Bedaquiline Fumarate

New Delhi: For more than a century, the onus of combating TB has relied upon the 20th-century breakthrough called the BCG vaccine (Bacillus Calmette–Guérin), which helps activate the immune response against the disease-causing bacterium Mycobacterium tuberculosis (Mtb). The data speaks for the effectiveness of the vaccine, which made it an integral part of various global and individual government efforts that helped save around 79 million lives (since 2000) from the deadliest infectious disease . However, being administered at birth under various elimination programs, including in India since 1985, the Global TB report 's revelation of the disease shifting burden among adults, increasing drug resistance, and a temporary blip due to the pandemic—which reversed the long-maintained downward curve both in terms of incidence rate—points to the limits in the conventional safety net and further reflects the ample scope for exploring and introducing newer innovations. Source: Global TB report 2024, WHO Moreover, as per the WHO, the existing “neonatal BCG vaccination offers partial protection for infants and young children against severe forms of TB, but it does not protect adolescents and adults, who account for the majority of TB transmission. Vaccines also offer the best chance to contain the accelerating spread of multi-drug resistant tuberculosis.” “The entire mycobacterium used in BCG is one that is related to Mycobacterium tuberculosis, but not the same. It is missing about 170 genes that Mycobacterium tuberculosis has, and this is possibly why the immunity offered tends to be very limited,” Dr Lancelot Pinto, Consultant Pulmonologist and Epidemiologist, P. D. Hinduja Hospital & Medical Research Centre, told ET Pharma. Nevertheless, beneath this cloudy landscape, there are rising signs of hope to combat the disease through a handful of new vaccines. As per the GlobalData drug pipeline database, currently, there are 15 prophylactic vaccines under different clinical development stages. Of these 15 under-trial candidates, three innovations— MTBVAC , M72/AS01E , and VPM1002—are in the Phase 3 clinical trial phase, while one candidate, GC-3107A, developed by GC Biopharma, is in the pre-registration phase, which initiates the regulatory review required for market roll-out of a product. Source: GlobalData pipeline products database Unlike the other versions, GC-3107A is a therapeutic vaccine indicated for latent or active TB patients. Among the three late-stage frontrunners, MTBVAC (Mycobacterium Tuberculosis [Live Attenuated] Vaccine) is developed by the University of Zaragoza, whose industrial partner, BioFabri—a Spanish biotech firm—overtook the clinical development in partnership with India’s Bharat Biotech. The candidate is stated to be developed from a genetically modified form of the pathogen isolated from the disease bacterium and, as per the partners, unlike BCG, it contains all the antigens present in strains that infect humans. Currently, the vaccine is being tested on over 7,000 infants in South Africa, Senegal, and Madagascar, with the BCG control arm. The second candidate, M72/AS01E, was initially developed by MNC giant GlaxoSmithKline or GSK, with the final phase of clinical development led by the Gates Medical Research Institute , supported by the Gates Foundation, and Wellcome (a healthcare charitable trust). M72/AS01E is a two-dose regimen version developed from two Mtb antigens—MTB32A and MTB39A—and in March 2024, the partners announced the initiation of Phase 3 trials in South Africa to assess the efficacy of the vaccine. Later, the candidate was also introduced at trial sites in Indonesia, Kenya, Malawi, and Zambia, with a total cohort size of 20,000. The Phase 3 trials for both of the aforementioned candidates are expected to conclude by August 2029. Lastly, VPM-1002 is an innovation from Serum Institute of India, developed by Serum Institute of India (SII), as a potential replacement for the standard BCG vaccine, aiming for improved safety and efficacy in preventing tuberculosis (TB). The candidate is in the Phase 3 trial phase, being tested in a multisite, randomized, double-blinded, placebo-controlled Phase III clinical trial among 6,940 newborn infants from Gabon, Kenya, South Africa, Tanzania, and Uganda, with the BCG control arm. The trial is supported by India’s Department of Biotechnology’s National Biopharma Mission. Several attempts by ET Pharma to obtain additional information from the Serum Institute did not elicit any response. As per the government department, the objective of this trial is to evaluate the ability of VPM-1002 to reduce infection incidence and severe disease outcomes of COVID-19 among high-risk persons of advanced age or comorbidities and high-exposure healthcare workers (HCWs). According to the WHO TB research tracker, the vaccine's Phase 3 trials are expected to conclude by October 2025. Dissecting the targeting mechanism of these under-trial candidates with the existing option, Dr. Pinto told ET Pharma, “The BCG vaccine has been shown to be effective against severe forms of TB in childhood, but its effectiveness beyond this has not been proven, and this possibly explains why, despite having a universal BCG vaccination at birth since 1985, India has not been able to eradicate the disease.” Dr. Pinto explained that the newer vaccines attempt to improve BCG in different ways: MTBVAC is live and attenuated but uses Mtb (and not bovis), with genetic modifications that render them safe. Meanwhile, VPM-1002 uses a recombinant BCG strain and has enhanced immunogenicity because of the expression of Listeriolysin-O, which allows the antigens to enter the cells and stimulate a stronger T-cell response. As per the expert, the pre-registration candidate GC-3107A of GC Biopharma has a similar mechanism as in the case of MTBVAC. Commenting on the best potential candidate to deal with the rising prevalence of TB among adults, Dr. Pinto said, “M72/AS01E is possibly one of the most promising vaccines, as the Phase 2b vaccine trial recruited adults aged 18 to 50 years with M.TB infection, and was found to be 49.7 percent efficacious at preventing TB in the 3-year follow-up period with two doses.” This demographic is possibly the most prevalent presently, and protecting them would be the most important priority in reducing the prevalence of the disease. This vaccine is also closest to completing its Phase 3 trials and is therefore likely to be the most relevant presently, he added. In contrast to this, Anaelle Tannen, Infectious Disease Analyst at GlobalData, expects BioFabri’s MTBVAC will provide an alternative way to treat the disease and has been shown to be safe and effective thus far in clinical trials. Notably, the GSK candidate has also received endorsement from the WHO, and the UN subsidy has said that the vaccine results (Phase 2b trial) are “unprecedented in decades of TB vaccine research” in terms of clinical significance and strength of evidence, and constitute an important scientific breakthrough.” Moreover, the body has also urged the “tuberculosis vaccine community to discuss future development options for this vaccine candidate.” Sharing a WHO estimate, Alexander Schmidt, Interim Head of Development and Chief Medical Officer, Gates Medical Research Institute, told ET Pharma that, “Their vaccine could save 8.5 million lives, prevent 76 million new TB cases, and save $41.5 billion for TB-affected households.” Commenting on the post-trial plans, including possible regional launches, Schmidt replied that, “We are working with our trial partners, as well as multilateral, regional, and country partners, to understand the potential demand for the vaccine so that we can build an end-to-end plan to ensure long-term sustainable access in communities of high disease burden, should the trial be successful.” For India, both the TB incidence rate and mortality count have been on the downturn, but considering the changing demographic profile of TB, the policymakers are exploring options like “BCG revaccination in adults,” and in January 2024, the Ministry of Health and Family Welfare, in collaboration with the Indian Council of Medical Research (ICMR), launched the "Adult BCG Vaccination Study" to explore the vaccine's effectiveness among high-risk individuals. Last year, Bharat Biotech announced its plans to test its candidate MTBVAC among Indian adults, and a company release states that the trials “are planned to start in 2025 to evaluate the safety and immunogenicity of MTBVAC among adults in India.” Making the announcement, Dr. Krishna Ella, Executive Chairman, Bharat Biotech, had said that, “Our goal to develop TB vaccines to prevent disease in adults and adolescents has taken a big step today. We are honoured to partner with BioFabri in this noble effort to reinvent TB vaccines.” As per the latest available update, in October 2024, the Indian drug regulator, CDSCO, asked the Hyderabad-based vaccine player to share its trial protocols. Over the inclusion of other under-trial candidates under India’s Universal Immunisation Program or as a booster dose option among already vaccinated individuals, Dr. Pinto suggested analysing the cost-effectiveness of each candidate. One of the Phase 3 candidates, M72/AS01E, if cleared by the regulatory review, is estimated to be priced at around $2.5 (around ₹214) per dose and is a double-dose regimen, whereas the available single-shot BCG brands, such as one from SII, are priced at around ₹60 for a 40 ml vial. A study comparing the financial cost of M72/AS01E with BCG found that initiating BCG revaccination in India could incur an average annual cost of around $23 million, whereas the M72/AS01E vaccine is projected to cost around $190 million per year. The emergence of multi-drug resistant (MDR) and extensively drug-resistant (XDR) strains has made the challenging TB terrain more bumpy, and compounding this, Dr. Pinto expects “Mtb strains are likely to become resistant to newer drugs such as Bedaquiline and Delamanid (the current line of treatment) as their use increases, and unless the new drug pipeline matches such resistance, we are likely to face serious challenges with treating the disease in the future.” However, as of now, the under-trial vaccines are viewed as the best option to safeguard the population from a preventable challenge. Medical innovation takes years to reach fruition and requires a heavy purse to sustain and survive that period, but with bipartisan consensus, the world has made significant strides towards the elimination of a condition where the fate of around. By Abhijeet Singh ,

iStock, Orla Congress did not reauthorize the rare pediatric disease priority review program at the end of 2024. Advocates say the ripple effect is already being felt across biopharma. The FDA has never handed out more priority review vouchers than it did in 2024. Depending on who you ask, that’s a sign that the program is working or that pharma is reaping huge benefits in a quid pro quo situation of the government’s own making. But now rare disease biotechs have been left scrambling, as Congress did not renew the rare pediatric disease portion of the program at its end of year deadline despite bipartisan support. “The impact on the rare disease drug developers and the investment community [is] already being felt because of the destabilizing effect of the failure to reauthorize the program prior to its expiration,” Stacey Frisk, executive director of the Rare Disease Company Coalition, told BioSpace in an interview. Her group is lobbying for a renewal to be tacked on to congressional efforts to address a looming March 14 budget deadline. “So really, the timeline is as soon as possible.” The priority review voucher (PRV) rare disease program, which began in 2012, had unanimous renewal support from the 118th Congress, which ended on Jan. 3, according to Frisk. The program passed the House without issue and was listed among the priorities for the resolution to avoid a government shutdown. But the health programs that included the PRV program—which had already begun to sunset—were stripped from the continuing resolution at the last minute. Despite the bipartisan support, the PRV program “got caught” as Congress’ timelines and priorities changed at the last minute, Matthew Winton, chief operating officer of Inozyme Pharma and a rare disease advocate , told BioSpace . A bill called the Give Kids a Chance Act of 2024 has now been proposed to get the PRV program moving again, as Congress works to avoid the shutdown. “Time is . . . sort of running out,” Winton said. “We need action on this immediately to continue the program but also continue investment in these pediatric rare diseases.” The FDA notified drugmakers in the fall that, absent the renewal passing, the agency would have to stop handing out the coveted fast-pass vouchers, which expedite the drug review timeline from 12 months to about 6 . The vouchers can be bought and sold, which provides a valuable fundraising boost for tiny rare disease biotechs. The current going rate on the open market is $150 million, the price Zevra Therapeutics earned just last week for its voucher that was granted from the September 2024 approval of Miplyffa. According to Winton, the cost of PRVs has risen to this rate as companies foresee the end of the program. Without renewal, the FDA began sunsetting the program as of December 20, 2024. The agency cannot award any new vouchers unless the drug already had the rare pediatric disease designation. If Congress does not act, companies with existing designations will only have until September 30, 2026, to get their drugs approved in order to earn a voucher. Already, companies with the rare pediatric disease designation for drugs in development are reeling, with many starting to warn investors in Securities and Exchange Commission filings that they may never get their coveted vouchers despite working for years to position for one. Winton said that companies make decisions to develop a drug years in advance, so having the rug pulled out suddenly due to a policy change can halt external investment. “With that uncertainty, you’re going to get a slowdown in decision making. You’re going to get a slowdown in people investing in R&D programs,” Winton said. See BioSpace ’s full analysis here . Quid Pro Quo The industry has spent at least $513 million on buying vouchers that were earned in 2024, although more could have been sold without public disclosures. These non-dilutive proceeds are often used by smaller companies to bolster their overall clinical programs. In a recent case that underscores the stakes, bluebird bio fought hard to get one for its sickle cell disease gene therapy Lyfgenia, which was approved in December 2023 . Bluebird had already lined up a buyer before it even received the approval, according to SEC documents dated October 2023. Novartis agreed to pay $103 million for the voucher if it were granted. While bluebird was granted rare pediatric disease designation in May 2020 for the treatment, the FDA did not hand out the coveted voucher. Bluebird appealed and was ultimately rejected three times. The agency did, however, hand one out to Vertex Pharma for rival gene therapy Casgevy, which was developed with CRISPR Therapeutics and approved on the same day as Lyfgenia . This unsuccessful effort was cited in bluebird’s recent announcement that it would sell itself to private equity firms in a deal valuing the gene therapy maker at just $30 million. Bluebird did not have enough cash to operate past the first quarter but had spied positive revenue later in the year. Eleven of the valuable trading cards were handed out to biopharma companies over 2024, across the three different programs that offer the vouchers. For the rare disease program specifically, indications that benefitted include sickle cell, Niemann-Pick type C, Duchenne muscular dystrophy and glioma, among others. With the pediatric rare disease program sunset announced, the FDA has handed out two already this year to Novo Nordisk for hemophilia A therapy Alhemo and Neurocrine Biosciences for congenital adrenal hyperplasia drug Crenessity. There are two other ways to get one beyond the rare disease program: through the development of drugs for tropical disease or a biological threat, such as COVID-19. Four have been awarded since the pandemic began for COVID-19: to Moderna, BioNTech, Pfizer and Gilead for their vaccines and antivirals. Neither of these programs are impacted by Congress’ recent actions, and so far, the FDA has granted one voucher under the tropical disease program this year: to Bavarian Nordic for its chikungunya virus vaccine Vimkunya. Bavarian Nordic has already indicated plans to sell the voucher “when appropriate.” Opponents of the voucher programs say the fast passes are not doing their job to expedite the approval of drugs to help fill unmet needs in the rare and tropical disease communities. In a December 2024 paper , U.K. researchers Piero Olliaro and Els Torreele called the program “a misconceived quid pro quo, whereby much is given for little public health return, promoting and rewarding monopoly pricing of high-revenue products, with no strings attached—which indeed makes it attractive to pharmaceutical companies and investors.” Bigger companies that earn or buy the vouchers use them to skip the line at the FDA for any drug they want. These vouchers are hard to track, as the companies do not have to report exactly where they got the voucher from when they use them. The FDA in recent years has occasionally posted Federal Register documents noting that a voucher was used for a particular drug, but these documents do not indicate where the voucher came from. From various records, it’s clear that many major blockbuster drugs of recent years have used these hall passes, from Eli Lilly’s Mounjaro, to AbbVie’s Rinvoq to Gilead’s portfolio of HIV meds and many more. In mid-February, Alnylam Pharmaceuticals cashed one in for a speedy review of Amvuttra in ATTR amyloidosis with cardiomyopathy, an indication that is one of the hottest market battles at the moment with offerings from Pfizer and BridgeBio now available. Vertex Pharmaceuticals did the same in July 2024 for cystic fibrosis triple med Alyftrek, receiving an FDA nod less than six months later, in December 2024. Novartis has by far been the most frequent patron of the fast passes, with as many as eight bought or earned over the years. The company has used the passes on Mayzent, Beovu, Kesimpta, Fabhalta and Kisqali, according to records. Gilead has spent as much as $621 million on known purchases of priority review vouchers. Olliaro and Torreele argue that the program does not actually encourage drug sponsors to ensure the availability of the medicines that get approved under the program, especially for tropical diseases. For instance, the makers of tuberculosis therapies Sirturo and Dovprela, a medicine that was approved under the tropical disease program as pretomanid, have been criticized for keeping the prices for the therapies too high to help in countries with a high tropical disease burden. Sirturo is manufactured by Johnson & Johnson while Dovprela (previously pretomanid) was developed by the TB Alliance . Frisk and Winton are aware of the criticisms but say that the rare disease program is working. You just have to look at the ramp up of drugs that have received a voucher over the years, with more handed out recently. That means that more companies are making these drugs and more rare diseases are getting new options for patients. As for the criticism of a handout for Big Pharma, Winton says this is a tax neutral program. No taxpayer funds are being given to these companies; it’s simply a market-based solution that ultimately helps smaller companies do what they do best: develop rare disease drugs for smaller populations. “Some of these drugs may not be developed or invented at all” without the voucher program, Winton said. “These [vouchers] are not necessarily going to the 17th, 18th statin—not that there’s anything wrong with that—but these are also going to feed the cycle of innovation and bringing drugs to patients in the U.S. who have no other options.” Planning Funerals One pediatric rare disease that has particularly benefitted is Duchenne muscular dystrophy, which has had seven drugs approved under the PRV program, including four from Sarepta Therapeutics. Each time, Sarepta sold its voucher and used the funds to continue its clinical programs. Another rare disease that now has multiple options is spinal muscular atrophy. Winton previously worked at Biogen as head of the SMA franchise, where he oversaw work on Spinraza, which received a PRV in March 2017. “That disease state has completely changed. You were used to planning funerals. And now you’re celebrating birthdays and you’re celebrating graduation into high school,” Winton said. “That’s an amazing success story.” These patients now have several different modalities to choose from, including Novartis’ gene therapy Zolgensma and Genentech’s Evrysdi, both of which received priority review and were granted vouchers at approval. These seminal approvals of complex technologies like gene therapy have also helped fuel other innovations in the modality, which is another legacy of the PRV program, Winton noted. Similarly, Biogen advanced its antisense oligonucleotide technology with Spinraza, which earned a voucher in March 2017 and was sold for $103 million last year . “When you talk to patients, when you talk to the rare disease community, the one thing they always say is ‘move faster.’ The one thing they don’t have is time,” Winton said. “The message we always take away when we talk to them is try to work hard or hurry up. This program does that. It speeds up our ability to get drugs to market. It speeds up our ability to do more research.” About the data: BioSpace compiled the list of priority review vouchers through dozens of sources, including the FDA, Federal Register, SEC, GAO, company reports, news articles and more. Still, the list may not be comprehensive, as some PRV transactions go unreported.