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

HIGH IMPACT – Iveric Bio announced topline data from GATHER2, its second phase 3 study of C5 aptamer, Zimura (Avacincaptad pegol) in geographic atrophy.

Efficacy (anatomical):

  • 14.3% reduction in mean rate of GA growth (slope; mm) at month 12 (p=0.0064).
  • 17.7% reduction in mean rate of GA growth (slope; mm2) at month 12 (p=0.0039).
  • Point analysis results were consistent with slope analysis.
  • Improvements were seen early in the study; 6 mos reduction in mean change in GA area of 14.1% (descriptive p-value 0.0293).

  • Mean rate of growth showed reduction for all analyzed subgroups based on baseline lesion size, baseline visual acuity, baseline auto-fluorescence pattern, age and gender.
  • Regional post-hoc analysis at 12 mos showed
    • 25.5% reduction in mean rate of GA growth (slope; mm) (descriptive p-value =0.0037).
    • 32.0% reduction in mean rate of GA growth (slope; mm2) (descriptive p-value =0.0033).
    • patients in US (42.7% of enrolled patients) had mean baseline lesion size 13% smaller than outside the US, which may have led to the differences.

Efficacy (functional):

  • Favorable trend observed for mean change in BCVA mirroring GATHER1 study.
  • No favorable  trends observed for  LLVA.


  • No endophthalmitis, intraocular inflammation events, or ischemic optic neuropathy.
  • Most frequent ocular AE was related to injection procedure.
  • 6.7% CNV events with Zimura vs  4.1% in sham
    • 4.9% eMNV vs 3.2% in sham
    • 0.5% neMNV vs 0% in sham
    • 1.3% peripapillary CNV vs 0.9% in sham

Upcoming milestones:

  • Results will be presented at AAO 2022.
  • Iveric plans to file for Zimura in the US by end of 1Q 2023.
  • Plans to meet with EMA in 1Q 2023 to discuss path forward.

Q&A from call

  • Q: Explain differences between slope analysis and observed analysis? What caused difference between the two? Baseline differences in GATHER1 and GATHER2?
  • A: Not that much of a difference between point and slope analysis, because data showed a linear progression. Still studying regional differences, current hypothesis is that lesions in US was smaller, may be a proxy to early stage of disease. Consistent with hypothesis that Zimura is more effective in patients earlier in disease. In GATHER1 75% were in the US, vs 40% in GATHER2, still looking at the data.
  • Q: Rate of CNV declined relative to GATHER1, why?
  • A: Inhibiting a C5 allows for a favorable safety profile. When physicians chose a drug, the safety becomes important. No endophthalmitis, inflammation and ION, very consistent with GATHER1.
  • Q: Comment on market research on how 14% reduction in GA growth would be?
  • A: Have 2 trials, only that have both been positive in 2 independent trials in this field. GATHER1 slope was 27% and 14% in GATHER2 with favorable and consistent safety profiles. Only 1 yr. data, confident will be able to show clinical impact in patients over their lifetime. Will do additional analysis to see if treatment can be personalized based on baseline characteristics.
  • Q: Color on trends in BCVA?
  • A: BCVA is not necessarily a good proxy for this disease. Saw a trend in improvement in GATHER1 and GATHER2. BCVA improvements usually lag behind, happy to see the trend. Will be reporting all functional outcomes at a future meeting.
  • Q: all eMNV receive VEGF? Any patients outside these numbers receive anti-VEGF?
  • A: All patients with CNV received anti-VEGF. Provided Eylea or Lucentis but required patient to be treated on label. None other received anti-VEGF.
  • Q: What’s left to file NDA with FDA? Comment on potential ex-US application?
  • A: All pieces in place to populate NDA including CMC. Plan is to be expeditious. Extremely pleased with safety results. Plan is to meet with EMA in 1Q 2023 to discuss path forward.
  • Q: Any imbalances between Zimura and sham arm in GATHER2? How can BCVA trend differentiate from competitors? Have you looked at other functional endpoints? Anything else from LL BCVA we can expect?
  • A: Baseline characteristics are well balanced (in 8K). Secondary endpoint will be presented at future medical meeting.
  • Q: Any other differences between US and ex-US beyond baseline lesion size? Between the ex-US regions were there any differences?
  • A: Very early stages of analysis, has only done US vs ex-US – lesion size is the only difference we see. Believes will find differences between ex-US regions too, hypothesis is that it depends on stage of disease when patients are recruited.
  • Q: What is the reason behind seeing trend in BCVA but not LL BCVA? EM vs EOM label? When will we get update on 2yr outcome?
  • A: Gain in BCVA will lag behind change in GA lesion. Seeing a modest trend at 12mos. Still have to investigate why there is no difference in LL BCVA. Premature to have label discussion. Results for EOM will be second part of the study, will have more information at that point.
  • Q: Confirm anti-VEGF decision was made by central reader? Regional differences in CNV?
  • A: PI was required to treat VEGF once CNV was reported. Very confident CNV numbers are comprehensive, confirmed by Duke reading center. Don’t have additional analysis on regional differences in CNV yet.
  • Q: Comments on 6 mos data? Differences in first and second 6 mos?
  • A: Too early to tell, will be looking at data.
  • Q: How representative is US population representative of GA population? What additional data do we expect to see at AAO?
  • A: Difficult to answer, hypothesis only that treating early might be better, but need to generate more data. Once approved will educate physicians to treat as early as possible. Not disclosed what will be presented at AAO, slated for 2 talks.

inThought Analysis

In Iveric Bio’s first pivotal trial, GATHER1, which was initially designed as a phase 2/3 study, Zimura 2mg achieved 27.7% reduction of mean rate of GA growth (slope; mm). Reduction in mean GA growth rate in GATHER2, although statistically significant, was less impressive than GATHER1. In contrast, 12 pegcetacoplan (targets C3) was only successful in achieving primary endpoint in one of its two pivotal trials; in the DERBY and OAKS studies showed 12% (p=0.0528) and 22% (p=0.0003) reduction in rate of GA growth versus sham respectively in the every month arm.

While numerically efficacy with Zimura might appear better than pegcetacoplan, there are a few differences in study design that preclude comparisons. First, the Zimura trials specifically recruited patients with extra-foveal lesions, a population which is thought to be more fast-progressing, with a more active complement pathway involvement and therefore potentially more amenable to complement inhibiting treatments. Pegcetacoplan trials on the other hand, recruited patients with both foveal and extra-foveal lesions. When only extra-foveal lesions were assessed in a pre-specified analysis of the combined DERBY and OAKS data, reductions in GA growth rates were 26% (p<0.0001). Second, the design of the GATHER1 study had several limitations which brings into question the validity of the data including treatment of sham data and accounting for missing data in the trial.

Long-term follow-up will determine whether the difference between treatment and sham arms continue to grow, similar to what has been observed with pegcetacoplan. While some experts note that any statistically significant difference is meaningful, others deem >20% reduction as clinically meaningful.

Zimura, interestingly, showed trends in BCVA improvement in both GATHER1 and GATHER2, as early as 12 mos, while pegcetacoplan 24-mos data failed to show a separation in BCVA between treatment and sham arms. However, it might not be appropriate to speculate too much on these signals, given that BCVA is not considered an appropriate functional outcome to study in GA.

On the safety front, Zimura presents a cleaner profile than pegcetacoplan as expected from its mechanism of action with no cases of intraocular inflammation and endophthalmitis; Zimura targets the more terminal part of the complement pathway leaving much of the C3-mediated mechanisms intact leading less changes of infection. The incidences of ischemic optic neuropathy were of particular concern with pegcetacoplan, an AE that was not observed with Zimura.

If the FDA considers GATHER1 as one of the two pivotal trials, Zimura is on track to be the second treatment approved in the US for geographic atrophy, after pegcetacoplan, expecting approval by November 2022. Given that pegcetacoplan will likely be in the market for >1 yr. when Zimura is approved, the former is likely to enjoy significant first-mover advantage. Secondly, pegcetacoplan’s every-other-month dosing also offers an attractive value proposition. The second part of the GATHER2 study will also evaluate every-other-month dosing but no data from this regimen is expected to be part of the initial NDA.


Source: Iveric Bio Press Release

HIGH IMPACT – The European Commission (EC) has granted conditional marketing authorization (CMA) to ROCTAVIAN (valoctocogene roxaparvovec) gene therapy for the treatment of severe hemophilia A in adults without Factor VIII inhibitors and without antibodies to AAV5.

  • Roctavian is the first approved gene therapy for hemophilia A.
  • BioMarin stated there are 3,200 patients who will be indicated for Roctavian within the 24 countries covered by the EMA approval.
    • Reiterated survey data that they expect 35% of eligible patients to be treated at peak and 80% of providers will prescribe to at least one patient
  • BioMarin reiterated it will seek to expand access outside the EU through named patient sales based on the EMA approval in the Middle East, Africa, and Latin America
  • The EC decision was based on:
    • Two-year outcome data from the Phase 3 GENEr8-1 study showed a reduction in the mean ABR and mean annualized FVIII consumption rate
    • Five and four year follow up data from the ongoing Phase 1/2 dose escalation study
  • The CMA recognizes that the benefit to public health of the immediate availability of Roctavian on the market outweighs the uncertainties inherent to the fact that additional data are still required. Standard marketing authorization will be contingent upon the provision of additional data:
    • Longer-term follow up data from Phase 3 GENEr8-1
    • Data from trial investigating efficacy and safety of Roctavian with prophylactic use of corticosteroids (enrollment now complete)
  • The EC also endorsed EMA’s recommendation for Roctavian to maintain orphan drug designation, thereby granting a 10 year period of market exclusivity versus similar medicines with the same therapeutic indication.
    • In response to question, noted that exclusivity will not have a huge impact because next hemophilia A gene therapies are far away from reaching market
  • BioMarin is targeting a BLA resubmission in the US for Roctavian by the end of September 2022
    • An additional three months of review may be required based on data read-outs that will occur during the review period
    • In the Q&A, the company stated that the BLA resubmission does not require data from the prophylactic steroid trial. They also stated that the EU CMA bodes well for U.S. approval

BioMarin hosted a conference call to discuss Roctavian’s EU approval, launch plans, and pricing agreements:

  • On the call: Jean-Jacques Bienaimé (CEO), Henry J. Fuchs (President, Worldwide R&D), Jeff Ajer (CCO), Brian R. Mueller (CFO)
  • Details on the expected label:
    • Contraindicated for active infections and known liver issues
    • Patients will have liver health screened prior to treatment and one year after treatment
    • Warnings will include instructions for managing liver health, preferred corticosteroid regimen, possible thrombotic events, and possibility of vector genome integration (though expect SmPC to also state that AAV integration leading to cancer has never been reported)
    • The SmPC will contain the preferred corticosteroid regimen. In the Q&A, the company stated they expect most patients to require corticosteroids that will be tapered off within 6 months
    • Patients are expected to enroll in a registry to follow-up on safety and efficacy for 15 years
  • Launch details:
    • Currently finalizing payer agreement in Germany, expected to start dosing patients in Q4 2022
    • Applied for early access program in France and waiting on review. France will be second market
    • Spain and Italy will be 3rd and 4th markets, followed by markets across EU, Middle East, Africa, and Latin America
    • Launch metrics including number of active markets will be shared starting in Q3 earnings call and updated on earnings calls thereafter
    • In the Q&A, the company stated that Roctavian launch will only require marginal investment due to BioMarin’s strong global operations
    • When asked about early adopters, the company did not provide specifics but, as previously guided, they are looking at Hemlibra patients who are looking for superior outcomes as well as factor replacement patients who are not adequately controlled
  • Pricing details:
    • EU net price including discounts and expected rebates will be ~€1.5 mil
    • Outcomes based agreement will be customized for each payer, but general terms will be to collect total price then set agreement time frame (anticipating 5-8 years) and rebate cost of treatment-year if patient goes back on prophylaxis
      • Example given: If payer agreement is for 5 years and patient requires prophylaxis after 4 years, company will rebate 20% of upfront cost (1/5 treatment years not met).
    • List price for Germany will be shared in October
    • US price will be higher than EU prices. Price is modeled based on cost of current SOC. Current SOC is cheaper in EU than in US.
    • The assumed non-responder rate used to derive net price is around the non-responder rate seen in Phase 3 trial (6/134 or ~4.5%)
    • In the Q&A, the company stated they are confident about achieving reimbursement even though the approval was conditional due to the quality and quantity of the data so far

inThought Analysis

Conditional approval in the EU has been widely expected since the CHMP gave a positive opinion in June. As expected, the price of Roctavian is modeled off the cost of current SOC and the outcome based agreement with payers described on the call is in line with expectations. Outcome based agreements are becoming the preference among payers for gene therapy. Bluebird Bio described a similar outcome based agreement for their recently approved gene therapy for beta-thalassemia.

The expected approval of the first hemophilia gene therapy will be viewed as a major milestone in the development of hemophilia treatments and will generate significant excitement in the hemophilia community. While eligibility restrictions, pricing, concerns about long-term durability/ability to re-dose, among other factors, may limit the initial uptake, the launch of a new class of hemophilia treatments will prompt many HCPs/patients to revisit treatment options and will likely add to patients exploring the potential of new technologies.


Source: BloMarin Press Release