Cytomegalovirus, or CMV, is a virus that is commonly transmitted in childhood and early adulthood. Approximately 60% of the U.S. population has been exposed and is latently infected. Worldwide data indicate that half the people in industrialized countries and up to 99% of people in developing countries, including China and India, have been infected.
Infections typically result in lifelong latent persistence of the virus with few symptoms, if any. However, in unborn children, when infected in utero, CMV infection can lead to significant morbidity and mortality.
In addition, in immunosuppressed patients, such as transplant recipients, primary CMV infection or reactivation of CMV causes significant morbidity, mortality and graft rejection. There are two scenarios in which CMV infections are relevant in the transplant setting. In one case, the recipient could be CMV negative, or previously uninfected, and the donor CMV positive. In this case, introduction of CMV into the immunocompromised recipient can lead to rapid virus spread and development of serious complications. In the other case, the recipient is already CMV positive, but the immunosuppressive treatments required as part of the transplant procedure lead to reactivation of latent virus.
Cytomegalovirus in Kidney Transplant Patients
High risk kidney transplant recipients are defined as CMV-negative patients receiving an organ from a CMV-positive donor. In this patient population, approximately 80% develop active CMV infection. But also CMV-positive individuals undergoing kidney transplantation are at risk of clinically significant CMV infection / re-activation (approximately 40 %). For this population the level of T cell immunity prior to transplantation is predictive of the likelihood that they will develop CMV disease after transplantation. In most solid organ transplant patients, complications from CMV develop between 30 and 90 days after transplantation and rarely after 180 days. In 2018, approximately 92,000 of the approximately 141,000 solid organ transplants performed worldwide were kidney transplants, an increase of 8.2% compared to 2015.
Our solution: HB-101
HB-101* is a non-replicating product candidate designed to stimulate the immune system against Cytomegalovirus (CMV) and to protect against future CMV infection or reactivation from latency. HB-101 is comprised of two non-replicating LCMV-based vectors:
- one vector expresses the gene encoding the CMV 65 kD pp65 protein, a validated T cell antigen; and
- another vector expresses the gene encoding the CMV gB protein, a validated B cell / antibody target.
We, and third parties, have shown that pp65 is immunogenic. Adoptive T cell transfer approaches performed by third parties, in which CD8+ T cells directed against pp65 are isolated from exposed individuals and transferred to patients with active CMV viremia, have also demonstrated the therapeutic efficacy of pp65. However, no vaccine approach to date has consistently induced CD8+ T cell levels high enough to be protective and has entered clinical Phase 2 testing in solid organ transplantation. gB has been shown in previous third-party clinical trials to be immunogenic and protective by inducing antibody responses but not CD8+ T cells. However, response rates were limited, immunity was transient and protection was incomplete. In our preclinical data, using pp65 and gB as targets, we have observed robust immunogenicity, durability thereby potentially overcoming the limitations of current approaches.
In our Phase 1 clinical trial, HB-101 was well tolerated and elicited a strong CMV-specific immune responses in all 42 of the treatment arm volunteers. Importantly, we observed robust CD8+ and CD4+ T cell responses as well as CMV-neutralizing antibody responses, without meaningful vector neutralizing antibody responses. These responses increased in a statistically significant manner upon repeat administration. The CD8+ T cell levels achieved in our trial were equivalent or higher than those published by third parties, in separately designed and conducted clinical trials, using adoptive T cell transfer approaches for the same antigen which have been shown to be therapeutic. We believe these results demonstrate the differentiating features of our arenavirus platform.
In 2018, we commenced a Phase 2 clinical trial for HB-101 in Cytomegalovirus-negative patients awaiting kidney transplantation from living Cytomegalovirus-positive donors. Based on HB-101’s tolerability profile in the target patient population dosed to date and to gain further insights that will inform the Phase 3 trial design, we added a new cohort of CMV-positive recipients awaiting kidney transplantation from CMV-positive or -negative donors to the trial protocol in early 2020.
We reported interim safety and immunogenicity data from evaluable patients in June 2020, in which HB-101 was observed to be well tolerated with fewer adverse events in patients with end-stage kidney disease than in the previous healthy volunteer trial. Patients who received three doses of HB-101 showed comparable immunogenicity to healthy volunteers in the Phase 1 clinical trial of HB-101. In November, we reported interim Phase 2 data for patients who received a three-dose CMV vaccination with HB-101 prior to a kidney organ transplantation. These interim results showed a reduction in CMV viremia, reduction in antiviral use, and no CMV disease in the CMV-negative kidney transplant recipients as compared to placebo. In addtion, we observed strong CMV-neutralizing antibody responses and a favorable tolerability profile. HOOKIPA believes that these interim data establish proof of concept for HB-101, a potential first-in-class vaccine candidate, which uses our non-replicating technology. We expect to conclude enrollment of the ongoing Phase 2 trial in mid-2021 and to report additional data in the second half of 2021.
*ClinicalTrials.gov Identifier: NCT03629080
An estimated 257 million people are living with HBV infection (defined as hepatitis B surface antigen positive). In 2015, HBV resulted in 887,000 deaths, mostly from complications including liver cirrhosis and hepatocellular carcinoma. HBV virus is especially common in China and other Asian countries mother-to-child transmission is an important source of viral carriage. HBV is second only to tobacco as a cancer-causing agent.
Our solution: HBV Therapy
The objective of the Hepatitis B virus (HBV) Program is to utilize the HOOKIPA Technologies to design arenavirus vectors (Lymphocytic Choriomeningitis Virus or Pichinde Virus based) suitable for treatment, cure or prevention of HBV. Together with our partner Gilead Sciences we intend to develop functional therapies for patients already infected with HBV.
HOOKIPA has completed the research milestone for HBV by designing and delivering 10 research-grade vectors to Gilead, along with the characterization of these vectors and delivery of a data package for the HBV program. The research vectors delivered by HOOKIPA will be subject to further pre-clinical testing in order to validate a clinical candidate for novel combination therapies for the treatment of HBV.
Human Immunodeficiency Virus (HIV)
Today, HIV continues to be a major global public health issue, having claimed more than 35 million lives so far and affecting approximately 36.9 million people at the end of 2017. HIV research has come a long way since the discovery of the disease in the 1980’s but there is no cure for HIV infection. There are antiretroviral (ARV) drugs that control the virus and help prevent transmission. The goal now is to find a cure for HIV to change the lives of millions affected by the disease.
Our solution: HIV Therapy
The objective of the Human Immunodeficiency Virus (HIV) program is to use HOOKIPA’s technologies to design arenavirus vectors (Lymphocytic Choriomeningitis Virus or Pichinde Virus based) suitable for treatment, cure or prevention of HIV. Together with our partner Gilead Sciences we intend to develop functional therapies for patients already infected with HIV.
During 2019, HOOKIPA received $6.0 million in milestone payments from Gilead for the delivery of research vectors and advancing the programs closer to clinical trials. Based on preclinical data generated to date, Gilead committed to preparations to advance the HBV and HIV vectors toward development. To enable the development activities and expanded research programs, Gilead agreed to reserve manufacturing capacity and increase reimbursement budgeted for our expanded resources allocated to the Gilead collaboration.