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AstraZeneca’s Anifrolumab For Systemic Lupus Erythematosus

PDUFA Date: 5 July

A decision from the US Food and Drug Administration is imminent for AstraZeneca PLC’s anifrolumab for the treatment of systemic lupus erythematosus (SLE). If successful, it would be the first treatment for SLE to be approved by the FDA since its 2011 approval of GlaxoSmithKline plc’s BLyS-specific mAb belimumab (Benlysta).

The UK drugs major recently presented a post hoc analysis of pooled data from the TULIP Phase III trials at the European Congress of Rheumatology (EULAR) showing that anifrolumab, a first-in-class type I interferon inhibitor, was consistently associated with improvements in both skin rash and arthritis across three different disease measures compared to placebo, in patients with moderate to severe SLE. (More Positive Data As Decision Day Looms For AstraZeneca Lupus Drug)

The two TULIP trials included in the approval application measured different endpoints and had differing results.

TULIP-1, which evaluated anifrolumab in patients with moderate-to-severe SLE, missed its primary endpoint of reduction in disease activity at 52 weeks using the SLE Responder Index 4 (SRI4), with response rates of 36% and 40% for the anifrolumab and placebo arms, respectively. However, results for a secondary endpoint based on the British Isles Lupus Assessment Group based Composite Lupus Assessment (BICLA) were suggestive of a benefit, with response rates of 46% and 30%, respectively.

The TULIP-2 study specified BICLA assessments at 52 weeks as the primary endpoint and 48% of patients receiving anifrolumab had a BICLA response compared with 32% of patients receiving placebo.

Additionally, 49% of patients receiving anifrolumab with moderate-to-severe skin disease experienced improved skin manifestations at week 12 compared with 25% of patients receiving placebo.

A key difference between the two response assessments is the extent of improvement in an organ. The SRI4 requires full improvement, yet not in all organs, whereas the BICLA requires only partial improvement but in all organs. Either assessment is acceptable to both the FDA and the European Medicines Agency.

The most frequent adverse events for anifrolumab in the TULIP trials were upper respiratory tract infection, bronchitis, infusion-related reactions and herpes zoster.

Type I interferons such as IFN-alpha, IFN-beta and IFN-kappa are cytokines involved in regulating the inflammatory pathways implicated in SLE and the majority of adults with SLE have increased type I interferon signalling.

Biomedtracker Likelihood of Approval opinion: Below average

Teplizumab For Type 1 Diabetes

PDUFA Date: 2 July (delayed)

A pharmacokinetic issue and likely a divided advisory panel are the reasons for a delay with the FDA’s decision on approval of Provention Bio, Inc.’s teplizumab  beyond its 2 July PDUFA date. If approved, teplizumab would be the first drug for type 1 diabetes prevention. (FDA Perturbed By Proventions Teplizumab Type 1 Diabetes Drug)

The product was originally developed by MacroGenics, Inc. and Eli Lilly and Company but was abandoned in 2010 following a failed Phase III trial in patients with newly diagnosed diabetes. Provention Bio acquired the rights to teplizumab in 2018 based on subgroup analysis of the failed trial which it believed may have been positive with a different endpoint and initiated a new late-stage development program in early onset type 1 diabetes.

However, a Phase II trial initiated by the US National Institutes of Health in 2010 looking at type 1 diabetes prevention in at risk relatives reported positive results in 2019, suggesting that a single 14-day infusion course of teplizumab delayed the onset of clinical disease and insulin dependence in individuals at risk of type 1 diabetes by approximately 2 years (2.7 years in subsequent data).

Based on these data, Provention Bio completed a rolling biologics license application for teplizumab in April 2020 for the delay or prevention of clinical type 1 diabetes in at-risk individuals, as indicated by the presence of two or more type 1 diabetes-related autoantibodies.

But the FDA advisory panel meeting in May 2021 had a split vote, with 10–7 in favor of approval, though most of the endocrinologists and diabetes doctors voted negatively. Although the pivotal study demonstrated a significant delay in the diagnosis of type 1 diabetes, the trial was small with some baseline imbalances, and some panellists were uncomfortable with the safety and aspects of the trial design. “Hence, even with a slightly positive vote, it is quite unclear whether the agency would approve it or want to wait for data from the company's PROTECT study in newly diagnosed type 1 diabetes, expected in the middle of 2023,” said Biomedtracker.

The FDA also had some concerns because a PK study did not show comparability between the to-be-commercial product and trial study product, and it is unclear how this will be resolved. The company has said PROTECT also uses both the older and newer drug product, so PK/pharmacodynamics  data from that study could help.

Provention Bio has already said it expected a delay due to the PK issue, but it remains to be seen if the FDA also raises clinical issues on the risk:benefit.

Teplizumab is a humanized, non-Fc-receptor-binding monoclonal antibody directed against the CD3 epsilon chain expressed on mature T lymphocytes. Its mechanism of action is not fully understood, but rather than providing long-term immunosuppression by T-cell depletion, it is thought to have partial or incomplete agonistic signaling of activated T-cells leading to a state of unresponsiveness, mediated by exhausted CD8+ T-cells, with rebalancing of immune activation and immune regulation.

Biomedtracker Likelihood of Approval opinion: Below average

Bylvay For Progressive Familial Intrahepatic Cholestasis

PDUFA Date: 20 July

The first of two new treatments for rare liver diseases, Albireo Pharma Inc.’s ileal bile acid transporter (IBAT) inhibitor Bylvay (odevixibat) for progressive familial intrahepatic cholestasis (PFIC) is set to get an approval decision from the FDA later this month.

There are currently no approved drug therapies for PFIC, giving Bylvay the potential to address a major unmet need if approved. Mirum’s similar product maralixibat is already filed for PFIC type 2 in the EU and is awaiting US approval for Alagille syndrome (see below).

Albireo is also developing Bylvay for Alagille syndrome and biliary atresia.

The NDA submission for Bylvay in PFIC, which has been granted a priority review, is supported by the Phase III double-blind, placebo-controlled PEDFIC 1 trial in which the drug met both the pruritus and serum bile acid (sBA) primary endpoints and was well tolerated with low incidence of diarrhea/frequent bowel movements. Data from the open-label PEDFIC 2 extension study also included in the applicationdemonstrated continued effect of Bylvay over 48 weeks and confirmed the drug’s ability to trigger sBA declines and reduce pruritus scores in PFIC patients.

One of Bylvay’s key differentiators from its  maralixibat is the lower incidence of diarrhea. Bylvay also triggers sBA declines in all three PFIC subtypes (albeit with seemingly lesser efficacy in PFIC1 after 12 weeks), whereas maralixibat only seems to possess efficacy in PFIC2 patients with non-truncating mutations.

Biomedtracker Likelihood of Approval opinion: Above average

Mirum Pharmaceuticals Maralixibat For Alagille Syndrome

PDUFA Date: 29 September

Mirum Pharmaceuticals is looking on course to launch its first product, maralixibat for Alagille syndrome, if it is successful at the FDA in September following a priority review.

The oral apical sodium dependent bile acid transporter (ASBT) inhibitor would also be the first approved treatment for the treatment of cholestatic pruritus in patients one year of age and older with Alagille syndrome. The genetic condition causes symptoms which often develop during the first three months of life, that include blockage of the flow of bile from the liver (cholestasis), jaundice, poor weight gain and growth, and severe itching.

However, competition in the form of Albireo Pharma’s IBAT inhibitor, Bylvay (odevixibat), is not far off, and analysts expect that this will eventually dominate the market due to its clinical profile (see above)

Maralixibat’s filing is based on the pivotal Phase IIb ICONIC study that improved in terms of efficacy over the disappointing Phase II IMAGO study that showed no significant difference over placebo on the primary endpoint of sBA level reductions from baseline, and had high rates of diarrhea and abdominal pain.

ICONIC used a higher dose (up to 400µg/kg/day vs 140-280ug/kg/day in IMAGO) and had improved efficacy with maralixibat leading to substantial declines in sBAs and itching scores over 48 weeks of treatment. The relatively high rate of GI adverse events continued but given the high unmet medical need in this area, analysts at Biomedtracker are confident that the FDA will rule in favor of approval. “The GI side effects are something to monitor, however they did settle down over time in the ICONIC study and should not preclude approval,” they said.

Biomedtracker Likelihood of Approval opinion: Above average

ChemoCentryx’s Avacopan For Antineutrophil Cytoplasmic Antibodies Associated Vasculitis

PDUFA Date: 7 July

Whether or not the FDA will opt to approve ChemoCentryx, Inc.’s oral selective complement 5a receptor inhibitor for antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is a matter of debate after its advisory panel was split on the question in May.

The company’s New Drug Application submission in July 2020 was mainly supported by results of a single pivotal Phase III trial known as ADVOCATE, which met both of its primary endpoints, disease remission at 26 weeks and sustained remission at 52 weeks. (ChemoCentryx Soars On Phase III Avacopan Data In ANCA Vasculitis)

But during the advisory panel meeting, the FDA argued that the complex study design confounded avacopan’s apparent clinical benefit and safety advantage. Both the FDA and many of its advisors found the study difficult to interpret due to the complicated study design including different background treatment regimens, one of which was different than the now standard of care, and the patients’ use of non-study provided steroids in the avacopan arm of the trial. Eventually, the panel voted 10-8 in favor of the drug’s risk-benefit profile after splitting 9-9 on its efficacy and 10-8 on the safety. (ChemoCentryxs Avacopan May Need Another Trial After Tepid Advisory Committee Vote)

Those in favor of approval were largely persuaded by the large need for more treatment options, particularly one that might limit the use of steroids in the hard-to-treat, life-threatening rare disease. Even they, though, acknowledged that the single pivotal study submitted for regulatory approval was mired by flaws leaving questions about the drug’s safety and how best to use the medication in clinical practice.

But the panelists who voted against approval noted that the FDA requires robust demonstration of efficacy for approval based on a single Phase III trial and they did not believe this threshold was met.

As a consequence, analysts at Biomedtracker said it seemed “more likely than not that the FDA will issue a complete response letter and ask for a confirmatory trial prior to approval.”

If approved, avacopan will be ChemoCentryx’s first approved candidate in this unmet therapeutic need, with 4,000 new US cases and 7,500 EU new cases annually.

Biomedtracker Likelihood of Approval opinion: Below average

Pfizer’s Abrocitinib For Atopic Dermatitis

PDUFA Date Range: 1 July – 15 August

Pfizer Inc. is hoping its next-generation oral JAK1 inhibitor abrocitinib will provide some competition for Sanofi/Regeneron Pharmaceuticals, Inc.'s Dupixent (dupilumab) in treating atopic dermatitis.

Pfizer is having to wait longer than anticipated for the agency’s verdict, however, after the FDA extended the drug’s review period by 90 days amid class-wide safety concerns over JAK inhibitors. Similar delays were seen for Pfizer’s blockbuster JAK inhibitor Xeljanz/Xeljanz XR (tofacitinib) in ankylosing spondylitis (AS), Lilly/Incyte Corporation’s Olumiant (baricitinib) in atopic dermatitis and AbbVie Inc.’s Rinvoq (upadacitinib), in psoriatic arthritis. (What Will JAK Inhibitor Safety Jitters Mean For Drug Sales)

Pfizer remains optimistic about the commercial potential of its JAK inhibitor portfolio despite the safety concerns and believes abrocitinib is sufficiently differentiated to make its mark. (Pfizer Says JAKs Have Their Place Despite Xeljanz Safety Issues)

Abrocitinib’s filings were based on the Phase III JADE MONO-1, JADE MONO-2 and JADE COMPARE studies in which it demonstrated statistically superior improvements in skin clearance, disease extent, and severity, as well as rapid improvements (measured as early as week two) in itch versus placebo. Abrocitinib was also generally well tolerated.

The product received breakthrough therapy designation from the FDA for moderate-to-severe atopic dermatitis and it is also awaiting EU approval, with a decision due later this year.

In the UK, abrocitinib received a promising innovative medicine designation from the Medicines and Healthcare Products Regulatory Agency, indicating that a product may be eligible for an Early Access to Medicines Scheme based on early clinical data.

Biomedtracker Likelihood of Approval opinion: Average

Sesen Bio’s Vicineum For Bladder Cancer

PDUFA Date: 18 August

Sesen Bio, Inc. has a lot resting on the FDA review of Vicineum (oportuzumab monatox) for high-risk, BCG-unresponsive non-muscle invasive bladder cancer: if approved, this would be the first product from Sesen Bio to reach the market after the firm suspended all its other products in the pipeline.

Vicineum is a locally administered fusion protein that targets epithelial cell adhesion molecule (EpCAM) antigens to deliver a protein payload of Pseudomonas exotoxin A. Once oportuzumab binds to EpCAM on the cancer cell surface membrane, it is thought that the molecule becomes internalized and then the exotoxin portion of the fusion protein induces apoptosis.

The approval submission is based on the Phase III VISTA study which showed a complete response rate of 39% after three months’ treatment with oportuzumab, and the drug was well tolerated. Further data suggested that 52% of patients had a complete response for 12 months or longer after starting therapy, and 90% of patients remained progression-free for two years or greater.

Analysts’ response to the data at the time were mixed, with some expecting rapid commercial adoption but others slashing sales forecasts on the basis that it provides only a modest improvement on current therapies. SC125691 The product may also face competition in this setting from checkpoint inhibitors including Merck & Co., Inc.'s Keytruda (pembrolizumab).

The product is licensed to Qilu Pharmaceuticals for Greater China and to Hikma Pharmaceuticals plc for the Middle East and North Africa.

Biomedtracker Likelihood of Approval opinion: Above average

Calliditas Therapeutics’ Nefecon For Immunoglobulin A Nephropathy (Berger’s Disease)

PDUFA Date: 15 September

Calliditas Therapeutics AB’s lead asset Nefecon is a locally acting formulation of the corticosteroid budesonide that targets the Peyer’s patches lymphoid follicles in the ileum, which some evidence suggests are an important source for the defective IgA1 antibodies that are deposited in the kidneys in IgA nephropathy (IgAN).

Although specifically designed for the treatment of IgAN, with the potential to be disease modifying, if approved Nefecon could face reimbursement issues, note the Biomedtracker analysts, since it is a formulation of a generic drug, “though officials have noted that open-label studies will be used to support the drug from a health economics perspective.”

Local delivery should improve the benefit:risk profile of corticosteroid treatment, which has substantial side effects when administered systemically.

Calliditas is seeking accelerated approval after the FDA granted priority review in April.

The NDA submission is based on data from Part A of the NefIgArd pivotal Phase III study of Nefecon compared with placebo in 200 adult patients which met its primary objective of a significant reduction in urine protein creatinine ratio after nine months of treatment, and significant continued improvement at 12 months.

The trial also met the key secondary endpoint of difference in estimated glomerular filtration rate (eGFR) after nine months, reflecting stabilization in the treatment arm and a 7% decline of eGFR in the placebo arm (p=0.0029). Clinical data from the Phase IIb NEFIGAN trial, which also met the same primary and secondary endpoints as the NefIgArd study, were included as part of the submission.

Biomedtracker Likelihood of Approval opinion: Average

Spectrum Pharmaceuticals’ Rolontis For Neutropenia/Leukopenia

PDUFA Date: Third Quarter

If approved, Rolontis (eflapegrastim), a long-acting granulocyte colony-stimulating factor (G-CSF) analog for the treatment of chemotherapy-induced neutropenia, will be the first FDA-cleared therapy for Spectrum Pharmaceuticals Inc.

Spectrum licensed Rolontis from Hanmi Pharmaceutical Co., Ltd., which received the world’s first approval for the product in South Korea in March. (WorldFirst Korean Nod For Hanmis Neutropenia Contender Rolontis) However, its progress in the US regulatory system was hampered by COVID-19-related difficulties in inspecting Hanmi’s production facility in South Korea during the review cycle. (Inspection Delay Puts Back HanmiSpectrums Rolontis)

In June 2021, Spectrum confirmed that the FDA was on site for the Rolontis manufacturing inspection and Biomedtracker analysts expect that a PDUFA decision will occur in the third quarter. The original target date was 24 October 2020.

Spectrum completed a pair of Phase III studies, ADVANCE and RECOVER, in a total of 643 early-stage breast cancer patients receiving docetaxel and cyclophosphamide to support the biologics license application.

In both studies, Rolontis met its primary endpoint of noninferiority in duration of severe neutropenia to pegfilgrastim, instead showing a slight numeric advantage. Additionally, safety profiles were similar for Rolontis and pegfilgrastim.

“While an approval is always welcome news, Rolontis would still face an uphill battle with a large array of biosimilars to pegfilgrastim approved and in development,” say the Biomedtracker analysts. “Spectrum will need a convincing strategy for prescribers to make the switch to a new therapy with marginal benefit from a well-established therapeutic with nearly 20 years of real-world evidence.”

Biomedtracker Likelihood of Approval opinion: Above average

Merck’s Belzutifan For Renal Cell Cancer

PDUFA Date: 15 September

Merck & Co’s inhibitor of hypoxia-inducible factor-2 alpha (HIF-2α) belzutifan (MK-6482) is up for approval at the FDA for von Hippel-Lindau disease (VHL)-associated clear cell renal cell carcinoma (ccRCC). But as VHL is a rare genetic disease and the benefits of the drug in a broader RCC population are unknown, it is assumed that initial uptake will be low, notes Biomedtracker.

The big pharma acquired the first-in-class drug candidate via its $1.1bn buyout of Peloton Therapeutics, Inc. in 2019, along with other preclinical candidates targeting HIF-2α for the treatment of cancer and other diseases. (Merck Buys Peloton On Eve Of IPO Expands Kidney Cancer Portfolio) Kidney cancer is an important indication for Merck's blockbuster PD-1 checkpoint inhibitor Keytruda, which earlier this year  yielded a disease-free survival (DFS) benefit in post-surgical kidney cancer patients in the Phase III KEYNOTE-564 study. This was the first to show benefit with a PD-1 or PD-L1 inhibitor in adjuvant RCC. (Merck Cos Keytruda Stakes Another Adjuvant Flag In RCC)

In ccRCC, there is an accumulation of HIF-2α when the tumor suppressor VHL protein is inactivated, which drives kidney cancer tumorigenesis.

The NDA was based on Phase II data from September 2020, showing an ORR of 36.1% and SD rate of 38%. the FDA granted orphan drug designation to belzutifan in June 2020 and the following month assigned it a breakthrough therapy designation.

Biomedtracker Likelihood of Approval opinion: Above average

Atox Bio’s Reltecimod For Skin and Skin Structure Infections

PDUFA Date: 30 September

If approved, Atox Bio would in reltecimod have the first therapy to treat suspected organ dysfunction or failure in patients with necrotizing soft tissue infection (NSTI).

The product is being developed for use n conjunction with surgical debridement, antibiotic therapy,and supportive care in patients 12 years of age or older. A novel small synthetic peptide that binds to the CD28 co-stimulatory receptor to modulate the host’s immune response to severe infections, reltecimod is designed to prevent acute inflammatory response getting out of control and leading to morbidity and mortality.

The NDA is based on results from the 290-patient Phase III ACCUTE trial, a Phase III randomized, which produced mixed results, reaching significance only in the per protocol analysis but not the modified intent to treat population.

The data showed a significant improvement in the percentage of patients achieving the necrotizing infection clinical composite endpoint (NICCE) primary endpoint with a single dose of reltecimod 0.5mg/kg IV compared with placebo (52.6% for reltecimod vs 40.3%, for placebo; p=0.039) in the per protocol analysis. When evaluating efficacy on the individual components of the NICCE, reltecimod’s success was primarily driven by improved organ dysfunction/failure resolution (70.9% vs 53.4%; p=0.005).

On safety, reltecimod’s profile was positive, with no clear differences in the frequency of adverse events compared to placebo.

In patients who survived the first 14 days, the 90-day mortality rate was 5.1% with reltecimod compared with 11.5% with placebo (p=0.07), which is supportive of the company’s claim that improvement in organ resolution has a beneficial effect on longer-term survival, though a larger study with more statistical power would be required to confirm this effect and support any mortality benefit claims.

Biomedtracker Likelihood of Approval opinion: Above average


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