthrough therapy designations this week – Alnylam Pharmaceuticals Inc., Proteostasis Therapeutics Inc. and Janssen Pharmaceutical Cos. – in what continues to be a busy year for the expedited pathway.

Merck & Co. Inc.'s PD-1 inhibitor Keytruda (pembrolizumab) scored a priority review for a cervical cancer indication, putting the supplemental biologics license application (sBLA) in line for a late June approval.

Merz GMBH & Co. KGAA has filed an sBLA for Xeomin (incobotulinumtoxinA), positioning the neurotoxin to be the first indicated for the treatment of chronic sialorrhea due a series of neurologic disorders, and Exelixis Inc. filed a supplemental new drug application (sNDA) with FDA for Cabometyx (cabozantinib) for the second-line-plus treatment of hepatocellular carcinoma (HCC),

Additionally, FDA approved a supplemental indication for CSL Behring's Hizentra (immune globulin subcutaneous [human] 20% liquid) for maintenance therapy in adults with chronic inflammatory demyelinating polyneuropathy (CIDP).

And now, your news in less brief:

BTD Could Put Alnylam's Lumasiran On Track For First PH1 Approval

Alnylam may be in position to win the first FDA approval for a primary hyperoxaluria type 1 (PH1) treatment by scoring breakthrough therapy status for its investigational RNA interference (RNAi) treatment lumasiran.

An ultra-rare disease with no approved treatment, PH1 involves excessive oxalate production resulting in calcium oxalate crystal deposition in the kidneys and urinary tract, which can lead to the formation of painful and recurrent kidney stones or nephrocalcinosis.

The breakthrough status is based on Phase I/II data, according to a March 12 announcement, where eight patients across two cohorts ranging from ages 6 to 19 were dosed with lumasiran or placebo on a 3 to 1 ratio. Patients in the first cohort demonstrated a mean maximal reduction in urinary oxalate of 66% after receiving 1 mg/kg monthly for three months. In the second cohort, which is still ongoing, patients have finished their first of three monthly 3mg/kg doses, showing a 47% mean reduction in urinary oxalate output relative to baseline.

"These initial results support the hypothesis that GO inhibition has the potential to reduce and possibly normalize levels of hepatic oxalate production, thus potentially halting PH1 disease progression," Alnylam said in a November 2017 statement.

Alnylam says it plans to begin a Phase III pivotal study in late 2018.

OxThera AB announced March 5 that it had randomized its first patient in its Phase III EPHEX trial for its PH treatment Oxabact. However, it does not appear to have breakthrough therapy status, which could give Alnylam a leg up in being the first to reach the market. Separately, Allena Pharmaceuticals Inc. has begun Phase III development for its enteric hyperoxaluria – a form of secondary hyperoxaluria – candidate ALLN-177. (Also see "Alnylam Plans Lumasiran Phase III As Market Landscape Gets Competitive" - Scrip, 13 Mar, 2018.)

Priority Review Positions Keytruda For Summertime Approval In Cervical Cancer

Merck's Keytruda is eying for an early summer approval with a priority review for its first cervical cancer indication, in what could be the PD-1 inhibitor's twelfth overall FDA-backed indication.

The agency awarded Keytruda a Prescription Drug User Fee Act (PDUFA) date of June 28, the drugmaker announced March 13, as it pursues accelerated approval for the treatment of advanced cervical cancer with disease progression on or after chemotherapy.

Merck says the priority review is based in part on data from the ongoing open-label Phase II KEYNOTE-158 trial. According to interim results of the trial presented at the American Society of Clinical Oncology (ASCO) annual meeting in June 2017, the overall response rate (ORR) was 17%, with three confirmed and five unconfirmed responses.

Keytruda is currently approved for 10 indications across the areas of melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma, urothelial carcinoma microsatellite instability-high cancer and gastric cancer. (Also see "FDA Approval Round Up: Keytruda, Opdivo Add Claims" - Pink Sheet, 24 Sep, 2017.) It is additionally under a priority review for the treatment of adult and pediatric patients with refractory primary mediastinal B-cell lymphoma (PMBCL). (Also see "Keeping Track: Approvals, A Burst Of Submissions, And Some Priority Reviews" - Pink Sheet, 16 Dec, 2017.)

Merz Eyes New Market For Neurotoxins With Xeomin Sialorrhea Filing

Merz' Xeomin is in position to be the first neurotoxin indicated for the treatment of chronic sialorrhea, or excessive drooling, due to Parkinson’s disease, stroke or other neurologic disorders in adults.

Merz expects an FDA decision on the sBLA for the new use of Xeomin in the fourth quarter of 2018. Given Merz' March 14, 2018 announcement of the sBLA acceptance, a standard review would place the user fee around November. As one of the later entrants into the botulinum toxin market that is dominated by Allergan PLC's Botox (onabotulinumtoxinA), Merz had had to look beyond the core spasticity and dystonia and aesthetics markets for neurotoxins. The company comes to the adult sialorrhea space with five years of commercial experience with an anticholinergic drug, Cuvposa (glycopyrrolate oral solution), for children ages 3-16 years with chronic severe drooling associated with neurological conditions like cerebral palsy.

The sBLA is based on the 184-patient Phase III SIAXI trial, which evaluated a single treatment of Xeomin administered in four injections into bilateral parotid and bilateral submandibular salivary glands. The higher of the two Xeomin doses tested showed statistically significant improvement over placebo on both co-primary endpoints, change in unstimulated salivary flow rate (uSFR) and physician Global Impression of Change Scale (GICS), at week four, according to Merz.

Proteostasis' PTI-428 Is First CF BTD For A Company Other Than Vertex

Proteostasis is looking not to challenge but to join Vertex in the cystic fibrosis space with PTI-428, a cystic fibrosis transmembrane conductance regulator (CFTR) amplifier that is being studied as an add-on to Vertex Pharmaceuticals Inc.'s blockbuster Orkambi (lumacaftor/ivacaftor).

Vertex has dominated the cystic fibrosis space since it inaugurated the CFTR modulator class with ivacaftor, which was first approved as a single agent (Kalydeco). Prior to granting the breakthrough therapy designation to Proteostasis, FDA had issued three breakthrough therapy designationd for treatment of cystic fibrosis – all to Vertex. [For more detail on BTD products, see the Pink Sheet's Breakthrough Therapy Designations chart in our FDA Performance Tracker.]

The BTD for PTI-428, announced March 12, is for treatment of CF in patients who are homozygous for the F508del mutation who are receiving Orkambi as background therapy. 

"PTI-428 works early during CFTR biogenesis to increase levels of newly synthesized CFTR protein," Proteostasis said. Orkambi contains a CFTR corrector (lumacaftor), which helps CFTR proteins reach the cell surface, and a CFTR potentiator (ivacaftor), which opens CFTR protein channels on the cell surface.

The Proteostasis BTD is based on results of a 24-patient Phase II trial that added PTI-428 or placebo once daily for 28 days to background Orkambi therapy. "Treatment with PTI-428 led to mean absolute improvement in percent predicted forced expiratory volume in 1 second (ppFEV1) of 5.2 percentage points from baseline through Day 28 compared to placebo," Proteostasis reported.

"Additionally, consistent with the CFTR amplifier mechanism of action, a positive increase in nasal mucosal CFTR protein was observed in PTI-428 treated subjects and the magnitude of change compared to baseline was consistent with the changes in CFTR protein levels observed in the in vitro human bronchial cell model, whereas the placebo subjects had no significant increase in CFTR protein during the treatment period," the company pointed out.

Proteostasis is developing PTI-428 as one of a suite of novel CFTR modulators for use in multiple combination settings. Results of a proof-of-concept study of PTI-428 plus Kalydeco are expected in the first half of 2018, with POC results in the second half for a triple combination of PTI-428 with two other novel Proteostasis candidates, the CFTR potentiator PTI-808 and the next-generation CFTR corrector PTI-801.

Janssen Rides Phase II Data To BTD For Bladder Cancer Candidate

In the third breakthrough therapy status announced this week, Janssen picked up the expedited designation for its pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib following its showing in a Phase II study of bladder cancer patients.

The breakthrough therapy designation for treatment of metastatic urothelial cancer is based on data from the Phase II BLC2001 trial, which enrolled relapsed or refractory mUC patients with actionable FGFR gene mutations; a Janssen assay was used to screen for FGFR status at a central lab.

The open-label Phase II found an overall response rate of 42% in 59 FGFR mutation-positive mUC patients, Janssen reported.

A Phase III trial is already planned for erdafitinib, with an anticipated spring 2018 start date, according the federal clinicaltrials.gov database. The trial will compare the targeted therapy erdafitinib to a PD-1 inhibitor immunotherapy – Merck's Keytruda – or chemotherapy (vinflunine or docetaxel) in 631 advanced urothelial cancer patients who progressed on or after one prior line of systemic therapy. Patients must have a selected FGFR aberration, identified with the FGFR clinical trial assay.

Exelixis Sends Cabometyx To FDA For HCC Indication With Eye On Unmet Need

Exelixis has filed an sNDA with FDA for a second-line-plus indication for Cabometyx to treat HCC, as the company looks to fill a need for the many patients who progress after first-line therapy.

“We look forward to working closely with regulatory authorities through the review process in anticipation of bringing Cabometx to people diagnosed with advanced hepatocellular carcinoma, an underserved patient community that urgently needs new treatment options,” Exelixis Chief Medical Officer Gisela Schwab said in a March 15 statement.

In the Phase III CELESTIAL study, Cabometyx demonstrated a statistically significant improvement in overall survival (OS) compared with placebo in second- and third-line patients. Median OS in the treatment arm was 10.2 months versus 8.0 months in the placebo arm. Additionally, patients taking Cabometyx had an objective response rate of 4%, while patients taking placebo had a rate of 0.4%.

In the commercial space, however, Cabometyx may have trouble competing with Bristol-Myers Squibb Co.'s Opdivo (nivolumab) and Keytruda. FDA approved Opdivo in September for the second-line treatment of HCC, and demonstrated a higher objective response rate than Cabometyx did in clinical development.  Keytruda is currently in clinical development for HCC, and also achieved a higher objective response rate than Cabometyx. (Also see "Exelixis' CELESTIAL Liver Trial Succeeds, But Can Cabozantinib Compete?" - Scrip, 22 Jan, 2018.)

A standard review would position the HCC indication for an approval by January 2019 or earlier, while a priority review would slate the PDUFA date for September 2017 or earlier.

Cabozantinib is currently approved for the treatment of advanced renal cell carcinoma (RCC) under the brand name Cabometyx, for the treatment of thyroid cancer under the brand name Cometriq.

CSL Behring Adds CIDP Indication To Hizentra

FDA has given its blessing to CSL Behring's sBLA for Hizentra for the treatment of CIDP as maintenance therapy to prevent relapse of neuromuscular disability and impairment, which the company says is now the only subcutaneous immunoglobulin with the indication.

A rare autoimmune disorder, CIDP affects the peripheral nerves and has the potential to cause permanent nerve damage.

The approval is based on the randomized, placebo-controlled Phase III PATH study, which CSL Behring called "the largest controlled clinical study in CIDP patients to date. (Also see "Keeping Track: Merck's Follow-On Insulin Edges Closer To Market; Braeburn Submits Another Buprenorphine Depot" - Pink Sheet, 24 Jul, 2017.)

Hizentra is also approved for the treatment of primary immunodeficiency in adults and pediatric patients ages 2 and older.