Keeping Track: Poteligeo, Onpattro, Galafold And Annovera Approved; Selinexor Submitted

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

The US FDA maintained a torrid approval pace, capping the week with three novel approvals on Friday Aug. 10 to bring the Center for Drug Evaluation and Research’s (CDER's) annual count to 30.

Orphan diseases dominated the approved indications. Kyowa Hakko Kirin Co. Ltd.’s Poteligeo (mogamulizumab-kpkc), for two rare types of cutaneous T-cell lymphoma, and Alnylam Holding Co.’s Onpattro (patisiran), for patients with the rare genetic disease hereditary transthyretin-mediated amyloidosis, also carry breakthrough therapy designations. Amicus Therapeutics Inc.’ Galafold (migalastat), which received priority review but does not hold a breakthrough therapy designation, became the first new medicine for Fabry disease to clear FDA in 15 years.

The fourth approval, in contrast, received standard review for a mass market indication. The Population Council Inc.’s Annovera (segesterone/ethinyl estradiol), which contains a novel progestin, is intended for prevention of pregnancy for one year.

FDA also approved the second NDA this summer for the antiparasitic tafenoquine – [60 Degrees Pharmaceuticals LLC]’ Arakoda for malaria prophylaxis – as well as Ironshore Pharmaceuticals & Development Inc.’s formulation of the ADHD mainstay methylphenidate for nighttime dosing, Jornay PM.

The submission front, in contrast, was quiet, with Karyopharm Therapeutics Inc.’s first-in-class candidate for penta-refractory multiple myeloma, selinexor, as the only new drug application (NDA) announced. 

And Array Biopharma Inc.’s BRAF inhibitor/MEK inhibitor duo earned a breakthrough therapy designation for a biomarker-defined subset of colorectal cancer patients.

FDA Says Yes, siRNA: Alnylam’s Onpattro Becomes First Small Interfering RNA Therapy

FDA highlighted Onpattro as a “first-of-its-kind targeted RNA-based therapy” in announcing its Aug. 10 approval of the Alnylam small interfering RNA (siRNA) product for treatment of adult patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR).

FDA noted that Onpattro is the first treatment for hATTR polyneuropathy, but the technology milestone was the focus of the agency’s public communication. While FDA approval announcements typically include comments from the review division or office director, the Onpattro release quotes FDA Commissioner Scott Gottlieb saying “this approval is part of a broader wave of advances that allow us to treat disease by actually targeting the root cause, enabling us to arrest or reverse a condition, rather than only being able to slow its progression or treat its symptoms.”

“New technologies like RNA inhibitors, that alter the genetic drivers of a disease, have the potential to transform medicine,” Gottlieb said.

Alnylam also describes Onpattro in transformational terms. At the recent Biotechology Industry Organization (BIO) meeting, Alnylam CEO Joseph Maraganore told the Pink Sheet that “we’re not just launching patisiran this year. We’re launching Alnylam, and we’re launching RNAi therapeutics.”

“Onpattro encases the siRNA into a lipid nanoparticle to deliver the drug directly into the liver, in an infusion treatment, to alter or halt the production of disease-causing proteins.” FDA explained. Patisiran silences a portion of RNA that produces an abnormal form of the protein transthyretin (TTR). “By preventing the production of TTR, the drug can help reduce the accumulation of amyloid deposits in peripheral nerves, improving symptoms and helping patients better manage the condition.”

Onpattro is the beneficiary of multiple FDA incentives. The Alnylam product is designated a breakthrough therapy and received fast-track status and priority review, as well as an orphan drug designation.

The pivotal trial supporting Onpattro’s approval randomized 225 patients to Onpattro or placebo infused once every three weeks for 18 months. “Patients who received Onpattro had better outcomes on measures of polyneuropathy including muscle strength, sensation (pain, temperature, numbness), reflexes and autonomic symptoms (blood pressure, heart rate, digestion) compared to those receiving the placebo infusions,” FDA summarized. “Onpattro-treated patients also scored better on assessments of walking, nutritional status and the ability to perform activities of daily living.”

Patients should receive premedication to reduce infusion reactions as well as vitamin A supplements, labeling advises.

Alnylam has also conducted post-hoc analyses of the trial data, which are not included in labeling, showing an approximately 50% decrease in the composite rate of all-cause hospitalization and mortality over 18 months. (Also see "Alnylam Set For Transformation As Patisiran Nears Market With Data Upgrade" - Scrip, 25 Apr, 2018.)

The company is pursuing value-based agreements (VBA) with insurers, and its Onpattro approval announcement reported that it has reached an agreement in principle with Harvard Pilgrim Health Care and other insurers. “The goal of these agreements is to ensure that Alnylam is paid based on the ability of Onpattro to deliver outcomes in the real world setting comparable to those demonstrated in clinical trials,” the company explained. “The agreements are structured to link Onpattro’s performance in real-world use to financial terms.”

Alnylam is also working to increase diagnosis of hATTR. The company’s Alnylam Act program offers third-party genetic testing services in the US and Canada at no cost to patients and physicians.

Amicus Galafold Becomes First Precision Medicine For Fabry Disease

Amicus’ Galafold received accelerated approval Aug. 10 for treatment of adults with Fabry disease who have an amenable galactosidase alpha gene (GLA) variant based on in vitro assay data, making the drug the first precision medicine approved for the rare genetic disease. The approval covers 348 amenable GLA variants, Amicus said. Globally, the company estimates that 35%-50% of Fabry patients have a GLA mutation expected to be responsive to treatment.

Galafold is the first new drug for Fabry disease in the US in more than 15 years, as well as the first oral drug for the disease, according to Amicus.

“Thus far, treatment of Fabry disease has involved replacing the missing enzyme that causes the particular type of fat buildup in this disease,” FDA noted in its approval announcement. “Galafold differs from enzyme replacement in that it increases the activity of the body’s deficient enzyme.” Amicus explained that the drug stabilizes the patient’s own dysfunctional alpha-Galactosidase A enzyme so the body can clear disease substrate that builds up in the kidneys.

The approval caps a long development saga for Galafold, which was once partnered with GlaxoSmithKline. The NDA submission in December 2017 was itself something of a surprise: FDA had rejected the company’s plan to file the NDA for accelerated approval and asked for a new 12-month gastrointestinal study, which would not be available until 2019. The agency, however, reversed its position and agreed to the accelerated approval plan after Amicus provided new cardiac and renal data, new analyses of existing data, and long-term extension studies and real-world data from Europe, which approved Galafold in 2016. (Also see "FDA Reversal Gives Amicus Renewed Hope For US Oral Fabry Launch" - Pink Sheet, 11 Jul, 2017.)

Galafold’s efficacy for FDA approval was demonstrated in the FACETS trial, a 6-month, placebo-controlled Phase III trial in 45 patients. “In this trial, patients treated with Galafold over six months had a greater reduction in globotriaosylceramide (GL-3) in blood vessels of the kidneys (as measured in kidney biopsy samples) as compared to patients on placebo,” FDA summarized.

FDA Greenlights Population Council's Novel Vaginal Ring Contraceptive

Continuing on the scorching hot August approval train, FDA gave the thumbs up Aug. 10 to the Population Council for its combined hormonal contraceptive Annovera, which the agency describes as "the first vaginal ring contraceptive that can be used for an entire year."

Indicated for females of reproductive potential to prevent pregnancy, Annovera consists of a reusable donut-shaped ring that is placed in the vagina for a three-week period. It is then removed for one week – during which time a withdrawal bleed may occur –  before restarting the four-week cycle. Annovera features segesterone acetate, a progestin and a new molecular entity (NME), in combination with ethinyl estradiol, the widely used estrogen.

Efficacy was demonstrated in two one-year trials of 2,265 women ages 18-40, which yielded a pregnancy rate of 2.98 per 100 women, as evaluated by the Pearl Index (PI). In an Aug. 10 statement, the Population Council says nearly 89% of women surveyed were satisfied Annovera as a method of contraception.

Annovera's label contains a boxed warning for cigarette smoking and cardiovascular events, as do many ethinyl estradiol-containing products.

TherapeuticsMD Inc., which is licensing Annovera from the Population Council, expects the product to be commercially available as early as the third quarter of 2019, and commercially launched by the fourth quarter of 2019 or the first quarter of 2020.

Kyowa Kirin’s Poteligeo Joins Growing CTCL Market

FDA’s approval of Poteligeo on Aug. 8 includes two subtypes of cutaneous T-cell lymphoma – mycosis fungoides (MF), a slow-progressing lymphoma which accounts for 50%-70% of CTCL cases, and Sezary syndrome (SS), an aggressive, leukemic type of CTCL that accounts for around 3% of cases.

Poteligeo is the first drug approved specifically for SS, FDA noted, observing that both MF and SS “are rare, hard-to-treat types of non-Hodgkin lymphoma and this approval fills an unmet medical need.” Poteligeo holds a breakthrough therapy designation and orphan designation for the approved indication, treatment of adult MF or SS patients who have relapsed after at least one prior systemic therapy.

Kyowa Kirin’s Poteligeo will compete with Seattle Genetics Inc.’s Adcetris (brentuximab vedotin), which received FDA approval for a biomarker-defined indication for CD30-expressing MF in November 2017 on the basis of an objective response rate benefit. (Also see "Keeping Track: A Massive Week Of Agency Approvals" - Pink Sheet, 12 Nov, 2017.)

Potilegeo’s approval and breakthrough status both rested on the 372-patient Phase III MAVORIC trial, which Kyowa describes as the largest randomized trial ever conducted in CTCL as well as the first pivotal trial in CTCL to use progression-free survival as a primary endpoint. Potilegeo patients in MAVORIC had a median PFS of 7.6 months, compared with 3.1 months for patients in the chemotherapy control arm, who received Merck & Co. Inc.’s Zolinza (vorinostat).

Poteligeo labeling comes with several warnings to address risks including dermatologic toxicity, autoimmune problems, and complications of stem cell transplantation after treatment with Poteligeo. The approval comes with one required post-marketing study, which will characterize complications after allogeneic hematopoietic stem cell transplantation (HSCT) following mogamulizumab-kpkc in at least 50 patients with hematologic malignancies.

Ironshore’s Jornay PM Approved As First ADHD Stimulant For Nighttime Dosing

Ironshore Pharmaceuticals’ development plan for Jornay PM started with a desired pharmacokinetic profile and culminated in FDA approval on Aug. 8 for treatment of attention deficit hyperactivity disorder (ADHD) in patients six years and older.

The new formulation of methylphenidate is dosed in the evening (labeling recommends administration between 6:30 pm and 9:30 pm), but drug release is controlled by the company’s Delexis technology, which uses two functional film coatings. One layer delays initial release of drug for up to 10 hours, Ironshore said, while the second layer controls the rate of release throughout the day.

Ironshore conducted two Phase III trials to support the Jornay PM NDA, which enrolled 278 pediatric patients between 6 and 12 years of age. In addition to the traditional scales used to assess ADHD drug effect, the Ironshore trials also relied on the morning subscale of the Parent Rating of Evening and Morning Behavior-Revised (PREMB-R AM) scale and the Before School Functioning Questionnaire (BSFQ).

Ironshore submitted the Jornay PM NDA on Sept. 30, 2016, but received a complete response letter on July 28, 2017. The company submitted an amendment in response to the CRL on June 8, 2018. (Also see "Keeping Track: Tpoxx Wins Green Light For Smallpox, Submissions Galore, And A Broader Approval For Xtandi" - Pink Sheet, 15 Jul, 2018.)

Early BEACON Data Earns Array’s Braftovi/Mektovi A BTD In CRC

Results of the 30-patient safety lead-in portion of the ongoing Phase III BEACON CRC trial helped Braftovi and Mektovi, Array’s BRAF/MEK inhibitor duo, to a breakthrough therapy designation for patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC) as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease.

“BRAFV600E-mutant mCRC patients have a mortality risk more than double that of mCRC patients without the mutation, and currently there are no therapies specifically approved for this high unmet need population,” Array stated.

The BTD covers a triplet regimen of the BRAF inhibitor Braftovi (encorafenib) and MEK inhibitor Mektovi (binimetinib) and the EGFR inhibitor cetuximab (Eli Lilly & Co.'s Erbitux). The regimen is currently being studied in the 615-patient Phase III BEACON trial, which randomizes patients to the triplet combo or a control arm of irinotecan-based therapy plus chemotherapy.

Data from the safety lead-in portion of the trial caused a splash when they were reported at a European Society for Medical Oncology conference in June. The 30-patient lead-in had one-year overall survival rate of 62% and median PFS of 8 months. (Also see "Array Celebrates BEACON Of Hope For Anti-BRAF/MEK/EGFR Triplet In Colorectal Cancer" - Scrip, 25 Jun, 2018.)

Braftovi and Mektovi only recently entered the US market: FDA approved the duo June 27 to treat patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. (Also see "Keeping Track: Pre-Independence Day Fireworks Crackle At US FDA With Burst Of Approvals And Filings" - Pink Sheet, 30 Jun, 2018.)

60 Degrees Nabs Tafenoquine Approval With Precautionary Labeling On Psychiatric Effects

60 Degrees Pharmaceuticals has completed its second-place finish in the tafenoquine approval race with FDA's nod for Arakoda, which comes with a contraindication for patients with a history of psychotic disorders or current psychotic symptoms, along with a standard warning for psychiatric effects in the label.

The Aug. 6 approval specifically clears Arakoda for the prophylaxis of malaria in patients aged 18 years and older.

FDA's Antimicrobial Drugs Advisory Committee previously voted 11-2 in July that the antimalarial demonstrated substantial evidence efficacy for malaria prevention for up to six months of continuous dosing. However, several members called for precautionary language in the label about neuropsychiatric effects.  (Also see "60 Degrees’ Arakoda Gets US FDA Panel Nod For Malaria Prophylaxis" - Pink Sheet, 26 Jul, 2018.)

"Serious psychotic adverse reactions have been observed in patients with a history of psychosis or schizophrenia, at doses different from the approved dose," labeling states. "If psychotic symptoms (hallucinations, delusions, or grossly disorganized thinking or behavior) occur, consider discontinuation of Arakoda therapy and, evaluation by a mental health professional as soon as possible."

GlaxoSmithKline PLC's Krintafel – the first tafenoquine medication approved by the agency – also contains a standard warning about psychiatric effects in the label, although it does not contain a contraindication for patients with psychotic symptoms.  (Also see "GSK Moves Closer To Priority Review Voucher As US Panel Backs Malaria Drug Tafenoquine " - Pink Sheet, 12 Jul, 2018.) and (Also see "GSK Wins First-Ever Voucher Race With Anti-Malarial Approval" - Pink Sheet, 23 Jul, 2018.)

The Arakoda new drug application (NDA) included data from six randomized, double-blind, controlled, efficacy studies.  (Also see "Tafenoquine Redux: 60 Degrees Pharma’s Malaria Drug Gets Its Turn At US FDA Panel" - Pink Sheet, 24 Jul, 2018.)

Karyopharm Targets Highly Resistant Myeloma With Selinexor NDA

Karyopharm completed a rolling NDA submission for its first selective inhibitor of nuclear export (SINE) compound, selinexor, to treat patients with penta-refractory multiple myeloma, the company announced Aug. 6. Priority review would put the user fee goal at April 6, 2019 or earlier.

The selinexor NDA is seeking accelerated approval for multiple myeloma patients who have previously received the two FDA-approved proteasome inhibitors, Velcade (bortezomib) and Kyprolis (carfilzomib), the two immunomodulatory drugs, Revlimid (lenalidomide) and Pomalyst (pomalidomide), and the anti-CD38 monoclonal antibody Darzalex (daratumumab) as well as alkylating agents. Patients should also be refractory to at least one PI, at least one IMiD, Darzalex and their most recent therapy. 

Karyopharm recently reported top-line results from part 2 of the Phase IIb STORM study, in which selinexor patients had an overall response rate (ORR) of 25.4% and a 4.4 month median duration of response.

The company is already conducting a Phase III study, BOSTON, that it is designed to support full approval of selinexor after an accelerated approval based on STORM. The BOSTON trial, which is on track to complete its enrollment of 360 patients by year-end, is testing Velcade and low-dose dexamethasone with or without selinexor in multiple myeloma patients who have had one to three prior lines of therapy.

Fourth CRL Marks End Of The Road For Remoxy

As expected, Pain Therapeutics Inc.'s Remoxy (oxycodone extended-release) landed its fourth complete response letter from FDA, the company announced Aug. 6, putting an end to any future approval prospects for the abuse-deterrent opioid candidate.

PTI didn't disclose many details about the complete response letter, other than FDA felt "The data submitted in [the] NDA do not support the conclusion that the benefits of [REMOXY] Extended-Release Capsules outweigh the risks.”

In June, members of the Anesthetic and Analgesic Drug Products Advisory Committee and Drug Safety and Risk Management Advisory Committee voted 14-3 against approval of Remoxy, citing concerns about the safety of intravenous abuse.  (Also see "Not Another Opana: US FDA Panel Rejects PTI’s Remoxy On Intravenous Abuse Concerns" - Pink Sheet, 26 Jun, 2018.)

With the drug getting its fourth FDA rejection, PTI will now focus its resources on its assets in Alzheimer's disease. The company announced it will be disclosing the full details of a reorganization plan on a conference call "within weeks." 

PTI CEO Remi Barbier previously said that this would be the drugmaker's final run at an approval for Remoxy due to the agency's changing goalposts for abuse-deterrent opioid formulations. He further asserted that the drug did not receive a fair advisory committee meeting, and slammed FDA's comparison of Remoxy with Endo Pharmaceuticals Inc.'s Opana ER (oxymorphone extended-release). (Also see "PTI’s Remoxy: Negative FDA Panel Review May Be The End Of Abuse-Deterrent Opioid's Road" - Scrip, 28 Jun, 2018.)

In the Aug. 6 statement, Barbier once again offered some harsh words for the agency following the decision.

“This is a bizarre conclusion to reach, especially during a time of staggering human and economic toll created by opioid abuse and addiction,” he stated. “We have an innovative drug with a social purpose, and a staggering amount of data that easily supports best-in-class abuse deterrence versus OxyContin.  We relied on the criteria of a fair, neutral and impartial regulatory review, as any sponsor would.  Instead, I believe Remoxy received an ideological judgement call that is vague in nature but conclusive in its damaging effects.”

FDA issued the first two complete response letters for Remoxy in December 2008 and June 2011, which were largely related to commercial manufacturing and non-clinical data. The third complete response came in September 2016, as the agency called for PTI to conduct a human intranasal abuse liability study and additional laboratory-based in vitro manipulation and extraction studies. After the 2016 rejection, PTI ruled out the possibility of obtaining an abuse-deterrent claim for the oral route. (Also see "PTI's Remoxy: US FDA Panel To Weigh Intranasal Abuse Deterrence Against Oral Abuse Potential" - Pink Sheet, 25 Jun, 2018.)