Dynavax's (NASDAQ:DVAX) hepatitis B vaccine, Heplisav, received a complete response letter (investors.dynavax.com/releasedetail.cfm) in February 2013. However, medical analysis indicates that the FDA's reasons for concern (Wegener's, Guillain-Barre, pulmonary embolism, etc.) are likely not related to Heplisav. This vindicates Heplisav's preceding trials - HBV-10 and HBV-16 - and could bode well for Dynavax's upcoming phase 3 data set for HBV-23.
I will reference the following sources:
a. Advisory Committee briefing document (PDF) www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/VaccinesandRelatedBiologicalProductsAdvisoryCommittee/UCM333727.pdf
b. Advisory Committee Review of Safety (PowerPoint) www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/VaccinesandRelatedBiologicalProductsAdvisoryCommittee/UCM345255.ppt
2. HBV-10 and HBV-16
Dynavax conducted two phase 3 trials. HBV-10 consisted of subjects aged 18 to 55. HBV-16 consisted of subjects aged 40 to 70. The population of each trial is shown below.
3. Adverse events of special interest (AESI) in HBV-10
In HBV-10, there were five AESIs in the Heplisav arm:
In HBV-10, there were six autoimmune events in the Engerix-B arm:
There are several obvious differences between the two groups. First, the Heplisav arm has more Grade 3 events than the Engerix-B arm, 3 vs. 1. Second, in the Heplisav arm, just two of the five events are not related to treatment, whereas in the Engerix-B arm all six events are not related to treatment. Below is a review of the three Grade 3 events in the Heplisav arm.
Granulomatosis with polyangitis (aka Wegener's granulomatosis)
The FDA placed HBV-10 on clinical hold as a result of this Wegener's diagnosis. The AdCom briefing document characterized this event as possibly related to treatment. However, upon reviewing this patient's medical history, it seems more likely that her Wegener's was caused by a deviated septum and two subsequent surgeries than by Heplisav.
Per page 123 of the AdCom briefing document:
Essentially, the subject had a deviated septum. She elected to undergo two surgeries for the deviated septum, and the second surgery may have caused hospital-acquired pneumonia (www.webmd.com/lung/tc/healthcare-associated-pneumonia-nosocomial-pneumonia-topic-overview). The subject was then hospitalized with the pneumonia, and the pneumonia progressed into the pericardial effusion (the fluid went from the lungs to the heart). At some point, the subject may have been mismanaged in the intensive care unit, which subsequently led to the glomerulonephritis and the loss of optimal kidney function. The glomerulonephritis is what prompted the positive ELISA test and the C-ANCA test, hence the diagnosis of Wegener's.
The subject should have either delayed the two surgeries until after the trial or been discontinued from the trial for undergoing the surgeries. She introduced too many external variables into her treatment by undergoing surgery.
Guillain-Barre Syndrome (GBS)
Very importantly, an independent investigator concluded that this case of GBS was "probably not related to study vaccine but instead related to influenza vaccination." The subject experienced an onset of GBS five days after she received a flu vaccine. The CDC acknowledges that "People also can develop GBS after having the flu or other infections. On very rare occasions, they may develop GBS in the days or weeks after getting a vaccination" - www.cdc.gov/flu/protect/vaccine/guillainbarre.htm.
The causal relationship between the flu vaccine and GBS is not particularly storng. This study in Oxford Journals (cid.oxfordjournals.org/content/48/1/48.full) estimates 1 GBS case per 1,000,000 vaccinations. However, the same study concedes that "GBS was significantly more likely to occur in the winter, with a relative risk of 1.5, compared to nonwinter months (P = .003)." The subject in this case received her flu vaccine on November 22 and was diagnosed on November 27. A different study published in Jama Medicine (archinte.jamanetwork.com/article.aspx) concludes "Influenza vaccination is associated with a small but significantly increased risk for hospitalization because of GBS."
The flu vaccine was first strongly associated with GBS in 1976, at which time there was a swine flu outbreak. People were vaccinated for the swine flu (H1N1), and within months, the incidence of GBS was just 1 per 100,000 vaccinations - www.cdc.gov/flu/protect/vaccine/guillainbarre.htm.
This strong link between vaccination and GBS is isolated to this one outbreak.
With respect to this trial subject, she received a flu shot five days before her GBS diagnoses, and she also had a medical history that may have compromised her immune system and contributed to her condition. According to the briefing document, the subject had undergone a "splenectomy for unknown reasons" and she had cancer - follicular variant of papillary carcinoma (thyroid). The combination of a compromised immune system and a flu shot likely contributed to the investigator characterizing this case as probably not related to treatment.
There were two cases of Basedow's (also known as Graves') disease in HBV-10 - one Grade 3 case in the Heplisav arm and one Grade 2 case in the Engerix-B arm. Basedow's disease causes the overproduction of thyroid hormones (hyperthyroidism). This is probably why an independent investigator deemed the Basedow's disease in the Heplisav arm as probably not related, and the Basedow's disease in the Engerix-B arm as not related. The subject in the Engerix-B arm had a "history of postpartum thyroiditis," meaning she had an inflamed thyroid gland and thus abnormal thyroid levels. The subject in the Heplisav arm did not have any thyroid-related medical issues. However, she did have a "positive pre-vaccination ANA titer of 1:320," meaning she may have had autoimmune disease before the start of the trial (www.uptodate.com/contents/antinuclear-antibodies-ana-beyond-the-basics). This likely precluded Heplisav from causing the Basedow's disease, and thus the independent investigator deemed this case as probably not related to treatment.
4. Adverse events of special interest (AESI) in HBV-16
In HBV-16, independent investigators screened for autoimmune events. If the investigators found a potential autoimmune event, they submitted the event to a safety evaluation and adjudication committee (NASDAQ:SEAC). The SEAC adjudicated the event.
Initially, investigators reported nine cases to the SEAC. Upon further review, investigators deemed two cases - microscopic colitis and hypothyroidism - as not autoimmune. Therefore, investigators submitted to just seven cases to the SEAC. The SEAC then adjudicated two of the seven cases as not autoimmune - erythema nodosum and VIIth cranial nerve paralysis (Bell's palsy) - and five of the seven cases as autoimmune. All five cases were deemed mild or moderate in severity and non-serious.
Of the five cases deemed autoimmune, four were hypothyroidism and one was vitiligo. Of the four cases of hypothyroidism, two subjects "were found to have a high thyroid stimulating hormone (NYSEMKT:TSH) and low free thyroxine-4 (T4) at screening, demonstrating pre-existing hypothyroidism, and 2 subjects had normal thyroid panels at screening." Based on this information, the SEAC concluded that these two subjects had a pre-existing condition, and therefore just 2 of the 4 AEs of hypothyroidism were new-onset.
In summary, the SEAC adjudicated seven cases. It deemed five cases as autoimmune (4 hypothyroidism, 1 vitiligo). Two of the four cases of hypothyroidism were pre-existing. This means that two cases of hypothyroidism and one case of vitiligo were new on-set. Very importantly, the SEAC concluded that while these three cases were new on-set, they were not related to Heplisav.
Importantly for Heplisav, even with these additional AESIs, the relative risk of all autoimmune events in the phase 3 safety population is .72 (see Table 29 on page 86), still favoring Heplisav.
The patient narratives for all seven cases are on page 132 (Appendix 6, Section A6.4.) of the AdCom briefing document. The three patients with new on-set are: hypothyroidism 58/F, hypothyroidism 53/F, vitiligo 69M.
5. Pulmonary embolism
Between HBV-10 and HBV-16, there were five patients with pulmonary embolism in the Heplisav arm (one of the patients died) and zero patients with pulmonary embolism in the Engerix-B arm. The FDA made note of this numerical imbalance during the Advisory Committee meeting, as illustrated by slide 45 of the AdCom Review of Safety:
While there is an obvious numerical imbalance of incidences in the Heplisav arm compared to the Engerix-B, all five subjects have risk factors or traits that explain their diagnosis. Below is an analysis of the five patients with pulmonary embolism:
(1) 32-year old female: obese, smoker, oral contraceptives, positive antiphospholipid antibodies
As the National Institute of Health warns, obesity, smoking and oral contraceptives are all risk factors for deep vein thrombosis (in a case of pulmonary embolism, the clot would simply travel to the lungs) - www.nhlbi.nih.gov/health/health-topics/topics/dvt/atrisk.
As for the antiphospholipid antibodies (also known as antiphospholipid antibody syndrome or APS), the National Institute of Health states that APS can lead to health problems including deep vein thrombosis and pulmonary embolism - www.nhlbi.nih.gov/health/health-topics/topics/aps.
(2) 26-year old male: ruptured anterior cruciate ligament
This man likely underwent surgery for his ruptured ACL. Venous thromboembolism and pulmonary embolism are very common risk factors for patients undergoing orthopedic surgeries that last longer than 30 minutes - www.outcomes-umassmed.org/dvt/best_practice/.
(3) 61-year old male: recent prolonged road trip
This is another easy-to-diagnose case. This man was on a prolonged road trip, and was likely immobile for a long period of time. The CDC warns that long-distance travelers are at risk for blood clots evolving into pulmonary embolism - www.cdc.gov/ncbddd/dvt/travel.html.
(4) 36-year old female: hospitalized with Guillain-Barre Syndrome
The AdCom says the following regarding this patient's pulmonary embolism: "The subject was hospitalized complaining of progressive weakness that progressed to respiratory failure. The diagnosis of Guillain-Barré Syndrome was subsequently made. The subject's hospitalization was prolonged by the diagnosis of a follicular variant of papillary carcinoma (thyroid) and
bilateral pulmonary embolism." The AdCom doesn't specify what may have caused the pulmonary embolism - the patient's litany of health problems (which included a splenectomy, in addition to the carcinoma) or her hospitalization for Guillain-Barre. If the Guillain-Barre caused the pulmonary embolism, it makes complete sense. Guillain-Barre often causes muscle weakness and paralysis, and hence inactivity. Inactivity due to weakness, paralysis and hospitalization may certainly result in pulmonary embolism.
(5) 46-year old male: died due to pulmonary embolism deemed not related to treatment
This subject died while playing softball. According to pages 125-126 of the AdCom briefing document, he "experienced swelling and leg pain, right pressure in his chest, and shortness of breath." An independent investigator attributed the death to pulmonary embolism and not Heplisav.
There aren't a lot of details available to assess this case. An EMT report was "not available," and an autopsy was "not received." The subject did experience swelling. This swelling may have been due to trauma or an existing blood clot in the subject's extremities.
The Heplisav arms of HBV-10 and HBV-16 certainly have more "warts" than do the Engerix-B arms. Fortunately for Dynavax, these "warts" all have very plausible medical explanations. Here they are in review:
Three Grade 3 AESIs in HBV-10: The Wegener's incident was likely caused by elective surgery for a deviated septum, which led to health care-associated pneumonia, which led to the pericardial effusion and ultimately Wegener's. The Guillain-Barre incident was preceded by a flu shot, and the subject had an extensive medical history that included a splenectomy and cancer. The Basedow patient had a positive pre-vaccination ANA titer.
Even with these three Grade 3 AESI's, the percentage of subjects with an AESI in the Heplisav arms is still similar to that of Engerix-B arms (.2% for Heplisav vs. .4% for Engerix-B).
Three new-onset AESIs in HBV-16: Again, all three cases were deemed by the SEAC as not related to Heplisav treatment.
Five patients with pulmonary embolism: Four of the five subjects had obvious contributing factors to their pulmonary embolism. Also, slide 46 of the Advisory Committee Review of Safety PowerPoint presentation illustrates that the rate of total (HBV-10 and HBV-16) thrombotic adverse events is identical for Heplisav and Engerix-B:
Disclosure: I am/we are long DVAX.