 the biologics license application (BLA), for priority review, for etranacogene dezaparvovec (also known as CSL222), an investigational gene therapy for the treatment of adults with hemophilia B. The clinical development program for etranacogene dezaparvovec was led by uniQure, and CSL Behring has acquired global rights to commercialize the investigational treatment.

Etranacogene dezaparvovec was specifically designed to make near-normal blood-clotting ability possible by addressing the underlying cause of hemophilia B: a faulty gene that causes a deficiency in clotting Factor IX. The therapy uses an adeno-associated virus as a vector that carries the Padua gene variant of Factor IX, which generates Factor IX proteins.

Etranacogene dezaparvovec has been shown in clinical trials to significantly reduce the rate of annual bleeds in people with hemophilia B after a single one-time infusion, and if approved, would be the first ever gene therapy treatment option for the hemophilia B community.

 from the pivotal HOPE-B trial, the largest gene therapy trial in hemophilia B to date. People with hemophilia B treated with etranacogene dezaparvovec demonstrated reduced adjusted annualized bleeding rate by 64% and superiority to prophylaxis treatment at 18 months post-treatment compared with a 6-month run in period.

The majority of adverse events (80.4%) were considered mild. One death occurred during the clinical trial and was considered unrelated to treatment by investigators. A serious adverse event of hepatocellular carcinoma was determined to be unrelated to treatment. No inhibitors to Factor IX were reported.

Articles


If approved, etranacogene dezaparvovec would be the first gene therapy for patients with hemophilia B. An FDA decision is expected in November 2022.



FDA Accepts BLA for Hemophilia B Gene Therapy

Denise Myshko is your editorial contact for the Formulary Watch. She joined Formulary Watch as editor is June 2021 from Oncology Live. Prior to that, she was managing editor of PharmaVOICE, a trade publication in the pharmaceutical industry. Email: dmyshko@mjhlifesciences.com

The Institute for Clinical and Economic Review (ICER) 

 the protocol for its second annual review of insurance company policies to assess fair access to prescription drugs. ICER will evaluate whether 15 large U.S. commercial payers, the two largest state health exchange plans, and the Department of Veterans Affairs have formularies and procedures that provide appropriate access to the prescription drugs reviewed by ICER in 2020. These drugs include those that treat patients with 

The analysis is expected to be completed in November 2022.

“The extent to which insurance coverage for drugs provides fair access to patients is not something that has been looked at systematically. It’s definitely an understudied area,” Molly Beinfeld, senior research lead, evidence synthesis at ICER, said in an interview with 

She said the goal of ICER’s first assessment, which was released in December 2021, was to show the organization’s methods. “There were a lot of limitations, so the second annual report will build on that initial body of work.”

 ICER analysts found that most of the payer pharmacy and medical policies available for review were structured to support fair access to medications. In 67 (96%), ICER rated the payer’s policies as consistent for all fair access criteria.

But ICER reviewers were unable to assess the full set of information for all drugs for all insurers. The database used, MMIT’s market access analytics solution, did not include all policies or coverage because those policies were not available from the payers. Tiering information or prior authorization and step policies could not be determined for all insurers.

“The biggest issue we found was the lack of transparency,” Beinfeld said. “We’re trying to do this in a systematic way, and we're trying to get equal amount of information for each payer. That just wasn’t possible. We call on insurers to make both their prior authorization criteria and cost-sharing information available to consumers prior to enrollment. This way, they can make informed decisions.”

The 2021 assessment reviewed drugs that ICER had considered cost-effective. The next review will include both therapies that are cost-effective, as well as those that ICER says are not priced fairly. “We believe there is a relationship between cost and access. So, the higher the cost, the more access issues. Some of the areas that we’re looking at moving forward, like cystic fibrosis and sickle cell disease, are drugs that were priced very high. We want to see what kind of barriers have been put in front of patients.”

ICER outlined a set of criteria for establishing for how it would assess fair access in a white paper in September 2020. The company has developed four key areas for reviewing fair access: cost-sharing, eligibility criteria, step therapy, and prescriber restrictions. These areas aim to balance the need for cost control with appropriate cost-sharing and utilization management strategies.

“In this world of very high-priced drugs, it is appropriate to limit access to patients who will benefit most from that drug for whom there isn’t a harm,” Beinfeld said. “But this should not be limited to the point where it narrows the population of eligible patients, relative to the common standards, such as the FDA label, or clinical guidelines, for example.”

On the clinical side, any limitations on access should be based on evidence, Beinfeld said. ICER looks at both the drug label and clinical guidelines. For example, in eczema, drug labels can be broad. “We will look at the coverage policy to see how it defines moderate to severe, for example, and we’ll look to see if the coverage policy is using a definition that’s stricter than a clinical guideline might say.”

If an insurer limits coverage to patients who are more severe than a clinical guideline, ICER would issue a fail on clinical eligibility. “Oftentimes, we did find examples where payers would limit the eligible population to something that isn’t a part of the label.”

Several payers changed their policies after ICER spoke with them. These include 10 coverage policies from six companies. (See table below.) In some cases, these changes were minor clarifications of clinical eligibility criteria, but other policy changes included more substantial broadening of coverage or important shifts in tiering placement that would lead to lower out-of-pocket cost sharing.

One insurer, for example, was limiting access to Dupixent (dupilumab), developed by Sanofi and Regeneron, to patients who had moderate-to-severe atopic dermatitis for more than three years. “The three-year requirement was arbitrary,” Beinfeld said. “That’s the kind of narrowing of the population who could get access in a non-evidenced-based way.”

Beinfeld also said ICER also looks at prior authorization closely in its analysis. “We look at whether a patient is eligible for therapy from a clinical perspective. Does the patient meet the definition of severity of the disease? We also look at what the step therapy requirements are or what are the other treatments that patients are going to have start with. ICER’s stated position is that patients should have at least one alternative among a class of drugs in the lowest relevant tier of the formulary.”

In the next assessment, Beinfeld said, ICER has added another dimension for review: documentation burden, including how difficult is it to get prior authorization, how transparent are the prior authorization requirements, and how easy is it for patients to access information before enrolling about the cost sharing and clinical eligibility requirements.

Table: Changes to Payer Policies after June 30, 2021

Removed its prior authorization criteria for sacubitril/valsartan, effective August 1, 2021

Added rimegepant to its formulary in a preferred brand position, effective October 1, 2021

Added ubrogepant to its formulary in a preferred brand position, effective October 1, 2021

Updated step therapy criteria for alirocumab to no longer require additional trials of statins for patients who are stable on a high-potency statin in combination with ezetimibe. This change is effective July 1, 2021

Updated clinical eligibility criteria for brodalumab and other non-preferred drugs to require a diagnosis of moderate-to-severe plaque psoriasis (previously severe plaque psoriasis).ICER was alerted to this change on August 30, 2021

Will be moving elagolix from its specialty tier to Tier 2 (Preferred Brand), effective January 1, 2022.

Moved dupilumab from Tier 3 (Non-Preferred Brand) to Tier 2 (Preferred Brand), effective October 1, 2021

Moved ubrogepant from Tier 3 (Non-Preferred Brand) to Tier 2 (Preferred Brand), effective October 1, 2021

Moved rimegepant from Tier 3 (Non-Preferred Brand) to Tier 2 (Preferred Brand), effective October 1, 2021

Removed criteria that differentiates between symptomatic infantile onset and later onset SMA, effective July 1, 2021

Molly Beinfeld, senior research lead, evidence synthesis at the Institute for Clinical and Economic Review, talks about the organization’s research assessing payer coverage policies of prescription drugs.

Shining Light on the Barriers Payers Place on Medications

Teva Pharmaceuticals has initiated a voluntary nationwide 

 of a single lot of anagrelide capsules, 0.5 mg. This recall was initiated due to dissolution test failure detected during routine stability testing. No other lots are impacted.

Anagrelide is used to decrease the number of platelets and is indicated to treat patients with thrombocythemia (a condition in which the body makes too many platelets), secondary to myeloproliferative neoplasms, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events

Taking longer to dissolve once ingested may result in decreased effectiveness or ineffectiveness of the drug to exert its platelet-reducing effect. Failed dissolution can result in a slower rate and extent of drug release leading to less anagrelide available in the body.

For seriously ill patients with elevated platelet counts, less available anagrelide in the body could increase the risk of clotting (blood coagulation), and clotting or bleeding events such as a heart attack or stroke, which could be life threatening

Teva has not received any reports of adverse events.

The effect lot is GD01090 and has an expiration date of May 2022.

The impacted lot failed a dissolution test, meaning it was taking longer to dissolve once ingested. This can result in less anagrelide available in the body, possibly leading to clotting or bleeding events such as a heart attack or stroke.

Teva Recalls One Lot of Anagrelide

The FDA has approved Vtama (tapinarof) for the topical treatment of plaque psoriasis in adults. This is the first steroid-free topical medication in its class. It is approved for mild, moderate, and severe psoriasis with no restrictions on duration of use. Vtama was developed by Dermavant Sciences, a subsidiary of Roivant Sciences.

Vtama is an aryl hydrocarbon receptor agonist and modifies the expression of interleukin-17 and the skin barrier proteins filaggrin and loricrin, which are involved in psoriasis.

“Following 20-plus years of minimal innovation in the topical psoriasis treatment space, I believe the approval of Vtama cream is an important step in establishing a new treatment option for adults with mild, moderate and severe plaque psoriasis,” Mark Lebwohl, M.D., said in a 

. He is dean for Clinical Therapeutics and Waldman Professor and chairman emeritus of the Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai in New York and lead author of the phase 3 studies of Vtama 

In the pivotal phase 3 clinical trial program, Vtama met all primary and secondary endpoints and demonstrated highly statistically-significant improvement with 36% of patients in the PSOARING 1 trial and 40% in PSOARING 2 trial achieving clear or almost clear skin at week 12. The median duration of clear or almost clear skin was about four months after cessation of treatment. The majority of adverse events were localized to site of application, and mild to moderate in nature.

About 8 million Americans and 125 million people worldwide are affected by psoriasis, which is a complex autoimmune disease. Plaque psoriasis is the most common form and affects about 80% to 90% of people with psoriasis.

Vtama is approved to treat adults with mild, moderate, and severe psoriasis. It is expected to be available in the first week of June 2022.

FDA Approves First Non-Steroid Cream for Psoriasis

 United Therapeutics’ Tyvaso DPI (treprostinil) inhalation powder to treat patients with pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease. Tyvaso DPI is a new formulation and inhalation device for inhaled treprostinil and is the only dry powder inhaler approved by the FDA for these indications.

Pulmonary arterial hypertension is life-threatening high blood pressure in the arteries of the lungs, affecting the ability of the heart and lungs to work properly. It affects an estimated 45,000 patients in the United States. Interstitial lung disease is a group of conditions in which marked scarring occurs within the lungs. It is often complicated by pulmonary hypertension, which is estimated to affect at least 15% of patients with early-stage ILD.

Tyvaso Inhalation Solution and Tyvaso DPI are the only therapies approved by the FDA to treat pulmonary hypertension associated with interstitial lung disease.

“The convenience and portability of Tyvaso DPI may make it an important new option for patients with WHO Group 1 PAH and with WHO Group 3 PH-ILD, with the potential for improving the quality of life for this patient population,” Shelley Shapiro, M.D., Ph.D., at the David Geffen UCLA School of Medicine Pulmonary Hypertension Program, said in a press release.

The approval for Tyvaso DPI is supported by data from BREEZE

an open-label study of 51 patients with pulmonary arterial hypertension taking Tyvaso who were transitioned to Tyvaso DPI. The new formulation demonstrated safety and tolerance during the three-week treatment phase with significant improvements in six-minute

, long-term open-label safety data were published in 

, and additional long-term safety and efficacy data were presented in 

Tyvaso DPI is a dry inhalation powder and new inhalation device to treat patients with pulmonary arterial hypertension, a life-threatening disease. It is expected to be available in June 2022.

FDA Approves New Formulation of Tyvaso

The Union for International Cancer Control (UICC) and multiple partners are establishing the 

Access to Oncology Medicines (ATOM) Coalition

, a new global partnership to increase access to essential cancer medicines in certain countries.

ATOM brings together “the most experienced organizations operating in the field to increase access to quality-assured essential cancer medicines in low- and lower middle-income countries (LLMICs) and to help countries develop the capacity for their proper use,” UICC said in a 

Partners in the Coalition include most of the major pharmaceutical manufacturers, including Gilead Sciences, AstraZeneca, Novartis and Roche. Other partners include the International Generic and Biosimilars Medicine Association, the Access to Medicine Foundation, and the International Federation of Pharmaceutical Manufacturers & Associations.

In 2020, more than 3.5 million new cancer cases were diagnosed in low- and lower middle-income countries and an estimated 2.3 million premature deaths were caused by cancer, according to UICC. “If left unchecked, deaths from cancer in LLMICs are expected to rise to 4 million by 2040,” the organization said.

 on the WHO Model List of Essential Medicines are currently available in low- and lower middle-income countries.

“Many LLMICs do not have sufficient resources to respond to the needs of people living with cancer and have a limited availability of essential medicines, diagnostics and complementary treatments required for good cancer treatment and care,” UICC said.

“Simply making affordable cancer medicines available does not guarantee that people living with cancer will receive the medicines they need at the right time,” Professor Anil D’Cruz, president of UICC and director of oncology at Apollo Hospitals in India, said in a press release. “This new partnership is set up to ensure that low- and lower-middle income countries get the support they need to receive the essential cancer medicines where they are currently lacking, as well as the training on their use so that their availability becomes sustainable long term and addresses the specific needs of each country with respect to its cancer burden.”

ATOM will build on UICC’s network of member organizations in selected countries, as well as on the range of global and country-level public and private sector partners with expertise in implementing cancer-focused access programs, according to UICC.

The Access to Oncology Medicines Coalition brings together phamra companies and other organizations to help countries develop the capacity and access to essential cancer medicines.

New Global Coalition Aims to Improve Access to Cancer Medicines

 Amneal Pharmaceuticals’ biologics license application for Fylnetra (pegfilgrastim-pbbk), a biosimilar referencing Amgen’s Neulasta (pegfilgratim). Fylnetra was developed in collaboration with Kashiv Biosciences. It is used to decrease the risk of infection after chemotherapy.

Four other biosimilars have been approved by the FDA: Fulphila, co-developed by Biocon Biologics and Mylan; Nyvepria, developed by Pfizer; Udenyca, developed by Coherus BioSciences; and Ziextenzo, developed by Sandoz, a division of Novartis.

This marks the third biosimilar approval Amneal received this year for products used in oncology. Earlier this year, the FDA approved Releuko (filgrastim-ayow), a filgrastim biosimilar referencing Neupogen, and Alymsys (bevacizumab-maly), a bevacizumab biosimilar referencing Avastin. Amneal expects to launch these three products over the second half of 2022, along with a full patient support program.

This is the fifth biosimilar of Neulasta and the third biosimilar from Amneal to receive FDA approval.

FDA Approves Amneal’s Biosimilar of Neulasta

The FDA has accepted for filing and granted priority review of the new drug application for Reata Pharmaceuticals’ omaveloxolone for the treatment of patients with Friedreich’s ataxia. Friedreich’s ataxia is a rare, genetic, degenerative neuromuscular disorder. If approved, the company anticipates omaveloxolone will be available in early 2023.

Patients with Friedreich’s ataxia typically experience symptoms in childhood, including progressive loss of coordination, muscle weakness, and fatigue that commonly results in motor incapacitation with patients requiring a wheelchair in their 20s. It impacts about 5,000 children and adults in the United States and 22,000 individuals globally. Currently, there are no approved therapies for the treatment of Friedreich’s ataxia.

Omaveloxolone is an investigational, oral, once-daily activator of Nrf2, a transcription factor that induces molecular pathways that promote the resolution of inflammation by restoring mitochondrial function, reducing oxidative stress, and inhibiting pro-inflammatory signaling.

The NDA is supported by the efficacy and safety data from the MOXIe Part 2 trial and additional supporting data from the MOXIe Part 1 and MOXIe Extension trials.

Omaveloxolone received Fast Track Designation in November 2021 and Rare Pediatric Disease Designation in May 2022.

The FDA has assigned a Prescription Drug User Fee Act target action date of Nov. 30, 2022. Regulators indicated they plan to hold an advisory committee meeting to discuss the application.

FDA Accepts NDA for Omaveloxolone for Friedreich’s Ataxia

 Servier Pharmaceuticals’ Tibsovo (ivosidenib) in combination with azacitidine for the treatment of patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML). It is indicated for adults 75 years or older or those who are ineligible for intensive induction chemotherapy.

Tibsovo is the first therapy targeting cancer metabolism approved in combination with azacitidine for patients with newly diagnosed IDH1-mutated AML.

AML is a difficult-to-treat cancer of the blood and bone marrow and is one of the most common types of leukemia in adults with about 20,000 new cases estimated in the United States each year. The IDH1 gene provides instructions for making the enzyme isocitrate dehydrogenase 1, which produces a molecule necessary for cellular processes. IDH1 mutations are present in about 6% to 10% of AML cases.

“People living with acute myeloid leukemia, especially those who are newly diagnosed and are not eligible for intensive chemotherapy, have had few treatment options,” Susan Pandya, M.D., vice president clinical development and head of cancer metabolism global development oncology and immuno-oncology at Servier.

The approval was based on the phase 3 AGILE trial, which demonstrated improvement in event-free survival and overall survival. Tibsovo plus azacitidine resulted in a threefold improvement in median overall survival (24 months) compared with placebo plus azacitidine (7.9 months) as a first-line treatment for IDH1-mutated AML. Results from the AGILE study were presented at the 2021 American Society of Hematology (ASH) Annual Meeting and Exposition, and recently published in the 

Tibsovo is also approved as monotherapy for the treatment of adults with IDH1-mutant relapsed or refractory AML, and for adults with newly diagnosed IDH1-mutated AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. Last year, the FDA approved Tibsovo for its first approval in a non-hematologic malignancy for patients with previously treated IDH1-mutated cholangiocarcinoma

Tibsovo is the first therapy targeting cancer metabolism for patients with newly diagnosed IDH1-mutated acute myeloid leukemia.

 FDA Approves Tibsovo Combination for Older Patients with Leukemia

 a complete response letter (CRL) for Verrica Pharmaceuticals’ new drug application (NDA) for VP-102 for the treatment of molluscum contagiosum, an infection caused by poxvirus. This infection is usually a mild skin disease characterized by lesions that may appear anywhere on the body, according to the 

. But there is currently no approved treatments for this infection, which affects about 6 million people worldwide, mostly children.

VP-102 is a proprietary drug-device combination product that contains a formulation of cantharidin delivered via a single-use applicator that allows for topical dosing and targeted administration. If approved, it would be the first product approved to treat molluscum contagiosum.

The FDA indicated in the CRL that there were deficiencies identified at a general reinspection of Sterling Pharmaceuticals, the contract manufacturing organization that manufactures Verrica’s bulk solution drug product.

Sterling advised Verrica on May 20, 2022, that it received notice from the called Official Action Indicated (OAI). This was the result of a week-long reinspection of Sterling conducted by FDA in February 2022. The reinspection was conducted about 90 days after Sterling was originally classified by the agency as Voluntary Action Indicated (VAI) on November 17, 2021.

Verrica indicated in a press release no other deficiencies indicated and that the deficiencies weren’t specific to VP-102.

FDA’s policy prevents it from approving the NDA when a contract manufacturing organization has an unresolved classification status or is placed on OAI status.

“Our understanding is that the division was ready to communicate our label, and we believe our NDA meets the statutory standards for approval and that any issues at Sterling do not impact the manufacturing, quality, efficacy, or safety of VP-102,” Ted White, Verrica’s president and chief executive officer, said in a press release. “However, we recognize that the dermatology division’s hands may be tied due to the reinspection issues at Sterling and thank them for their efforts working with us to date.”

This is the second CRL issued for VP-102. The first was in September 2021 because of the VAI status of Sterling’s manufacturing plant.

The NDA submission was based on positive results from two identical phase 3 clinical trials (CAMP-1 and CAMP-2) that evaluated the safety and efficacy of VP-102 compared with placebo in a combined 500 subjects two years of age and older diagnosed with molluscum. In both trials, a clinically and statistically significant number of patients treated with VP-102 met the primary endpoint of complete clearance of all treatable molluscum lesions at the end of the trial. VP-102 was well-tolerated in both trials, with no serious adverse events reported and a dropout rate of less than 2%.

Deficiencies at the contract manufacturing company are, for the second time, holding up approval of VP-102 to treat molluscum contagiosum, a mild skin infection.

New Global Coalition Aims to Improve Access to Cancer Medicines

FDA Approves Amneal’s Biosimilar of Neulasta

FDA Accepts NDA for Omaveloxolone for Friedreich’s Ataxia

FDA Approves Tibsovo Combination for Older Patients with Leukemia

FDA Issues Second CRL for Poxvirus Treatment