HIGH IMPACT – CSL/uniQure’s Hemgenix (etranacogene dezaparvovec, Etranadez) was approved by the FDA for hemophilia B.

Key Takeaways

  • Hemgenix was approved for adults with hemophilia B who currently use FIX prophylaxis, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes
  • Hemgenix is the first hemophilia B gene therapy approved and the first hemophilia gene therapy approved in the U.S. (Roctavian was approved in August for hemophilia A in Europe)
  • CSL emphasized that Hemgenix is the first therapy for hemophilia B that offers patients and caregivers the possibility of freedom from regular, ongoing infusions
  • The initial reports suggest an initial list price of $3.5 million


  • Steven Pipe quote from CSL press release emphasized the freedom from regular infusions: “HEMGENIX is unique in its approach to increasing mean factor IX activity and hemostatic protection in those with hemophilia B, and today’s approval could fundamentally transform the treatment paradigm for this life-long condition,” said Dr. Steven Pipe … a lead investigator in the HOPE-B study. “As a clinician, I look forward to being able to provide a new treatment option that may help patients treated with HEMGENIX become free from the regular infusion schedule that many people living with hemophilia B rely on to protect them from the debilitating effects of the condition.”

Details of USPI

Indication:  Adults with hemophilia B who: currently use FIX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes


  • 2e13 genome copies (gc) per kg. Administered as an IV infusion at a rate of 500 ml/hr (8 mL/min). Provided in kits containing 10 to 48 single use vials. For an average 72kg patients, 144 mL and 15vials will be required
  • The USPI specifically states that Hemgenix can only be administered once

Patient Selection:

  • Perform FIX inhibitor testing – if test and retest are positive, do not administer Hemgenix
  • Perform liver health assessments including: ALT, AST, ALP, total bilirubin and hepatic ultrasound and elastography. In the case of liver abnormalities, consider consultation with a hepatologist to assess eligibility for Hemgenix.
  • The USPI states that the safety and efficacy of Hemgenix has not been studies in patients with advanced hepatic impairment and Hemgenix was not studied in patients with severe renal impairment
  • A test for AAV5 neutralizing antibodies is not required.  The USPI discusses the results in patients who were positive for preexisting AAV5 NAb using an unvalidated assay in the Hemgenix trials.  Patients intending to receive Hemgenix are encouraged to enroll in a CSL study to measure pre-existing NAb to AAV5 to determine any affect on the risk of bleeding
  • The prescribing information states that 6 geriatric subjects (age 68-75) were in the trials with no meaningful differences in safety and efficacy profiles

Monitoring and warnings

  • Monitor for infusion reactions during and for at least 3 hours after end of infusion.  If symptoms occur, slow or interrupt administration. Re-start at a slower rate once resolved
  • Closely monitor ALT and AST levels once per week for 3 months. Continue to monitor in all patients who developed elevated liver enzymes until they return to baseline.
  • Consider corticosteroids if liver enzyme elevation (above normal limits or 2x patient’s base level) occurs. Starting dose of 60mg with tape (week 2 – 50mg; week 3 – 30mg; week 4 – 30mg; maintenance until ALT returns to baseline – 20mg and then reduce by 5mg/week). Mean duration of steroid use in trials was 81.4 days (51-130 days)
  • Hepatocellular carcinogenicity: For patients with preexisiting risk factors (e.g. cirrhosis, advanced hepatic fibrosis, hepatitis B or C, NAFLD, chronic alcohol consumption, NASH, and advanced age) perform regular (annual) liver ultrasound and alpha-fetoprotein testing. The prescribing information states that integration of AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development. It also states that no Hemgenix associated clonal expansion or carcinogenicity has been observed in clinical studies
  • Monitor FIX activity – suggestion of weekly for 3 months.
  • Monitor for FIX inhibitors if bleeding is not controlled or FIX levels decrease


  • Shipped and stored at 2 to 8 degrees C

Adverse Reactions: elevated ALT, headache, blood creatine kinase elevations, flu-like symptoms, infusion-related reactions, fatigue, malaise and elevated AST

Clinical data

  • The USPI contains a chart with stable FIX levels out to month 24 with the median FIX activity at month 24 of 33.9 (4.7, 99.2) using a one-stage assay
  • Mean ABR from months 7 to 18 was 1.9 compared to 4.1 during the lead in period. Subjects with zero bleeds was 63% versus 26% in the lead-in study
  • 2 patients did not stop prophylaxis.  One additional patient received prophylaxis for 20 weeks between days 396 and 534.

inThought Analysis

The first gene therapy approved for hemophilia was BioMarin’s Roctavian in the EU. The FDA is also set to decide on Roctavian in 2023 and has reported plans to consult an advisory committee on the company’s approval application. While there are differences in the drugs, Hemgenix label appears to be less restrictive and more favorable in terms of appropriate patients and post-dose monitoring requirements compared to Roctavian’s SmPC.  FIX and liver enzyme monitoring are only being required for 3 months versus up to 2 years for Roctavian.  Unlike the Roctavian SmPC, the Hemgenix USPI does not mention restrictions such as active infections, refraining from drinking alcohol, and does not require testing for AAV5 NAbs. Also, this approval did not require an FDA adcomm.

Overall, regulatory agencies are showing they will not make class-wide restrictions on gene therapies, and are practicing flexibility in approving and labeling of two AAV gene therapies for the same disease.


Source: FDA Press Release, BiopharmaDive

HIGH IMPACT – Surface Oncology provided a corporate update, including the decision to pause internal clinical development of SRF617 (CD39 mAb) and early clinical data for SRF388 monotherapy in NSCLC. The company intends to open a SRF388 + pembrolizumab study for 2-4L NSCLC.

Pipeline updates:

  • SRF617 (CD39 mAb) development will be paused, with a corresponding reduction of 20% of Surface’s workforce, to focus on SRF388 and SRF144, which the company claims have the greatest near-term potential.
  • Surface also announced SRF144 (CCR8 mAb) has been cleared for its IND application and expects to enroll the first patient soon.

Early signals of efficacy:

  • SRF388 as monotherapy in NSCLC achieved 2 partial responses in patients treated at or above the RP2D, both in patients with squamous NSCLC. A third patient with nsqNSCLC achieved durable disease stabilization for over 56 weeks. All three patients had previous chemotherapy and anti-PD-(L)1 therapy.
    • ORR: 22% (2/9) All NSCLC
    • ORR: 100% (2/2) sqNSCLC
  • The SRF388 monotherapy trial will progress to its second stage, enrolling 40 patients total.
  • The upcoming Phase 2 study for SRF388 + pembro for 2-4L NSCLC will enroll up to 40 patients.
  • Additional data for the SRF388 monotherapy and SRF388 + pembro trials will be shared 1H:2023.

inThought Analysis

Despite already established collaborations with pharma giants Novartis and GSK, Surface looks to be struggling, as it sheds dead weight in hopes of identifying its next, most valuable, asset. The CD39 mAb SRF617 was in Phase 1 trials as a monotherapy (NCT04336098) and Phase 2 combination trials for prostate cancer (NCT05177770), with promising data released last year at ESMO-IO 2021 showing 10/30 patients achieving stabilized disease at 8 weeks (link). However, it appears Surface does not find SRF617’s outlook compelling enough and is now looking to offload the asset and cut its workforce by a fifth. Surface also is prioritizing indications for SRF388, pausing enrollment for its Phase 2 RCC trials (NCT05359861) in favor of NSCLC and HCC. With these plans, leadership claims Surface has sufficient cash runway until Q2 2024.


Source: Surface Oncology Press Release

HIGH IMPACT – Travere hosted a call to discuss the recent regulatory update for sparsentan

  • Travere’s sparsentan was previously assigned a PDUFA target action date of November 17, 2022 for its NDA under accelerated approval for the treatment of IgAN, which has been extended by 3 months following late-cycle review interactions with the FDA.
  • The FDA has requested the company to update its proposed Risk Evaluation Mitigation Strategy (REMS) to include liver monitoring for sparsentan, consistent with some, but not all approved products in the endothelin receptor antagonist class. No additional clinical data or studies have been requested, but the updated submission is likely to be considered a major amendment to the NDA.
    • The REMS plan monitors risk of teratogenicity, as this is universal across endothelin receptor antagonists.
    • The FDA noted that there is added caution for sparsentan as it’s the first-time nephrologists will be using this class of medications.
  • Travere expects to submit an updated REMS plan in the coming days, and expects confirmation of a February 17th, 2023 PDUFA date from the FDA.
  • Travere says this request for additional monitoring within the REMS came unexpectedly, but its goal remains for sparsentan to become a new treatment standard for IgAN.

inThought Analysis

Travere’s timeline for sparsentan in the U.S. has been set back once again, following a recent announcement that the company will pursue traditional approval of sparsentan in the U.S. for its other indication FSGS, which is also expected in 2023. Travere has also applied to the EMA for IgAN with an expected decision in H2 2023 and plans to submit to the EMA for FSGS around that time, making 2023 an important year to keep an eye on for sparsentan in both the IgAN and FSGS space.

Despite the labeling update, there has not been strong evidence of liver toxicity with sparsentan. The phase 2 data showed mild elevation in liver enzymes. Although the phase 3 results aren’t yet clear, the company stated during the call that among 800 participants in the phase 3 studies, ALT/AST elevations were comparable between sparsentan and irbesartan. Although there is still a strong likelihood sparsentan will be approved (notably, Travere received a draft label), the updated REMS may slow uptake. Based on the complexities involved with administering a REMS program and the data requirements outlined, products with REMS requirements are frequently dispensed by specialty pharmacies in limited networks. Many traditional pharmacies do not have the ability to report on REMS appropriately and adhere to the FDA’s strict guidelines. However, if efficacy and safety of a product can be proven post-launch through other supplemental data provided to the FDA, REMS program requirements can be eliminated.

Chinook might also face the same REMS plan when they seek approval for atrasentan.


Source: Company Transcript

HIGH IMPACT – Wave Life Sciences hosted an investor call titled “Towards the Clinic: Spotlight on RNA Editing for AATD” to discuss their technology, preclinical results, and path forward for WVE-006, their mRNA editing treatment for patients with alpha-1 anti-trypsin deficiency (A1ATD).

On the call: Dr. Paul Bolno (CEO), Dr. Paloma Giangrande (VP, WVE-006 Program Lead), Dr. Kyle Hogarth (U. of Chicago), Dr. Chandra Vargeese (CTO)

  • Reiterated the science behind RNA editing using AIMers, which incorporate A-to-I editing oligonucleotides using endogenous ADAR enzymes
  • WVE-006 is a GalNAc conjugated AIMer which corrects the mutation in the SERPINA1 Z allele which most frequently causes A1ATD (transforming from Z allele to M allele). This approach should treat both the liver damage that results from AAT protein aggregation in the liver as well as lung damage that results from a lack of AAT in the lungs.
  • Emphasized that an editing efficiency of ~50% would convert Pi*ZZ phenotype into Pi*MZ phenotype, which carries much lower risk of emphysema and liver disease
  • Preclinical data for WVE-006:
    • M-AAT levels increase in dose dependent manner in human hepatocytes

    • WVE-006 leads to 7-fold increase in circulating AAT levels

    • WVE-006 leads to restoration of confirmed, wild-type M-AAT protein in serum

    • Restored M-AAT is functional, leading to increased serum neutrophil elastase inhibition

    • WVE-006 (pre-optimization) alleviates aggregation of Z-AAT and inflammation in liver

    • AIMer-directed editing is highly specific in mice

  • Next Steps:
    • Phase 1/2 clinical trial is currently being planned
    • The trial will occur in a single-ascending dose phase in healthy volunteers then Pi*ZZ patients followed by a multiple-ascending dose phase in Pi*ZZ patients.
    • Primary outcomes include safety, tolerability, PK, and changes in relevant biomarkers, including serum AAT
    • Wave expects to submit the CTA for this trial in 2023
  • Dr. Kyle Hogarth of the University of Chicago provided a clinical perspective on A1ATD, briefly discussing his opinions on the current and future treatment landscape:
    • Augmentation therapy does provide benefit to patients with emphysema but requires once weekly IV of very expensive product
    • Recombinant AAT being developed by InhibRx may be longer lasting, but will still require frequent IV. Currently unclear how much of the product makes it into the lungs
    • Inhaled AAT being developed by Kamada may not get AAT levels high enough, especially in patients who already have airflow obstruction in the lungs
    • The neutrophil elastase inhibitor being developed by Mereo is an exciting approach but is more likely an add-on therapy
    • Various RNAi/sRNA products in development offer a good approach for treating the liver disease aspect but could cause levels of circulating AAT to go down, which could cause or exacerbate lung damage
    • While gene therapy is a promising option, in his experience taking a straw poll with patients, he has witnessed that many patients have concerns with gene therapy, including questions about efficacy and off-target effects
    • Both of Vertex’s small molecule programs have been stopped
    • Emphasized that WVE-006 is a promising option because it can treat both the lung and liver manifestations of A1ATD. Since it does not cause permanent genetic changes, it likely has a benign safety profile.
  • Wave also presented on some future applications of the AIMer program
    • AIMers can also upregulate gene expression and modulate protein-protein interactions
    • Showed data upregulating an undisclosed liver target with “high unmet need”
    • Showed data that a delivery vehicle may not be needed to get high levels of delivery to CNS
    • In response to question, Wave discussed the potential to apply this technology to any loss-of-function caused disease, but more specifically in hepatocyte driven disease, liver disease, kidney disease, and CNS disease

inThought Analysis

Wave first announced WVE-006 during its Q2 2022 earnings presentation. This investor call expanded upon the pre-clinical data the company has already shown, but there is no new guidance about its development. CTA submission is scheduled for 2023.

The company brought in a KOL to provide expert opinion on the current treatment landscape for A1ATD. While the discussion was biased and heavily favored WVE-006, it provided insight into potential messaging and counter positioning that Wave will likely use for WVE-006. Emphasis will likely be on the potential of WVE-006 that it can be more potent than current treatments since it corrects the genetic mutation that causes both lung and liver disease. The ASO’s selectivity will also decrease risk as it does not cause permanent genetic change. This messaging may be meant to bolster ASO therapies and discredit gene therapies in development by tapping into anxieties patients have about the permanence of gene therapy especially if it does not work or causes side effects.


Source: Wave Life Science Investor Call

HIGH IMPACT – In an SEC filing, BioMarin disclosed that they were notified on August 19th, 2022 that a participant in the Roctavian Phase 3 trial was diagnosed with B-cell acute lymphoblastic leukemia (B-ALL). Based on BioMarin’s assessment of the case to date, including initial genetic testing of the leukemic cells, BioMarin believes at this time that this cancer is unrelated to Roctavian.

  • The overall rate of all cancers observed in all Roctavian trial patients (2 in approximately 400 patient years of observation) appears consistent with expected rates of cancer in persons with hemophilia.
  • Testing on leukemic cells enriched to 90% purity from peripheral blood carried negligible levels of Roctavian vector DNA (less than 1 copy per 500 cells). These negligible, near background levels of Roctavian indicate that Roctavian is not clonally expanding in these leukemic cells.
  • Additional genomic analyses are underway, which BioMarin expects to confirm the absence of Roctavian vector integration events contributing to leukemic growth, as well as to provide further insights into the underlying genetic etiology of this case.

inThought Analysis

This is the second known case of a patient treated with Roctavian developing cancer, following a patient in the Phase 1/2 trial who developed a carcinoma. In both these cases, the malignancy was ruled unlikely related to the gene therapy, and the rate of cancer among hemophilia gene therapy patients remains consistent with the rate of cancer among hemophilia patients in general.

There has not been a cancer event attributable to treatment with a hemophilia gene therapy, and this cancer disclosure is not likely to affect the upcoming BLA submission expected by the end of September. However, the risk of vector genome integration leading to cancer remains a concern among physicians and the patient communities for which gene therapies are being developed.


Source: BioMarin Form 8-K